Engineering Biology Problems Book (2021, Obninsk Edition)

ENGINEERING
BIOLOGY
PROBLEMS
BOOK
I. KLABUKOV, D. VLADIMIRTSEV, A. NIKOLAEVA, E. ARKSAND, M. LI, B. WANG

Egineering Biology Problems Book contains more than 200 physical, design and biomedical
problems, the solution of which with the help of biological tools may one day benefit
humanity. The collection consists of seven chapters, divided by applications of biological
technologies to various aspects of modern and promising economic activity: improving the
quality and prolonging life, transforming nature and improving human nature.
The topic of the tasks is devoted to methods of modification of biological objects and options
for the application of engineering biosystems for solving medical, industrial, agro-industrial,
ethical and other problems. The solution of the proposed tasks can be based on the original
use of modern methods of molecular and cellular biology, genome editing systems, synthetic
biology, and other methods.
For a significant number of tasks, answer options have been proposed, however, considerable
scope has been left for the flight of thought of biological creativity. The collection is designed
for students with an engineering mindset who want to find themselves in the design of
supersystems in the future a new industry of biotechnological excellence.
The idea of such a collaboration appeared spontaneously. Engineering Biology Problems
Book was written by Ilya Klabukov in 2019. This book is a collection of problems in
engineering biology.
In the middle of the 20th century, the Nobel Laureate, Richard Feynman, presented a series of
books “Feynman Lectures on Physics". They were simple, but very creatively formulated the
basic postulates and problems of physics. We believe that engineering biology is the new
physics of the 21st century. There are many unresolved problems in it, and we are sure that
they can be solved only through international cooperation.
Driven by these ideas, we tried to gather teams to get at least a little closer to this goal.
This version of the book is the result of the interaction of a large number of people and teams.
The following teams participated in this collaboration: MEPhI, MIPT_MSU, Siberia,
Phystech_Moscow, LMSU, Moscow_City, CAU_China, Stockholm.
Special thanks to:
Ilya Klabukov as the creator of this idea and the I version of the Book
Dmitrii Vladimirtsev, Anastasia Nikolaeva, Mingyang Li, Boshuang Wang, Elsa Arksand for
their great contribution to the II version of the Book.
Olesya Galanova and Rimma Shatalova for decoration and design of the Book
And teams MEPhI, MIPT_MSU, Siberia, Phystech_Moscow, LMSU, Moscow_City for the
translation of the Engineering Biology Problems Book in English.

1. Bioengineering devices
Engineering solutions that replicate modern technical devices and are implemented in living
organisms. The ability to understand the principles of morphogenesis and regulation of living
organisms allows not only to creatively interfere in the molecular foundations of life, but also opens
the way to the implementation of completely new biotechnological productions based on "living
machines".
1.1. Stalker-bacteria. The Fukushima Daiichi accident of 2011 required the use of special robots to
carry out remediation work. Using the suggested elements (Fig. 1.1) assemble the construction of a
stalker bacterium consisting of a plasmid and chromosome components that would guide the stalker
bacterium towards the radioactive elements.
Figure 1.1 Bioblocks for constructing stalker bacteria and cleaner bacteria. © 2011 iGEM, Team
SYSU-China.
1.2. Janitor bacterium. Using the bio blocks from task 1.1, develop a bacterium that would absorb
radioactive cesium ions (Cs+). Ready-made container bacteria are already available for manual
removal.
1.4 Protein calculation. The actin protein consists of 374 amino acid residues. Determine the length
of the primary amino acid structure and the molecular weight of this protein. Assume that the linear
size of the amino acid is 0.35 nm and the mass of the amino acid residue is 110 Da.
SOLUTION:
By performing simple arithmetic operations, we obtain a primary amino acid sequence length of 130.9
nm and a molecular mass of 41,140 Da.
1.6. The living solar cell. Modern solar cells require the use of monocrystalline silicon, which is
produced by a complex and non environmental chemical process. In addition, such semiconductor
devices require repair in case of breakage and periodic dust washing. Proteins exist in nature that can
produce electricity from sunlight. Various conductive polymers such as polypyrrole and polyacetylene
are also known [1]. Propose a design for a living solar cell (bacteria in biofilms of conductive
polymers) capable of growing on natural and artificial (house roofs) surfaces and capable of
producing electricity for use in the home.
[1.Shi, Y., Peng, L., Ding, Y., Zhao, Y., & Yu, G. (2015). Nanostructured conductive polymers for
advanced energy storage. Chemical Society Reviews, 44(19), 6684-6696.]
SOLUTION:
The creation of bioengineered devices - living organisms that replicate the functions of man-made
technical solutions - represents one of the directions of creating a self-healing environment.
At present, approaches to the realization of a living solar cell are already known, for example, based
on electron transport in cyanobacteria [2]. Based on thermodynamics calculations, the efficiency of
living solar cells is estimated at 6-10% without taking into account the additional optimization
possibilities achieved using engineering biology. One example of a solar cell scheme based on
cyanobacteria is shown in Fig. 1.2.

[2. Schuergers, N., Werlang, C., Ajo-Franklin, C., & Boghossian, A. (2017). A Synthetic Biology
Approach to Engineering Living Photovoltaics. Energy & Environmental Science.
doi:10.1039/C7EE00282C]
Figure 1.2 Schematic diagram of the implementation of a solar cell based on cyanobacteria [3].
Abbreviations: EET (excitation-energy transfer) - energy transfer (electronic) excitation.
[3. Szczupak, A., Halámek, J., Halámková, L., Bocharova, V., Alfonta, L., & Katz, E. (2012). Living
battery–biofuel cells operating in vivo in clams. Energy & Environmental Science, 5(10), 8891-8895.
doi:10.1039/C2EE21626D]
1.7. The Mushroom Smart Grid. Using a palette of additional symbiotes you have been able to
deploy a living solar array over a vast expanse of Arctic swamps. The problem now, however, is the
preservation of the hard-earned electricity. For various reasons, primarily the consequence of high
humidity and a sharply continental climate, the use of existing batteries is impossible. However, there
are mechanisms in nature that allow electricity to be stored (e.g. muscle-like cells in the body of an
electric stingray). Propose a design capable of harvesting electricity and delivering 10 kW of constant
power.
SOLUTION:
This problem proposes to implement a complex system consisting of a variable input power
accumulator and an output voltage source (DC) with physical current limitations.
To date, there are ideas of building accumulators from living cells, such as cell cultures of mollusks
(Fig. 1.3) [4]. In our opinion, however, the realization of large-scale "living batteries" can be
implemented in plant macro-objects, such as a growing fungus.
[4. Szczupak, A., Halámek, J., Halámková, L., Bocharova, V., Alfonta, L., & Katz, E. (2012). Living
battery–biofuel cells operating in vivo in clams. Energy & Environmental Science, 5(10), 8891-8895.
doi:10.1039/C2EE21626D]
Figure 1.3. (A) Photo of a clam with implanted biocatalytic electrodes. (B) Schematic of the connected
external variable load to the battery with biofuel, to measure the voltage and current produced under
in vivo conditions. (C) Charging performance of a

1.8. Bacterial antenna. It may seem that the use of radio waves for receiving and transmitting signals
is exclusively a human privilege. However, it is possible to imagine a mechanism made of living
bacteria capable of transmitting and receiving radio signals. Propose an implementation of such an
antenna for receiving and transmitting short-wave signals (l=100 m, f=3 MHz).|
SOLUTION:
Various features of the organization of bacterial cells, which allow detecting radio emission of a
certain frequency are now described. The basis of such sensitivity to the cells to radio waves is the
presence of dipoles in the form of metal-containing dimers[5] [6].
[5,6. Kirschvink, J. L. (2014). Sensory biology: Radio waves zap the biomagnetic compass. Nature,
509(7500), 296-297. Clites, B. L., & Pierce, J. T. (2017). Identifying Cellular and Molecular
Mechanisms for Magnetosensation. Annual review of neuroscience, 40(1).]
To realize such an antenna, we can consider a bacterial cell as a dipole with its dipole momentum.
However, the frequency of short-wave signals apparently will not allow to use of the cells themselves
as dipoles, but perhaps only their membrane elements or special synthetic organelles. There is also the
question of modulation - it is proposed to consider only amplitude modulation. Considering the
receiver and transmitter as one device, it is possible to calculate the channel width of such a receiving
and transmitting antenna.
1.10. Living refrigerator. Refrigeration is used by humans to inhibit the growth of microflora and
prevent spoilage. The same effect of preventing the growth of microorganisms is given by the internal
environment of microorganisms, which is rich in bacteriostatic compounds. Suggest a design for such
a "living refrigerator”. How would it be able to operate for a long time without the use of electricity?
SOLUTION:
Currently, anaerobic methods of food preservation are known, showing their effectiveness, however,
only in the presence of a critical mass of safe anaerobic microflora.
We suggest preserving products in a special gas environment that prevents prokaryotic growth and, if
possible, reduces the activity of proteolytic enzymes.
This effect can be achieved by using compounds based on the cyclic peptide Lassomycin in
combination with other compounds with antibiotic properties [7].
[7. Wencewicz, T. A. (2016). New antibiotics from nature’s chemical inventory. Bioorganic &
medicinal chemistry, 24(24), 6227-6252.]
1.11. Terminators-totiextremophiles. In the 1980s, organisms capable of surviving in abnormal
conditions of elevated temperature and acidity were found. For example, the animal totiextremophiles
("little water bears") can withstand cooling to -271 °C, heating to 100 °C, radiation of 570,000 X-rays,
the pressure of about 6000 atmospheres, and being in open space. The use of such organisms with
added special functions would be possible in conditions aggressive for humans and all living things in
general. Suggest at least 4 uses for such organisms in the national economy.
SOLUTION:
The authors propose to use such organisms in rather obvious fields of human activity in which
humans need help: 1) energy (especially nuclear), 2) chemical industry, 3) in Antarctic and Arctic
conditions; 4) in space exploration.
The reader may have a dissenting opinion on the ranking of priorities.
1.19. Biological construction. The use of bacteria and some natural compounds in concrete makes it
possible to repair microcracks that occur over time. For example, when a crack occurs in concrete, air
and moisture enter it, which awakens the bacteria and they begin to feed on calcium lactate. In the
process, they also absorb oxygen and the soluble calcium lactate is converted to insoluble limestone.
The limestone hardens in the cracks, re-sealing the structural layer. Suggest compounds and metabolic
reactions that increase (!) the strength of concrete over time when microcracks form.

SOLUTION:
It would seem that microcrack formation can in no way improve the structural properties of a
material. However, the process of formation, growth, and filling of such microcracks with special
connections can be considered as an additional reinforcing network working in tension and
shear/bending.
1.20. The Home Cultivation. The use of bacterial concrete only requires tweaking technology and
existing regulations to accommodate living organisms. However, we would like to take the next step,
to learn how to grow a whole house as if it were a tree or a coral reef. Suggest a way to do this (e.g.,
from calcium contained in calcareous soils) and estimate the speed of erecting a 30-story house in this
way. Suggest an alternative to rebar (e.g., spidroin), and a way to mold the supporting and enclosing
structures.
SOLUTION:
A way to mold such a "life-like" house could be to use communities of microorganisms that form
large-scale colonies. The problem is the need for rapid growth to fit into a single season, which may
require prior preparation of the site (e.g. with special fertilizers).
Variant shaping under the influence of external factors can also be a problem (or an advantage - due to
the possibilities of individual customization of such a dwelling).
1.21. Bacteria-made camera for the new iPhone. The modern Nikon digital camera gives a
resolution of more than 16 Megapixels. It seems attractive to create analogs of cameras based on
living organisms, using the properties of photosensitive proteins for this purpose. For example,
bacteriorhodopsins - membrane light-sensitive proteins that carry a proton across the plasma
membrane. What resolution can a camera matrix assembled from Nanoarchaeum equitans archaea
with a diameter of 0.35-0.50 µm provide?
SOLUTION:
A photographic matrix digitizes (divides into pieces - "pixels") the image that is formed by the camera
lens. There is an approximate relation in photographic optics: if we express the resolution of the
photodetector in lines per millimeter (or pixels per inch), let`s designate it as M, and let`s express the
resolution of the lens (in its focal plane), let`s designate it as N, then the resultant resolution of the
lens+photodetector system, let`s designate it as K, can be found by the formula
or
This relation is maximal at N=M when resolution is N/2, that is why the resolution of the lens should
correspond based Several models describing that of the photodetector.
Modern digital matrices have the pixel size defining resolution, which varies from 0,0025 mm to
0,0080 mm for different matrices, while most modern matrices have 0,006 mm. Since two dots will
differ if there is a third (unlit) dot between them, the resolution corresponds to a distance of two
pixels, i.e:
M=1/2p, where p is the pixel size.
Digital matrices have a resolution from 200 lines per millimeter (large-format digital cameras) up to
70 lines per millimeter (web cameras and cell phones).
In our case, the answer will depend on the characteristics and form factor of such a device. In the case
of the bacterial film the "pixel" size will be approximately 0.0001 mm (linear size of the bacterium),
so using other standard characteristics of the photographic circuit its resolution will be 5 Mpixels in
the monochrome version. If we want to get a color image, the resolution will be no more than 1-2
Mpix.
1.22. Human Blood Biofactory. In 2011 the U.S. agency DARPA completed a project to produce
human blood cells from stem cell culture. Theoretically, this should make the institute of blood donors
unnecessary for humans. However, the blood obtained by such technology is embryonic, and its use
may be risky. A biofactory for the production of blood would include a bone marrow analog, a "niche"

in which cell differentiation would take place. Evaluate the production capabilities of such a "factory."
SOLUTION:
Human cell division occurs approximately once every 24-48 hours. Production cycles of erythroid cell
differentiation are shown in Fig. 1.5. We propose to consider the production module in a container
form factor to ensure its maximum mobility and unification with different chassis.
The volume of biomass in such a container can be estimated at 0.25 tons, which will probably require
up to 3-4 cascades of "maturation" (cycles) thus for a factory in the form factor of a 20-foot shipping
container the production volume of human blood cell components can be estimated at 30-50 kg per
day.
Figure 1.5. Production cycles of erythroid cell differentiation [8]
[8. Caminal, M., Labrozzi, J. P., Oliver-Vila, I., Alzaga-Gragera, M., Marín-Gallén, S., Pla, A., ... &
Vives, J. (2015, December). Ex vivo production of red blood cells from human cord blood. In BMC
proceedings]
The mystery of stone disease. Common to epithelial organs is the problem of stone formation. For
example, stone formation in the kidney, bladder, liver, gallbladder. Assume the molecular and cellular
mechanisms of a stone formation common to epithelial organs.
SOLUTION:
A solution to the problem is in progress.
1.24. The Bee drug control. Poppy cultivation in Central Asian countries can have a devastating
effect on the economies of developed countries. The way to control poppy fields is to spread
phytoviruses that can infect sprouts and inhibit seed emergence (spring-autumn seasons). However,
the use for this task of a suitable insect with the right cycles of reproduction and migration - the bee
Apis cerana F. - is hampered by the fact that it is not a vector of such a pathogen. Suggest a useful
symbiont of the Apis cerana F. bee as an intermediate host of the desired phytovirus for the control of
drug-containing plants in the region.
SOLUTION:
Bees are capable of detecting low molecular weight compounds in minimal concentrations. Let's take
a closer look at this phenomenon: Bees' olfactory organs are special olfactory sensillae, which are
mainly located on the antennae. Each antenna of the worker bee has about 6000 sensillae [9]. And
some insects have even more of them: for example, male Antheraea Polyphemus butterflies have up to

60,000 of them. And if a human senses a sweet taste if the sugar concentration in the solution is 0.02
mol/l, bees feel it at 0.06 mol/l, and the moth-admiral Pyrameis Atalanta - at 0.01 mol/l [10].
[9,10. Bey-Bienko G. Ya. General entomology. - 3rd edition., add. - M.: Higher. school, 1980 — - 416
p., ill. Zatvatkin Yu. A., Course of general entomology, Moscow, "Kolos", 2001-376 p.]
1.27. Leather for the car. The surface properties of metals and their oxides are not very suitable for
the cultivation of eukaryotic cells. On the other hand, it is known that bacterial biofilms accompany
modern technology, polluting its surfaces. Suggest a way to organize living flesh on a metal
endoskeleton, for example, using an intermediate form in the form of symbiotic microorganisms.
SOLUTION:
The reader is invited to choose a model organism from several candidate microorganisms, for
example, lithoautotrophs or iron bacteria [11].
[11. Hedrich, S., Schlömann, M., & Johnson, D. B. (2011). The iron-oxidizing proteobacteria.
Microbiology, 157(6), 1551-1564. DOI: 10.1099/mic.0.045344-0]
1.28. Wonder Beat S Nanomotor. The movement of soil bacteria Myxococcus Xanthus is enabled by
the rotation of flagella using T4PM molecular motors in the membrane with 1.5×10-16 W per
flagellum (Fig. 1.7). Combining this motor in liposome membranes or on the surface of non-liposomal
vectors, propose a mechanism for directed or controlled transport of such "nanorobots" in the human
body. [12]
SOLUTION:
One can imagine a mechanism for directional movement of an object with such an engine along a
concentration gradient of some substance in a living organism, such as calcium.
[12. Chang Y-W, Rettberg LA, Treuner-Lange A, Iwasa J, Søgaard-Andersen L, Jensen GJ, et al.
Architecture of the type IVa pilus machine. Science (New York, NY) 2016;351:aad2001.
doi:10.1126/science.aad2001.]
Figure 1.7: Model of the T4PM protein complex: with flagella (left) and empty (right) © Science,
2016.
1.29. The Living Desalination Plant. The problem of desalination and water purification plays a
major role in Southeast Asian societies. Filters being developed for this purpose have received
extensive support from the Bill & Melinda Gates Charitable Foundation. Propose a biological filter
device that would surpass the functionality of algae or the glomerular organoids of mammalian
kidneys.
SOLUTION:
Maxwell's Demon was an 1867 thought experiment that looked at "smart" semi-permeable
membranes capable of reducing the entropy of closed systems, for example by separating molecules
by velocity or mass.

It seems promising to use cellular systems for the physical implementation of such a "Maxwell
demon" with predetermined characteristics (energy required to reduce entropy of the system, and
limits of acceptable pressure difference) not only for desalination but also for biological treatment of
drinking water.
1.29. Artificial Ontogenesis Test Beds. In his works, the outstanding transplantologist Vladimir
Demikhov created animal models on which the technique was practiced and the consequences of
transplantations were studied (Fig. 1.8). Suggest ways to assemble models of living systems
(xenohimer) for use in optimizing living systems and designing parameters for artificial ontogenesis.
SOLUTION:
The problem of building life-like models that are physiologically relevant to humans is currently a set
of unsolved problems. The thoughtful reader might be advised to make a list of such problems, the
consistent resolution of which would lead the development team to a satisfactory way of creating such
stands.
Figure 1.8. Scheme of transplantation of a puppy's head to the neck of an adult dog from V.
Demikhov's book "Transplantation of Vital Organs in Experiment", 1960.
1.30. Artificial human chromosome. One of the attractive tools of genetic engineering is the delivery
of a whole extra chromosome with the coding sequences and regulatory elements located on it into the
cell [13]. Since synthesizing a ready-made chromosome from scratch is still a laborious task, it seems
attractive to use one of the existing chromosomes of an organism as a model to make the necessary
changes. Which chromosome would you use? Explain your choice.
[13. Liskovykh, M., Kuprina, N., Larionov, V., & Tomilin, A. (2012). Artificial chromosomes for gene
therapy and tissue replacement. Genes and Cells, 7(4), 8-20].
SOLUTION:
It is proposed to use the smallest non-sex chromosome in human DNA, namely chromosome 21,
about 48 million bp long. It is proposed to use its functional centromere, about 10 million bp long,
removing about 40 million base pairs of 300 genes and non-coding sequences, trisomy on which is
responsible, including the development of Down syndrome.
1.31. Mammoth. The concept of de-extinction refers to the process of recreating organisms from
species that existed on Earth but later became extinct for some reason or creating organisms that are
genetically similar to those that became extinct. One of the varieties of xenotransplantation is the
interspecies transfer of somatic cell nuclei (iSCNT) of one biological species into the oocytes of
another species. In the work, they investigated the possibility of obtaining cloned embryos by
interspecies transfer of nuclei from somatic cells of bovine, mice, and chicken into enucleated pig
oocytes [14]. Researchers were able to support the development of such embryos in vitro to the
blastocyst stage. In the framework of the Australian project "Lazarus" method iSCNT managed to
revive the frog species that have disappeared since 1983 [15]. For this purpose, the nucleus from the
cryopreserved material was transferred to the eggs of another species of living frogs. Suggest ways to

resurrect an extinct species using preserved or newly synthesized genetic material.
SOLUTION:
This problem is currently being addressed by researchers from the University of Pennsylvania (USA),
Sooam Science Center (South Korea), and Northeastern Federal University (Russia). However, there
have been criticisms regarding the preservation of ancient DNA [16].
[14,15,16. Gupta MK, Das ZC, Heo YT, Joo JY, Chung H-J, Song H, et al. Transgenic chicken, mice,
cattle, and pig embryos by somatic cell nuclear transfer into pig oocytes. Cellular Reprogramming
2013;15:322–8. doi:10.1089/cell.2012.0074. Stone R. A Rescue Mission for Amphibians at the Brink
of Extinction. Science 2013;339:1371–1371. doi:10.1126/science.339.6126.1371. Grigorenko, A. P.,
Borinskaya, S. A., Yankovsky, N. K., & Rogaev, E. I. (2009). Achievements and features in working
with ancient DNA and DNA from complex forensic samples. Acta Naturae (Russian version), 1(3).]
1.32. Designing the Dragon. Tales of the peoples of the world contain descriptions of many amazing
animals that have never existed in nature. How can a person design and assemble a dragon?
SOLUTION:
Can a person design and assemble a dragon? Theoretically, yes. However, at today's level of science,
this would require a texture - a living object taken as the basis.
Figure 1.9. Dragon, 1896. Joannes Jonstonus (A Description of the Nature of Four-footed Beasts).
It is suggested to use the tools available today in the laboratory.
The chassis can be a small lizard from Madagascar. This is a good model organism to start
experimental work.
Figure 1.10. the girdle-tail.
However, introducing growth hormones alone will not produce the desired result. Introducing changes
into an organism means studying its genome and the principles of gene regulation. Therefore, first of
all, it would be necessary to sequence its genome and study the transcriptome at different stages of
embryogenesis. Thus, revealing the gene networks responsible for the growth and the mechanisms of
their regulation.

The most difficult part is the realization of fire breathing, safe for the dragon itself. Using the
engineered microbiota, we could realize an additional symbiotic organ in which boric acid esters
would be produced by microorganisms, for example through enzymatic catalysis, while phosphorus
extraction in sulfur would be performed by surface lined epithelial cells.
Additionally, a diet of special foods with elevated levels of phosphorus and single-atom alcohols
would have had to be carefully formulated.
1.34. The Mitochondrial Bridge. The phenomenon of directed lipid nanotubes for mitochondrial
exchange between closely spaced eukaryotic cells has recently been discovered [17]. Suggest options
for its use as a broadband information exchange channel for various purposes.
SOLUTION:
The solution to the problem is under development.
[17. Vignais, M. L., Caicedo, A., Brondello, J. M., & Jorgensen, C. (2017). Cell connections by
tunneling nanotubes: Effects of mitochondrial trafficking on target cell metabolism, homeostasis, and
response to therapy. Stem cells international, 2017.]
Figure 1.11. Scheme of mitochondria transport from MSCs to epithelial cells [18].
[18. Cárdenes, N., Cáceres, E., Romagnoli, M., & Rojas, M. (2013). Mesenchymal stem cells: a
promising therapy for the acute respiratory distress syndrome. Respiration, 85(4), 267-278.]
1.35 A range of bioengineering devices. Suggest a concept of the trial zone for checking of tactical
and technical characteristics, setting, performance tuning, and estimation of the safety of
bioengineering devices. How much more complex will this project become if we move from a single
cell system to systems as large as a small cat?
SOLUTION:
The modern ideas of biosafety are perceived with the realization of such concepts as “clean zone”,
“gateway” and “isolation of space”. This makes sense when it comes to handling hazardous biological
objects, however, it does not always work. For instance, Antonina Presnyakova passed away because
of the Ebola virus in 2004. She was a 46-year old technician in the laboratory of significantly
hazardous virus infections in the research institute of molecular biology (Novosibirsk oblast). 2 weeks
before her death she has accidentally pricked her double laboratory glove, while she was making
injections to the experimental guinea pigs [19].
However, when it comes to devices, which present no infectious danger, then more preferable would
be the concept of inducible endemics.
[19. ​Miller, J. (2004). Russian scientist dies in Ebola accident at former weapons lab. New York Times,
25.]
1.36 Shmoo is a comic character, invented in 1948 by American cartoonist and humorist Alfred
Caplin (Al Capp). Shmoos have a very pleasant taste and are eager to be eaten. If they notice a hungry
sight of a human, they will sacrifice themself and with no doubt jump into a pan. They have no bones,

which leads to no waste. Their eyes are perfect as buttons for suspenders and their whiskers can be
used as toothpicks. All in all, kind from nature shmoos are just perfect pets. They require very little
care and are wonderful friends for children. Shmoos have a talent to entertain people better than TV or
cinema do.
Industrial evolution might reach a limit and start degrading, which might lead to the disappearance of
significant differences between human and industrial “machines”. This is quite hard to imagine
though. What do you think: would that mean that a human would be able to produce all that he needs
for maintaining life in his or her own body. Or would rather biological machines supply human-being
just like shmoos?
SOLUTION:
Suggesting a solution is hard due to the numerous bioethical restrictions. However, you might suggest
your view and perceptions of technical prospects and borders of ethics.
1.37 The theory of appendix. Currently, there are a few theories of evolutionary functions of the
appendix, e.g. maintaining a normal gut microbiome during gut infections. Suggest the evolution of
the appendix from the perspective of its function of “immunological education” of T-cells for
declining the reaction on antigens of normal gut microbiome bacteria.
SOLUTION:
The solution is under development.
1.38 Virus as a super parasite. In virology, satellites are a group of sub-virus agents, which consist
of nucleic acids. For propagation, the host cell must be infected by another virus.
Some protein structures in eukaryotic cells and virus proteins look alike. [20]
Suggest an architecture of sub-virus agent which uses host-cell proteins for composing of virus
particles.
SOLUTION:
Presumably, for a tight folding of nucleic acid, it might require modification of the N-terminal of such
proteins with the use of specific microRNAs during the process of protein folding. Interesting to note,
that with such architecture of virus it would be invisible for the immune system of the host.
[20. Alcami, A. (2003). Viral mimicry of cytokines, chemokines, and their receptors. Nature Reviews
Immunology, 3(1), 36.]
1.39 The borders of co-cultivation. Co-cultivation influences the regulation, proliferation, and
differentiation of somatic cells. Suggest a mechanism of interaction of different cell types during
co-cultivation.
SOLUTION:
The solution is under development.
1.40 Biobricks. In the article “Can a radio be repaired by a biologist?” [21] the resolution of the lens
should correspond to the problem of biological abstractions, which usage could simplify the
development and modification of biological objects, is observed. Nowadays, the closest thing to that
described a forehead is iGEM Toolkit. The last contains sequences and functions of particular parts of
DNA, which can be used for cloning functional genome parts (“bio-bricks”). Suggest your own set of
bio-bricks for the projection of life machines.
SOLUTION:
Answering this question, use your imagination and break through the borders of already common
biological (e.g. iGEM Registry Part) and medical perceptions. In the figure below an example of
bioengineer is depicted: the components with the approximate time of activation for the subsequent
creation of cell-based and cell-free bioengineering devices.
[21. Lazebnik Yu. Can a biologist fix a radio? — Or, what I learned while studying apoptosis //
Cancer Сell.—2002.—Vol.2.—Р. 179–182.]

