MRC National Institute for Medical Research Mill Hill Essays 2010

Mill Hill Essays 

2010 

MRC National Institute for 

Medical Research


2010 

MRC, National Institute for Medical Research 

The Ridgeway 

Mill Hill 

London NW7 1AA

ii 

Foreword 

CONTENTS 

The 2009 H1N1 swine flu pandemic: don’t panic but you 

are all going to die 

Peter Coombs 

A dangerous occupation 

Zhores Medvedev 

Bringing it all back home: next-generation sequencing 

technology and you 

Mike Gilchrist 

Immortality and obscurity 

Harriet Groom 

Conquistadores and cot death 

Marianne Neary 

Is immunotherapy the ultimate solution for Alzheimer’s 

disease? 

Marina Lynch 

Lithium, manic depression and beyond 

Qiling Xu 

Translation: beating scientific swords into medical 

ploughshares 

John Galloway 

What makes bone marrow such a versatile resource for 

curing human diseases? 

Thomas Elliott 

A selection of science books 

Reviewed by members of NIMR staff 

About the authors 

iii 

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12 

24 

38 

48 

52 

60 

70 

80 

83 

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Foreword 

The Mill Hill Essays address aspects of current medical science of interest to the public. 

2009 saw the first influenza pandemic for several decades. Peter Coombs describes the 

outbreak and the measures to contain the pandemic and characterise the virus. 

Zhores Medvedev describes his early life and education in Soviet Russia during the second 

world war and immediate post-war years. He also describes the influence of Trofim 

Lysenko on Soviet science. 

Gene sequencing has helped to transform biomedical science. Mike Gilchrist unpicks the 

details of how high-throughput sequencing works and what we can learn from its results. 

Harriet Groom reviews Rebecca Skloot’s best-selling book about Henrietta Lacks, which 

won the 2010 Wellcome Trust Book Prize. She explains why HeLa cells are both remarkable 

and very useful to science. 

Marianne Neary’s essay was shortlisted for the Max Perutz Science Writing Award this 

year. She describes an interesting link between research into cot death and adaptation to 

life at high altitude. 

Marina Lynch, from Trinity College Dublin, explains what Alzheimer’s disease is and how 

immunological therapies are showing great promise as treatments for Alzheimer’s. 

Qiling Xu’s essay on lithium describes its pharmacological effects, its use in bipolar affective 

disorder and its effects on major developmental signalling pathways. 

Biomedical research funders are keen to bridge the gap between basic biomedical science 

and clinical benefits for patients. John Galloway, from the Eastman Dental Hospital, explores 

what translational research means. 

Thomas Elliott won the 2010 NIMR Human Biology Essay Competition for local schools. 

His essay explains why bone marrow is an important therapeutic tool. 

New this year is a selection of science book recommendations from NIMR staff. They range 

from popular science books to fiction, by way of scientific history and autobiography. 

We hope there is something to interest you and we would value your comments. 

Frank Norman Jim Smith 

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A view of NIMR from Totteridge

The 2009 H1N1 swine flu pandemic: don’t 

panic but you are all going to die 

‘Don’t Panic But You Are All Going To Die’ is a headline from the satirical news website 

The Daily Mash at the time of the swine flu outbreak, published 27 th April 2009. 

In August 2010 the World Health Organisation (WHO) declared that 

the ‘swine flu’ pandemic was over. In the preceding 17 months, the 

pandemic had spread across the world infecting millions of people. Since 

the announcement of the end of the pandemic the WHO, national health 

organisations and the media around the world have been questioning 

whether the response to it, and the associated cost, was warranted. 

Outbreak 

Peter Coombs 

The first confirmed human cases of the new swine flu were in Mexico 

in March 2009, where a number of serious cases drew attention to 

the outbreak. Mexico informed the WHO and the United States, and 

attempts were made to contain the spread. Later analysis has revealed 

that there were probably hundreds of non-lethal cases before March; the 

virus appears to have first passed to humans at the end of 2008. In mid- 

April 2009 the first cases in the US were confirmed, and by the end of 

April the first cases in Europe were being reported. On June 11th 2009, 

the WHO raised its influenza pandemic alert to phase 6 and declared 

that the virus was causing a global pandemic. 

