YSM Issue 95.1

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NEWSBiochemistryTHESE ARE NOTTHE GENES YOU’RELOOKING FORFiltered editing opens doors to newpossibilities in genome editingBY SOPHIA BURICKSince its inception in the early 2000s, genome editing has beenrevolutionizing biotechnology. Methods like CRISPR/Cas9empower scientists with “genetic scissors” that allow them tomake remarkably precise edits to DNA—the genetic instructions incells that control cell function, development, and reproduction.This technology has widespread applications, from engineering togenetic diseases to globally threatening plant pathogens. However,CRISPR/Cas9 is greatly limited by its inability to distinguishbetween genetic sequences that repeat several times throughoutthe genome, which occurs often. Farren Isaacs, Associate Professorof Molecular, Cellular, and Developmental Biology at YaleUniversity, and his colleagues have discovered a powerful methodto uniquely alter the genetic address of repeated genetic sequences.This method of “filtered editing” allows CRISPR to identify andedit specific sites of repeated sections of DNA.For Felix Radford, a graduate student at Yale and first author of arecently published Nature Communications article on filtered editing,this discovery has been a long time coming. “As an undergradtaking molecular biology, I started to think more about biology as atechnology,” Radford said. “Previously, I was thinking about biology asvarious processes in life, in the human body, but these very complicatedsystems started to remind me more of how computers work.”Radford’s view of biology as a tool to facilitate creative engineeringwas foundational to his interest in synthetic biology and ultimatelyled him to the Isaacs Lab as a graduate student. “When I first joinedthe Isaacs Lab, my initial project was to engineer the ribosome, amolecular machine central to the function of all living organisms thatare responsible for the synthesis of proteins or protein biomaterials,”Radford said. But he quickly ran into an issue—even in bacteria,which generally have much less repetitive genomes than humans,their genomes contained seven repeated copies of the ribosomal DNA,genetic material serving as a template for the production of ribosomes.CRISPR/Cas9 was unable to distinguish the repeated sites of ribosomalDNA, preventing Radford from making the edits he wanted.“It’s like on the computer—you find a string that you want to editin a sequence. How do you search for that and find it?” Radfordsaid. “It’s like Ctrl-F in the genome, but we have these repeatedsequences that will lead you astray.”PHOTO COURTESY OF NORVIN WESTYale Ph.D. candidate Felix Radford picking bacterial colonies for genome editing.Radford needed a solution. So he turned to self-splicingintrons. These are RNA sequences that do not code for proteinsand can excise themselves from exons (segments of RNA thatdo code for proteins). “You can put them into an RNA, and theywill cut themselves out, leaving only the sequence that you wantto edit remaining,” Radford said.DNA segments encoding self-splicing introns can be insertedinto the genome to distinguish one repetitive site from another,providing a unique genetic address for CRISPR to recognize andtarget. When the DNA is transcribed into RNA, the self-splicingintrons cut themselves out of the RNA strand and stitch togetherthe gap. This solution was incredibly exciting to the Isaacs Labsince it would allow them to edit these repetitive sequenceswhich had previously been exceptionally difficult to target.After the initial discovery, Issacs posed an interestingquestion to Radford: what if he expanded this methodto modify many sites at once instead of just one site in theribosome? “To do that, I needed to have different types ofintrons that could work in parallel,” Radford said. “We endedup combining two different introns into one, and it worked inthe same way as the original intron.” This only widened thedoor to applications of this technology.“One application of this is that these repetitive genetic elementsare found in many different organisms,” Radford said. Repetitivegenetic elements comprise over 50 percent of the human genome.The ability to specifically edit these repetitive sequences offersgreat potential for studying and combatting genetic diseases.Another application that the Isaacs Lab is readily exploring isthe use of filtered editing to alter ribosomes and translation factorsin the cell, repurposing cells to manufacture new sequencedefinedpolymers, proteins, and biomaterials. “This can be veryimportant in utilizing biology as a means to evolve new materialsand medicines,” Radford said.As for Radford’s future, he is interested in applying this techniqueto new problems. “In science, when you have new techniques,they open up a lot of possibilities that were not possible before,”Radford said. “I’m curious to see where this goes, to see what newcapabilities are available now that we can do this.” ■8 Yale Scientific Magazine March 2022 www.yalescientific.org