Fig. 1.12. The main elements of bio-bricks: components and their activation time[22].
[22.Miyamoto T, Razavi S, DeRose R, Inoue T. Synthesizing biomolecule-based Boolean logic gates.
ACS Synthetic Biology 2013;2:72–82. doi:10.1021/sb3001112.]
1.41 The face of the Tasmanian devil. A Tasmanian devil is a carnivore and an Australian marsupial
is threatened with extinction due to the spreading of a fatal disease. A huge malignant tumor hinders
the animal from eating. You were asked to seek the reasons for such uncommon cancer. You suppose,
that quite probably, this disease can be spread from devil to devil because of their fights which are
accompanied by biting around a mouth. To find the spring of cancer you isolate and investigate the
samples of tumors from 11 devils from distinct from each other regions. As expected, karyotypes of
tumor cells were grouped differently as opposed to the wild-type devil (Fig. 1.13). Interestingly, after
observation, it could be noticed that all 11 tumor karyotypes looked very much alike. Moreover, one
Tasmanian devil had an inversion on the 5th chromosome, which is not found in the tumor cells. Do
you think that this cancer is spread from devil to devil? Could this cancer appear as a consequence of
virus infection? Explain your thoughts. © John Wilson, Tim Hunt. Molecular Biology of the Cell 6E -
The Problems Book, 2015. (20-65)
SOLUTION:
The complexity of karyotypes and the resemblance between different tumors let us think that those are
the tumor cells that are spread from one devil to another. It is quite unlikely that virus infection can
cause the same genome malfunctions in different animals. Another argument for this hypothesis is that
one of the Tasmanian devils had an inversion in the 5th chromosome which was not observed in any
tumor cells. Therefore, tumor cells are not generated from the cells of the host organism. It appears
that this cancer was formed from a generation of tumor cells-” outcasts” with unknown roots which
adapted to parasitism. This is one of the examples of a natural spreading of cancer with cells. Another
example is a venereal disease in dogs. Sometimes this might also happen after the transplantation of
organs. However, the requirements to the transplanted tissue and repression of the immune response
make it almost impossible for the natural spreading of the disease to happen. The face tumor cells in
Tasmanian devils must have found a way to circumvent the immune defense of a new host body[23].
[23.Pearse A-M & Swift K (2006) Allograft theory: Transmission of devil facial tumor disease.
Nature 439, 549.]

Fig. 1.13. A) Tasmanian devil. B) Normal karyotype of a male: 14 chromosomes including XY. С)
Karyotype of tumor cells, observed in all 11 tumors: 13 chromosomes, 2nd chromosome and sex
chromosomes are absent, a single 6th chromosome, the 1st chromosome pair has restricted long arms,
four very disorganized chromosomes (M1-M4).
1.42 Microtubules in mitosis. Evaluate the amount of DNA that is transferred by one microtubule
during one cycle of mitosis. Evaluate the mean length of chromosomes in each organism in base pairs
(bp) and millimeters (1 bp = 0.34 nm) based on the data in table 1. Then evaluate the mean amount of
DNA in which is separated during mitosis. Is the last parameter the same in different organisms? ©
John Wilson, Tim Hunt. Molecular Biology of the Cell 6E - The Problems Book, 2015. (17-65)
Table 1. Amount of DNA, haploid number of chromosomes, and the number of microtubules for 1
chromosome in different organisms.
type species amount of
DNA (bp)
number of
chromosomes
number of microtubules for
1 chromosome
Yeast S. cerevisiae 1.4 × 107 16 1
Yeast S. pombe 1.4 × 107 3 3
Protist Chlamydomonas 1.1 × 108 19 1
Fly Drosophila 1.7 × 108 4 10
Human Homo sapiens 3.2 × 109 23 25
Plant Haemanthus 1.1 × 1011 18 120
SOLUTION:
The mean length of a chromosome and the mean number of bp transferred by one microtubule can be
seen in table 2. The value of length on DNA molecules varies from 0.9x10^6 bp in single-cell yeast
S.cerevisiae to 5.1x10^7 bp in the monocotyledon plant Haemanthus (difference of about 50 times).
Despite this parameter appears to be quite variable in different species, it is much more constant in
comparison to the mean length of chromosome DNA.
Table 2. Mean lengths of chromosomes and mean a number of bp for one microtubule in different
organisms.
type species mean
chromosome
length (bp)
mean length of
denatured
chromosome (mm)
Mean amount of
DNA for one
microtubule (bp)
Yeast S. cerevisiae 0.9x10^6 0.3 0.9x10^6
Yeast S. pombe 4.7x10^6 1.6 1.6x10^6
Protist Chlamydomonas 5.8x10^6 2.0 5.8x10^6

Fly Drosophila 4.3x10^7 15 4.3x10^6
Human Homo sapiens 1.4x10^8 47 5.6x10^6
Plant Haemanthus 6.1x10^9 2100 5.1x10^7
1.43 An extreme fusion. Cell fusion is a phenomenon in cell biology through which cells undergo the
exchange of genetic material in conjugation. In extremophilic archaea this might cause the
development of novel organisms, combining the extremophilic features of parent phenotypes. [24]
Suggest a selection method of polyextremophiles with particular features based on a combination of
cell fusion and targeted mutagenesis.
SOLUTION:
The solution is under development.
[24. Naor, A., & Gophna, U. (2013). Cell fusion and hybrids in Archaea: prospects for genome
shuffling and accelerated strain development for biotechnology. Bioengineered, 4(3), 126-129.]
1.44 Non-congealing fish. Antarctic notothenioid fish (Fig. 1.14) circumvent freezing in cold water
because they have a special antifreeze protein in their blood. This adaptation of suborder
Notothenioidei let them become a dominating species in the congealing Southern ocean. It is
considered that all proteins function by binding to other molecules. What do you suppose to be a
ligand for antifreeze proteins in these fish? Can this molecule be an example of a protein that can
function without any molecular interactions with other molecules? © John Wilson, Tim Hunt.
Molecular Biology of the Cell 6E – The Problems Book, 2015. (3-56)
SOLUTION:
Today it has already been deemed that antifreeze proteins are rich in alanine (up to 60% of a
molecule). These proteins are secreted in the liver of some aquatic organisms (boreal fish and
invertebrates) [25]
[25. Biotechnologia Acta, 6(6), 45-57. https://elibrary.ru/item.asp?id=21023339. ]
Antifreeze proteins bind to tiny crystals of ice, preventing them from growth and subsequent
congelation of fish. Crystals of ice that are formed in the present of antifreeze proteins appear to be
abnormal as long as their surface becomes cambered and not level. Different types of antifreeze
proteins in these fish consist of repeats of a simple glycoprotein (Thr-Ala/Pro-Ala) with disaccharide
bonds to each threonine.
Genes of these antifreeze proteins were likely developed due to a repetitive duplication of a small
segment of the protease gene. [26]
[26. Cheng CHC & Chen L (1999) Evolution of an antifreeze protein. Nature 401, 443–444.;52. Jia Z
& Davies PL (2002) Antifreeze proteins: an unusual receptor-ligand interaction. Trends Biochem. Sci.
27, 101–106.]

Fig. 1.14. Two notothenioid fish. Currently, notothenioid species are dominating the continental shelf
of Antarctica (50% of all species and 95% of fish biomass). For instance, Chilean sea bass is often
served in restaurants.
1.45 A mystery of chameleon. Some animals can change coloration. For instance, chameleons can
change their coloration from green-blue to bright-red and viсe versa шт a few minutes. In the past, it
was considered that the coloration changes are linked to the function of special skin cells —
chromatophores, which were able to rearrange the pigments of four colors. Nowadays, the role of
iridophores is already known. Iridophores are special cells, which contain regularly arranged
nanocrystals of guanidine and can change the spectrum of reflected light by changing the step of
guanidine lattice. [27]
SOLUTION:
The solution is under development.
[27. Teyssier, J., Saenko, S. V., Van Der Marel, D., & Milinkovitch, M. C. (2015). Photonic crystals
cause an active color change in chameleons. Nature communications, 6, 6368. Suggest the possible
reasons for regular structures of guanidine crystals in the cell, mechanisms, and limitations of color
control.]
1.46 A trap as a niche. Carnivorous plants adapted to catching and digestion of small animals,
mainly insects. This is an addition to their autotrophy (photosynthesis) with one of the forms of
heterotrophy. Take a look at a plant-trapper as a distinct ecological niche. ( © Biological seminars -
Vasiliev A.A. Course “Quantitative biology” MIPT)
SOLUTION:
The solution is under development.
1.47 Non-cooperative tissue games. Imagine the processes of organogenesis as a non-cooperative
game. If needed, suggest other definitions of organs than in the traditional anatomy.
SOLUTION:
The solution is under development.

2. Human construction
This chapter is about humanity’s dreams of longevity, curing malady and reaching happiness, and
proper biological tools to achieve it. The topics of inheritance and disease, ethical concerns, and
practical implementation challenges are considered.
2.1 Blade runner. German physicist Helmholtz, who studied the optics of the human eye, once said:
«If an optical workshop had sent me such a device, I would’ve sent it back for a redesign». Discovery
of what features led to this being said? Why does the human eye develop in this particular way?
SOLUTION:
The optic nerve is connected to the light-sensing cells from atop. The light needs to pass through the
nerve, the neurons, and only then does it reach the rods and cones. This makes the human eye prone to
the detachment of the retina from the supportive tissues, leading to rapid vision loss. It would be way
more rational to connect the optic neurons to the bottom (back) of the retina, as it does in squids. Such
structure of the human eye is caused by the development of the eyes from a nerve tube in chordates,
and there is no other way for an eye to form [28][29].
[28,29. Olshansky, S. J., Carnes, B. A., & Butler, R. N. (2001). If humans were built to last. Scientific
American, 284(3), 50-55. HOMO SAPIENS, MODEL 2. Nauka i zhizn. 2002.
https://www.nkj.ru/archive/articles/4620/ ]
2.2 New Vision. Visible light (280 to 720 nm diapason of wavelengths) detection is performed by the
opsins — light receptors of photosensitive cells, which are activating the phototransduction cascade.
Suggest an eye structure that could perceive ultraviolet (>720 nm) or infrared (<380 nm) light. Can
such construction be used for radio frequency vision?
SOLUTION:
Infrared light, despite being absent in higher primates and humans, for the time being, can be found in
several snake species. It allows them to see infrared light and hunt their warm-blooded prey in the
dark. Some fish (piranhas, goldfishes) and insects (mosquitoes) also possess infrared vision.
Ultraviolet light, which can be used to detect fluorescence, is also found in numerous mammal
species.
Radiowave vision (0.1 mm to 100’000s km) is complicated due to antenna size requirements (½
wavelength) and directional resolution of a signal but can be implemented using a distributed base
transceiver station.
2.3 Ageing deceleration. One of the aging mechanisms is supposed to be an expression
downregulation of genes that encode proteins that are responsible for the repair of damaged structures
(reparation genes). It is connected to the cell’s inner processes homeostasis. Suggest a scheme of
external manipulations, which could compensate for the reduction of reparation activity in the cell.
SOLUTION:
It seems like the spectrum of possible manipulations is limited to the activators of reparation genes:
transcriptional factors, non-coding RNAs, and (low molecular mass?) protein ligands.
Additionally, the reparation could be activated by the elimination of the secondary biochemical
pathways from the energetic metabolism. Maximal efficiency will be achieved if more efficient
analogs of naturally occurring biochemical reactions are used (as nowadays high-efficiency insulin
analogs are applied instead of regular insulin).
2.4 DNA-application. Estimate the mass of nucleic acids that have to be removed from an organism
or a human with Down’s syndrome for a complete cure (to make his/her genotype wild-type).
SOLUTION:
Assuming that every somatic and stem cell is subject to removal of the excessive 21 st chromosome
(with a length of 48 Mb, and the base pair weighs about 10E-21 g), and the number of cells in a
human organism estimates around 10E14, 1 mg of DNA (and some RNA) is going to be removed.

2.5 Peripheral equipment. According to one of the theories, tumors played a significant role in
evolution, being a proto-organ in animals. Suggest a way to design new organs for humans (bio
extensions) consisting of tumors and/or parasites. Possible functions may include infection filtration,
essential amino acid synthesis, etc.
SOLUTION:
Design and assembly would be facilitated with the previously developed Bioconstructor toolkit.
2.6 Bait receptors. Fas receptors and Fas ligands mediate cancer cells elimination by T-killer cells.
Investigation of 35 lung and colon tumors revealed that half of the tumors activated the expression of
the FasL-binding secretable protein. Why and how the overexpression of this protein could further the
survival of the tumors?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E - The Problems Book, 2015. (pr. 18-24)
SOLUTION:
Overexpression of a secretable protein, which binds FasL, protects tumor cells from T-killer attacks.
Upon binding, the mentioned protein prevents the interaction of FasL and tumor Fas receptors, thus
isolating the tumor cells from the deadly T-killer cells. Secreted proteins are known as decoy
receptors, and play a significant role in the modulation of Fas-dependent cytolysis. The
overproduction of decoy receptors allows the tumor cells to escape immune-cytotoxic attacks by
blocking FasL [30].
[30. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ,
Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard
AD, Botstein D & Ashkenazi A (1998) Genomic amplification of a decoy receptor for Fas ligand in
lung and colon cancer. Nature 396, 699–703.]
2.7 Immune engineering Suggest a method to engineer the immune system for complex peripheral
bio extensions compatibility, including cells of xenogeneic origin.
SOLUTION:
Possible solutions may include a way to select and genetically alter the immune cells, and
immunotolerance training on donor tissues. More radical methods could involve the transplantation of
complex bone marrow grafts to provide induced mixed chimerism [31].
[31. Sykes, M., Preffer, F., McAfee, S., Saidman, S. L., Weymouth, D., Andrews, D. M., ... & Spitzer,
T. R. (1999). Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after
non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. The Lancet,
353(9166), 1755-1759.]
2.8 Parent multiplicity. In 2013, transplantation of donor mitochondria into blastomeres was
approved in GB. This kind of operation is necessary when both parents are diagnosed with hereditary
mitochondrial diseases (e.g. Bart syndrome, Kerns-Sayre syndrome, Pearson syndrome, etc.) Such
egg manipulations have practically allowed for a donor woman to be a third parent. However, there
exist other forms of inheriting, such as microRNAs and egg cytoplasmic protein profiles, which affect
the offspring. A cytoplasm transplant may serve as a way of treatment, which has the effect of
changing the history of a parent (eliminating the consequences of working at hazardous production
facilities, emergency sites, or hunger).
Propose possibilities of using cytoplasm transplantation for preventing the development of certain
diseases.
SOLUTION:
The method could be used when using EF if parental biomaterial contains abnormal non-coding RNA
concentrations.
2.9 Bioethics limits. Nowadays ethical concerns limit the administration of certain drugs, which,
despite being proven effective on a patient’s cell culture, have not passed costly clinical studies. This
principle leads to the illegality of usage of the already available preparations. How bioethical concerns
could be surmounted with the help of new technology?

SOLUTION:
Ethical concerns of human modifications are discussed in numerous articles [32,33]. Quantitative
methods of philosophy and social sciences are also of interest.
[32,33. Hofmann, B. (2017). Limits to human enhancement: nature, disease, therapy or betterment?.
BMC medical ethics, 18(1), 56. Earp, B. D., Sandberg, A., Kahane, G., & Savulescu, J. (2014). When
is diminishment a form of enhancement? Rethinking the enhancement debate in biomedical ethics.
Frontiers in Systems Neuroscience, 8, 12.]
2.10 Mummy. African chironomid mosquito Polypedilum vanderplanki larvae possess a remarkable
feature: during desiccation, water in their bodies is exchanged for trehalose (glucose-based
disaccharide) molecules, and the organism enters cryptobiosis when all functions are paused. This
feature is determined by a kynurenine gene kynU. Find a mammal homolog of the kynU gene, which,
when mutated, could enhance humans with such features. Can the preservation of Buddhist lamas be
explained by a certain gene or mutation, specific for the South-East Asian natives?
SOLUTION:
The solution for this problem is yet under development.
2.11 Genome and epigenome redactor. Prenatal discovery of incurable diseases in fetuses at the
pre-EF stage is possible. However, some dramatic maladies can manifest years after the child’s birth.
Propose methods of therapy for such diseases, caused by gene regulation disturbance.
Solution
Nowadays two main strategies are in sight: therapeutic microRNAs and genome editing techniques.
2.12 Immune engineering against cancer. Propose a technique for T-helper and T-killer cells
modification to combat cells with abnormal transcription levels, induced by a viral, intracellular
bacterial infection, or oncological transition.
SOLUTION:
The human organism can poorly discern single molecular events, relying mainly on abnormal antigen
presentation on the cellular membrane. Simply altering existing T-cells is insufficient.
2.13 Mixed chimerism. The mixed chimerism phenomenon consists of weakening of the immune
response against foreign antigens in case of transplantation of allograft red bone marrow along with
the target organ. Propose a way to use and specific physiological functions of such a «second immune
system» with a limited functioning lifetime in order to improve the quality of life or longevity.
SOLUTION:
The solution for this problem is yet under development.
2.14 Surrogate organ bioreactor. Surrogate maternity comprises bearing a fertilized egg. The
creation of bioengineered organs may require the incubation of an underdeveloped organ draft inside
of a human body for further transplantation. Nowadays, surrogate incubation is used in clinical
operations to grow cartilage tissue. What issues may arise when applying this technique not to tissues,
but full organs?
SOLUTION:
In the first place, the risk of donor and recipient immunological incompatibility should be assessed.
From an ethical point of view, one should consider the consequences for donor health conditions.
2.15 Spare organs. In the human body, some vital organs are paired, and some are not. The organ bud
concept includes the transplantation of an organ draft, of which organogenesis terminates in an adult
human. In case of trauma or pathology, a draft could function at a minimal level, while the increased
burden serves as a signal for development into a fully functional organ. Suggest a model for the
development or engineering, transplantation, and maturing of organ drafts.
SOLUTION:
The solution for this problem is yet under development.

2.16 Molecular surgery. Modern visualization and surgical techniques allow for unprecedented
precision, and Da Vinci robots demonstrate that. However, it is supposed that the usage of molecular
robots — enzymes, immune drugs, other instances of molecular machinery, and their conjugates —
has the potential for performing surgical operations via transdermal or intravenous injection. In a 1966
paper, the notion of molecular DNA surgery was coined [34]. In the modern vision, this term
corresponds to applying genome editing for treatment. Suggest methods for molecular surgery for
human embryos, including reversible.
[34. Denkewalter RG, Tishler M. Drug Research — Whence and Whither. Fortschritte der
Arzneimittelforschung / Progress in Drug Research / Progrès des recherches pharmaceutiques, Basel:
Birkhäuser Basel; 1966, p. 11–31. doi:10.1007/978-3-0348- 7059-7_1. ]
SOLUTION:
The solution for this problem is yet under development.
2.17 The term enzymatic surgery was coined in 1981 [35]. Despite the widespread usage of enzymes
for gastrointestinal system therapies, enzyme-based reconstructive solutions, e.g. metalloproteinase
delivery at the fibrous tissue overgrowth site, have not been developed.
Suggest a molecular surgery technique for a cholecystectomy (gall-bladder removal), accounting for
the high risk of cholecystolithiasis (bile duct stones). Given the necessity for toxic products removal,
propose a way to deactivate and harmonious disposal with systems and organs present in the human
organism (liver, gastrointestinal tract, kidneys, lungs, perspiration glands).
[35. Paterson MC, Bech-Hansen NT, Smith PJ. Heritable Radiosensitive and DNA Repair- Deficient
Disorders in Man. Chromosome Damage and Repair, Boston, MA: Springer US; 1981, p. 335–54.
doi:10.1007/978-1-4684-7956-0_40. ]
SOLUTION:
The solution for this problem is yet under development.
2.18 Synthetic morphogenesis. Synthetic morphogenesis is a way to replace lost tissues, organs, and
cellular function(s) by inducing local iteration of normal ontogenesis or forming organs with
fundamentally different functions [36]. Propose methods for synthetic morphogenesis of lost or
mal/non-functioning organs instead of transplantation or lifelong drug therapy.
[36. Teague BP, Guye P, Weiss R. Synthetic Morphogenesis. Cold Spring Harbor Perspectives in
Biology 2016;8:a023929. doi:10.1101/cshperspect.a023929.]
SOLUTION:
This challenge is considered in detail in Jamie A. Davies papers [37][38]. Induction of morphological
organization in vivo and in vitro, methods for shaping organoids and biodrafts are discussed.
[37,38. Davies, J. A. (2008). Synthetic morphology: prospects for engineered, self‐constructing
anatomies. Journal of Anatomy, 212(6), 707-719. Cachat, E., Liu, W., Hohenstein, P., & Davies, J. A.
(2014). A library of mammalian effector modules for synthetic morphology. Journal of biological
engineering, 8(1), 26.]
2.19 Minimally invasive transplantology. Transplantation of organs and tissues is a painful
procedure, associated with surgical intervention and a risky rehabilitation period. New technologies,
(e.g. laparoscopic methods, fast track surgery) allowed to simplify such operations. Apart from
surgical robotics, suggest some ways to reduce the labor intensity of transplantations into the
abdominal zone.
SOLUTION:
The solution for this problem is yet under development.