The initial outbreak gave rise to a massive amount of media attention. 

The tabloid press in the UK did not hold back; ‘Third of world could 

catch swine flu’ said a Daily Mail headline. Despite the sensationalism 

of the tabloids, the new outbreak did represent a very real risk. It was 

a novel strain, so there would be no, or only limited, immunity in the 

population; the severity of infection and ease of spread of the virus were 

unknown. Estimates of the numbers who would be infected worldwide 

and how many would die varied massively, and the mass media tended to 

focus on the biggest ‘worst case scenario’ numbers. Ben Goldacre in his 

excellent Bad Science column commented on the difficulty of predicting 

what would happen with the swine flu outbreak, ‘infectious disease 

epidemiology is a tricky business: the error margins on the models are 

wide, and it’s extremely hard to make clear predictions’. The reality was 

that early on no-one knew what would happen - it could be bad, or it 

might not be. 

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Early on in the swine flu outbreak some indicators weren’t good. The 

virus emerged quite quickly and spread rapidly. It appeared to be infecting 

significant numbers of young people, which was also a noted characteristic 

in reports of the 1918 pandemic, which killed tens of millions worldwide. 

It was also an H1N1 virus strain, the same as in 1918. Initial cases in 

the United States and Europe were mostly mild but even with a low 

mortality rate, if enough people were infected, the numbers of deaths 

could be large and the strain on health services significant. A critical 

concern was that if the new swine flu strain was to mutate or combine 

with another influenza strain, then a more virulent and dangerous strain 

could emerge. 

Headline writers always choose the highest estimate of potential fatalities 

The sensationalism of the tabloid newspapers was only surpassed by 

the ill-conceived conspiracy theories on the internet. Fuelled perhaps 

by fear of the unknown, combined with a large dose of imagination, 

some of the more outlandish rants suggested that the virus had been

The 2009 H1N1 swine flu pandemic: don’t panic but you are all going to die 

created as a government ploy to reduce the world’s population, or that 

pharmaceutical companies had produced and released the virus to make 

billions of dollars in vaccine and drug sales. 

As part of the media hype, particularly a few weeks into the outbreak, 

another tack was seen with a selection of ‘what is all the fuss about’ 

stories. One of the most outspoken people was Simon Jenkins writing in 

the Guardian, who wrote a couple of articles early on in the pandemic 

saying that the ‘risk to Britons’ health is tiny’. He suggested that the 

scaremongering coverage was about selling drugs and justifying budgets 

and was a waste of resources. Several rebuttals from people both within 

and outside the scientific community commented on the reality of the 

risk and the need to act rationally in the face of media hype and the 

necessity of being prepared. 

A range of scientists and health advisors gave multiple interviews in the 

media. The health secretary and the government chief medical officer 

were among those constantly in the news media explaining what was 

happening, what the plans were and encouraging people to be aware 

of the danger but not to panic. Virology experts, including NIMR’s Alan 

Hay and John McCauley (the past and current Directors of the WHO 

Collaborating Centre for Reference and Research on Influenza at Mill Hill) 

gave interviews with daily newspapers, BBC radio and TV programmes, 

explaining the unusual genetic make-up of the virus, progress in vaccine 

development and how severe the spread might be. Estimates of the 

spread and severity of the pandemic were always qualified with the 

caveat that these were estimates based on available evidence, but that it 

was unknown how it would progress and we should be prepared. 

Public perception of swine flu and the media coverage is likely to have 

been affected by experience with other recent potential pandemics, 

particularly the SARS outbreak and the threat of H5N1 bird flu in the early 

2000s. That these viruses did not result in worldwide devastation after 

the surrounding tabloid hysteria has made people more sceptical. Does 

that mean that the swine flu outbreak was overhyped? Not necessarily. 

It is sometimes difficult to accept, certainly in the cut-and-dried world of 

the mass media, that things are unknown. Risks exist everywhere, though 

particularly for things like influenza pandemics, the severity and impact 

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of a new outbreak are very difficult to estimate early on, and things can 

change as the pandemic spreads. 