NeuroscienceNEWSDELVING INTODOPAMINEEnvironmental factorscould affect our brainchemistryIMAGE COURTESY OF ISTOCK PHOTOSBY VICTORIA VERADopamine, a chemical that acts as a neurotransmitter, isresponsible for sending thousands of tiny “messages”that ultimately help generate several of our thoughts andactions. It has a myriad of functions within the body and brain,but it is best known for allowing us to feel pleasure, satisfaction,and motivation. With this in mind, it is no surprise that it is amajor point of focus when discussing addiction and reward. Socialfactors are also known to heavily influence the human brain andpsychiatric outcomes, although there is scarce research proving abiological connection. Because of that, leading researchers at Yalehave set out to explore these connections.In this project, Katina Calakos and Aleksandra Rusowicz, researchassistants at the Yale University School of Medicine, used PositronEmission Tomography (PET scans) to image dopamine receptor(D 2/3R) availability. This data was obtained from previous studiesand then correlated to population and socio-economic measuresobtained from the Social Explorer Analyses of the 2014-2018 Census.The results were surprising. For one, they found that higherD 2/3R availability was significantly associated with a higher totalpopulation in residential ZIP codes. Similarly, in zip codes where alower percentage of the population possessed a bachelor’s degree orhigher, there was a higher dopamine D 2/3R availability. Functionally,this could mean that environment does have a significant impacton our brain chemistry.Dopamine in and of itself is extremely useful and, as previouslymentioned, necessary for normal bodily functions. However,issues can arise when there is too much or little of it. For example,excessive dopamine activity has been linked to anxiety, insomnia,and mania. On the other end of the spectrum, low dopamineactivity can cause problems like muscular issues, cognitiveimpairment, and attention deficits. Considering this backgroundand the findings from this research, one could assume that theenvironment does impact the way your brain works.David Matuskey, Associate Professor of Radiology andBiomedical Imaging and Medical Director of the Yale (PET) Center,and Aleksandra Rusowicz, PhD, discussed both the inspirationand the implications of this research, in addition to what it couldmean going forward. This project was driven by prior animalstudies focusing on how dopamine availability was affected bythe animal’s position within its “society” and how that could laterpredispose them to develop drug dependency. Initially, this teamasked questions focused on how green spaces could affect brainchemistry, as environmental surroundings have been shown toaffect brain activation. All those contexts came together to producethis more recent research.Their findings represent one small step in filling this gap that isall too common for health research. Most of the evidence comesfrom epidemiological or longitudinal studies focusing on certainaspects of a population—living conditions, education, health,and correlations. However, the biological data to back-up thesefindings is simply scarce and a relatively new area of focus. Thisis why research like this could help inform future findings thatfocus even more closely on the type of social factors that impactsocial development. The investigators also expressed their hopethat research like this could potentially have policy implications,providing a biological backbone to diversity and educationinitiatives in communities that are often neglected.While Matuskey described the use of census data as“advantageous” because they could focus on surroundings andenvironments, their research had some limitations. Despite howuseful it was in gaining insight into these communities, it wasfairly broad and could be considered outdated when we take intoaccount the changes brought about by newer factors such as theCOVID-19 pandemic. It is likely that if this team had had access tomore specific data, they would have been able to discern even moredetailed patterns about how location and social circumstancesimpact the brain developments in question.Social factors have been correlated to health for years, but thusfar, we have lacked the biological data to support this claim.Thanks to work like this, we now have biological data that cansupport the existing studies. As this type of science gains moretraction, we will see more and more detailed results. Maybe oneday, we can use those findings to push for policy change thatameliorates the roots of these problems. ■www.yalescientific.orgMarch 2022 Yale Scientific Magazine 9
Page 1 and 2: Yale ScientificTHE NATION’S OLDES
Page 3 and 4: CONTENTSMore articles online at www
Page 5 and 6: The Editor-in-Chief SpeaksMICROSCAL
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Page 11 and 12: PhysicsNEWSHELLOHALOSCOPESA new det
Page 13 and 14: IMAGE COURTESY OF JACK RUSKMap of m
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Page 17 and 18: ImmunobiologyFOCUSWho is Mr. G?Mr.
Page 19 and 20: Ecology / Environment FOCUSTHE META
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Page 35 and 36: ALUMNI PROFILEJAMES DIAOMY ’18BY
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Page 39 and 40: BY DHRUV PATELHIDDENHISTORIESTHE SH

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