2.20 Surgery 2.0. Annually I.M. Sechenov First Moscow State Medical University hosts surgical
contests, in which the participants are challenged to perform operations on model organs. One of the
tasks in 2016 proceeded as follows: «Prepare the supra- and subhepatic part of the inferior vena cava
(IVC) on the donor liver, as well as the elements of the donor hepatoduodenal ligament with ligation
of the crossed vessels; Prepare the elements of the recipient hepatoduodenal ligament with ligation of
the crossed vessels''. Suggest a format of a similar contest in the field of regenerative medicine, and
human and animals bioengineering.
SOLUTION:
The solution for this problem is limited by the sole imagination of the reader.
2.21 Surgeon-bioengineer. Theoretical surgery is a notion based on the integration of the
non-operative decision analysis and a system of clinical and fundamental studies, supporting the
invasive therapy methods. It was developed in the 1960s-70s by German surgeon and scientist
Wilfried Lorentz at Marburg University [38]. Nowadays such a personalized approach to surgical
treatment seems appealing due to considering the individual organism features.
Please describe the professional duties of a surgeon-bioengineer. What would his job look like?
SOLUTION:
In the authors’ mind, nowadays the mix of a bioinformatician and a therapist fits the described
profession the most. More ideas could be gained at the Moscow Management School «Skolkovo» and
Strategic Initiative Agency project «The atlas of new professions'' [39].
[38, 39. Koller, M., Bath, H., Celik, I., & Rothmund, M. (2004). A short history of Theoretical
Surgery. Inflammation Research,53, S99-S104. Atlas of new professions 2.0.
https://doi.org./10.5281/zenodo.1253766]
2.22 Beauty bioengineering. People with physical defects or appearance dysphoria resort to plastic
surgery, which is artificial. Bioengineering has the potential to recreate the traditional body looks. The
implantation of organs including actively proliferating tissues (e.g. breasts), coupled with abnormal
innervation and neovascularization issues, poses a threat of canceration, fibrosis, or local necrosis.
Suggest an arrangement of termination construction for arresting the epithelial to mesenchymal
transition of cells in bioengineered organs
Solution
The solution for this problem is yet under development.
2.23 Natural toothpaste. Some bacteria convert sucrose into lactic acid, which leads to the
destruction of tooth enamel. Suggest possible ways to use microorganisms for endogenous protection
of the enamel coating of teeth.
SOLUTION: Researchers from the University of Edinburgh have suggested using Streptococcus
Streptococcus salivarius, which secretes the enzyme FruA. This enzyme breaks down sugars that are
part of the Streptococcus mutans biofilm [40]. However, it would be more effective to use alkalophilic
bacteria that prevent the growth of colonies of acidophilic microorganisms dangerous for the enamel.
The vital activity of such microdantists, associated with the releasing of sodium ions, will lead the pH
level to the state of the physiological norm ~(6.0-9.0).
[40. Kolenbrander, P. E., Andersen, R. N., Blehert, D. S., Egland, P. G., Foster, J. S., & Palmer, R. J.
(2002). Communication among oral bacteria. Microbiology and molecular biology reviews, 66(3),
486-505. Engineering Biology Problems Book — 53 — 4. ]
2.24 Blood pathophysiology-I An increase in the right kidney was found in a 36-year-old man during
an ultrasound examination of the abdominal organs. Computed tomography revealed a 1.2×1.5×1.5
cm formation at the upper pole of the right kidney. Due to this, the man was hospitalized. Tests, taken
at the hospital: Hb 180 g / l, erythrocytes 7.5×10 12 /l, reticulocytes 10 %, leukocytes 4.0×10 9 /l,
platelets 250×10 9 /l, Ht 0.61, erythropoietin-20% higher than normal, blood pressure 150/90 mm Hg.
Histological examination of the formation punctate found at the upper pole of the right kidney showed
the presence of renal cell carcinoma. The patient underwent surgery to remove the tumor. 3 weeks
after the operation, his health and laboratory parameters returned to normal. 1. What form of

pathology has developed in the patient due to the growth of hypernephroma? Describe this pathology
using the data from the task. 2. What is the cause of this form of pathology? 3. What are the
mechanisms of its development and the symptoms that the patient has? 4. What other types of primary
and secondary forms of this pathology can occur in humans?
© P. F. Litvitsky "Tasks and test tasks in pathophysiology". Moscow: GatarMed, 2002 (task 59)
SOLUTION: 1. The patient developed secondary (acquired) absolute erythrocytosis – a pathological
condition characterized by an increase in the concentration of red blood cells (erythrocytes) in the
bloodstream. It is characterized by increased erythropoiesis in the bone marrow and the release of
excess red blood cells into the vascular channel. The number of red blood cells in the blood
сonsequently increases (7.5×10 12 /l), reticulocytes (10 %), the level of Hb (up to 180 g/l), Ht (0.61),
blood pressure increases (150/90 mm Hg). 2. In this case, the cause of the secondary absolute
erythrocytosis development is the hyperproduction of erythropoietin (its level in the blood is 20%
higher than normal) by the tumor cells of the right kidney. 3. An increase in the level of erythropoietin
in the blood causes the stimulation of erythropoiesis in the bone marrow and the release of excess red
blood cells (including their young forms) into the circulating blood. This, in turn, leads to
erythrocytosis, an increase in Ht and Hb content in the blood. Increased blood pressure is the result of
erythrocytosis, which caused hypervolemia. 4. Types of erythrocytosis: primary - erythremia (for
example, Vaquez's disease), familial (inherited) erythrocytosis; secondary - absolute and relative.
2.25 Blood pathophysiology-II. A 50-year-old patient, a photographer, was hospitalized with
complaints of an increase in the lymph nodes of the neck, which he began to notice during the last
month. Objectively: the skin is of ordinary color. Enlarged cervical and subclavian lymph nodes are
palpated, the size of beans and hazelnuts, of a dough-elastic consistency, mobile, not soldered to each
other and the surrounding tissues, painless. From the side of the chest organs without features. The
liver is not enlarged. The lower pole of the spleen is palpated (16 cm long). The blood test showed:
Hb 123 g/l, erythrocytes 4,7×10 12 /l, color index 0.9, l. 51,0x10 9 /l, e. 0, 5%, p. 1%, p. 24. 5%,
monocytes 2%, lymphocytes 72%, platelets 210×10 9 /l, ESR 17 mm per hour. Among the peripheral
blood lymphocytes, small narrow-cytoplasmic forms (almost bare nuclei) predominate, and
Botkin-Gumprecht shadows are found in a significant amount. Prolymphocytes make up 1.5%. 1.
What kind of disease can you think about in this case? 2. What confirms this disease? 3. What is the
stage of leukemia in the patient?
4. What are the most common complications in patients and why?
© P. F. Litvitsky "Tasks and test tasks in pathophysiology". Moscow: GatarMed, 2002 (task 59)
SOLUTION: 1. The patient has chronic lymphocytic leukemia (CLL), which is 85% of cases that
arise from the precursors of B-lymphocytes. There are two types of B-CLL: B-CLL, the substrate of
which is the cells of the T-independent pathway of differentiation, and B-CLL, the substrate of which
is the memory B-cells of the T-dependent pathway of differentiation. In the latter case, the disease is
more benign. 2. The age of the patient, an increase in the lymph nodes of the neck and a blood test
(leukocytosis up to 50-200×10 9 /l), lymphocytosis, and relative neutropenia. Small lymphocytes with a
narrow ring of cytoplasm located on the periphery of the nucleus. Typical in a blood smear is
Botkin-Gumprecht corpuscles. These are artifacts of tumor cells that occur during the preparation of
smears. 3. The patient has stage II since splenomegaly is observed and there is no anemia. 4. Anemic,
hemorrhagic syndromes are caused by damage to the bone marrow and the appearance of antibodies
to red blood cells and platelets. Infectious complications are caused by hypogammaglobulinemia,
disturbance of the cellular link of immunity. Allergic reactions of the immediate type (most often on
vaccinations, mosquito bites).
2.26 Knockout of filaments. Intermediate filaments are a class of cytoskeletal filaments with a
diameter of about 10 nm, which are composed of five types of structural proteins, each of which is
tissue-specific: neurofilament proteins (molecular weight 65, 100, and 135 kD), fibrillar acid protein
GFAP (50 kD), cytokeratin, desmin, and vimentin. Although knockouts of some intermediate
filaments genes manifest a certain phenotype in mice, knockouts of genes of vimentin or another
member of the vimentin family, glial fibrillar acid protein (GFAP), do not manifest themselves.
However, in mice with knockouts of both vimentin and GFAP, the functions of astrocytes, which are

auxiliary cells in the central nervous system, are impaired. Explain why a separate knockout of
vimentin or GFAP does not manifest itself, but a combined knockout exhibits pronounced pathology?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E - The Problems Book, 2015. (16-95)
SOLUTION: Surprisingly, so many knockouts of intermediate filament genes have so little effect on
mice. The amino acid sequence of mice vimentin, for example, is 98% identical to a hamster, chicken,
mouse, and human, which implies its important function, but knockouts of mice look completely
normal. The absence of a knockout effect of such a conservative gene is usually interpreted in terms
of a " backup system” that compensates for the loss. In the case of intermediate filament genes, this
backup system may be other intermediate filaments. The fact that the combined knockout of vimentin
and GFAP has phenotypically defected astrocytes suggests that these two intermediate filaments grow
back into each other in astrocytes. Astrocytes express genes for three intermediate filament proteins:
vimentin, GFAP, and nestin, for which the properties of purified proteins have been studied. Nestin
cannot independently form intermediate microfilaments, which apparently explains its inability to
compensate for the loss of vimentin and GFAP. Vimentin can form intermediate microfilaments, but
only together with nestin or GFAP, and GFAP can independently form several abnormal intermediate
filaments. Thus, these three proteins interact to form the correct intermediate filaments in astrocytes.
Function disturbance of one of these proteins may be permissible, but not of two [41][42].
[41,42 Herrmann H & Aebi U (2000) Intermediate filaments and their associates: multi-talented
structural elements specifying cytoarchitecture and cytodynamics. Curr. Opin. Cell Biol. 12, 79–90.
Eliasson C, Sahlgren C, Berthold CH, Stakeberg J, Celis JE, Betsholtz C, Eriksson JE & Pekny M
(1999) Intermediate filament protein partnership in astrocytes. J. Biol. Chem. 274, 23996–24006.]
2.27 Heart pathophysiology. Patient V. 46 years old was hospitalized in the intensive care unit of the
hospital with complaints of severe compressive pain behind the sternum, lasting for 1.5 hours. From
the anamnesis: the day before, he worked intensively for a week, had little sleep, smoking more than
usual, drank tea and coffee. Before the present disease considered himself a healthy person, exercised.
Examination showed: the general condition is severe, the skin is pale, acrocyanosis. Auscultation
showed: vesicular breathing in the lungs, no wheezing, the frequency of respiratory movements is 28
per minute, heart tones are muffled, arrhythmic, blood pressure is 100/70 mmHg. ECG results:
periodic atrial fibrillation with a frequency of 360, pulse blockage in the right leg of the Xis beam,
ST-segment elevation in I, AVL, V1-V4 leads. Blood test results: leukocytes 9.2×10 9 /l, other
parameters are within the normal range. 1. What forms of heart pathology has the patient developed?
Explain the answer. 2. What, in your opinion, is the causal relationship between the forms of
pathology you have named? Reason your answer. 3. What caused the condition accompanied by pain
behind the sternum? 4. What additional examination should be performed to confirm myocardial
damage?
© P. F. Litvitsky "Tasks and test tasks in pathophysiology". Moscow: GatarMed, 2002 (task 75)
SOLUTION: 1. Coronary failure, angina pectoris or a state of early angina pectoris (basis: changes in
ECG and blood pressure), arrhythmia (basis: the presence of atrial fibrillation). 2. The most probable
cause-and-effect relationship between these forms of pathology: coronary failure, myocardial
ischemia - > decrease in ATP production -> ion pumps functional disturbance -> formation of
pathological foci of excitation in the myocardium -> violation of the conduction of excitation pulses
(atrial fibrillation) -> right Bundle branch block. 3. The most likely cause of chest pain in coronary
failure is the accumulation of biologically active substances in cardiomyocytes due to myocardial
ischemia. 4. It is necessary to determine the content of macromolecules in the blood that are normal in
cardiomyocytes: the MV fraction of CPK and the myocardial pool of lactate dehydrogenase (LDH1).
2.28 Oguchi's disease. Patients with Oguchi's disease have a hereditary form of night blindness. After
a flash of bright light, these people restore their vision at night very slowly (gradually adapt to the
dark). Night vision depends almost entirely on the visual responses of rod photoreceptor cells. What
aspect of the visual response in the rod cells of these patients, in your opinion, is defective? Defects of
which genes can cause Oguchi's disease?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E - The Problems Book, 2015. (pr. 15-71)

SOLUTION: Since these patients recover abnormally slowly from a flash of bright light, they are
likely based on several models are describing cancer cells indeed differently damaged as a result of
activated rhodopsin returning to its inactive state. This process begins with the phosphorylation of the
rhodopsin’s cytosolic part by a rhodopsin-specific kinase. Then the phosphorylated rhodopsin binds to
arrestin. Additional reactions remove the phosphate and replace all-trans retinals (the end product of
the normal rhodopsin photolysis process) with 11-cis-retinals, eventually regenerating the rhodopsin
molecule, which is ready for the next phototransduction cycle. It was found that patients with
Oguchi's disease have defects in the rhodopsin-specific kinase gene or the arrestin gene (a retinal
protein that controls the photosensitivity of rhodopsin by binding to it).
2.29 Supersoldier. According to the concept of “enhanced warfighters” (DARPA), extending human
survival limits in extreme conditions is supposed to be done via activation of reparation and
regeneration mechanisms as well as cognitive abilities enhancement [43]. Suggest a scheme of
simultaneous activation of tissue-specific oxygen transport and metabolism and extraction
generalization of endogenous blockaders of amino acid neurotransmitters.
SOLUTION: It is clear from the question that the target is hypothalamus cells. However, the task does
not allow us to use only one of the known receptors (ex: vasopressin [44]). We suggest using a
two-stage reaction involving consequential tissue-specific activation of mitochondrial functions and
wide non-specific expression of stress-mediating proteins such as chaperones HSP70 and HSP90 and
interleukins 6 and 8. [45]
[43,44,45. Friedl KE. U.S. Army Research on Pharmacological Enhancement of Soldier Performance.
Journal of Strength and Conditioning Research 2015;29:S71–6. doi:10.1519/JSC.0000000000001027.
Ohbuchi, T., Haam, J., & Tasker, J. G. (2015). Regulation of Neuronal Activity in Hypothalamic
Vasopressin Neurons. Interdisciplinary information sciences, 21(3), 225-234.
Moskalev, A. A., Shaposhnikov, M. V., Shostal, O. A., Plyusnina, E. N., Romanova, E. V.,
Velegzhaninov, I. O.,... & Chernyshova, D. O. (2011). The relationship between the genetic
mechanisms of stress resistance and longevity. Bulletin of the Institute of Biology of the Komi
Scientific Center of the Ural Branch of the Russian Academy of Sciences, (4-5), 33-40.; 73.
Moskalev, A. A., Proshkina, E. N., Bely, A. A., & Solovyov, I. A. (2016). Genetics of aging and
longevity. Vavilovsky Journal of Genetics and Breeding, 20(4), 426-440. ]
2.30 Mission Everest. Researchers Houston and Ryley (the USA) conducted an experiment called
“Mission Everest” in a diving chamber in 1946. 4 males aged between 19 and 27 volunteered for it.
The duration of the experiment was 35 days, 32 out of which the volunteers spent in the diving
chambers. The pressure in the diving chamber was slowly decreasing to mimic an ascend to
mountains. At first, it was “going up” 600 m per day until “the height” of 2400 m; then 300 m until
6000 m; and then 150 m per day until the end of the experiment. On the 27 th day, the volunteers
achieved “the height” of 6850 m and remained there for several days. After that, the investigators
imitated storming the summit by decreasing the pressure in the chambers to 235 millimeters of
mercury – the atmospheric pressure on the peak of Everest [46]. During the 6-hour long “storming”, 2
volunteers needed oxygen, and 2 “made it to the peak” without assistance and spent 30 minutes there.
1. Which experimental conditions provided increased tolerance to hypoxia in the volunteers?
2. What is the name of the form of tolerance to repeated hypoxic conditions the volunteers
developed? What are the mechanisms of development of such tolerance?
3. What are the exact mechanisms of increasing tolerance to hypoxia in the given experimental
settings?
4. Why in the same conditions different healthy or almost healthy men displayed different
degrees of adaptation to hypoxia?
SOLUTION: The solution is under development.

[46. Cymerman, A. L. L. E. N., Reeves, J. T., Sutton, J. R., Rock, P. B., Groves, B. M., Malconian, M.
K., ... & Houston, C. S. (1989). Operation Everest II: maximal oxygen uptake at extreme altitude.
Journal of Applied Physiology, 66(5), 2446-2453.]
2.31 Suxamethonium. Surgeons use an analog of acetylcholine called suxamethonium as a muscle
relaxant. A muscle relaxant is a substance that decreases muscle tone of skeletal muscles together with
decreasing motion activity down to complete immobilization. It is important to use muscle relaxants
cautiously because some rare patients can take an anomalously long to recover from such temporary
paralysis, which can cause life-threatening consequences. These patients do not have enough ferment
called pseudocholinesterase in their blood. This ferment is responsible for suxamethonium
disintegration into choline and succinate. If suxamethonium is an analog of acetylcholine, why does it
relax muscles instead of making them contract as acetylcholine does?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E – The Problems Book, 2015. (pr. 15-31)
SOLUTION: Although suxamethonium binds acetylcholine receptors very strongly, it does not create
the receptor conformational change needed for the ion channel opening and muscle contraction
initiation. Suxamethonium prevents normal muscle contraction by competing with acetylcholine for
receptors and blocking the action of acetylcholine. Thus, suxamethonium is an acetylcholine
antagonist.
2.32 Galatea. In 2016, a Japanese company “Toyota Motor” created a robot Kirobo Mini, which was
able to hold a dialogue with a human and react to their emotions. These functions were supposed to
increase the bond an owner would get with the robot. According to the company, Kirobo Mini is an
important step to creating more sophisticated emotion-detecting robots. This is not a novel idea. In a
Greek myth, a sculptor named Pygmalion created a beautiful woman statue and fell in love with her.
Suggest a technical and normative solution to developing a human-like bioengineered system that
would be able to respond to sculptor’s love.
SOLUTION: in development.
2.33 Cosplay. This popular hobby of trying on costumes of famous characters and heroes can be taken
to a completely new level with the use of realistic minimally invasive methods. Suggest a way of
temporary induction of unique powers of a certain hero/heroine with no more than four injections.
SOLUTION: A modern movement of biohackers suggests mostly using electronic implants, open
data, taking biologically active additives, a healthy lifestyle, and other small interventions [47]. The
reader still can utilize ideas from genome editing and cell transplantation.
[47.Yetisen, A. K. (2018). Biohacking. Trends in biotechnology.). Biohacking-based genetic or
fermentative modifications are only emerging (76.Ledford, H. (2015). Biohackers gear up for genome
editing. Nature, 524(7566), 398-399.]
2.34 Born an Electrician. A human body in an electric field shows the qualities of a complex
transmitter surrounded by an imperfect dielectric – skin. Electrical breakdown of the keratinized
epithelium is possible if the electric intensity of the electric field in it is higher than its breakdown
electric intensity. The breakdown electric intensity of human keratinized epithelium equals 500-2000
V/mm. The electric intensity of 200 V always causes the electrical breakdown of the keratinized
epithelium. 30 thousand people die of electricity annually. Which gene overexpression in the
epithelium could notably decrease the number of deaths by making people more resistant to
electricity?
SOLUTION: The solution is under development.
2.35 Human Evolution. Studying different ethnic groups, scientists frequently find surprises. For
instance, a special shape of erythrocytes of Pacific Islanders makes them resistant to malaria [48].
Nowadays researchers are studying the effects of horizontal gene transfer on human and animal
evolution [49]. Suggest some surprising qualities (genes and regulatory schemes) that we observe in
plants, birds, and insects that could be useful for human evolution.
SOLUTION: The solution is under development [50].

[48,49,50.Rosanas-Urgell, A., Lin, E., Manning, L., Rarau, P., Laman, M., Senn, N., ... & Aponte, J. J.
(2012). Reduced risk of Plasmodium vivax malaria in Papua New Guinean children with Southeast
Asian ovalocytosis in two cohorts and a case-control study. PLoS medicine, 9(9), e1001305.
Crisp, A., Boschetti, C., Perry, M., Tunnacliffe, A., & Micklem, G. (2015). The expression of multiple
horizontally acquired genes is a hallmark of both vertebrate and invertebrate genomes. Genome
Biology, 16(1), 50.
Genetically modified people. The Economist. 14 March 2015. Retrieved 17 March 2015.]
2.36 The Equation of Life. Humanist ideas, scientific, technical, and medical progress lead
humankind out of stabilizing natural selection. This leads to the accumulation of detrimental
mutations that can potentially cause the extinction of the species. Create a mathematical model to
show if the accumulation of detrimental mutations can lead to humankind’s extinction.
SOLUTION: the task is dedicated to fundamental processes lying based on species formation. While a
species is the main unit of evolution, the main material of evolution is genetic mutations. Several
models are describing the dynamics of the world population [51]. At the same time, mathematical
models that would take into account harmful mutations accumulation are not extant yet.
[51 Korotaev A.V., Malkov A.S., Khalturina D.A. "Mathematical model of population growth,
economics, technology and education" - M., Institute of Applied Mathematics. M.V. Keldysh RAS,
2005 - http://www.keldysh.ru/papers/2005/prep13/prep2005_13.html.]
2.37 Precision Oncology. Comparisons of the patterns of mRNA levels across different human cell
types show that the level of expression of almost every active gene is different. The patterns of mRNA
abundance are so characteristic of a cell type that they can be used to determine the tissue of origin of
cancer cells, even though the cells may have metastasized to different parts of the body. By definition,
however, cancer cells are different from their noncancerous precursor cells. How do you suppose then
that patterns of mRNA expression might be used to determine the tissue source of human cancer?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E - The Problems Book, 2015. (7-12)
SOLUTION:
Although cancer cells indeed differ the resolution of the lens should correspond to their normal
precursors, they typically differ in their expression of only a relatively few genes (oncogenes and
tumor suppressor genes). When the overall patterns of mRNAs in cancer cells are compared with the
patterns of mRNAs in normal tissues, they match for the great majority of mRNAs. This RNA
signature allows a tumor to be definitively assigned to a particular tissue type. The field of medicine
based on this principle is called precision (personalized) oncology [52].
[52.Mileyko, V., Ivanov, M., Novikova, E., Telysheva, E., Chernenko , P., Breder, V., ... & Baranova,
A. (2016). NGS for precision medicine in non-small cell lung cancer: Challenges and opportunities.
Annals of Oncology, 27 (suppl_6), 119P. doi: 10.1093 / annonc / mdw363.6]
2.38 False progress. Progress in cancer therapy is often measured in terms of the fraction of patients
that are alive 5 years after their initial diagnosis. For example, in the United States in 1970, 7% of
lung cancer patients were alive after 5 years, whereas in 2000, 14% survived for 5 years. Although
this modest improvement might suggest a corresponding improvement in lung cancer therapy, many
oncologists don’t think therapy for this form of cancer has improved at all. In the absence of a
significant change in treatment, how can it be that a higher percentage of lung cancer patients now
live 5 years after their initial diagnosis?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E - The Problems Book, 2015. (pr. 20-68).
SOLUTION:
disease is caused by an autosomal mutation leading to a deficiency of the enzyme
N-acetylglucosamine phosphotransferase, as a result of which the formation of mannose-6-phosphate
does not occur. The GNPTA gene is localized to region q21-q23 on chromosome 4.

Patients with I-cell disease are missing the enzyme GlcNAc (O-N-acetylglucosamine)
phosphotransferase, which catalyzes the first of the two steps required for the addition of phosphate to
mannose to create the M6P marker (see Figure 2.1). In the absence of the M6P marker, the M6P
receptor cannot bind to the protein and deliver it to a lysosome. How do you suppose that the
lysosomes in some cells from these patients’ liver cells, for example, acquire a normal complement of
lysosomal enzymes?
Figure 2.1. Synthesis of the M6P marker in a liposomal hydrolase.
© John Wilson, Tim Hunt. [Molecular Biology of the Cell 6E - The Problems Book, 2015. (pr. 13-62)
SOLUTION: This striking result indicates that there must be a lysosomal delivery pathway that is
independent of M6P and the M6P receptor. The M6P- independent pathway might operate inside the
cell to accomplish sorting, presumably, from the tram Golgi to lysosomes, or as a scavenger pathway
that picks up lysosomal enzymes from outside the cell and delivers them to lysosomes, where they are
perfectly happy. Studies with M6P-receptor-deficient mice indicate that both types of pathways may
operate. In thymocytes from such mice, lysosomal enzymes appear to be delivered via an intracellular
route, whereas liver and skin cells can pick them up via an extracellular route [54].
[54. Dittmer F, Ulbrich EJ, Hafner A, Schmahl W, Meister T, Pohlmann R & von Figura K (1999)
Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6- phosphate
receptor-deficient mice are cell type-specific. J. Cell Sci. 112, 1591–1597].
Technological advances in our ability to detect cancers since 1970 mean that we can diagnose them at
earlier stages in the course of the disease. Thus, even in the absence of better treatment regimes, a
patient might be expected to survive somewhat longer now than in the past because they will be at a
slightly earlier stage of the disease at the 5-year mark [53].
[53. based on several differ can hemorrhoids differ the models are describing the resolution of the
lens should correspond Weinberg RA (2006) The Biology of Cancer, p. 726. New York: Garland
Science].
2.39 I-cell disease. I-cell disease or type II mucolipidosis is characterized by the presence of
numerous inclusions in the cells of connective tissue, manifested in growth retardation, etc. The 1.
Bioengineering Devices
Engineering solutions replicating modern technical devices and implemented in living organisms. The
ability to understand the principles of morphogenesis and regulation of living organisms allows not
only us to creatively intervene in the molecular basis of life but also opens the way to the realization
of completely new biotechnological productions based on "living machines".
2.40 Selective activation of brain regions. Optogenetic methods make it possible to activate
individual parts of the brain through the transfection of a photosensitive regulatory circuit into cells
and its subsequent activation using optical radiation [55]. This method, however, mainly allows
working with laboratory animals. Suggest a method for electro- or optical stimulation of certain areas
of the cerebral cortex to improve wellbeing and increase the work capacity.
SOLUTION:
Although optogenetics seems to be a promising technology for targeted cell stimulation, its direct use
is associated with a number of neurosurgical difficulties. The use of electromagnetic fields with a

high-intensity gradient seems to be a less invasive technology. The use of photosensitive proteins (not
necessarily membrane proteins) can enhance the sensitivity of cells to visible light.
[55. Deisseroth, K. (2011). Optogenetics. Nature methods, 8(1), 26].
2.41 Microbe voodoo. Neuroregulation of the functions of somatic tissues through the stimulation of
peripheral nerves isn’t limited to the internal organs and systems of a person. The intestinal microflora
produces a sufficient amount of serotonin and cytokines by exchanging signals with the nervous
system. Suggest a feedback mechanism that would theoretically overcome coccal infection with the
“power of thought! by stimulating a specific metabolic cascade.
SOLUTION:
The problem lies in the density of the peripheral nervous system, and its capacity for the transmission
of such a diverse repertoire of signals. In the intestinal wall, this problem is partially addressed by the
physical proximity of the nerves to the lumen. Stimulation of the innate immune system is an
energy-consuming method from the point of view of cellular physiology, therefore, it would be
necessary to assume the need to engineer specific signal transmission mechanisms, or use specific
humoral regulation.
2.42 Sleep, my little prince, fall asleep. The functions of the waking brain, the implementation of its
cognitive capabilities, and the efficiency of human activity depend on the quantity and quality of sleep
every night. Sleep disorders are a fairly common problem. Frequent complaints of poor sleep are
reported by 8-15% of the adult population of the world, and 9-11% use various sleeping pills.
Research on the use of pharmacological drugs to improve sleep quality indicates that long-term use of
such drugs can lead to addiction or severe side effects. Suggest some new non-pharmacological forms
of therapy for sleep and cognitive disorders that enhance the natural restorative functions of sleep.
© Problems from the final stage of the student BioTournament-2017. www.bioturnir21.ru. The
problem was proposed by Dr. Dorokhov Vladimir Borisovich, the Vice-President of the Russian
Society of Somnologists of the Pavlov Russian Physiological Society, at the Institute of Higher
Nervous Activity and Neurophysiology RAS, Moscow.
SOLUTION:
One of the options for non-invasive therapy for sleep disorders can be the use of transcranial magnetic
stimulation (TMS). Despite numerous positive examples of the use of magnetic effects [56], the
detailed mechanisms of TMS action on the most complex "electromagnetic organ" - the human brain,
remain unexplored.
[56. George M. S. et al. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in
depression. // Neuroreport : 1995. — Vol. 6, no. 14. — P. 1853—1856].
2.43 Mitochondrial Medicine. Human diseases can be associated not only with disorders of organs
and tissues of the body but also with cellular organelles such as mitochondria. Suggest some
mitochondrial treatment options for a patient suffering from faulty mitochondria.
SOLUTION:
To solve this problem, we recommend using ideas from [57].
[57. Rahman, J., & Rahman, S. (2018). Mitochondrial medicine in the omics era. The Lancet. doi:
10.1016/S0140-6736(18)30727-X]
2.44 Tricorder. The notion of a tricorder, a medical handheld device that can remotely scan a person's
body to determine their health status and detect the presence of certain diseases, has been popularised
in the Star Trek science fiction films. Suggest the physical principles on which this technical solution
could be based.
SOLUTION:
Possible technologies that can be used in such a "tricorder" include:
- Raman spectroscopy to determine minimal concentrations of an analyte by detecting giant Raman
light scattering in the desired range;

- Cell electrical potential measurement to determine vascular pathological conditions;
- A high-resolution infrared camera to determine not only body temperature but also temperature
patterns associated with pathology
- Microfluidic devices for analyzing the biochemical composition of biological fluids and gases (for
example, the composition of saliva and exhaled air).
Examples of parts of a Theranos miniLab, similar in concept to the tricorder, are shown in Figure 2.2.
Figure 2.2. MiniLab (Theranos) mini-laboratory for performing a bedside multiplex blood test
(point-of-care).
2.45 Theranos. In 2012, a company in California offered a commercial micro drop (5 µl) multiplex
blood test service, not only for clinical analysis but also an immunoassay for biomarkers of infectious
diseases. What was the reason behind the differences in results between patients tested by Theranos
and those tested by other clinical laboratories, as shown in Figure 2.3?
SOLUTION:
The company's problem was the limitation of modern biochemical methods for the qualitative
detection of biomarkers and the instrumental error of such methods, which made quantitative
immunoassays, and biochemical analysis fundamentally impossible [58].
[58. "A short history of Theranos" https://defense-network.livejournal.com/173606.html ]
Figure 2.3. Differences in blood test parameters at Theranos and other laboratories as obtained by
Wall Street Journal reporters.