It is very difficult to predict the spread and severity of a novel influenza 

outbreak, or indeed any disease outbreak. Early reports and fatality 

numbers can be inaccurate and deceptive due to factors such as 

selection bias (only those with serious problems are observed), media 

bias (people dying is more likely to be reported than people getting 

better), and incorrect reporting (for example, the initial estimated fatality 

rate of the outbreak in Mexico proved to be too high and was later 

revised downwards). Complications such as delays in reporting and 

sample testing, non-reported cases, and confusion with other illnesses 

with flu-like symptoms, further confuse the matter. Yet the scale and type 

of response needed to combat the flu outbreak would depend on how 

the virus was spreading and behaving. 

Looking at the influenza pandemics from the 20th Century, the mortality 

rate has varied considerably, ranging from around 1 million deaths in the 

1968 Hong Kong flu to an estimated 20-100 million deaths in the 1918 

Spanish flu. These figures should be placed in the context that 250,000- 

500,000 deaths worldwide are attributed to seasonal flu each year. 

Influenza is a big worldwide killer, even outside pandemics. 

In typical influenza infections it is the very young, the elderly and those 

with underlying health problems who usually suffer the most. However, 

with the 2009 outbreak elderly populations only showed low levels of 

illness. Studies showed that a significant proportion of those in the 60plus 

age range had some degree of immunity to the new pandemic strain, 

either from exposure to circulating strains when they were very young 

or from earlier vaccinations. This is because the 2009 swine flu virus 

shares some immune characteristics with the viruses that were around 

60-plus years ago. 

The part of the population most affected were people less than 30 years 

old, mostly having mild symptoms. A small proportion of infections during 

the pandemic resulted in quite severe viral pneumonia; especially among 

30-50 year olds. This group of people are not typically a high risk group, 

though many of those affected had underlying medical conditions.


The virus 

So what makes the swine flu virus different and where did it come from? 

The swine flu virus is of the influenza strain H1N1. The H and N refer 

to the proteins found on the surface of the influenza virus, hemagglutinin 

and neuraminidase, which are numbered (H1-H16; N1-N9) depending 

on which subtype they belong to. The hemagglutinin binds to host cells, 

allowing the virus to enter the cells. The neuraminidase is an enzyme 

which helps newly produced viruses escape from the host cell. These 

two proteins are present in large numbers on the surface of the virus, 

and so are also the parts of the virus that the host immune system 

will see. When the human body is infected with the virus or vaccinated 

it will develop antibodies against the virus, and be immune to further 

infections by the same virus. However, the influenza virus has evolved 

to regularly mutate these exposed surface proteins, so that the human 

immune system does not recognise them. 

Structure of the influenza virus 

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The influenza virus contains 8 gene segments, each of which contains 

the information necessary to make the proteins that the virus needs 

to help it infect a cell, to replicate, and for its progeny to escape the 

host cell and go on to infect other cells. Sequencing of the genes of the 

2009 H1N1 swine flu virus led to the finding that the strain is related 

to viruses recently circulating in pigs in North America and in Europe/ 

Asia. The strain is made up of a mixture of these genes, for example the 

hemagglutinin is descended from the North American ‘triple reassortant’ 

strain and the neuraminidase from recent European/Asian swine viruses. 

The strain itself had not been detected previously in human or swine 

populations. The ‘triple reassortant’ viruses from North America have 

been in circulation in pigs since the late 1990s, and contain genes from 

older avian, human and swine viruses. 

Pigs have been termed a mixing vessel for influenza viruses because 

they can be infected by both avian and human influenza viruses. If pigs 

become infected by more than one virus at the same time, the viruses 

can swap genes producing new variants, potentially producing a strain 

that is transmissible to and by humans. 

Drugs and vaccines 

Since the H5N1 bird flu outbreaks in South-East Asia in 2004 onwards, 

the UK government had been stockpiling the antiviral drugs Tamiflu and, 

to a lesser extent, Relenza for use in the event of a pandemic. Tamiflu and 

Relenza, also known as oseltamivir and zanamivir, work by blocking the 

neuraminidase on the virus surface, so that new viruses that are produced 

can’t escape from the host cell. The drugs are effective in reducing the 

length and intensity of flu infections if taken within the first few days of 

contracting the virus. This stockpile in the UK amounted to 30 million 

doses, enough for half the population, and more were ordered when the 

pandemic arrived. 

A few years ago, a mutation in neuraminidase was discovered which 

makes the virus partially resistant to Tamiflu. Work conducted by scientists 

at NIMR has shown how and why this happens. In the pre-2009 seasonal 

H1N1 influenza virus, there was a high occurrence of this mutation in 

some areas of the world. There was concern that this mutation might


occur in the swine flu pandemic virus and spread. This led some countries 

to increase their stocks of Relenza, to which the Tamiflu-resistant strains 

were still susceptible. Tamiflu is generally preferred to Relenza for 

treatment because Tamiflu is taken as a tablet, whereas Relenza is taken 

using an inhaler. Fortunately, only isolated cases of Tamiflu-resistant strains 

were found during the pandemic. 

A national flu service was established in the UK to reduce the strain on 

hospitals and GPs, and a system for providing antiviral drugs (Tamiflu and 

Relenza) to people who needed them was set up. The Health Protection 

Agency (HPA) and the NHS, as well as the WHO, provided guidelines 

and information on what to do if you were infected and how to minimise 

the spread of the virus. 

Each year the UK, and many other countries, enact a large scale influenza 

vaccination scheme targeting the currently circulating seasonal influenza 

strains. The seasonal influenza vaccine was found to give very low 

protection against the new swine flu strain. The early decision to produce 

a vaccine for the swine flu for the northern hemisphere winter 2009- 

2010 was influenced not just by the unknown severity of the new virus, 

but given that the virus appeared to be spreading worldwide even if it 

was mild, the lack of protection from the seasonal vaccine would be 

like not having a vaccine at all, which would result in many more deaths, 

particularly in the young, elderly and infirm. 

By mid-May 2009 the UK government had agreed with vaccine 

producers that a separate swine flu vaccine would be produced if the 

WHO pandemic level was raised to 6, with enough doses for the whole 

population. A high-yield virus is needed for producing vaccine, where 

the virus grows in large amounts in the chicken eggs used to produce 

it. Candidate vaccine strains were developed that grew well, followed by 

safety testing and scaling up. However, this process takes several months, 

meaning the first batches of vaccine were available in the UK only by late 

autumn, separate from the seasonal vaccine which would be delivered 

on its own at the start of autumn in the northern hemisphere as usual. 

The first batches of vaccine arrived after the predicted autumn wave of 

cases had started, slightly earlier than expected, coinciding with children 

returning to school after their summer break. The people at most risk 

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were prioritised for vaccination: children, pregnant women, people 

with medical complications and healthcare workers. If a strong immune 

response was not observed with the vaccine then a second dose would 

be required so orders were scaled to account for this. 

The usual timescale for flu vaccine production, about 6 months, was not 

possible given the timing of the pandemic outbreak, so various processes 

were sped up when possible to produce the vaccine before the northern 

hemisphere winter arrived. Unfortunately, this led to speculation in some 

parts of the media that the vaccines would therefore not be safe. The 

WHO and other scientists were quick to reassure that the fast-tracking 

of the vaccine production process would not compromise the safety or 

quality control. However, the scaremongering in the media continued, 

with stories about possible neurological complications, suggestions 

that the pharmaceutical companies didn’t care if they were safe, use of 

‘dangerous’ adjuvants (agents that are added to vaccines to increase the 

immune response), and the lack of safety testing in people. The swine 

flu vaccine was created in a similar way to how the seasonal vaccine is 

created each year, but including the hemagglutinin and neuraminidase 

from the new strain. The vaccine has been shown to have an excellent 

safety profile. 