2.46 A moveable feast. One study shows that strong love for life is a necessary factor for taking care
of one's health [59]. Induced overexpression of endorphin, dopamine or the use of another
endogenous hormonal neurostimulator is theoretically capable of providing short-term pharmaceutical
support. However, it is noted that the body eventually gets used to the new level of stimulation, and
the induced inhibitory effect will require the use of higher doses with reduced efficacy. How can you
prevent habituation in brain cells to the new basal hormone levels?
SOLUTION: The solution to this problem is still being worked on
[59. Cusack, S. A., Thompson, W. J., & Rogers, M. E. (2003). Mental fitness for life: Assessing the
impact of an 8-week mental fitness program on healthy aging. Educational Gerontology, 29(5),
393-403.].
2.47 Burnout. Burnout syndrome is a reaction of the body to long-term occupational stress of
moderate intensity. At the WHO European Conference (2005) it was noted that work-related stress is
a significant issue for about one-third of workers in the European Union. The cost of solving related
mental health problems averages 3-4% of the gross national income. Assuming burnout manifests as a
systemic effect, suggest some possible molecular biological mechanisms of its relief.
SOLUTION: The solution to this problem is still being worked on
2.48 The neuroeconomics of happiness. Problems with supersystems are directly related to the
quantitative parameters that characterize them. With regard to existing systems e.g. national
economies, such a parameter is their growth rate. Recently, economists have increasingly used
quantitative methods to study the level of happiness. Back in the 1970s, economists noted that the
growth of the so-called "level of happiness" reliably correlates with the expectation of future GDP
growth, but in countries with developed economies (i.e. the USA, West Germany, Australia, the
United Kingdom) this effect no longer works (the so-called Easterlin paradox) [60]. Cross-country
studies and nationals surveys show that there is an almost linear relationship between happiness and
the logarithm of income, one that is the same for both the rich and the poor.
Using this model, estimate the scope of radical biopharmaceutical measures to stimulate economic
growth.
SOLUTION: The solution to this problem is still being worked on
[60. Sergey Guriev (NES). Quantitative research on happiness..].
2.49 Cloning-related pharmacy. Humanity is heterogeneous by nature, making it very difficult to
select drug therapies, personalized treatments, and individualized nutrition for two different people.
Costly screening or clinical studies are required, as well as the study of incidents related to individual
phenotypic development. Human cloning opens the door to cost-effective therapies, with standard
drug responses. Assuming that human nature will prove so complex that there will be no other way to
ensure human expansion other than cloning, suggest ways to make differences in appearance that
would not affect important regions of the genome for a standard pharmacological response.
SOLUTION:
Modern studies make it possible to identify the regions of the genome responsible for individual
phenotypic manifestations of various characteristics and patterns of a person's appearance [61]. Thus,
by introducing single-nucleotide polymorphisms (SNPs) into the OCA2 and HERC2 genes, you can
get the desired eye color, the polymorphisms in the ASIP / PIGU gene will allow you to choose the
hair color, and in the PAX3, PRDM16, TP63, C5orf50, and COL17A1 genes, to select the appropriate
face shape. Selecting genes for intervention, for which mutations have not been previously shown to
be associated with a personalized pharmacological response, will allow the creation of clones
differing in phenotype that demonstrate standard pharmacological response.
[61. Kayser, M. (2015). Forensic DNA phenotyping: predicting human appearance from crime scene
material for investigative purposes. Forensic Science International: Genetics, 18, 33- 48.].
2.50 Your own normal. Relatively recently, researchers have drawn attention to the importance of
individual variation in what is considered to be “normal” not only in the field of biochemical

parameters but also in anatomy. What changes would accompany the introduction of the concept of an
“individual norm” to therapy and surgery?
SOLUTION:
The first work on the concept of the individual norm "Biochemical individuality" was written by R.
Williams [62]. It was noted that the activity of many enzymes in healthy people differs by a factor of
10 to 50, and hormonal activity may differ by a factor of 5 to 40. At present, it is possible to
distinguish such groups of indicators characterizing individual characteristics of organisms [63] as:
- anatomical (variant anatomy),
- cytological,
- physiological,
- biochemical,
- immunological,
- genetic (pharmacogenetics),
- biorhythmological.
Consideration of individual differences in the preparation of therapeutic intervention allows not only
to exclude therapeutic errors, but also to increase the effectiveness of a treatment, and to prepare a
theoretical basis for the use of such means as "personalized drugs"[64].
[62,63,64. Williams, R. J. (1956). Biochemical individuality; the basis for the genetotrophic concept.
Lekakh, V.A. (2005). Applied medicine - setting and solving problems: technological approach. M .:
KomKniga. - 456 p.
Cerullo, M. A. (2016). The ethics of exponential life extension through brain preservation. Journal of
Evolution and Technology, 26(1), 94-105.].
2.51 Knowledge from ashes. Resurrecting a person-hours, days, weeks, or longer after death is
contingent on the restoration of the structure of connections of the brain's connectome. Some
connections can be restored with a fraction of errors. For example, patients with memory impairment,
provided that their functional elements are intact, can correspond based recover their identity.
Scholastically, this can be compared to reconstructing a drawing from an element of a broken
hologram.
Propose models, schemes, and methods for a "minimal resurrection" of a deceased person's
personality depending on time after death, using the following tools:
a) differing degradation rates of lipid membranes, protein structures, RNA, and DNA sequences;
b) the restoration of the inventory of microRNA in neurons;
c) the restoration of axonal connections microstructure by spatial reconstruction of ligand-receptor
connections.
SOLUTION:
There is currently no solution to this problem. We recommend using the ideas of technological
resurrection from the work of (Turchin & Chernyakov, 2018) [65] and data on postmortem gene
expression in animals [66].
[65,66. Alexey Turchin & Chernyakov Maxim (2018). Classification of Approaches to Technological
Resurrection. https://philpapers.org/archive/TURCOA-3.pdf
Ferreira, P. G., Muñoz-Aguirre, M., Reverter, F., Godinho, C. P. S., Sousa, A., Amadoz, A., ... &
Nurtdinov, R. (2018). The effects of death and post-mortem cold ischemia on human tissue
transcriptomes. Nature communications, 9(1), 490.].
2.52 Cryonics. Many cold-blooded animals tolerate freezing and prolonged storage at temperatures
down to -35oC, some insects even down to -70oC. However, long-term storage at liquid nitrogen
temperatures (-195.75°C) for large biological objects would require the use of novel techniques such
as vitrification [67]. Suggest options for cryopreservation and subsequent thawing of whole
warm-blooded creatures.
SOLUTION:
There is currently no acceptable solution to this problem, but we suggest taking note of current patents
and presentations at conferences on this topic by companies such as Kriorus and Alcor.

[67. Bates, F. (2014). Nanomedicine: A Hyper-expectation and Dawning Realisation?. In
Nanomedicine (pp. 271-304). Springer, New York, NY.].
2.53 Neurorehabilitation. Following a traumatic brain injury accompanied by large-scale
hemorrhage and ischemia, patients are often in a state of "low consciousness" characterized by
reduced brain function, abnormalities in the neuroregulation of internal organs, etc. These conditions
can be rehabilitated, but often remain for life. Propose a way to induce plastic growth of axons to
prevent the development of post-traumatic disorders and neurorehabilitation.
SOLUTION:
There is currently no solution to this problem. However, the reader can try to find an acceptable
solution.
2.54 Self-making. Many of the structural imperfections and “design flaws” of the human body are
related to what anthropologist Neil Shubin refers to as the "inner fish" [68]. The “inner fish” is a
concept that explains our imperfection by the fact that human beings did not emerge as a finished
project designed for sedentary work and corporate events but as one of the links in a continuous
evolutionary chain in which fish came to land and conquered a new habitat. What features of the
human body can be explained by this concept?
SOLUTION:
In addition to what was stated in Problem 2.1. "Blade Runner", the following can be noted (text
provided by [69], Figure 2.4 by [70]):
1. The gastrointestinal tract of mammals overlaps with the respiratory tract, as a result of which, it’s
impossible to breathe and swallow at the same time. Moreover, this also creates a risk of choking and
is the reason behind the occurrence of nighttime apnea. The evolutionary explanation behind these
problems is that the ancestors of mammals were a species of keystone fish that swallowed air to
breathe.
2. A thoracic aortic aneurysm and a giant left atrium (in the advanced stages of mitral insufficiency)
may be the cause of hoarseness of the voice. This is due to compression of the recurrent laryngeal
nerve, which goes into the thorax as part of the vagus nerve and then returns to the larynx. The
recurrent nerve, for example, in the giraffe is up to 4 meters long. As we know from personal
experience, the more complex a device is, the more often it breaks. So why create such a long
structure? After all, the distance from the nerve exit point to the larynx itself is no more than four
centimeters! The fact of the matter is that the organs, which are innervated by the vagus nerve were all
formed from the 6th gill arch of fish, and, in the process of evolution, became separated by a
considerable distance. And, as we all know, fish don't have necks.
3. The main cause of reduced cardiac output, and hence blood delivery to organs (e.g. kidneys) in
human ancestors was an injury accompanied by blood loss. The kidneys reacted by retaining salts and
fluids to replenish the circulating blood volume. Nowadays the main cause of reduced cardiac output
is not blood loss, but rather myocardial infarction. When a piece of the heart muscle dies off, the heart
no longer properly performs its pumping function. Decreased cardiac output, just like millions of
years ago, leads to compensatory fluid retention in the body. Fluid is retained in the large and small
circulatory systems. Swelling of the lungs, liver, and legs occurs. The signs of heart failure appear.
Therefore, diuretics are the main way to combat heart failure.
4. One of the hypotheses explaining obesity formed by anthropologist James Neill was the concept of
the 'frugal genotype'. Its essence was that the ancestors of modern humans, as hunters and gatherers,
lived in alternating periods of abundance and famine. In periods of plenty, humans stored food in the
form of fat deposits, so that later, in times of famine, they survive off of them until the next successful
hunt. This mechanism works perfectly fine for boom and bust cycles but fails miserably when
high-calorie food is available all day and all year round in supermarkets. Cardiovascular disease and
type 2 diabetes as a consequence of obesity are also consequences of this evolutionary mechanism.
5. During physical activity, a large number of capillaries in the muscles open, and the surface area of
the endothelium (the cells of the inner membrane of the vessels) that is washed by the blood increases
hundreds of times. It is at the boundary of blood and endothelium where shear stress occurs during
physical activity and leads to the production of divalent nitrogen (NO) and other biologically active
and beneficial substances. NO expands blood vessels, lowers blood pressure, improves blood

rheology, fills cavernous bodies with blood, reduces the aggressive effects of free radicals and
cholesterol on vascular walls, and most importantly, halts the aging processes programmed into cells.
From the point of view of evolution, it will take millions of years for a mechanism to appear, which
enables the production of NO from the interaction of the gluteal area with the surface of the chair.
Unfortunately, for now, physical activity is the only option.
6. Sitting, which is not typical of the ancestors of modern humans, leads to stagnation of blood in the
pelvis. Pelvic veins dilate, their walls become inflamed, and the inflammation can lead to thrombosis
(Virchow's triad) and consequently to hemorrhoids differ.
[68,69,70. Shubin, N. (2018). Inner Fish. A history of the human body from ancient
Times to the present day. Litres.
HOMO SAPIENS, MODEL 2. Science and Life. 2002. https://www.nkj.ru/archive/articles/4620/.
Olshansky, S. J., Carnes, B. A., & Butler, R. N. (2001). If humans were built to last. Scientific
American, 284(3), 50-55.
http://eebweb.arizona.edu/faculty/Michod/Classes/182/182%202006/Better%20huma
n%20design.pdf.].
Figure 2.4. Human organs of intact and corrected morphology: male prostate (left) and female bladder
(right) © Patricia J. Wynne, Scientific American
2.55 Essential amino acids. Some amino acids cannot be synthesized due to a lack of the appropriate
enzyme. There are only 8 such amino acids, which are called essential, for adults and 10 for children.
Suggest possible modifications to ensure that the human body synthesizes all the amino acids it needs.
SOLUTION:
The use of additional sections of the intestine for this purpose seems appealing.
2.56 Functional anatomy. Modern anatomy considers groups of organs in accordance with their
general features or topographic characteristics. Propose a model for an alternative classification of

2. Mutations in mitochondrial DNA. Spare copies of mitochondrial genes in nuclear DNA will solve
the problem of mtDNA damage.
human organ systems based on tissue functions, the association of organs or their functional
components with stem cell niches, or another alternative classification.
SOLUTION: The solution to this problem is still being worked on
2.57 Disease patterns. Some unfortunate versions of current expert diagnostic systems are based on
binary tree models. However, the use of such systems tends to fail to benefit clinicians because of the
historical tradition of systematizing diseases. Propose a system for classifying human diseases that are
not inconsistent with diagnosis.
SOLUTION: The solution to this problem is still being worked on
2.58 Fetal surgery. Fetal surgery is performed in cases where antenatal correction of the condition
can improve the health and life outcomes of the newborn. As a rule, such operations are currently
performed in cases of cardiac pathologies. Biliary atresia is a rare congenital pathology in which the
biliary tract is obstructed or absent. Reconstructive surgery cannot be performed if the intrahepatic
ducts are obstructed, and liver transplantation is therefore indicated. Suggest a method of surgical
therapy for biliary atresia based on existing methods of fetal surgery.
SOLUTION:
We propose to use methods of fetal molecular surgery based on the injection of a modified hepatitis
virus with a cloned growth factor sequence and a removed replicative part of the virus.
2.59 Fetus in fetu. Fetus in the fetus is a pregnancy disorder with a frequency of 1 in 500,000 cases
which is associated with abnormalities in embryogenesis. Suggest a surgical method to treat such
systemic disorders of morphogenesis.
SOLUTION: The solution to this problem is still being worked on
2.60 Code "Prometheus". In 2013, the Russian Ministry of Defense announced a competition for the
development of a bioengineered human liver based on cellular technologies, publishing detailed terms
of reference and a work plan [71]. Evaluate the feasibility and effectiveness of the proposed approach.
SOLUTION: The solution to this problem is still being worked on.
[71 Bioengineered liver (code "Prometheus"). http://doi.org/10.5281/zenodo.2549274.].
2.61 Medicines for old age. Currently, there is no unified theory of aging that would explain the
observed effects. Among the most popular concepts are the following: a) Medawar’s evolutionary
concept (the "mutation accumulation theory", according to which an organism accumulates mutations
during life, thereby disrupting normal protein synthesis); b) the theory of "spent soma" proposed by T.
Kirkwood, which postulates the existence of genes that control the redistribution of energy resources,
and the weakening of repair mechanisms throughout life; c) the theory of the "life expectancy
program", which formulates the possibility of survival in extreme conditions, in which this program
allows the body to exceed its normal life span by entering a "maintenance mode". Suggest ways to
prolong life, the implementation of which corresponds to each of the above theories of aging.
SOLUTION: The solution to this problem is still being worked on
2.63 Biological waste. British biogerontologist Aubrey de Gray, within the framework of the SENS
program ("Strategies for achieving negligible aging by engineering methods") for an increase in life
expectancy, assumes getting rid of the damage that accumulates in the human body throughout life.
Suggest your ideas, what damage would you like to get rid of, and how?
SOLUTION: In the book by A. Turchin and M. Batin "Futurology", the scientific foundations of the
SENS program are described as follows:
1. Mutations in nuclear DNA. Replacing cells with short telomeres with your own cells with long
telomeres, created in the laboratory. Such periodic transplantations would make it possible to maintain
a constant number of functional cells in all organs in the absence of the threat of the emergence of
tumors.

3. Aggregates inside the cell. To break down intracellular "waste" – insoluble protein and lipid
aggregates (insoluble non-functional accumulations of proteins and other molecules formed due to the
"sticking" of deformed or incorrectly folded proteins with each other), from which the cell itself is not
able to get rid of – soil bacteria enzymes can be used which can break down such aggregates.
4. Aggregates in the extracellular matrix. To combat harmful aggregates that accumulate in the
intercellular space, for example, accumulations of amyloid protein, you can use vaccination to tune
the immune system to destroy them.
5. Cross-linking of proteins in the extracellular matrix. To destroy cross-links (bonds that connect long
polymer molecules of proteins or DNA to each other), it is possible to find substances that would
recognize them and destroy them.
6. Accumulation of unkillable cells. There are two possible routes of action - activation of the immune
system to remove harmful cells (for example, anergic T-lymphocytes and visceral fat cells) or
triggering their “suicide” genes
7. Loss of functional cells. The periodic addition of stem cells, as well as directed and controlled
differentiation of them, will be able to maintain the organ at the level of functioning of a young
organism for a very long time.
2.64 Asymmetry of the lifeline. In the paradigm of the existing living world, death is a natural
consequence of the course of things, and an abnormal life expectancy from a physiological point of
view can be an anomaly. Developmental anomalies associated with disruption of natural processes of
embryogenesis lead to spontaneous abortion for periods up to 20 weeks. What data on morphological
disorders of such fetuses can be used to understand the fundamental mechanisms of aging?
SOLUTION: The solution to the problem is under development.
2.65. Pushing death aside. The determination of the moment of death has been continuously altering
with the development of medicine: if the initial criterion was the cessation of respiration, and then the
cessation of cardiac activity, currently the criterion for a person's death is the cessation of the
electrical activity of the brain. However, recent scientific works have shown that pathological changes
in nerve cells occur only 3-4 hours after the cessation of the normal blood supply to the surrounding
tissues. What conclusions and suggestions can be drawn from this fact?
SOLUTION:
For example, it can be assumed that the death of an organism is a multistage process, and at the first
stage, the sequence of biochemical processes is regulated by the expression of specific genes involved
in pro-inflammatory reactions, apoptosis, and the response to cellular stress [72] [73]. The result of
the activity of such “postmortal genes” can help in reversing the developed pathological process.
[72,73. Gonzalez, K., & de Sousa, N. C. (2017). Thanatotranscriptome: genes actively expressed after
organismal death. Revista Intertox de Toxicologia, Risco Ambiental e Sociedade, 10(1).
Pozhitkov, A. E., Neme, R., Domazet-Lošo, T., Leroux, B. G., Soni, S., Tautz, D., & Noble, P. A.
(2017). Tracing the dynamics of gene transcripts after organismal death. Open biology, 7(1), 160267.]
2.66. Immortality of a man. The Roadmap for achieving immortality [74] considers various aspects
of realizing unlimited life extension: defeating infections, brain transplant, social change, cryonics,
cyborgization, artificial intelligence, reducing external causes of death, nanomedicine, regeneration
and artificial organs, digital immortality, antiaging therapy, genome and cell management, cloning.
Considering the phenomenon of human immortality as an achievable social change, and using the
tools proposed in the Roadmap, suggest a rational strategy for achieving it.
SOLUTION:
Currently, there is no solution to this problem, however, different scientific groups all over the world
suggest strategies, which differ in their content.

[74. Batin, M., Konovalenko, M., & Turchin, A. (2013). Roadmap to Immortality. Moscow, Russia:
Science for Life Extension Foundation. http://doi.org/10.5281/zenodo.1204219]
English biogerontologist Aubrey De Gray within the framework of the program SENS («strategies for
engineered negligible senescence ») offers to get rid of the damage that accumulates during aging.
Russian scientist corresponding member of RAS Alexey Moscalev suggests increasing life
expectancy by activating the repertoire of stress resistance genes.
American futurologist Ray Kurzweil assumes reaching digital immortality.
Russian futurologist Mikhail Batin (“Science for Life Extension” Foundation) sees the ways to
achieve physical immortality in an integrated approach, first of all, solving the problem of life
extension for people already living.
Probably it is you, the reader, who will become an engineer of technologies for human immortality.
2.67. Get root authority of your body system. (by Boshuang Wang, CAU_China team iGEM 2021)
Root authority of phones is the highest authority of the Android system. After acquiring root authority
of your phone, one can easily exeturate important commands such as uninstalling or restoring system
files. Is there a possibility that one can get the root authority of his or herself body? Namely one can
control his or herself any biological processing or organ states, such as turning off your ears, fasten
growth of your hair initiatively, or even control your heartbeat. Of course, you can return these
authorities back to your body anytime and anywhere. You only need to acquire the authorities to
control these processes when necessary.
SOLUTION:
The solution to the problem is under development.
2.68. Forever chemicals (by Elsa Arksand, Stockholm team iGEM 2021)
Chemicals such as PFAS are called forever chemicals since they are very stable and do not degrade in
normal conditions. These chemicals have been a popular additive in different products such as fire
extinguisher foam, teflon pans and special heat and clean sensitive products. Even though they do not
degrade, they spread out and accumulate in different environments such as soils, fatty fish and in
humans. [1] High concentrations of these chemicals can cause negative effects on the health of
humans and other organisms and are difficult with today's technology to clean or degrade. These
forever chemicals will not stop posing as a threat in the future unless new technology and regulations
are put in place to protect humans and organisms from these pollutions.
[1. https://www.epa.gov/pfas/basic-information-pfas]
2.69. Tricky solutions (by Dmitrii Vladimirtsev, MIPT_MSU team iGEM 2021)
Sometimes, when preparing complex solutions (that is, solutions consisting of several components), a
situation arises that during the preparation process, when absolutely all components of the solution are
mixed in the correct proportions, it is still not a true solution (that is, a phase separation is visible in it:
for example, turbidity and precipitated salts). And only with intensive stirring for several minutes does
the solution become true. Why?
SOLUTION:
The thing is that some salts dissolve when the required pH of the solution and/or sufficient ionic
strength is reached. If the solution is complex (that is, containing several components), then some of
its components will begin to dissolve only after its other components have dissolved. A good example
is the preparation of a solution of TBE (Tris, Boric acid, EDTA) — if you simultaneously throw into
the water the amounts of substances required by the protocol, the experimenter will see that the
solution has become heterogeneous and most of the added precipitated. Only with intensive stirring
for several minutes will boric acid begin to dissolve in the solution, creating the necessary pH for the
complete dissolution of Tris and EDTA.

3. Technopolis "Planet"
Technological solutions that make humanity a new geological force. In the work of V.I.Vernadsky
humans and microorganisms were considered as the most powerful form of the geochemical effect of
living matter on the transformation of the planet. Learning the nature of managing his body,
influencing its vital capacity, humans will be able to influence the environment in the same way,
receiving everything they need from nature with the help of "life-like" machines, creating man-made
living communities (biocenoses), preserving natural enclaves, and increasing the size of the planet's
metagenome on an incredible scale.
[75. The lecture is the first public presentation of the idea of science as a geological force, as a natural
phenomenon. Read on October 18/31, 1920 in Simferopol at a meeting of the Commission for the
Study of the Natural Productive Forces of the Crimea. The manuscript remained unfinished. Name
given by the compilers.]
3.1. The power of the Earth. The classification of astrophysicist Nikolai Kardashev defines different
levels of development of civilizations. Type I civilizations are those that can fully use the sunlight
falling on the planet. Currently, humanity uses about 0.0005% of the total energy budget of the planet
(1016 W or 3.15 × 1023 kWh). Estimate the power available to humans when using terrestrial “living
power stations” (plants) with an efficiency of 6-7%, with the possibility of increasing it by
engineering methods by another 2-3%.
SOLUTION:
The solution to the problem is under development.
3.2. The power of the oceans. The surface of the Earth is 75% covered with water, and 90% of the
sunlight is absorbed in a depth of 40 m. How can ocean power stations be organized to harness solar
energy?
SOLUTION:
It is suggested to use planetary systems based on plankton or spirulina.
3.3. Biological reserve. The large-scale use of genetically engineered living machines and natural
communities might lead to an uncontrolled evolution of the functions of living machines, which are
not always favorable for humans. Suggest mechanisms or new enzymes to control evolution, suppress
mutagenesis (the emergence of dangerous mutations), and natural selection.
SOLUTION:
The solution to the problem is under development.
3.4. Greenhouse resource. Currently, the mass of carbon bound in the Earth's biosphere is estimated
at 550 gigatons, of which: viruses - 0.2 Gt, land plants - 470 Gt, animals - 2 Gt (of which 1 Gt is
arthropods, for example, insects, and 0.7 Gt - fish), humanity - 0.06 Gt [76]. The use of living
machines, organized based on a carbon form of life, will lead to a radical decrease in CO2
concentrations in the Earth's atmosphere, which, hypothetically, could lead to global cooling. Estimate
the optimal mass of the Earth's biosphere provided that this effect, opposite to the greenhouse, is
realistic.
SOLUTION:
The solution to the problem is under development.
[76. Bar-On, Y. M., Phillips, R., & Milo, R. (2018). The biomass distribution on Earth. Proceedings
of the National Academy of Sciences, 201711842.]
3.5. Carbon resource. Under the conditions of problem 3.4 “Greenhouse resource” estimate the
volume of annual needs for burning coal to ensure the normal growth of the functional biosphere.
SOLUTION:
The solution to the problem is under development.