In reality, vaccines are not 100% safe. There are very rare cases where 

individuals have a severe allergic response to vaccination. The benefits of 

vaccination far outweigh these extremely rare risks, which are continually 

researched and minimised. Influenza vaccination programs save hundreds 

of thousands of lives each year around the world. Vaccine uptake was 

hindered by these sensationalist scare stories, even the quick response of 

the WHO and other scientific advisers to assure people of the vaccine 

safety were reported by some parts of the media with scepticism. It 

does bring up an important factor in communication between scientific 

experts, the media and the public, and how scientific experts are viewed 

and the responsibility of media organisations, especially in cases of public 

health. 

Post-pandemic 

It has been estimated that in excess of 160,000 deaths worldwide were 

associated with the swine flu pandemic. This is slightly less than the


number of deaths attributable to seasonal influenza in a typical year, but 

it could have been a lot worse. Of the very limited number of confirmed 

human cases of H5N1 ’bird flu’ (~450), the mortality rate is over 50%. If 

a form of H5N1 that could pass from human to human developed that 

was equally virulent, then it could be catastrophic. 

The world has never had such detailed knowledge of influenza viruses or 

been as prepared as it currently is for a pandemic. The rapid sequencing of 

the genes of the H1N1 novel strain, the collaborations between scientists, 

doctors and government health departments around the world, the 

sharing of information between such people and the monitoring of the 

spread and mutations in the viruses have all been important. The access 

to information in the media and on the internet, and the production of 

a successful vaccine and use of antiviral drugs in severe cases have been 

major successes in the response to the pandemic, without which many 

more lives would have certainly been lost. 

In terms of what could be improved, it is often easy to criticise actions 

with hindsight after the event. Evaluation of the effectiveness of response 

and what decisions were made is an important part of planning for the 

future. That the 2009 H1N1 pandemic was not worse was very fortunate, 

but it doesn’t mean that this will be the case when the next influenza 

pandemic arrives. The WHO and government health authorities around 

the world have learnt a lot in terms of which parts of their responses to 

the pandemic worked well, and which could be improved on. 

One aspect of the swine flu pandemic response that is commonly 

criticised is the early decision to produce a vaccine. Because of the time 

taken to produce a vaccine, the decision was taken early. However, at that 

time little was known about the morbidity and mortality of the pandemic 

virus strain. One key lesson is that comprehensive, reliable serological 

testing is needed early on in order to make a well-informed decision 

on how dangerous the strain is likely to be from the numbers of people 

who have been infected. With greater epidemiological and serological 

information early on in the pandemic, the scale of vaccine production 

and antiviral drug orders would probably have been scaled back, reducing 

the massive cost. 

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From the standpoint of the post-‘mild’-pandemic phase we are now in, 

the scepticism of some commentators about the proposed risks in spring 

2009 seem fair in an ‘I told you so’ way. But this is to ignore the very real 

risk that existed. The virus may have been much more virulent, caused 

more severe disease, or may have mutated into a more dangerous strain 

before spreading through the world population. Unfortunately, predicting 

whether a new pandemic will be as mild as the 2009 one, or as deadly as 

the 1918 outbreak, is currently impossible. 

There have been calls for greater transparency, particularly at the WHO, 

over who made the recommendations of vaccine production and drug 

stockpiling and their connections to the pharmaceutical companies 

producing vaccines and drugs. There is no need for media conspiracy 

stories to run wild, but openness is needed when decisions influence 

massive public spending. The WHO has taken the need for transparency 

seriously and addressed concerns that were expressed. 

The UK spent approximately £1 billion on stockpiling antiviral drugs 

and producing vaccines. The stockpiling had been initiated some years 

previously in case of a H5N1 ‘bird flu’ outbreak. There can be no doubt 

that several pharmaceutical companies have made a lot of money out of 

the pandemic, although it should be remembered that no-one else is in a 

position to produce such vast quantities of vaccines quickly enough. The 

drugs and vaccines have undoubtedly saved lives and, to put the cost in 

context, even a massive cost like £1 billion is only about 1% of the NHS 

annual budget. Government health departments may well be considering 

how they negotiate with the pharmaceutical companies, for example, 

it may be in the interests of the health budget to have a more flexible 

approach to orders, especially when it was found that a single dose of 

the vaccine was usually sufficient for immunity to develop. Despite the 

scepticism of vaccine uptake in some countries, it has been estimated 

that 350 million doses of vaccine were administered and the vaccine was 

~95% effective. It is difficult to calculate how many lives have been saved 

by vaccine uptake, but it could be a huge number. In the future, people 

are looking at ways to produce vaccines more quickly, using technological 

advances and better processes, in preparation for the next pandemic. 