Figure 3.1. Nordic poultry © Simon Stalenhag, Sweden
3.6. Virus of intelligence. In some cases, it would be nice if the animals could clearly understand
commands or even words. It was shown that an artificial increase in the expression of the KIF17
protein in mice allowed them to pass the proposed tests faster and to memorize better than the control
group. In this area, a radical technological solution is the excision of the entire gene sequence with
regulatory regions in humans and the formation of an artificial chromosome of an animal (for
example, the 20th "mind chromosome" of a cat). However, it seems that a significant effect can be
achieved using a non-pathogenic virus with a rather large cassette. Suggest viruses based on which
such a "virus of intelligence" could be constructed?
SOLUTION:
The solution to the problem is under development.
3.7. Inhibitors of consciousness. Nowadays, it is planned to use genetically engineered animals for
growing human organs, such as mini-pigs, from which HLA-complex is removed via endogenous
retroviruses and replaced (for example, in the company eGenesis). On the other hand, the organ bud
approach is a collection of methods for fabricating tissue-engineered constructs, in which human or
animal body cavities are used as a bioreactor at the last stage of morphogenesis. Thus, the
development of therapeutic cloning technologies, the evolution of animals, and large-scale genetic
engineering interventions will ultimately lead to the ethical problem of precisely determining the
presence of consciousness in a living being. For example, proteomic profiles of some proteins of the
nervous system could become such a marker of consciousness. Suggest schemes for inhibiting the
expression of a wide class of proteins to ensure the lack of consciousness of the laboratory animal.
SOLUTION:
The solution to the problem is under development.
3.8. Friendly nature. In March 2014, Lisenne Frunn and her friend Chris Kremers, nationals of the
Netherlands, went on an ethnographic journey to Panama. They were not prepared for traveling in
conditions of jungle, and they got lost and died horribly. Suggest what functions a person should have
at hand anywhere on the planet so that travel in the wildest areas does not lead to the death of even a
child.
SOLUTION:
The solution to the problem is under development.
3.9. Additional animal brain and its interfaces. Primitive parasites can often control the behavior of
their more highly organized hosts. For example, it is beneficial for a parasite that lives on only one
species to protect its hosts: for example, to drive the fish into a dense flock for their own safety,
having received an additional benefit from this - the proximity of a mating partner traveling on a
neighboring host individual. Develop a scheme for transplanting a parasitic neurosystem into a
transgenic animal with specialized decision-making functions, including maintaining life after brain
loss.
SOLUTION:
The solution to the problem is under development.

3.10. Bacterial division scale. The division of bacteria in the nutrient medium occurs every 40
minutes. With this mitotic division, the bacterium produces a cell similar to itself. The mass of one
bacterium is 5 × 10-15 kg. Let's imagine that we put one such bacterium in an unlimited ocean of
nutrient medium. How long must it take before the weight of the bacterial biomass exceeds the mass
of the planet Earth (5.9742 × 1024 kg)?
SOLUTION: Litersll takes 195 hours (a little over 8 days) until the weight of the bacterial biomass
exceeds the weight of the planet Earth.
Figure.3.2. Large-scale biosynthesis in swamps of northern latitudes © Simon Stalenhag, Sweden.
3.11. Biogenic origin of oil. According to one of the theories, oil may have a biogenic origin.
Theoretically, its formation could occur due to the transformation of the heat of the earth's core in the
thickness of the crust by microorganisms. For example, in the Northern Caspian region at a depth of
3-4 km, the temperature and pressure reach 100-150 ° C and 700-1000 atm, respectively. Taking the
heat flux from the earth's core near the planet's surface as 0.03-0.05 W / m2, estimate the possible rate
of hydrocarbon accumulation due to the vital activity of anaerobic bacteria.
SOLUTION:
The solution to the problem is under development.
3.12. Bacterial weather. In the 1950s, it was discovered that spores of bacteria and fungi can rise to
heights of 20-22 km and higher. A study of the microbial composition of the troposphere, carried out
in 2010 as part of the NASA program, showed that viable bacterial cells account for approximately
20% of particles with a diameter of 0.25 to 1 micron contained in the air at an altitude of 8-10 km
(that is, in the middle layers of the troposphere ). The concentration of aerosol particles of this size
varied depending on the height, ranging from 59 million particles per cubic meter at altitudes of 0-1
km up to 2.6 million per cubic meter at an altitude of 7-8 km. In theory, the expression of specific
membrane proteins in such bacteria could stimulate the formation of droplets and precipitates
(hydrophilic proteins) or, conversely, prevent the formation of droplets (hydrophobic proteins).
Suggest genes and their regulation scheme to stimulate the formation of precipitation at night and
during the day with low humidity.
SOLUTION:
We propose to consider schemes based on changes in the temperature of microorganisms and

temperature-dependent expression of proteins and metabolism in them. The method of “switching”
could be regulatory proteins that denature at the temperatures you want.
3.13. Bacterial Klondike. Hypothetically, in the future, the exhaustion of the known sources of some
ores may become a problem, and their new search may be difficult or limited. Bacteria are capable of
degrading metal sulfides, making it cost-effective to develop landfills, dumps, and other potential
sources of rare earth and precious metals (bioleaching). At the same time, the stage of cyanidation
remains relevant, based on the selective dissolution of metals in weak solutions of cyanides (NaCN,
Ca (CN) 2, KCN) and their subsequent precipitation from solutions on zinc dust, ion exchangers,
activated carbon. Describe a biotechnological process for extracting metals from poor ores based
solely on biotechnology.
SOLUTION:
Bacterial leaching is a well-known method of intensifying the process of extracting valuable
components from rocks (for example, U, Cu, Au, etc.) using microorganisms. For example,
chemolithotrophic bacteria of the genus Thiobacillus leach iron, copper, zinc, uranium, and other
metals, oxidizing them with sulfuric acid, which is formed by these bacteria from sulfide; the
chromobacterium Chromobacterium violaceum dissolves gold. However, a completely
biotechnological process of enrichment of poor ores will require either 1) the accumulation of metal
salts in bacteria, or 2) the inclusion of compounds in the matrix of bacterial biofilms.
3.14. Artificial uterus. The development of the fetus in placental mammals requires not only
nutrition but also the presence of a wide repertoire of proteins, signaling molecules, etc. Of interest
are the ability of marsupials to carry a fetus in a pouch from the 12th to 28th day of embryo
development, as well as the principle used by oviparous mammals. Compare these approaches
(placental, marsupial, oviparous) for the technological simplicity of in vitro implementation of an
artificial womb for reproductive genetics and cloning.
SOLUTION:
The solution to the problem is under development.
3.15. Large production facilities. In 2003, in the state of Oregon (USA), the largest living object on
the planet was discovered - the mycelium of common honey agarics (Armillaria ostoyae), with an area
of almost 10 km2 and an age of up to 8500 years. Most of it is hidden from view and lies underground
in the form of a massive bed of tendril-like white mycelium (mycelia, the mushroom equivalent of
roots). This concept of mega-organisms seems attractive for organizing agricultural objects. Suggest a
scheme for their use to eliminate the need for measures to restore soil fertility.
SOLUTION:
The problem of genome homogeneity and high risks of infection with one effective parasite. We invite
the reader to consider the case of "Pando" - a clonal colony of aspen poplar, which covers 43 hectares,
the weight of the plant is estimated at 6,000 tons, which makes it the heaviest known organism. The
age of origin is estimated at 80 thousand years [77].
[77. Genetic Variation and the Natural History of Quaking Aspen, Jeffry B. Mitton; Michael C. Grant,
BioScience, Vol. 46, No. 1. (Jan., 1996), pp. 25-31]
3.16. Food engineering. You can imagine a world in which the best fruit is the one that you not only
grew but also designed yourself. Seedling preparation, greenhouse equipment, fertilization, lighting,
and watering may well be deployed at home. Offer a technological platform for the design and
implementation of the principle of self-design of fruits and vegetables for an ordinary citizen with
minimal skills.
SOLUTION:
The solution to the problem is under development.
3.17. Home kitchen. Using the result of task 3.16 “Food engineering” suggests a model for growing
plant products in a city apartment. Which plant would you choose as a basic organism for further
development and implementation of functional modules
SOLUTION:

The solution to the problem is under development.
3.18. Michurin-in-the-kitchen. Suggest a way to create functional modules of a basic organism from
task 3.17 “Home kitchen” for food production at home. How safe and effective would it be to use the
modules using the following methods: 1) grafting; 2) bacterial infection; 3) phytoviruses; 4)
combinations of the listed methods.
SOLUTION:
The solution to the problem is under development.
3.19. Chimera house. The phenomenon of chimerism means the presence in one organism of cells
with two or more different genotypes. Imagine what useful functions could be carried in the
household by chimeric animals or plants containing the cells of the owners of the house?
SOLUTION:
The solution to the problem is under development.
3.20. Agricultural bio-robot. A hypothetical agricultural robot for autonomous cultivation of crops
and operations in closed compact ecosystems would be especially useful in a sharply continental
climate. Suggest the layout of such a human assistant, capable of performing basic agricultural
operations, in a biorobot format.
SOLUTION:
The solution to the problem is under development.
3.21. Cultured meat. In 2013, bovine muscle cells with a total mass of 85 g were grown by
researchers from the University of Maastricht (Netherlands), which is enough to form a hamburger
patty [78]. However, such "meat", devoid of the structure of normal tissue layers, turned out to be
extremely unappetizing. Suggest ways to grow meat that would make large-scale animal husbandry as
we know it irrelevant.
SOLUTION:
The solution to the problem is under development.
[78. Kadim IT, Mahgoub O, Baqir S, Faye B, Purchas R. Cultured meat from muscle stem cells: A
review of challenges and prospects. Journal of Integrative Agriculture 2015;14:222–233.
doi:10.1016/S2095-3119(14)60881-9.]
3.22. Auto-fertilization mechanisms. Symbiotic plant systems, such as the root nodule systems, are
characterized by the ability of microorganisms to bind nitrogen for plant absorption [79]. It seems
promising to use this phenomenon to create engineering agricultural crops with induced symbiosis.
SOLUTION:
The solution to the problem is under development.
[79. Glick BR. Plant growth-promoting bacteria: mechanisms and applications. Scientifica
2012;2012:963401. doi:10.6064/2012/963401.]
3.22. Vertical farming. Vertical farm technologies are designed to increase productivity, reduce costs,
and expand food and material production across arid and desert areas. Offer a closed ecosystem for
agriculture in unsuitable conditions, and the creation of life support systems for autonomous space
stations.
SOLUTION:
The solution to the problem is under development.
3.23. «6 areas». The gene pool of agricultural plants is one of the most valuable resources of
mankind, without which the survival of our species is impossible due to the constantly increasing need
for food. The search for the most successful genotypes, their hybridization or other methods of
improving the applied qualities of plants can be carried out only on the basis of the available
collections of varieties and forms of agricultural plants. Collections of annual plants are maintained in

the form of a periodically updated seed bank. Collections of perennial woody plants exist in the form
of plantations occupying vast areas, which leads to high economic costs for their maintenance or to a
limitation of the number of samples in the collections.
Suggest an alternative version of the collection of genetic resources of perennial crops, the number of
samples in which can be increased indefinitely, allowing you to test the properties and use the plants
in it as breeding material.
© Sundyreva M.A., senior researcher laboratory of physiology and biochemistry of plants of the
North Caucasian Zonal Research Institute of Horticulture and Viticulture. All-Russian Student
BioTournament -2017. www.bioturnir21.ru
SOLUTION:
Achievements in the field of cell and tissue culture led to the creation of a fundamentally new method
of vegetative propagation of plants - clonal micropropagation (obtaining in vitro, asexually, plants
genetically identical to the original specimen). For such plant cells, cryopreservation methods have
been developed and continue to be improved, implying long-term storage of breeding material.
However, even more, traditional methods, such as grafting several plant species on one stock at once,
can save significant areas and resources.
3.24. Grapes: Reboot. Grapes are one of the most capital-intensive agricultural crops. The lion's
share of the costs is spent on protecting plants from diseases and pests. Systemic chemicals (for
example, fungicides: Poliram, Kabriotop, Quadris, Topaz, insecticides: Calypso, Bi58, Insegar,
Fastak) are toxic to the environment and act for a strictly defined period until excretion from the plant.
Suggest a method for simultaneously fixing plant protection agents and reducing toxicity to the
environment and humans.
© Problem from scientists-winegrowers of the North Caucasian Zonal Research Institute of
Horticulture and Viticulture, Krasnodar. All-Russian Student BioTournament-2016.
www.bioturnir21.ru
SOLUTION:
The development of a solution to this urgent all over the world problem is going in two directions.
First, the use of more specific pesticide preparations as the main active ingredient in comparison with
classical FOS (or other chemical nature), for example, δ-endotoxin secreted by Bacillus thuringiensis,
to combat leaf-eating insects, or subtilin, an antibiotic produced by Bacillus subtilis 6633, which
inhibits the growth of a number of phytopathogenic fungi. The second is the development of methods
for fixing old and new drugs. In particular, the use of surfactants to reduce droplet evaporation. And
also, the development of adhesives that provide not only reliable and long-term fixation of the active
substance on any surface but also protection against drying out and sunburn, reducing the
development of fungal diseases. The combination of these approaches will significantly reduce the
chemical load on the plant and on the environment.
3.25. Living underwater vehicle. Long-term autonomous oceanological research is very difficult
because of the need to solve the problem of long-term maintenance of scientific equipment. Suppose
that an underwater research vehicle can be created on the basis of a reduced sperm whale organism. In
this case, the bandwidth of the data transmission channel in the audio frequency range may be
insufficient. How can the problem of transferring large amounts of data be solved? What additional
ways can there be to improve this method of communication?
SOLUTION:
The solution to the problem is under development.
3.26. Terrestrial solar concentrator. Solar concentrators offer energy storage by directing light with
mirrors to a container of salt crystals or other concentrators. The concentration of the energy of living
systems can be carried out through the transport of vesicles with chemical compounds through the
capillary network due to hydrodynamics, concentration gradient, temperature, or other gradients.
Moreover, the cell size of one such cluster cannot be too large. Propose a 2D diagram of the

organization of traffic flows in such an energy concentrator of living systems.
SOLUTION:
The solution to the problem is under development.
3.27. Marine solar concentrator. It is known that marine organisms occupy certain niches,
determined by depth, which is concentrated in the open ocean, or around reefs or coastal zones.
Develop a model and propose a 3D diagram of the organization of a system of concentrating
organisms for maximum absorption and storage of solar energy (for example, based on algae and
engineered epibionts) [80].
SOLUTION:
The solution to the problem is under development.
[80. Wahl M, Goecke F, Labes A, Dobretsov S, Weinberger F. The second skin: ecological role of
epibiotic biofilms on marine organisms. Frontiers in Microbiology 2012;3:292.
doi:10.3389/fmicb.2012.00292.]
3.28. Useful swamps. The use of growth acceleration systems to obtain nutrients. In this case, the
receipt of some substances may require additional fermentation processes. Using models of bog-like
objects for anaerobic fermentation, suggest methods for industrial production of a) fuel; b) building
materials; c) food products.
SOLUTION:
The solution to the problem is under development.
3.29. Who lives under the sea? At the very bottom of the ocean, where hydrothermal vents pour out
their reagents, there is no light at all and only a small amount of oxygen is present, giant two-meter
tubular worms happily live there. These wonderful creatures have no mouth and no anus, they live off
excretory products and dead cells of their symbiotic lithotrophic bacteria. These tubular worms are
bright red as they contain high amounts of hemoglobin, which is critical for the survival of their
symbiotic bacteria and therefore the worms themselves. This specialized hemoglobin carries O2 and
H2S. In addition to delivering O2 to support the oxidative metabolism of the tubular worm, what role
could this specialized hemoglobin play in the symbiotic relationship that is critical to life in such a
hostile environment?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E – The Problems Book, 2015. (1-31)
SOLUTION:
The hemoglobin of giant tubular worms binds O2 and H2S and transports them to symbiotic bacteria,
which use H2S as an electron donor and O2 as an electron acceptor to generate ATP and reduce power
to meet their energy needs. The resulting bacterial growth benefits the worms by providing increased
waste and dead bodies living on. Moreover, this makes toxic H2S a harmless pathway of oxidation to
elemental sulfur, thereby preventing it from poisoning worms.
3.29. Bananas of Eastern Siberia. Banana palms for fruit ripening require temperatures above
16-250C, sufficient lighting, and watering, which is impossible to achieve in a continental climate. In
addition, mass cultivation of banana palms may require special soil composition and strength (layer
thickness). Suggest economically feasible ways of industrial banana cultivation in the conditions of
Eastern Siberia, in the regions of the Yenisei and Lena rivers.
SOLUTION:
The solution to the problem is under development.
3.30.Super-population. Currently (2016) the population of Earth is 7.9 billion people, which is
considered by some researchers as a state of overpopulation threatening the depletion of resources.
However, in solving some of the most important tasks of mankind, the absolute number of inhabitants
of the planet can be of great importance. Suggest a model for organizing an economy to ensure a
comfortable life for 250 billion of the world's population.
SOLUTION:
Solving this problem will require the reader to develop an economic model of management, including

the production and organization of commodity markets, which would exclude niche and zonal
imbalances.
3.31. Sources of accelerated evolution. It is known that, within isolated populations, the emergence
and consolidation of unique characters characteristic exclusively for a given biotope can occur. For
example, the natural oasis of Australia for 50 million years of isolation has produced a lot of living
objects with interesting functions and properties that are absent from the living world of the rest of the
planet. Such oases are of interest as material for the creation of genetically engineered constructions
that can influence the evolution of living nature. Give examples of objects that are separated by large
distances due to species boundaries, territorial boundaries, land-water environment.
SOLUTION:
The solution to the problem is under development.
3.32. Acceleration of embryogenesis. The development of the organism of large mammals today is
limited by the period of normal embryogenesis. (Fig. 3.3). For example, for a human, this period is 9
months, and for an elephant, almost 2 years. The consequence of premature birth can be the
development of various pathologies or even early death. Suggest ways to accelerate the normal
development of the fetus, both in normal pregnancy and in vitro. Consider not only the conditions for
cell division and differentiation but also the limitations of spatial organization. What evolutionarily
inherited stages of embryogenesis could be avoided in such a process?
SOLUTION:
The solution to the problem is under development.
Figure 3.3. Stages of normal embryogenesis.
3.33. Natural Economics. This task examines the problems of the economy of conditionally
intelligent organisms. Imagine a world in which some animals are capable of primitive economic
activities. How much will the growth potential of such an economy be higher than existing models?
What crises of consumption can be expected from the self-organization of the behavior of such
agents?
SOLUTION:
The solution to the problem is under development.
3.34. Sustainable development. The concept of sustainable development assumes that the needs of
present generations are met without compromising the ability of future generations to meet their own
needs [81]. The implementation of this concept presupposes the development of green energy
technologies, biotechnologies, but does not take into account the economic and investment feasibility,
as well as damage to the existing sectors of the economy. Propose inequalities that would formalize
the concept of sustainable development for the biotech excellence industry.
SOLUTION:
The solution to the problem is under development.

[81. Report “Our Common Future» (1987 г.)]
3.35. Mass extinction. According to one theory, the cause of the Permian mass extinction about 250
million years ago, during which 96% of all marine species and 73% of terrestrial vertebrate species
became extinct, was the acquisition of the ability by archaea to process organic matter with the release
of large volumes of methane [82]. Assuming gene drift in the as yet unstable genome of eukaryotes,
hypothesize models for the predictable periodicity of mass extinctions.
SOLUTION:
The solution to the problem is under development.
[82. Rothman, D. H., Fournier, G. P., French, K. L., Alm, E. J., Boyle, E. A., Cao, C., & Summons, R.
E. (2014). Methanogenic burst in the end-Permian carbon cycle. Proceedings of the National
Academy of Sciences, 111(15), 5462-5467.]

4. Living starship
Technological solutions for long-term space exploration using biological instruments. Representing
the most daring embodiment of the ideas of Russian cosmists, the biological mechanisms of
conquering the vast expanses of the Universe constitute the very bridge between reality and fantasy.
4.1. Living starship. Science fiction films often show unsolvable problems that arise during the
failure of individual life support modules. One of these problems was the failure of the system during
the Apollo 13 mission when the astronauts had to repair the support systems for several days with the
help of available materials on board, and for a long time to stay at a temperature of 6-11 ° C. The use
of living systems would theoretically make it possible to transform a “living” oxygen supply system
into liquid fuel, or vice versa. Estimate the efficiency of such transformations "fuel <-> food",
"oxygen supply system <-> fuel".
SOLUTION:
The solution to the problem is under development.
4.2.Life detector. Imagine that NASA has asked you to develop a module that will identify signs of
life on Mars. What will your module look like?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E - The Problems Book, 2015.
SOLUTION:
Such functional modules today, as a rule, are designed to search for organic molecules characteristic
of various life forms. The first Mars probe analyzed soil samples for organic matter but did not find a
single compound. Subsequently, the probes discovered a highly acidic surface layer, which would
inevitably destroy the organic matter that got there. Reliable signs of possible Martian life would be
the presence of water in ancient times and the flowing traces of methane in the atmosphere. The
question of the existence of life on Mars remains open, as well as the rational design of the module for
detecting it.
4.3. Walk on the Sun. Interstellar flight can be dangerous not only for the crew but also for the
"living" spacecraft due to damage to biomolecules by radioactive parts, in particular, by hard gamma
radiation. Now electrical repair mechanisms, amber mutations, etc. are used to correct breakdowns.
Suggest new mechanisms for DNA repair, for example, fundamentally new enzymes.
SOLUTION:
Use ideas from work “Vive la radiorésistance!” [83].
[83. Cortese, F., Klokov, D., Osipov, A., Stefaniak, J., Moskalev, A., Schastnaya, J., ... & Sapetsky, A.
(2018). Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance
human radioresistance for deep space exploration and colonization. Oncotarget, 9(18), 14692.
https://doi.org/10.18632/oncotarget.24461]
4.4. Interstellar planet. In the 2000s, billions of wandering planets in interstellar space were
discovered in our galaxy, usually orbiting the galactic core. Such planets can, due to several
gravitational maneuvers, leave the galaxy and fly to another in several tens of millions of years. In
1999, Professor Stevenson published a paper on the possibility of life in interstellar space, in which he
described the possible mechanisms for maintaining a comfortable temperature on the planet's surface
due to a dense shell of light gases (while the pressure on the surface can be up to 1000 atm) [84].
Assuming the heat flux equal to that of the Earth, estimate the parameters of the planet's surface by
the type of the Earth for such a flight through interstellar space.
SOLUTION:
The solution to the problem is under development.

[84. Stevenson DJ. Life-sustaining planets in interstellar space? Nature 1999;400:32.
doi:10.1038/21811.]
4.5. Terraforming Mars. According to Dr. Chris McKay, the first step in turning Mars into a
habitable planet should be to determine the possibility of the development of terrestrial life forms on
Mars. The short-term goal should be to test the use of Martian soil and atmosphere for a plant growing
module. In the longer term, the possibility of restoring the suitability of Mars for life. The optimal
strategy for warming up the planet would be to release a mixture of perfluorocarbons. The planet will
take about 100 years to warm up, but it will take another 100,000 years to produce enough O2. This is
where Dr. McKay's second condition arises for the five species of super microbes. First of all, all
super microbes must tolerate intense ultraviolet radiation and high concentrations of oxidants, lack of
water, cold, and the presence of perchlorates. Five types of super microbes are needed: aggressive
mineral breakers, organic producers, cellulosic builders (to release O2), perfluorocarbon producers,
and organisms that can bind N2 at low pressure [85]. Propose a scheme for terraforming the planet
Mars by successive "bombardment" with biological objects to create planetary conditions close to
those on Earth.
SOLUTION:
The technological ideas of Mars terraforming are discussed in detail in the works [86],[87]. Use the
ideas outlined in them, or come up with your own.
[85,86,87. Alekhin MD, Klabukov ID, Musienko SV (2012). Nanobiotechnologies in Advanced
Space Experiments. SSRN Electronic Journal. doi:10.2139/ssrn.2456693
Zubrin, R. M., & McKay, C. P. (1997). Technological requirements for terraforming Mars. Journal of
the British Interplanetary Society, 50, 309.
Beech, M. (2009). The Terraforming of Mars. In Terraforming (pp. 125-173). Springer, New York,
NY.]
4.6. IR photosynthesis. Recently, the mechanism of photosynthesis was discovered under conditions
of radiation in the near-infrared range, using an organelle called "chlorophyll-f" [88]. Suggest options
for using infrared photosynthesis for the metabolism of a plant and cyanobacterial cells near
geothermal sources, as well as inside asteroids with a hermetic shell.
SOLUTION:
The solution to the problem is under development.
[88. Dennis J. Nürnberg, Jennifer Morton, Stefano Santabarbara, Alison Telfer, Pierre Joliot, Laura A.
Antonaru, Alexander V. Ruban, Tanai Cardona, Elmars Krausz, Alain Boussac, Andrea Fantuzzi, A.
William Rutherford. Photochemistry beyond the red limit in chlorophyll f–containing photosystems.
Science, 2018; 360 (6394): 1210 DOI: 10.1126/science.aar8313]
4.7. Ark -RAR. The Iranian myth of Visnobish (“the tree of all seeds”) suggests the possibility of the
source of all the botanical diversity of the planet in the form of a single seed. Try to go further and try
to "package" the genetic diversity of all living things on the planet in the form of a single cell.
Estimate the length of the super genome of such a cell, from which theoretically it would be possible
to obtain the full genetic diversity of the planet Earth.
SOLUTION:
The solution to the problem is under development.
4.8. Tsiolkovsky probes. The futuristic project of 2016 by famous scientist Stephen Hawking and
billionaire Yuri Milner [89] assumed the spread of research probes in open space by the mechanical
action of laser radiation. Suggest the form and functionality of such a probe - "microcapsules of life"
for the propagation of life in space.
SOLUTION:
The entry into the atmosphere of an asteroid planet is accompanied by heating to high temperatures. It
is advisable to organize such probes in the form of gliding objects with an ablative coating, made of

abrasive material, the shape, and composition of which would prevent the destruction and overheating
of such a probe.
[89. Aron J. The $100 million plan to get to Alpha Centauri. New Scientist 2016;230:9.]
4.9. Endogenous engine. Suggest a diagram of the power plant of a "living" spacecraft for movement
in outer space.
SOLUTION:
The solution to the problem is under development.
4.10. Extraterrestrial clouds. The peculiarities of the natural conditions of planets such as Venus
and Jupiter leave no room for landing on a solid surface. Suggest a system of vital activity of
microorganisms (or life-like objects) in the high layers of the atmosphere.
SOLUTION:
The solution to the problem is under development.
4.11. Anabiosis. The long-term stay of the crew in the mode of induced suspended animation can
help in overcoming long Spatio-temporal distances. Suggest technologies of reversible suspended
animation and hibernation, for example, associated with suppression of cytochrome C-oxidase activity
or activation/inhibition of some other molecular biological mechanism.
SOLUTION:
The solution to the problem is under development.
4.12. Closed life support system. The functioning of the life support system of a modern orbital
station is associated with the constant replenishment of the necessary resources, as well as the removal
of large volumes of various substances from the system, such as crew waste and waste from the
functioning of the life support system itself. Suggest a closed-loop life support system layout,
independent of external nutrient replenishment, with fully biologically controlled oxygen and carbon
dioxide levels. At the same time, to create such a transported autonomous habitat, higher organisms
with improved functionality should also be used by reprogramming individual sections of the genome.
SOLUTION:
The solution to the problem is under development.
4.13. Synthesis. A promising solution for the design of interplanetary ships is the development of
highly productive supraorganism complexes in which nutrition, development, reproduction, and
adaptation of plants are carried out through interaction with symbiotic microorganisms with minimal
use of agrochemicals. Propose methods of co-cultivation of functional bacteria with photosynthetic
and nitrogen-fixing organisms to provide a closed cycle for the production of bio-structural materials.
SOLUTION:
The solution to the problem is under development.
4.14. Space 3D Bioprinter. Suggest ways of frameless molding of bioengineered organs in zero
gravity. Use, for example, animal totipotent cells as bio-ink: sequential differentiation into blastocytes,
blastomeres, and pluripotent cells.
SOLUTION:
Bioprinting of tissues in zero gravity is discussed in detail in the works [90][91][92]. Use ideas from
these case studies, as well as original ideas, for example, to create bio-nano-satellites in the CubeSat
format [93].
[90,91,92,93. Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature
biotechnology, 32(8), 773.
Vellinger, John C., et al. "Biomanufacturing System, Method, and 3D Bioprinting Hardware in a
Reduced Gravity Environment." U.S. Patent Application No. 15/225,547.
https://patents.google.com/patent/US20170029765A1
Zhang, Y. S., Yue, K., Aleman, J., Mollazadeh-Moghaddam, K., Bakht, S. M., Yang, J., ... &
Dokmeci, M. R. (2017). 3D bioprinting for tissue and organ fabrication. Annals of biomedical
engineering, 45(1), 148-163.

Kornakiewicz, A., Mielczarek, J., & Zadrozny, A. (2018). A concept of biopharmaceutical
nanosatellite. arXiv preprint arXiv:1802.04078.]
4.15. Drone bacteria. Suggest a method (for example, a method for selecting clones) for creating
polyextremophilic organisms to explore new worlds.
SOLUTION:
Directed evolution (induced mutagenesis using physical, biological, or chemical mutagens) and clone
selection (various display options) are used in microbiology to create new strains. With regard to the
problems of astrobiology, the problem of creating new organisms can be solved by creating special
conditions that simulate aggressive conditions of new worlds, changing conditions in order to exclude
permanent protective forms (spore-like states), stimulating the exchange of genetic information,
adding species known in nature to the environment to stimulate an exchange of genetic information.
4.16. Cosmological effects change the activity of quantum effects in relativistic conditions. What
positive and negative results at the level of a living cell can be obtained when a living object moves in
a gravitational field with a relativistic speed?
SOLUTION:
The solution to the problem is under development.
Figure 4.1. Tardigrade. Scanning Electron Microscopy [94]
[94. MITCHELL, C., & MILLER, W. R. (2008). A simple SEM (Scanning Electron Microscope)
preparation protocol for tardigrades. Journal of The Pennsylvania Academy of Science, 86-90.]
4.17. A Living Ark. Suggest a mechanism for using live tardigrades (Fig. 4.1) for the preservation
and long-term storage of exogenous biomaterial (for example, human tissue). For example, using
microRNA to prevent local inflammation at the site of biomaterial implantation, or by increasing the
intercellular transport of specific signaling proteins in microvesicles.
SOLUTION:
It seems attractive to create induced chimeras upon implantation of multipotent human cells into
tardigrades. Presumably, due to the nonspecific stimulation of stress resistance in the implanted cells,
the effects of resistance to drying out, radiation and high temperatures will be observed.
4.18. Radiobiological effects. It is known that radiation affects biological processes in the body,
damaging DNA, increasing the permeability of membranes. Suppose the possible effects associated
with both the direct effect of radiation on cells and the effect of isotopes on intracellular processes, for
example, intra- and intercellular transport, energy metabolism, protein synthesis, and others. To what
extent can a change in the usual isotopic composition affect these processes?
SOLUTION:
The solution to the problem is under development.
4.19. Do you know that more than half of the cells in our body are not human?
(by Anastasia Nikolaeva, MEPhI team iGEM 2021)
It's composed of symbiotic microorganisms.

What if you could modify them to diagnose and treat diseases? Several companies are testing whether
engineered bacteria can treat conditions that affect the brain, liver and other organs, kill harmful
microbes and even cancers!
One of the problems of engineered microbiota is to prevent its spreading outside the human body.
SOLUTION:
The solution could be in using a toxin controlled by a low-temperature inducible promoter. As soon as
bacteria leave the human, they would be killed by the toxin
4.21. Fluorescent bacteria(by Dmitrii Vladimirtsev, MIPT_MSU team iGEM 2021)
For the experiment, you need to prepare bacteria with genes for fluorescent proteins. Bacteria with
RFP (red fluorescent protein) protein, which was expressed from the plasmid with the ampicillin
resistance gene jv, grew on a Petri dish.
We took a smear of bacteria and set them to grow in a liquid medium at 37 degrees and stirring (500
rpm). Arriving at the laboratory the next day, they found that the bacteria had grown, but they did not
fluoresce. Why?
SOLUTION:
There may be 2 reasons that overlap with each other. The main reason is that the antibiotic was not
added to the liquid medium. It follows from this that bacteria that did not carry the fluorescent protein
plasmid multiplied faster than those that did. The second reason is that due to the lack of need for
resistance to ampicillin, bacteria could simply "throw out" the plasmid.
4.22. Green light(by Dmitrii Vladimirtsev, MIPT_MSU team iGEM 2021)
It is necessary to make a plasmid with GFP for transfection of eukaryotic MCF7 cells. To produce a
plasmid, E. coli was transformed, but not a single colony glowed, even when excited with ultraviolet
light. However, upon transfection with MCF7, a green glow is observed in most of the cells. How can
this be explained?
SOLUTION:
It's all about the promoter, which is in front of the GFP in the plasmid. Since the ultimate goal was the
fluorescence of eukaryotic cultures, a strong eukaryotic promoter (for example, the CMV promoter)
was inserted into the plasmid. However, this promoter was extremely weak for E. coli, so no GFP
expression was observed in it.

5. Theoretical Biology
Topical problems of molecular and cellular biology are considered, the solution of which can simplify
the design of bioengineering solutions. Innovative solutions will make it possible to change a person
and the world around him from the inside, causing the forces of nature, which are hidden in genes and
cells, to work in accordance with the desires of a person and in accordance with his needs.
5.1. Bistable system. The bifurcation point is the critical state of the system, at which the system
becomes unstable with respect to fluctuations and uncertainty arises: whether the state of the system
will become chaotic or it will move to a new, more differentiated and high level of order. Imagine that
a random perturbation overtakes a bistable system exactly at the interface between two stable states
(on the orange dot in Fig. 5.1). How will the system respond?
© John Wilson, Tim Hunt. Molecular Biology of the Cell 6E – The Problems Book, 2015. 8-114)
SOLUTION:
If the perturbed system was exactly at the interface between two regions of attraction - two stable
states - it would be balanced in a state of unstable equilibrium. The slightest random fluctuation would
lead the system to one or the other of two stable states.
Figure 5.1. Disturbances of a bistable system. As the green lines show, after disturbance # 1, the
system returns to its initial stable state (green dot on the left), and after disturbance # 2, the system
goes over to another stable state (green dot on the right). Perturbation # 3 moves the system to the
exact boundary between two stable states (orange dot).
5.2. Reverse ribosome. The central dogma of molecular biology prohibits the transfer of genetic
information from protein to nucleic acids. However, upon detection of unknown single extraneous
proteins in the extracellular space, it seems appropriate for the cell itself to identify and analyze their
sequence, for example, to solve the problems of intracellular immunity. In the work of Lazar Mekler, a
hypothetical mechanism of immunological memory due to the binding of RNA-amino acid complexes
with their complementary antigen determinants was considered [95,96]. Propose a method and
molecular mechanism for reverse translation of proteins from the point of view of modern concepts of
molecular biology.
SOLUTION:
Currently, various ways of implementing reverse translation have been proposed, for example,
“Methods and compositions for reverse translation”[97]
[95,96,97. Mekler LB. Mechanism of biological memory. Nature 1967;215:481–4.
doi:10.1038/215481a0
Cook ND. The case for reverse translation. Journal of Theoretical Biology 1977;64:113–35.
doi:10.1016/0022-5193(77)90116-3
Methods and compositions for reverse translation”. Patent US №7169894
http://www.google.com/patents/US7169894]
5.3. DNA at the speed of light. Solving the problems of industrial biotechnology or therapy seems
promising by controlling an arbitrary cell using light or electricity. Now a similar principle is used in
optogenetics to stimulate the expression of individual genes with light. But in the practice of

engineering, it may be necessary to "upgrade" the cell by transferring to it some previously unknown
nucleotide sequence. How is it possible to transmit such a sequence into a cell using light or
electricity? What would such a mechanism look like from the point of view of molecular biology?
SOLUTION:
The solution to the problem is under development.
5.3. Smart ribosome. Intracellular organelles that translate the amino acid sequence from RNA are
used by viruses to replicate within the cell. It would be nice if the ribosome memorized viral
sequences and prevented the translation of proteins unknown to the body. Having accepted the use of
such a smart organelle of the principles of the bacterial immune system, estimate the approximate
mass of such a "smart ribosome."
SOLUTION:
The solution to the problem is under development.
5.4. Membrane-transformer. The lipid membrane of a cell is a completely separate object for
engineering, due to which there is a regulation of the transport of substances between the external and
internal environment of the cell [98]. L-forms of bacteria that have completely or partially lost the cell
wall, but retained the ability to reproduce, are a form of survival and reproduction of microorganisms.
How can the membrane be transformed due to internal processes of biosynthesis regulation? How can
a gram-negative bacterium be obtained from a gram-positive bacterium?
SOLUTION:
The solution to the problem is under development.
[98. Kuruma Y, Matsubayashi H, Ueda T. Autonomous construction of synthetic cell membrane.
ADVANCES IN ARTIFICIAL LIFE, ECAL 2013, Taormina, Italy: 2013, p. 9–10.
doi:10.7551/978-0-262-31709-2-ch002.]
5.5. The protein problem of the century. One of the unsolvable problems of modern biology is the
restoration of the tertiary structure of a protein by a known sequence of amino acids. While this
problem cannot yet be solved by humans, it is being successfully addressed right now in all 100
trillion cells in your body. What mathematical approaches, discovered recently, could be used to solve
this problem in the form of an algorithm?
SOLUTION:
The solution to the problem is under development.
5.6. Mirror Proteins. For synthetic regulation, it is proposed to use "orthogonal gene networks", the
products of which do not affect the natural genome. Is it possible to build a parallel system of
translation and transcription based on optical isomers of amino acids, "invisible" to the natural
molecular genetic systems of the cell?
SOLUTION:
The solution to the problem is under development.
5.7. Denaturation – a change in the native conformation of a protein molecule under the influence of
various destabilizing factors, for example, a chemical reaction or high temperatures. So, for some
proteins of living organisms, denaturation occurs already at temperatures of 6оС. How can this
“low-temperature denaturation” effect be used in cellular thermodynamics?
SOLUTION:
The solution to the problem is under development.
5.8. Membrane Engineering. Imagine that morphogenesis is possible in one organism based on cells
with different types of lipid membranes. Modify the conductance of axons by proposing an
engineering way to modify the cell membrane of nerve cells. List the cognitive macro-effects that can
hypothetically be observed in this case.
SOLUTION:
The solution to the problem is under development.

5.9. Anaerobic metabolism. In the absence of oxygen transport across the membrane, oxidative
stress occurs in the cell, expressed in abnormal protein expression. Suggest a scheme for an additional
cellular organelle that consumes ATP and releases oxygen.
SOLUTION:
The solution to the problem is under development.
5.10. Limitations of nature. Some physical forms, due to the peculiarities of the laws of nature, are
terra incognita in living nature. For example, these include nanoparticles, as well as molecules, the
synthesis of which is possible only with intermediate ("forbidden") states, some metal compounds,
toxins, conductors, nanolayers. Make a list of at least 5 mechanisms, the implementation of which in a
living cell would be impossible.
SOLUTION:
The solution to the problem is under development.
5.11. Regular structures and self-organization. What simple circuits can be used to assemble a
regular structure with a period of 1 mm?
SOLUTION:
The solution to the problem is under development.
5.12. Self-assembly of molecules. Self-assembly of protein molecules, for example, of the viral
capsid, is known in nature. Propose methods for obtaining self-structuring biomatrices for creating
supercomposite materials with new properties based on them.
SOLUTION:
The solution to the problem is under development.
5.13. Supercell. Currently, the largest unicellular organisms are represented by xenophyophores -
single-celled shell organisms that live on the ocean floor at a depth of 10,641 m. Xenophyophores
reach 10 cm in diameter and serve as a habitat for a variety of multicellular animals. These
foraminifera contain a lot of lead, uranium and mercury - heavy metals that are extremely toxic to
ordinary living cells. Estimate the maximum size of a single cell based on the limitations of
membrane composition, regulation and metabolism.
SOLUTION:
The solution to the problem is under development.
5.14. Chained werewolf. The mythology of humanity contains a description of a creature with the
ability to transform from one animal to another. Assess the possible biological basis for such a
phenomenon. In the nucleus, each chromosome occupies its own space. For example, in the nuclei of
many vertebrates, chromosomes with low gene density are stored in the periphery, while
chromosomes with high gene density are stored in the very middle. Chromosomes can be transported
along microtubules in the nucleus, taking up to 4 hours. What mechanisms will the chain regulation of
the genes of the organism have to obey in order to allow one species to turn into another by
“replacing” one chromosome with another?
SOLUTION:
The solution to the problem is under development.
5.15. Supermembrane. The cell membrane is a lipid bilayer, on the surface of which there is a nearly
chaotic change in the states of hydrophilic and hydrophobic groups. Suggest a membrane structure
with original properties different from those found in nature.
SOLUTION:
The solution to the problem is under development.
5.16. Supramolecular complexes. Мechanically interlocked molecular architectures are an
interesting example in which molecular biological mechanisms are combined with the laws of
mechanics. For example, rotaxanes are a long molecular chain threaded through a macrocycle. The

massive groups of atoms at the ends of the chain prevent the cycle from sliding off the axis. The
action of the so-called lasso-peptides is built on the rotaxan principle, which embraces their target,
tightening the macrocycle [99]. How can such complexes be used to create new molecular machines?
SOLUTION:
The solution to the problem is under development.
[99.Abendroth JM, Bushuyev OS, Weiss PS, Barrett CJ. Controlling Motion at the Nanoscale: Rise of
the Molecular Machines. ACS Nano 2015;9:7746–68. doi:10.1021/acsnano.5b03367.]
5.17. Increased biological complexity. Compared to bacteria, eukaryotic cells have a nuclear
envelope separating DNA from the cytoplasm, which makes it possible to implement
post-transcriptional RNA modifications, for example, alternative splicing. It can be assumed that this
property of animal cells makes it possible to increase the “number of freedoms” in the biosystem in
comparison with prokaryotes. Suggest possible ways to increase the number of freedoms in the cell /
cellular community to increase the complexity of promising life forms.
SOLUTION:
The solution to the problem is under development.
5.18. Molecular errors. The enzyme RNA-dependent DNA polymerase in E. coli cells, when
transcribing an RNA sequence, allows 1 error per 1 billion base pairs. At the same time, the ribosome,
when translating the amino acid sequence, allows 1 error per 10,000 amino acids. Estimate the
probability of errors in protein expression and their influence on the emergence of new protein
proteoforms. How could the likelihood of molecular errors be reduced?
SOLUTION:
The solution to the problem is under development.
5.19. Invisible changes. The tertiary structure of a protein is the mutual arrangement in space of
β-chains, β-folded layers and α-helices. The quaternary structure of a protein is the mutual
arrangement of individual monomers: 2 monomers form a dimer, three form a trimer, four form a
tetramer, etc. Oligomers are composed of a large number of monomers. With age or due to various
diseases in humans, the ratio of the concentrations of intracellular metabolites changes, which may
affect the statistics of such modifications. Estimate how much the tertiary, quaternary structure of
proteins can change from chemically induced dimerization, depending on the physical presence or
concentration of intracellular metabolites?
SOLUTION:
The solution to the problem is under development.
5.20. “Noiseless” cell. In developmental biology, the phenomenon of organizational complexity and
resistance to noise during gene expression is considered. Currently, there are various models of
genetic processes, but we are far from understanding the whole picture, in particular, in
morphogenesis, in which gene expression must be tightly regulated. Fundamental research is needed
on the regulation of gene expression by controlling the development of the organism, withstanding
various external influences and internal stochasticity. [100]. For this purpose, various modeling
methods are currently used [101]. The Shannon-Hartley theorem states that the bandwidth of channel
C, which means the theoretical upper bound on the data rate that can be transmitted with a given
average signal power S through an analog communication channel subject to additive white Gaussian
noise of power N, is: , where C is the channel bandwidth, bit / s; B - channel bandwidth, Hz; S is the
total signal power over the passband, W or W²; N is the total noise power over the passband, W or
W²; S / N - Signal to Noise Power Ratio (SNR). Engineered cell communities will differ in their
transcriptional profiles, and gene expression patterns will change as a result of the collective dynamics
of cell communities [102]. This phenomenon can be used in the design of complex multicomponent
tissues, some design flaws of which can be compensated for by self-organizing and adaptive cell
communities. How can the Kotelnikov-Shannon theorem be used to design such communities?
SOLUTION:
The solution to the problem is under development.

[100,101,102. Elowitz MB, Levine AJ, Siggia ED, Swain PS, Guptasarma P, Spudich JL, et al.
Stochastic gene expression in a single cell. Science 2002;297:1183–6. doi:10.1126/science.1070919.
Rekhi R, Qutub AA. Systems approaches for synthetic biology: a pathway toward mammalian design.
Frontiers in Physiology 2013;4:285. doi:10.3389/fphys.2013.00285.
Stolovicki E, Braun E. Collective Dynamics of Gene Expression in Cell Populations. PLoS ONE
2011;6:e20530. doi:10.1371/journal.pone.0020530.]
5.21. Restoration of pathogenic material. In the case of severe brain injuries, the biomaterial looks
like disorganized elements, the reliable restoration of the native state of which is a difficult task from
the field of information theory. Suggest a system of decision-making algorithms that could be used in
radical neurotherapy.
SOLUTION:
The solution to the problem is under development.
5.22. Ultimate efficiency. In accordance with the second law of thermodynamics, the efficiency
cannot exceed the value of T heat -Т cool ./Т heat . With regard to biological systems, this means low
efficiency of metabolic processes. The use of quasi-low temperatures due to various physical effects
(for example, quantum mechanics) can increase the efficiency. Suggest ways to modulate quasi-low
temperatures in a living cell.
SOLUTION:
The solution to the problem is under development.
5.23. Millennium Challenge. NP-complete problem - in the theory of algorithms, a problem with the
answer "yes" or "no" from the class NP, to which any other problem from this class can be reduced in
polynomial time (that is, using operations, the number of which does not exceed some polynomial
depending on the size of the original data). As part of the Aldeman experiment, the estimated speed of
DNA computation was 10 14 cycles / sec, and many researchers believe that this speed can be increased
to 10 15 -10 20 cycles / sec. Is this enough to implement a biological supercomputer to solve a random
NP-complete problem?
SOLUTION:
The solution to the problem is under development.
5.24. Carcinogenesis of space. According to quantum theory, pairs of symmetric particles (quantum
foam) can spontaneously generate in space. Can quantum fluctuations damage DNA in animal cells,
thereby inducing the development of cancer? Suppose in what case the very properties of the physical
space of the Universe could provoke cancer and other diseases associated with dysregulation of the
genome?
SOLUTION:
It is enough to consider the probability of the spontaneous appearance of a pair of high-energy
particles in a gravitational field of a given intensity and taking into account the cross section of such a
reaction, to obtain the necessary estimate of the probability of such spontaneous carcinogenesis for a
multicellular human body.
5.25. Quantum entanglement — the phenomenon of quantum mechanics, in which the quantum
states of two or more objects are interdependent (for example, the spin or polarization of a photon).
This interdependence persists even if these objects are separated in space beyond any known
interactions. Currently, quantum entangled states are obtained by irradiating a nonlinear material with
a laser beam of a certain frequency and intensity. Propose a chemically induced quantum
entanglement method for synthesizing quantum entangled particles in living cells.
SOLUTION:
It should be considered that chemical induction in this case means rather quantum-chemical reactions
with high energy. It seems that the reader could detect such reactions on his own and choose from
them suitable for biochemical transformations.

5.26. Quantum telepathy. In what case could various methods of induction of quantum entanglement
(problem 5.24 “Quantum entanglement”) lead to the development of macro-effects similar to
telepathic ones?
SOLUTION:
We do not yet know the physical basis for such effects, but the reader may have some interesting
ideas.
5.27. Objective reduction. It is a hypothetical process of spontaneous collapse of the wave function
of a system due to gravitational effects at the micro-level. According to Penrose's hypothesis, this
process is the physical basis of consciousness. Imagine the physical mechanisms that can form the
basis of this hypothesis.
SOLUTION:
A solution to this problem is in development.
5.28. Radiant humanity. Konstantin Tsiolkovsky in his works presented the phenomenon of radiant
humanity as an optimal model for the spread of intelligent life in the Universe. Suggest physical ways
to implement such an idea based on new physical principles
SOLUTION:
Unfortunately, we do not yet know such methods. Recently, however, practical implementation has
been discussed in Craig Venter's “Life at the Speed of Light” [103].
[103. Venter, J.C. (2014) Life at the speed of light: from the double helix to the dawn of digital life.
Penguin]
5.29. Gilbert's Challenges for the 21st Century. In 2008, at the initiative of DARPA director
Anthony Teaser, 23 key mathematical problems were formulated (the so-called “Gilbert problems of
the XXI century”) [104], nine of which were directly related to biology. Explain what applications of
modern biology and medicine require a new mathematical apparatus at the level of new objects and
rules?
SOLUTION:
Tasks such as 1) the integration of heterogeneous data in a single coordinate space, 2) overcoming
stochasticity in the regulation of the genome, 3) the introduction of biological metrics for assessing
various interventions at the genome level, 4) as well as other tasks that still require their formalization.
[104. Jackson A. DARPA and Hilbert. Notices of the American Mathematical Society 2008;55:445]
5.30. Brain mathematics. Develop a good mathematical theory for building a functional brain model
that is mathematically consistent and predictive, not just biologically based.
SOLUTION:
A solution to this problem is in development.
5.31. Dynamics of networks. Develop the high-level mathematical tools needed to accurately model
and predict behavior in large-scale, distributed networks that are emerging in today's networked
communications, biology, and social sciences.
SOLUTION:
A solution to this problem is in development.
5.32. Binding and parking of stochasticity in nature. Note the call of mathematician David
Mumford for new mathematics in the 21st century [105,106]. Develop methods that remain robust in
stochastically changing environments.
SOLUTION:
A solution to this problem is in development.
[105,106. Mumford, D. (2002). Pattern theory: the mathematics of perception. arXiv preprint
math/0212400. https://arxiv.org/abs/math/0212400
Mumford, D. (2000). The dawning of the age of stochasticity. Mathematics: frontiers and

perspectives, 197-218.]
5.33. Biological quantum field theory. Quantum and statistical methods have had great success in
modeling the evolution of the viral genome. Can such methods be used to model more complex
biological systems such as bacteria? Can these methods be used to control and manage the evolution
of pathogens?
SOLUTION:
A solution to this problem is in development.
5.34. Algorithmic origami and biology. Build a mathematical theory of isometric and the theory of
rigid attachments that can explain the principles of protein folding.
SOLUTION:
The solution to the problem is in development, but the latest achievements in this area can be found in
the works [107] [108] [109].
[107,108,109. Borcea, C., & Streinu, I. (2010, January). How far can you reach?. In Proceedings of
the twenty-first annual ACM-SIAM symposium on Discrete algorithms (pp. 928-937). Society for
Industrial and Applied Mathematics
Borcea, C. S., & Streinu, I. (2012). Combinatorial and Algorithmic Rigidity: Beyond Two
Dimensions (No. HR0011-09-0003). SMITH COLL NORTHAMPTON MA.
www.dtic.mil/dtic/tr/fulltext/u2/a579251.pdf
Borcea, C., Streinu, I., & Tanigawa, S. I. (2015). Periodic body-and-bar frameworks. SIAM Journal
on Discrete Mathematics, 29(1), 93-112. https://doi.org/10.1137/120900265 ]
5.35. Information theory for viral evolution. Could Shannon's theory cast a light on such a
fundamental area of biology as the evolution of viruses?
SOLUTION:
Try to find interesting ideas and approaches to answer this question in [110] [111].
[110,111. Shadrin, A. A., Grigoriev, A., & Parkhomchuk, D. V. (2013). Positional Information
Storage in Sequence Patterns. Computational Molecular Bioscience, 3(02), 18.
doi:10.4236/cmb.2013.32003
Elena, S. F., Codoner, F. M., & Sanjuan, R. (2003). Intraclonal variation in RNA viruses:
generation, maintenance and consequences. Biological Journal of the Linnean Society,
79(1), 17-26. doi:10.1046/j.1095-8312.2003.00173.x]
5.36. Genome geometry. The term "distance" in mathematics is associated with the concepts of
metric and metric space, and the non-negativity of the distance function follows from the axioms.
What concept of “distance” should be introduced to calculate biological utility?
SOLUTION:
A solution to this problem is in development.
5.37. What are the requirements for symmetry and principles of action as applied to biology?
Expand our understanding of symmetry and operating principles in biology per classical
thermodynamics to include important biological concepts such as reliability, modularity, evolutionary,
and variability.
SOLUTION:
A solution to this problem is in development.
5.38. Basic principles of biology. This question from DARPA ex-director Dr. Anthony Teser will
remain relevant for the next 100 years. This task is the last in the list of mathematical problems since
the search for the mathematical basis of biological principles will require the development of a
mathematical apparatus capable of answering many of the above questions. What existing
mathematical concepts and theories could be used to formulate the basis for such principles?
SOLUTION:

This apparatus can be based on symmetry, graph theory, and group theory. A detailed solution to the
problem is under development.
5.39. Critical complexity. This problem was taken from the unsolved mathematical problems
formulated in Bellman's book [112]. Develop a way to determine how complex a system (such as a
molecule), made up of its constituent parts, must be to be capable of self-replication and evolution
with the complication of offspring?
SOLUTION:
A solution to this problem is in development.
[112. Bellman R. Mathematical problems in biology. - Moscow: Mir, 1966 — - 277 p.]
5.40. Proton tunneling mutagenesis. It is assumed that proton tunneling between DNA bases can
cause spontaneous mutations [113]. Evaluate the viability of this hypothesis with both the synthetic
theory of evolution and the epidemiology of mankind.
SOLUTION:
A solution to this problem is in development.
[113. Löwdin P-O. Proton Tunneling in DNA and its Biological Implications. Reviews of
Modern Physics 1963;35:724–32. doi:10.1103/RevModPhys.35.724.]
5.41. Mathematical riddles. In the book by mathematician Vladimir Arnold "What is mathematics?"
[114] along with other facts that have not been explained, the following are also given: "The
metabolic rate is proportional to the power of 3/4 of the body weight (and not to the power of 2/3, as
would result from a simple dependence of metabolism on the area of the smooth surface of chemical
contact)" and "The number of cell types in an organism is proportional to the square root of the
number of genes in its genome." Is it? Guess why this is so?
SOLUTION:
A solution to this problem is in development.
[114. Arnold V. I. What is mathematics?. – 2011.]
5.42. Bio-logic. The first official mention of the word "bug" to computers was in 1945. At the time,
the Harvard Mark II computer was in use at the Naval Research Center in Dahlgren, Virginia. On
September 9, 1945, a moth crawled into one of the computer relays, disrupting its operation. Today,
the use of living cells to satisfy various functional needs cannot bypass the field of computing and
work with "big data". However, the processes in such homeostatic objects are subject to chaotic
external influences and cannot be determined to exclude the possibility of errors. Propose logic,
possibly based on quantum computing, to implement robust computing in a living cell.
SOLUTION:
A solution to this problem is in development.
5.43. Synthetic chemistry. Chemoinformatics is a new scientific field that studies the application of
informatics methods to solve chemical problems. Among the areas of application of
chemoinformatics: the prediction of the physicochemical properties of chemical compounds (in
particular, lipophilicity, water solubility), material properties, toxicological and biological activity,
ADME / T, ecotoxicological properties, development of new drugs and materials. What will it look
like and how to synthesize a combinatorial library of chemical compounds focused on a given type of
biological activity?
SOLUTION:
A solution to this problem is in development.
5.44. Standardization. The issues of standardization of biological systems are not only interesting but
also a highly controversial area. The proposed approaches to standardization are based on the use of
concepts from the field of programming, such as functions and syntax. Suggest other approaches to
multilevel standardization of biological systems components.
SOLUTION:

5.47. Multidimensional life.
Some contemporary theoretical works consider the emergence of life in alternative universes with
dimensions of space and time different from ours. At the same time, the authors accompany their
analysis with conclusions about the impossibility of the existence of living organisms, for example, in
A solution to this problem is in development.
5.45. Quantum effects in biology. Coherent quantum processes can play an important role in the
macrocosm. Among the most famous examples are the ability of migratory birds to navigate using the
Earth's magnetic field lines (magnetoreception, shown in Figure 5.2) and some features of
photosynthesis [115].
[115. Chugunov A. O. (2011). The origin of quantum biology.
https://biomolecula.ru/articles/zarozhdenie-kvantovoi-biologii]
Several review papers are devoted to considering coherent effects in living systems [116][117].
Assume the molecular and cellular biology role of quantum effects such as the uncertainty principle,
tunneling, bound quantum states of particles, etc.
SOLUTION:
A solution to the problem is under development.
[116,117. Lambert, N., Chen, Y. N., Cheng, Y. C., Li, C. M., Chen, G. Y., & Nori, F. (2013).
Quantum biology. Nature Physics, 9(1), 10.
Mohseni, M., Omar, Y., Engel, G. S., & Plenio, M. B. (Eds.). (2014). Quantum effects in
biology. Cambridge University Press.]
Figure 5.2. The quantum compass of birds (Lambert et al., 2013).
5.46. Cell bound energy.
Energy in the animal cell is produced indirectly by the mitochondria, in which ATP is produced.
However, activation of the mitochondria and releasing a significant amount of ATP can lead to cell
division. Suggest a way of binding ATP and hypothetical organelle-specific transport mechanism for
a time separated activation of only necessary functions.
SOLUTION:
A solution to the problem is under development.

universes with three-dimensional space and two-dimensional time or four-dimensional space and
three-dimensional time. Why do you think the dimensions of space and time may theoretically impose
restrictions? How can these models be used in formalizing physiological functions?
SOLUTION:
In general, consideration of properties of universes with multidimensional space and time (Fig. 5.3) is
connected with laws of conservation and, consequently, symmetry properties. The consideration of
these laws is devoted to a small number of scientific works to consider these regularities.
Figure 5.3. Properties of S+T-dimensional space-time
5.48. Interstitial conjugation (tissue culture).
Why do some tissues only grow in the presence of very specific other tissues? For example, some
tissues take root well when implanted, but others do not. Based on existing data on the morphology of
organisms, identify the nature of the common features, and possibly some quantification of them
SOLUTION:
A solution to the problem is under development.
5.49. The supersymmetry of life.
A careful study of the processes of mitosis, meiosis, embryogenesis, and organogenesis to note
individual symmetry mechanisms. The presence of similar individual artifacts suggests more general
symmetry mechanisms and associated conservation laws. Suggest which symmetries are represented
in living systems and what conservation laws are their consequences?
SOLUTION:
No such laws of symmetry have been found at present. The ideas of symmetry of living organisms can
be read in [118][119][120]. Considering Nether's theorem in the context of the search for the form of
conservation laws in complex systems seems to be the most promising. One day, discovering such
conservation laws will make it much easier to understand and even create living organisms.
[118,119,120. Longo, G., & Montévil, M. (2017). Comparing symmetries in models and simulations.
In Springer Handbook of Model-Based Science(pp. 843-856). Springer, Cham.
Longo, G., & Montévil, M. (2017). From logic to biology via physics: a survey. arXiv
preprint arXiv:1709.06001.
Montévil, M., Mossio, M., Pocheville, A., & Longo, G. (2016). Theoretical principles for
biology: Variation. Progress in Biophysics and Molecular Biology, 122(1), 36-50.]
5.50. Expression rate.
The rate of transcription and transcription and translation rate in the cell is mainly dependent on the
intracellular concentrations of nucleotide bases and amino acids. Alterations in the nutritional regime
may alter the attention of these compounds in cells throughout the body. To what extent can changes
in nutritional status change the rate of transcription or translation?
SOLUTION:
This problem has been addressed in [121][122][123].

[121,122,123. Chaveroux, C., Lambert-Langlais, S., Cherasse, Y., Averous, J., Parry, L., Carraro, V.,
... & Fafournoux, P. (2010). Molecular mechanisms involved in the adaptation to amino
acid limitation in mammals. Biochimie, 92(7), 736-745. doi:10.1016/j.biochi.2010.02.020
Mordier, S., Bruhat, A., Averous, J., & Fafournoux, P. (2002). Cellular Adaptation to
Amino Acid Availability: Mechanisms Involved in the Regulation of Gene Expression and
Protein. Sensing, Signaling and Cell Adaptation, 3, 189.
Bruhat, A., Chérasse, Y., Chaveroux, C., Maurin, A. C., Jousse, C., & Fafournoux, P.
(2009). Amino acids as regulators of gene expression in mammals: molecular mechanisms.
Biofactors, 35(3), 249-257.]
5.51. Stages of evolution.
The synthetic theory of evolution Describes the mechanisms of processes involving the continuous
emergence and the fixation of traits. However, is evolution also discrete? Is there a discrete pattern as
well? Think of it as the sudden emergence of enzymes with significantly lower energy and less
energy required for activation, which could have a decisive effect on the competitiveness of the
individual and its progeny.
SOLUTION:
A solution to the problem is under development.
5.52. High molecular weight machines.
Figure 5.4 shows two oxygen-transferring proteins on the same scale; two oxygen-transferring
proteins are shown on the same scale: human hemoglobin and earthworm erythrocruorin. The
molecule hemoglobin has four subunits, and the erythrocruorin molecule erythrocruorin has 144
subunits. The difference in the quaternary structure is because human haemoglobin is confined inside
erythrocytes, whereas the earthworm's erythrocruorin is dissolved in blood plasma; the relatively large
erythrocruorin does not penetrate the vascular wall. A similar principle is laid down in the blood
substitute Perftoran, a submicron emulsion based on PFO compounds with an oxygen transport
function. Suggest, what other high molecular weight compounds could replace cellular processes in
the human body?
SOLUTION:
A solution to the problem is under development.
5.53. Translation without factors.
The phenomenon of non-enzymatic or translation without factors is the fact that under in vitro
conditions (in cell-free systems), ribosomes are only provided with a matrix polynucleotide and
aminoacyl-tRNA, and slow non-enzymatic, or translation without factors, translation without any
additional energy sources in the form of GTPase or ATP. in the form of GTP or ATP. Suggest a
possible role for this effect on the regulation of an organism in vivo.
SOLUTION:
A solution to the problem is under development.
5.54. Electrophoresis.
The gel electrophoresis method for separating nucleic acids by mass is based on the braking effect of a
charged DNA molecule in an agarose gel when it moves in a constant electric field. However, the
more massive the DNA molecule, the greater its charge and the greater the force acting on it. Why do
weaker charged short DNA molecules travel longer distances in the gel?
SOLUTION:
The force acting on a denatured DNA molecule from the electric field is proportional to the mass of
the molecule ~Mw. Estimation of the average drift velocity in experimental observations shows that
v~1/log(Mw)
5.55. Construction cage.

Quite a few works in the field of quantitative biology present the living cell as a closed system, which
can be described in full energy operators [124][125][126]. Try to imagine the cell as a conglomerate
of subelements, for which only separately the conservation laws apply.
SOLUTION:
A solution to the problem is under development.
[124,125,126. Davies, P. C., Rieper, E., & Tuszynski, J. A. (2013). Self-organization and entropy
reduction in a living cell. Biosystems, 111(1), 1-10.
Sandler, U., & Tsitolovsky, L. (2017). Fuzzy Logic and S‐Lagrangian Dynamics of Living
Systems: Theory of Homeostasis. In Lagrangian Mechanics. IntechOpen.
Sandler, U., & Tsitolovsky, L. (2017). The S-Lagrangian and a theory of homeostasis in
living systems. Physica A: Statistical Mechanics and its Applications, 471, 540-553.]
5.56. Self-synchronizing rhythms.
Circadian rhythms are cyclical fluctuations in the intensity of various biological processes. Suggest if
there could be a physical sense in the regulation of human rhythms, e.g. related to synchronization of
cellular regulation. What physical manifestations might reflect dysregulation of human circadian
rhythms? Is such dysregulation associated with aging?
SOLUTION:
A solution to the problem is under development.
5.57. Physiological noise.
Assume the sources of physiological noise in humans, its sources, role, and effects at the cell, tissue,
and whole-body levels. Estimate the limits of noise levels to maintain the stability of cell regulation,
tissue function or homeostasis at the organism level
SOLUTION:
A solution to the problem is under development
5.57. Histological units. The theory of morphological units by G.A.Sevostianov introduces gestation
as a term - it is an elementary unit of multicellularity that emerges due to cell specialization and
integration. This theory connects the number of cell potentials m with the number of stationary cell
conditions n, where m ≤ n. In this theory, adaptive features of cell clusters can be expressed as the
sum of all unrealized potentials Snc of all gistion function S nc=(m - n)n. To what extent can this
model predict variations in well-studied nematode embryogenesis processes? [127]
SOLUTION:
A solution to this problem is in development.
[127. Savostyanov, G. A. (2016). The emergence of stem cells in the development of
multicellularity and their quantitative characteristics. Cytology, 58(8), 577-593.]
5.58 Phase spaces. Propose different variants of phase spaces realization for describing living
systems.
SOLUTION:
A solution to this problem is in development.
5.59. Non antibiotic resistance gene. (by Mingyang Li, CAU_China team iGEM 2021)
Without antibiotics, the gene in plasmid transformed into bacteria is not expressed and the plasmid
will soon disappear with bacterial passage. However, the excessive use of antibiotics will lead to the
resistance of a small number of untransformed bacteria to them, and even the birth of "super bacteria",
which will seriously endanger the medical system and disease control. Is it possible to design such a
resistance gene, which can make the transformed cells have the ability to resist natural environmental
stress, such as extremely low water potential, the presence of harmful compounds, etc.
SOLUTION:
The solution to the problem is under development.

6. Ethics of biosecurity
The future and current problems of life organization that can threaten humanity’s existence.
6.1 Biodrug. Ex-employee of “Biodrug” company Kanatzhan Alibekov fantasized about the creation
of a hybrid bacterium-viral pathogenic strain. In the 1980s it was impossible. What would such strain
look like in reality? And what would you do to create protection from it? [128]
SOLUTION:
A solution to this problem is in development.
[128. Alibek K. Caution! Biological weapons! / Ken Alibek, Stephen Handelman. - Moscow:
Gorodets-izdat LLC, 2003.]
6.2 Synthetic biology. Modern methods of synthetic biology allow developers creation and
modification of living organisms quite fast, but not always for safe goals. Describe the main dangers
that can be connected with the mass distribution of such technologies.
SOLUTION:
You can look up ideas in the report of the National Science Academy of the USA [129].
[129. National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of
Synthetic Biology. Washington, DC: The National Academies Press. DOI:
https://doi.org/10.17226/24890]
6.3 Induced extremophilic. While looking for extremophilic cell mechanisms, scientists suggested,
that the treatment of cells with a weak base, such as ammonia or chloroquine, will raise the pH of
intracellular organelles to neutrality, and as a result, M6P receptors will
accumulate in the Golgi apparatus, because they can’t connect to lysosomal enzymes. Is this
hypothesis valid?
SOLUTION:
The hypothesis is not correct. Adding a weak base would lead to M6P receptors accumulation in late
endosomes (multivesicular bodies). M6P receptors, which bind well to lysosomal enzymes in neutral
pH, usually release bound enzymes at lower pH in the late endosome, and then are processed in the
Golgi apparatus. If the pH of the late endosome were to increase, the M6P receptors could not release
bound enzymes, and since they could not be reworked, they would be trapped in the late endosome.
6.4 Prions in plants. Prions are a special class of infectious agents that are represented by proteins
with abnormal tertiary structure and without nucleic acids. Prion proteins hypothetically can replicate
in plants. Describe possible prion proteins recombination methods in plant cells. Guess what functions
they can perform and in what processes they can participate, in order not only to exclude the loss of
the gene and its apparatus of
post-translational modifications, but also increase their copy number?
SOLUTION:
A solution to this problem is in development.
6.5 Spiegelman's parasite. Spiegelman's monster is a name given to one RNA molecule, consisting
of 218 nucleotides, that can replicate very quickly using RNA replicase. Suggest intracellular parasitic
mechanism aimed exclusively at the synthesis of non-coding
RNA sequences, which are complementary to the regions of ribosomal RNA. Although RNA itself
lives inside and outside the body for a relatively short time, can such a mechanism cause an epidemic
even in the absence of a virulent form?
SOLUTION:
A solution to this problem is in the development
6.6 An all-out threat. Currently, a person can predict the consequences of natural mutations and the
evolution of known pathogens. However, hypothetically, unknown pathogens can cause great danger,

using fundamental physical and chemical laws for replication (this hypothesis is called “gray mucus
"). For example, organisms with enzymes that use less Gibbs energy in known reactions. What
molecular mechanisms can be used to predict the possible nature of such agents?
SOLUTION:
A solution to this problem is in development.
6.7. The deceiving pathogen. Conditionally pathogenic microorganisms show their pathogenic
properties only under certain conditions. Imagine a pathogen that mimics a symbiont up to the
absence of immunogenic proteins on its membrane. How is it possible to detect such a deceiving
pathogen?
SOLUTION:
A solution to this problem is in development.
6.8. A virus with a potential. Penetration of only one spermatozoid into the ovum is achieved by
changing membrane potential after the dissolution of the shell and the release of hereditary genetic
information. Suggest the ways to combat such a "smart" virus with a division that occurs in the cell
only once, releasing vesicular transport with RNA and enzymes.
SOLUTION:
A solution to this problem is in development.
6.9. Virion-transformer. Influenza virus is resistant to vaccination as a result of antigenic variability,
which often makes vaccination ineffective in preventing epidemic danger. Suggest a hypothetical
mechanism of alternative pathogen sequences assembly, e.g. based on the principles of alternative
splicing and mobile elements, which would lead to random changes in the tertiary/quaternary structure
of virion proteins, while maintaining work and properties within a limited range.
SOLUTION:
A solution to this problem is in development.
6.10. Identity forgery. In the film, "Gattaca" dentity identification is associated with a constant
passing DNA test. Today (2018), personality identification is based on counting the number of
STR-repeats, and promising systems will be based on a comparison of SNP mutations. Suggest a
system of genomic editing, allowing you to specifically make necessary mutations in the nuclear and
mitochondrial DNA of buccal epithelium cells of the oral mucosa, hematopoietic cells, keratinocytes,
and melanocytes of the skin, which will be safe and painless for humans.
SOLUTION:
At present, the idea of ​forging an identity has been implemented in the art project “Stranger Visions”,
within the framework of which DNA samples, collected from discarded garbage, were sequenced and
could be synthesized anew in the required amount, including for criminal usage. There are other use
cases mostly related to poor quality laboratory analysis and genetic characteristics of the subject.
[130],[131]
[130,131. Kelomees, K. (2015). Artist’s experiment and scientific experiment: The “provability”
and creative distinctiveness of an artwork. In Proceedings of the 21st International
Symposium on Electronic Art.
https://motherboard.vice.com/en_us/article/gyma7m/dont-sequence-your-dnagoldenstate-killer]
6.11. Substitution of parents. Assess the risks of extended system usage from task 6.7 "Identity
forgery" for editing the DNA of the embryo to change the personality of a parent/parents.
SOLUTION:
A solution to this problem is in development.
6.12. First Pregnant Man. Carrying a fetus by a man seems an insoluble task by existing methods.
Various developers suggest the implantation of an artificial uterus in a man, for example, obtained by
genetic engineering methods. Such an implant may require transplantation into a cell with an
additional X chromosome that regulates the process of fetal maturation. Also, it would be

methodologically complex to perform a surgery for temporary or permanent implantation of such
bioengineered construct into the body. Suggest your variant of solving this problem.
SOLUTION:
A solution to this problem is in development.
6.13. Super centenarians in business and politics. In the film “Time” (In Time, 2011) the life
expectancy of a person was equivalent to the amount of money on his “biological account ". If
biomedical technologies succeed, conditional immortality, when the maximum life span
exceeds the duration of an era, the technologies will be available primarily to those who have the
desire and opportunity to take advantage of them. Assess the consequences of the appearance of
people whose planning horizons due to natural biological reasons will greatly exceed the traditional
ones.
SOLUTION:
A solution to this problem is in development.
6.14. Genome stability. Interventions in genetic consistency lead to different consequences for
different species due to the presence of interspecies differences in the organization of the genome
(Fig. 6.1). Differences in polyploidy and copies of genes can lead to different effects from exposure to
genetic engineering tools. For example, the genome of wheat with a size of 17 Gb is 5 times longer
than a human one and almost consists of "genetic parasites" - retrotransposons, constantly moving and
self-replicating genetic elements for 68%. Suggest a rating system for genome resistance to various
interventions.
SOLUTION:
A solution to this problem is in development.
Figure 6.1. Values of: a) The order of different interventions, b) The size of the
genome of different species.
6.15. Very home first aid kit. During humanitarian disasters people’s dependence on drugs becomes
obvious. They are vital for people with chronic diseases, who must take their medication every day.
An example of such a drug is insulin, which any other counterpart cannot replace. Develop a kit for
'homemade' (homemade) production of medicines in emergencies. If necessary, use the experience in
this area for point-of-care systems based on synthetic biology principles [132].
SOLUTION:
A solution to this problem is in development.
[132. Perez-Pinera P, Han N, Cleto S, Cao J, Purcell O, Shah KA, et al. Synthetic biology and
microbioreactor platforms for programmable production of biologics at the point-of-care.
Nature Communications 2016;7:12211. doi:10.1038/ncomms12211.]
6.16. In search of biodiversity.
Despite the apparent progress of the biological sciences, to date, 95% of micro-organisms have yet to
be discovered, and the potential of their industrial applications may be far beyond the wildest
imagination. It seems that for every trait of an organism, there is an environment in which its
detection is most likely to be detected. For example, thermo-extremophiles are best found near
geothermal sources, the most efficient mechanisms of light conversion mechanisms are best found in
dark caves and deep in the ocean, etc. Suggest a way to map potential "deposits" of interesting
genetic "mechanisms" in the image of geological maps of ore deposits.

SOLUTION:
A solution to this problem is in development.
6.17. Unknown planet.
Changing climatic and human intervention can direct the evolution of individual organisms or their
communities in unexpected ways. Suggest a model for finding and studying natural habitats whose
evolutionary properties may pose potential threats to humanity.
SOLUTION:
A solution to this problem is in development.
6.18. Inferno.
In Dan Brown's novel Inferno, one of the characters created a viral vector: "A virus causes no
apparent symptoms, signaling that it is changing something in our genes. An extremely contagious
pathogen that spreads through the air and deprives humans of the ability to procreate on a genetic
level. An infertility virus that activates randomly. Everyone has the virus, but one-third of the
population will be infertile. In this way. The hero of the book tried to solve the problem of
overpopulation of the planet. Confirm or deny the biological possibility
create such a viral vector and consider the mechanism
pathogenicity.
SOLUTION:
This 'folklore' challenge is about analyzing the latest genetic engineering techniques. At the moment,
it is not possible to create just such a viral vector.
6.19. Welcome, or no entry for outsiders.
The rate at which epidemics spread changed with the advance of civilization. The bubonic plague in
the fourteenth century crept across Europe at a pace of 300-600 kilometers a year. The most
dangerous instrument of swine flu, the Boeing 747, takes three hours to travel from Mexico City to
Los Angeles. An effective way to fight the spread of the epidemic could be the early Diagnosis of
infected people at the airport could be an effective tool in the fight against the spread of the epidemic.
Developing an automated diagnostic system is hampered by high flows of people through large
airports. Suggest a method for detecting infected people using any known epidemiological hazardous
disease.
SOLUTION:
Since the late 2000s, airports have been used to isolate individuals in the flow of people suspected of
being infected by a pathogen and therefore suffering from elevated body temperatures; thermal
imaging cameras have been widely used at airports since the late 2000s. Such equipment has now
been installed at most airports in the Russian Federation. In this case, the device does not need the
constant attention of the operator because the audio and visual alarms, duplicating each other, will
immediately inform about the passage of the person with a body temperature exceeding the specified
parameters with an accuracy of a tenth of a degree. However, such a non-specific method cannot be
universal, and other options for identifying ill travelers are being developed. One of these could be
the analysis of passengers' exhaled air directly on board the aircraft. If some infectious disease marker,
or directly viral particles, are detected, the plane could be quarantined, preventing further spread of
the epidemic
6.20. Environmental Barrier.
High risks for humans are economic activities with hazardous working conditions and some rare
natural phenomena. Limnological disasters are the phenomenon of the release of large amounts of
CO2 from an open water body, accompanied by a massive loss of human and animal life. In 1986
Lake Nyos in Cameroon, such a catastrophe caused the deaths of more than 1700 people. Today, there
are at least eight bodies of water at high risk of such discharges. There are currently at least eight
reservoirs at increased risk of such emissions, including the introduction of micro-organisms whose
waste products can be used in geological structures, micro-organisms whose waste products reduce
the porosity of geological structures. However, the delivery of such organisms to the seabed could be
difficult. Suggest ways in which such functional organisms could become benthic structures, typically
represented by volcanic rocks.

SOLUTION:
A solution to this problem is in development.
6.21. Parasite dietitian.
It is now known that numerous studies have shown that a special diet can reduce the risk of
developing parasites. A well-chosen diet helps to reduce the chances of disease development and
promote life expectancy [133]. However, not all people have enough willpower to follow such diets.
Suggest a design for an intestinal parasite that would recycle the excessive nutrients consumed
compounds.
SOLUTION:
A solution to this problem is in development.
[133. Batin M. A., Veremeenko D. E. Diagnostics of aging. M.: Batin M. A., 2018 — - 124
p.]
6.22. A waste-free world.
Imagine a world that does not produce rubbish and waste. Suggest a model linking producers,
consumers, and decomposers into working biological chains and biological resource exchange
networks.
SOLUTION:
A solution to this problem is in development.
6.23. The legal status of "billets" and incidents involving them. The evolution of ideas about the
vesting of rights in living beings goes back millennia of debate and compromise. The use of blanks in
designing bioengineered devices and systems will inevitably face the clarification of their formal
status. Manufacturing incidents can be the cause of unanticipated entities and situations. Develop
rules for such billets, similar to Isaac Asimov's "three laws of robotics" by Isaac Asimov, but taking
into account the different nature of living machines.
SOLUTION:
A solution to this problem is in development.
6.24. The rights of living machines.
Engineered bioengineered devices can demonstrate sufficient autonomy in their decision-making and
their actions. Imagine an embedded intelligent home device in the form of a genetically engineered cat
that can make its own decisions about certain purchases. Propose rules governing the consumer and
financial activity of bioengineered devices.
SOLUTION:
A solution to this problem is in development.
6.25. Unattainable credibility.
Current medical research uses a p-value < 0.05 as the criterion for conclusion confidence, which
effectively means that this hypothesis is three times as likely as the inverse hypothesis. However, the
heterogeneity of the human population makes it easy to select a sample in which the conclusions
would be highly inconsistent. Alternatively, p<0.005, Bayes criterion, and others are suggested.
Suggest other variations of the test for the validity of medical hypotheses.
SOLUTION:
A solution to this problem is in development.
6.26. Stagnation.
Ideas change the world, so the spread of religious fanaticism, for many reasons in competition with
progressive ideas in the Middle Ages, has slowed progress in medicine and science. What
fundamental acts might have a similar effect on the development of revolutionary biomedicine in the
foreseeable future?
SOLUTION:
A solution to this problem is in development.

6.27. BioAnclave.
To exclude negative consequences from Task 6.26 Stagnation, propose realistic principles for
organizing a 'bio-enclave' for revolutionary biological research.
SOLUTION:
A solution to this problem is in development.
6.28. The basics of homeopathy.
Various authors have claimed an effect of homeopathy that manifests itself in the body's response
more to extremely low doses of the drug than to pharmacological concentrations. Assuming the
physical existence of such an effect, explain what hypothetical mechanism it may be based on.
SOLUTION:
Assuming the existence for some molecules, signaling pathways, or even cells of the existence of
receptors with competitive binding to the substrate, as well as assuming the existence of specialized
cells for the transduction of chemical signal into intercellular signaling, we can assume a hypothetical
mechanism of such "homeopathic" stimulation by activation of single cells, further signal
transmission from which is limited by broadband chemical noise from high concentrations of the "also
preparation". Conversely, the activation of single specialized cells then stimulates native intercellular
communication signal propagation in one or more specialized tissues.
6.29. Applied mathematics.
There is increasing use of quantitative techniques in Clinical medicine is increasingly using
quantitative methods for planning experiments and evaluating results, to ensure their relevance and
validity. Quantitative methods are also increasingly being used in the humanities. Humanities
disciplines such as philosophy. List the main methods that could be used in Planning a surgical
experiment (theoretical surgery).
SOLUTION:
A solution to this problem is in development.
6.30. RNA robot.
The use of tissue-specific delivery systems allows selective delivery of coding sequences into cells,
subject to transfection or surface adsorption. One component of such tissue-specific systems may be
RNA and DNA aptamers. The use of various delivery vectors such as aptamers (C1- and Otter-) [134]
allows specific delivery of encoding nucleic acid sequences, some proteins, and possibly
nanoparticles, without inducing an immune response. Develop an RNA-robot design for targeted
delivery into animal cells:
a) RNA sequences in mitochondria,
b) a protein up to 30 kDa in the Golgi
SOLUTION:
A solution to this problem is in development.
[134. M. L. Magalhães, M. Byrom, A. Yan, L. Kelly, N. Li, R. Furtado, D. Palliser, A. D.
Ellington, and M. Levy, “A General RNA Motif for Cellular Transfection,” Molecular
Therapy, vol. 20, no. 3, pp. 616–624, Mar. 2012]
6.31. Bacterial interference.
Bacterial interference is a competitive interaction between closely related microorganisms, which may
lead to replacing one species with another [135], which is a healthy person is expressed in the
expulsion of pathogenic microorganisms. in a healthy person is expressed in the expulsion of
pathogenic microorganisms by normal microflora. Among the potential mechanisms of bacterial
interference are distinguished by competition with pathogenic strains for nutrients and the
production-specific bacteriocins, competition with pathogenic strains for sites for adhesion,
prevention of biofilm formation, specific immunomodulation as well as regulation of the genes of
pathogenic strains [136]. Suggest promising methods for the use of the phenomenon of bacterial
interference to control the infectious status of humans.
SOLUTION:

A solution to this problem is in development.
[135,136. Darouiche RO, Hull RA. Bacterial interference for prevention of urinarytract infection.
Clin. Infect. Dis., 2012, 55: 1400-1407.
I. N. Zakharova, I. M. Osmanov, E. B. Mumladze, E. B. Machneva, V. I. Svintsitskaya,
A. N. Kasyanova, I. S. Oblogina, E. V. Tambieva, G. B. Bekmurzayeva, T. M. Vasilyeva,
I. N. Lupan. Genetic and molecular bases of asymptomatic bacteriuria in
children: what's new?]
6.32. Alzheimer's.
The current search for a cure for Alzheimer's disease focuses on selecting monoclonal antibodies to
different beta-amyloid epitopes. However, if Alzheimer's disease is a generic name for a group of
pathologies, some common manifestation of the formation of beta-amyloid plaques, this search
strategy is doomed to failure. Suggest a strategy to find a cure for Alzheimer's disease, assuming
there are pathological processes that are different in nature and manifestation. pathological processes.
SOLUTION:
A solution to this problem is in development.
6.33. The Hidden Threat. Not so long ago, medical diagnostics used such terms as "cough", "worm"
(diarrhea), "itch" (scabies, itching), "perhui" (cough with shortness of breath), which were united by
symptoms of diseases completely different in their etiology. Assume that many of today's modern
diseases - type 2 diabetes, Alzheimer's disease, cholelithiasis - are not independent pathologies of the
same etiology, but the same conglomerates of diseases different in their molecular cause, united only
by their uniform manifestations. What new approaches to diagnosis and the search for promising
therapies would you suggest in this case?
SOLUTION:
A solution to the problem is under development.
6.34. Artificial Intelligence for Curing Aging. Decision support systems based on "machine
intelligence" appear to be a field of promising development at the moment. Using such systems to
search for biological mechanisms to cure aging could lead to new solutions, the format of which
would depend on the training sample of the neural network. Suggest solutions that would help in such
a sampling-unspecific associative search for aging therapies.
SOLUTION:
The solution to the problem is under development.
6.35 Health Net. Propose marketing strategies for the production, sale, and service of human
bioengineered organs in national and international markets.
SOLUTION:
A preliminary competitive advantage analysis suggests the following competencies:
- Designer of finished products and services, which implies entering the global market with a wide
range of biocomponents to create individualized medicines and ways to use them.
- Standards and practices, implying development of international clinical protocols and standards for
application of SynBio market technologies, experimental operations, validated by WHO, international
professional organizations, well-known brands.
- IT and scaling in the form of corporate communication channels to integrate omics data and make
decisions based on the available information about the person and his ecosystem, which become the
main element and risk of scaling the business.
6.36 Technology Officers. In the 1940s there was an acute problem of personnel training for the
previously non-existing industries - Minsredmash, Minobshchemash and the Academy of Sciences of
the USSR. These problems were solved by organizing MEPhI, Bauman Moscow State Technical
University and MIPT. Today this problem is also acute for genomic medicine and personalized

medicine [137]. In 2000, with the support of Academician V.I. Shumakov, an attempt was initiated at
MIPT to jointly train doctors on the basis of a natural science baccalaureate with medical universities.
It is likely that the training of bioengineers in the context of designing and constructing functional
living beings, including humans, is also an area for which training requires the use of new approaches.
One application of such approaches would be to resolve the tensions of the balance between brilliant
theoretical training and the amount of practical skills.
Suggest ways to train a critical workforce for the biotechnology excellence industry.
SOLUTION:
Options for solving the problem are under development.
[137. A. P. Kiyasov, R. V. Deev, E. V. Kiyasova, A. A. Gumerova . Medical education at a crossroads.
How to step into the future of medicine and the medicine of the future? Genes & Cells, Volume XII,
No. 4, 2017 DOI: 10.23868/201707035]
6.37. CAD Life. Computer Aided Design (CAD) systems are designed for the functional design of
technical facilities and systems. Propose the functionality and operations of CAD systems for the
design of humans and other mammals, including those based on reverse engineering of living things.
6.38. Bio-emancipation. By means of various genetically engineered interventions regulating
morphogenesis it is possible to achieve manifestation of various signs of intelligence in the living
beings considered unintelligent [138]. Suggest conditions, criteria, and ways for such individuals to
acquire civil rights and freedom of religion.
SOLUTION:
The solution of this problem is in the process of development.
[138. Nesbeth, D. N., Zaikin, A., Saka, Y., Romano, M. C., Giuraniuc, C. V., Kanakov, O., &
Laptyeva, T. (2016). Synthetic biology routes to bio-artificial intelligence. Essays in biochemistry,
60(4), 381-391.]
6.39. Biopolitics. Some of the laws and regulations that exist today may not allow human beings to
reach their full potential. Examples of such laws and regulations are GINA (Genetic Information
Nondiscrimination Act, 2008), the ban on human cloning, the difficulties of WHO initiative groups in
recognizing aging as a disease, etc. Suggest ways to overcome the mechanism of generation of such
bans, in addition to the activities of public movements of transhumanists [139] and organizations of
people with disabilities [140]. To what extent can economic agents be more effective than social
movements?
SOLUTION:
The solution to the problem is under development.
[139,140. Bernstein, A. (2019). The Future of Immortality: Remaking Life and Death in
Contemporary Russia (Vol. 3). Princeton Studies in Culture a.
Wolbring, G., & Diep, L. (2016). The discussions around precision genetic engineering: role of and
impact on disabled people. Laws, 5(3), 37.]
6.40. Difficulties of restriction analysis. (by Dmitrii Vladimirtsev, MIPT_MSU team iGEM 2021)
Dmitrii instructed the student to conduct a restriction analysis of the pLKO plasmid.1, the genetic map
of which is shown in the figure on the left. Restriction analysis is one of the analytical methods of
molecular biology, which consists in the processing of genetic material by restrictases (that is,
enzymes that introduce a double-stranded break in certain places called restriction sites).

After treatment with restrictases, the reaction mixture is separated by electrophoresis in order to
identify the length of genetic fragments in the reaction mixture. If fragments of the same length (and
their number does not exceed the expected) are present in the reaction mixture, which were expected,
then it is believed that restriction analysis confirmed the presence of one or another plasmid in the
sample.
Dmitrii asked the student to treat the plasmid with EcoRI and KpnI restriction (the restriction sites of
these plasmids are shown on the genetic map).
Question 1. Theoretically, how many fragments should be present in the reaction mixture after such
treatment? What are their lengths? Restriction treatment and incubation were performed according to
the standard protocol, time incubation at 37°C was 1.5 hours. Then the student performed
electrophoresis in agarose gel (TBE buffer, 2% gel). To the first track she placed the DNA Ladder in
the second reaction mixture, and in the third – the plasmid, the restriction of which she carried out.
Electrophoresis was performed for 20 minutes, at 135 V. The result of electrophoresis is shown in the
figure on the left.
SOLUTION:
As can be seen from the genetic map, the presence of two fragments with lengths of 1399 bp and 7502
bp is expected
Question 2. Suppose why there are three fragments on the second track? Consider that the original
analyzed genetic material was pure, that is, only plasmid was present in it.
SOLUTION:
As you can see, the uppermost band corresponds to the length of the entire plasmid, which is 8901 bp.
Hence, it can be assumed that such a band corresponds to the case when only one of the restrictases
cut the original plasmid. The middle band (~7000 bp) and the lower band (~1600 bp) correspond to
the expectations for cutting the plasmid.
Question 3. Suppose why electrophoresis shows the length of the plasmid in 5500 pairs of
nucleotides, although in reality the length of the plasmid is 8901 pairs of nucleotides (see the third
track)?
Question 4. If you look closely at the third track, you can see a faint glow in three areas marked with
the letters a), b) and c). Suppose, because of what happens? Consider that the original analyzed
genetic material was pure, that is, only plasmid was present in it.
SOLUTION:
The fact is that the plasmid is in solution (especially if it lies for a long time) it can be in three forms.
The first form is a super-twisted form. Due to the super-twisting of the DNA helix, this form runs

faster through the gel, so it turned out to be much lower than expected on the gel, and corresponds to
the letter c). This form is the main one, it is most in the test tube, so the strip is quite bright. The
second form is a less stressed form, where one of the chains could undergo a break (single-stranded
DNA break). Therefore, it runs a little slower than the first form, and corresponds to the letter b).
Finally, the letter a) corresponds to the form in which the plasmid has a double-stranded break, and it's
linearized. The second and third forms are presented in a plasmid solution in a very low concentration,
but they are still there and make themselves felt on electrophoresis.
Question 5. Was the experiment successful? That is, whether the restriction analysis confirmed the
presence of the pLKO plasmid in the analyzed genetic material 1?
SOLUTION:
Summarizing all of the above, we can conclude that the experiment was a success.

7. Life Super Systems.
Solving problems related to systems engineering and complexity management of biological
super-systems.
7.1 Mega-machine. According to Mumford's concept [141] a typical megamachine is a social system
composed of elements, parts, and fragments of other social systems. Describe the living megamachine
and the mechanism of its behavior in the context of the world around it.
SOLUTION:
The solution to the problem is in progress.
[141. Mumford, L. (1991). The myth of the machine. Utopia and Utopian Thinking, 79-97.]
7.2 Watson. In 2011, IBM introduced Watson, an artificial intelligence system specializing in
selecting personalized therapies for cancer. However, this project encountered difficulties in its
implementation and translation to the clinic. Why do you think that is?
SOLUTION:
The developers of the project faced the following problems: a) the complexity of creating ontologies
(data presentation format); b) the inability to digitize and parse raw data (e.g., glass scans), etc.
Ultimately, the system appeared to rely on systematic reviews and meta-analyses with p<0.05-0.001
reliability, which did not allow for proper personalization of treatment.
7.3 Biostimulation Chips. The closest method of cyborgization today is to train living systems to
perceive electrical or optical (optogenetics) signals. Develop a way for a plant/animal cell
culture/embryo to communicate with a computer by influencing the receptor properties of the cells
with electrical potentials.
SOLUTION:
The solution to the problem is in progress.
7.4. Pet interface. Nowadays, the term "embedded system" means specialized architectures
embedded directly into the device they control. Propose a mobile application interface architecture for
controlling smart home systems and security features in the form of a pet (cat, dog, or other animal
with developed vocal cords and an adaptive joint and muscular system).
SOLUTION:
A solution to the problem is under development.
7.5 Smart Home. Propose the concept of a smart suburban home that uses the capabilities of its living
environment to solve the tasks of the control program. Realism implies a limitation of action: this
means that tasks are performed by living cells solely in the vicinity of the house. The use of chemical
compounds is also limited due to acute odors, harmful effects on humans. To what extent can a
properly selected repertoire of odors offset the effects of weather conditions on crop growth? Would
the extraction of specially selected phages into water for watering plants in the lawn help increase the
temperature in the house in winter?
SOLUTION:
The solution to the problem is under development.
7.6 Smart City. Propose the concept of a smart home that solves its residents' problems on its own, in
an urban area.
SOLUTION:
The solution to the problem is under development.
7.7. The friendly world of the future. The world is full of dangers. About 475,000 people are killed
each year in the world from attacks by wild animals (Figure 7.1). Propose a scheme, such as one
based on engineered pheromones, that would incorporate the innate freeze reflex when a human
approaches.
SOLUTION:

A solution to the problem is under development.
Figure 7.1. The number of deaths from animal attacks and bites © Daily Mail (dailymail.co.uk)
7.8 The Isolated Brain. The work of Alexis Carrel, one of the pioneers of transplantology, considered
an operation [142] in which non-vital organs were sequentially removed from an animal, providing
researchers for a time with a system of interrelated organs - the visceral organism. Propose a scheme
for maintaining the vital functions of the isolated brain.
SOLUTION:
A solution to the problem is under development.
[142. Carrel A, Lindberg CA. The culture of organs. The American Journal of the Medical Sciences
1938;196:732.]
7.9. Modular brain. Modern cluster solutions allow the construction of computing systems by
increasing the number of servers in the network. Present the physical possibility of the existence of
neuromodules (e.g. in the form of an isolated brain (see Problem 7.8. "Isolated brain"); neural tissue
on a semiconductor substrate; etc.), in relation to which it is possible to connect them by appropriate
interfaces. Propose an architecture for a modular neural network in which: a) an increase in the
number of neuromodules is not accompanied by an increase in complexity; b) an increase in the
number of neuromodules is accompanied by an increase in complexity.
SOLUTION:
The solution to the problem is under development.
7.10. Intelligence on Demand. In their daily activities, humans encounter IT systems on different
operating systems and architectures, but using standard data communication protocols according to
the OSI network model, humans are able to interact with any technical solution. The same can be said
for verbal language when interacting with people of different cultures. Suggest a minimal mind
(universal interface) that, if necessary, could be implemented in any living organism for human
interaction with it.
SOLUTION:
The solution to the problem is under development.
7.11. Intelligent Ocean. The ability to arbitrarily control real world events through virtual spaces is
definitely a stepping stone to the human creator. The idea of the supersense of existence has never left
human thought, embodied in a variety of forms.
Today it is actually a whole complex of convergent technologies of the future, implementing Vladimir
Vernadsky's doctrine of the noosphere [143] - the sphere of interaction between society and nature,
within which reasonable human activity becomes the determining factor of development. Perhaps it is
better that all these fantastic technologies are presented in Stanislaw Lem's book Solaris [144].
SOLUTION:
The solution to the problem is under development.

[143. Vladimir Vernadsky argued that humanity in the course of its development is turning into a new
powerful "geological force", transforming the face of the planet with its thought and work.
Accordingly, in order to preserve it, it will have to take responsibility for the development of the
biosphere, which is turning into a noosphere, and this will require it to have a certain social
organization and a new, ecological and at the same time humanistic ethics.]
[144. "Solaris" is a fantastic novel by Stanislav Lem, describing the relationship of people of the
future with the intelligent ocean of the planet Solaris. The substance of the ocean could change the
orbit of the planet without any tools, by directly influencing the metric of space-time. Found out, that
the ocean is able to form intricate structures on its surface, built using the most complex mathematical
apparatus]
7.12. C5ISR: the biological Internet. In 1969, researchers at the Massachusetts Institute of
Technology created the ARPANET network (Figure 7.2.), which was the prototype of the modern
Internet. The creation of biological information systems, in which information reading as well as
feedback and data transfer to the biosystem could be done without signal loss, could be a basic
element of the biological Internet. Suggest a way to organize such a system.
SOLUTION:
A solution to the problem is under development.
7.13. A biological computer. The classical Turing machine is an unrestricted ribbon divided into cells
in both directions and a control device capable of being in one of many states. The control device can
move left and right on the The Turing machine is an extension of the Turing machine, which can read
and write symbols of some finite alphabet into its cells.
The Turing machine is an extension of the finite automaton and, according to Church-Turing's thesis,
is capable of imitating all executors (by setting transition rules) that in some way implement a
step-by-step calculation process in which each calculation step is quite elementary. The similarity of
such a learning model to the processes of transcription and modification (methylation) of DNA
pushed researchers to create models for simulating a Turing machine in a living cell, which would
surpass electronic machines in performance and energy efficiency.
For example, existing supercomputers spend about 1 J per 109 operations. In [145], the Gibbs free
energy change for DNA binding was -8 kcal/mol, so 1 J of energy would theoretically be enough to
perform 2×1014 such reactions.
Evaluate the efficiency of such a biological Turing machine compared to modern supercomputer
systems.
SOLUTION:
The solution to the problem is under development.
[145.Adleman LM. Molecular computation of solutions to combinatorial problems. Science
1994;266:1021–4.]
7.14. Smart Dust. Molecular nanotechnology can be used as a tool for modification of cell organelles,
implementation of cell communication elements and computer technology, creating manufacturing
nanorobots for self-assembly of complex structural elements (building frame, strong hull of ships,
etc.). Propose a nanorobot model to catalyze elementary physical and chemical processes.
SOLUTION:
The solution to the problem is under development.
7.15. The nature of superconsciousness. In the human brain, signals are transmitted and stored by
changing the electrical potential of axon membranes. Suggest ways of increasing "number of
freedoms" in a supercomplex brain, in which signal storage and transmission could be carried out
according to augmented physical parameters, including by reducing energy efficiency (connections
could consume substantial amounts of energy). Can similar connections be realized in modified
neuronal cells by modifying the membrane and intracellular organelles? Could the development of a
neuron with a new type of axons that carry proton pumps with better efficiencies help to solve this

problem?
SOLUTION:
A solution to the problem is under development.
7.16. The vacuum brain. Boltzmann brain is a hypothetical object arising as a result of fluctuations
in some system and capable of being aware of its existence [146]. Estimate the probability of such an
event occurring.
SOLUTION:
The reader is invited to read the work of Andrei Linde on calculating the probability of such an event
[147].
[146,147. Linde A. Sinks in the landscape, Boltzmann brains and the cosmological constant problem.
Journal of Cosmology and Astroparticle Physics 2007;2007:22. doi:10.1088/1475-7516/2007/01/022.
Sinks in the Landscape, Boltzmann Brains, and the Cosmological Constant Problem
https://arxiv.org/abs/hep-th/0611043 DOI:10.1088/1475-7516/2007/01/022]
7.17. Game Theory. Mathematician John Nash's theory suggests the possibility of cooperative
activity in non-cooperative games with non zero sums [148]. Propose the use of Nash equilibrium to
explain the processes that accompany wound healing and the integration and interpretation of
heterogeneous omics data.
SOLUTION:
A solution to the problem is under development.
[148. Nash J. Non-Cooperative Games. The Annals of Mathematics 1951;54:286–95.
doi:10.2307/1969529.]
7.18. Subject capital. Until now, subject money (capital) has been an attribute solely of the living
human being. By imagining that non-humans are capable, through virtual or physical events, of
earning and increasing the value of assets, we can also imagine the intervention of such systems in the
real world. Although the "Turing test" has not yet been passed by machines at this time, with respect
to trading robots and brokers the difference remains insensible. Propose norms and rules describing
the existence of a non-human who, reacting to external events, is able to manage his capital.
SOLUTION:
The solution to the problem is under development.
7.20. Pharmacological analogue of sleep. In the animal world, sleep is a necessary physiological
state to restore the function of normal brain axon conduction. Propose a functional pharmacological
analogue of sleep that would restore myelin sheath function and other effects of the sleep state.
SOLUTION:
A solution to the problem is under development.
7.21. Playing God. Planning designs for creatures that can make the world a better place, or creating
entire "worlds" with engineered inhabitants, may encounter problems finding isolated "niches,"
building ecosystem dividing barriers, or finding other solutions to coexist. For example, one of the
ideas of synthetic biology is the use of orthogonal (independent) gene networks to implement
individual functions [149]. Suggest a way to divide the created worlds into separate "levels," and not
only spatially, as far as it is possible to separate their participants? Is it possible to propose a method
of mass creation of "worlds" existing in parallel and independently, but isolated from interaction with
each other by the mechanisms available to them?
Use the mechanisms of plankton biodiversity permanence in the world's oceans to solve this problem
[150].
SOLUTION:
It is still quite difficult to imagine how such a hierarchical structure could be implemented in the real
world. However, in the case of virtual space, imagining a similar and much more complex structure
seems quite a realistic task.

[149,150. Wang B, Kitney RI, Joly N, Buck M, Lim WA, Morris MK, et al. Engineering modular and
orthogonal genetic logic gates for robust digital-like synthetic biology. Nature Communications
2011;2:508. doi:10.1038/ncomms1516.
Mitchell, J. G., Yamazaki, H., Seuront, L., Wolk, F., & Li, H. (2008). Phytoplankton
patch patterns: seascape anatomy in a turbulent ocean. Journal of Marine Systems, 69(3-4), 247-253.]
7.21. Stereochemical evolution. Imagine the evolution of living organisms in terms of increasing
degrees of free biochemical reactions in the cell. Suggest the next step similar stereochemical
evolution of the cell, and describe the characteristics and properties of such a "synthetic god".
SOLUTION:
The solution to the problem is under development.
7.22. Biotechnological construction of a human being. Propose the stage of biotechnological
reengineering, design and construction of a living human being in the context of problem 7.21.
SOLUTION:
The solution to the problem is under development, but an introduction to this problem in the context
of social technology assessment (technology assessment) can begin with the works of philosopher
B.G. Yudin [151] for an initial introduction to the terminology of "human nature as a polygon",
"limitations of human physical and intellectual abilities as a problem", "transformation of the human
cure problem into its improvement", "redesigning human beings", and other notions.
[151. Yudin, B. G. (2008). Medicine and human design. Knowledge. Understanding. Skill, (1).]

Appendixes
The conceptual design of living machines requires the researcher to be able to quickly estimate the
characteristic dimensions, masses, and other characteristics of the designs being created. Below are
tables with characteristic parameters of key elements of living organisms that may be useful to the
designer of bioengineering devices.
For more on biology in numbers, visit the Cell Biology in the Numbers" http://book.bionumbers.org/

Acknowledgements
The preparation of this collection would not have been possible without the support and ideas of my
good friends, all the participants of Foresight-Fleet-2015, the conferences "Genetics of Aging and
Longevity" (2012-2014), working groups of the National Technological Initiative, the Laboratory of
Innovative Educational Technologies at MIPT (head of the lab - Taras Pustovoy), and especially the
help of Olga Krasilnikova, Vasily Stepanenko, Maxim Alekhine, Dmitrii Filchakov, Mikhail Batin,
and all my good friends and comrades.