It is expected that the swine flu pandemic virus will become a seasonal


virus, and looks to have displaced the old seasonal H1N1 virus lineage. 

The new swine flu H1N1 strain is included in the seasonal vaccine for 

winter 2010-2011. 

As the WHO director-general Margaret Chan said in her postpandemic 

conference statement, ‘this time around we have been 

aided by pure good luck’. The pandemic virus was much milder than 

it might have been, the virus did not mutate into a more lethal form 

during the pandemic, there were very limited cases of Tamiflu resistant 

viruses and the vaccine was a good match for circulating strains. 

The 2009 swine flu has been a significant test for our pandemic 

preparedness, and it was thankfully mild in its severity. We have learnt 

a lot, which can only be a good thing, as the next pandemic might 

not be so mild. 

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In December of 1938 my family and I - my mother Yulia and my twin 

brother Roy - were evicted from our Moscow apartment following the 

arrest of my father Aleksander Medvedev, who was a professor at the 

military academy during the final stages of Stalin’s “Great Terror” campaign 

of 1937-38. My father had been arrested in August as a supporter of 

Nikolai Bukharin, a communist leader who had opposed Stalin’s plan of 

forced collectivisation in agriculture, and he was sentenced in December 

to eight years of hard labour. As the family of an “enemy of the people” 

we therefore lost the right to live in our apartment, which belonged to 

the military academy. We moved to Rostov-on-Don to live with my aunt 

Nadia and my grandmother, who was very ill and partially paralyzed after 

a stroke five years earlier. Nadia was a single mother with a 5 year old 

daughter, so there were six of us living in a one-bedroom flat. My mother, 

who was a cellist, managed to find a job at the local theatre. 

When the German army invaded the USSR on June 22, 1941, I was 15 

years old. Three months later German troops occupied Taganrog, a port 

town only 100 km from Rostov. Two weeks before Rostov was taken 

by the Germans we fled, this time to Tbilisi, leaving all our possessions 

behind. In Tbilisi, the city where I had been born in 1925, I had an aunt 

and an uncle. Our Tbilisi aunt was a piano teacher and she lived with her 

husband and two daughters in a comfortable three-bedroom apartment. 

Our uncle Misha’s family also lived in Tbilisi and my brother Roy moved 

to live with them. By the end of 1941 our family suffered further great 

losses. My grandmother died of heart failure at the age of 69 and my 

uncle Misha died in a typhoid epidemic; he was only 41. 

Why ageing? 

My interest in the problems of ageing and longevity developed in 1939 

when I was still at school. The main influence on me was a book by an 

American biologist, Paul de Kruif, called Microbe Hunters - a brilliantly 

written collection of biographies and achievements of famous scientists. I 

was also attracted by the biography of Elie Metchnikoff, the great Russian 

scientist who discovered phagocytes and immunity. Metchnikoff’s book 

The Prolongation of Life: Optimistic Studies was originally published in 

Russia in 1908 and was reprinted many times. His ideas about ageing as 

a treatable pathology were immensely inspiring. Metchnikoff coined the 

term “gerontology” for the new science of ageing and longevity. Ageing

esearch was very popular in the USSR at this time because the Census 

of 1939 declared the Caucasus as the world centre of longevity. This 

legend about Georgian and Abkhazian longevity survived until 1975. 

During 1942 at school I continued my study of ageing and was a regular 

reader at the Tbilisi State Library. Another book which influenced my 

thinking at that time was a brilliant monograph: The Problem of Ageing 

and Longevity by A. V. Nagorny, a Professor at Kharkov University. It 

was probably the best book on ageing at that time and presented a 

comprehensive analysis of age-related changes, as well as a review of 

existing theories. 

On 1st February 1943 I received call-up papers for military duty 

although I was only 17 years old and still at school. The Red Army was 

liberating the North Caucasus and approaching Rostov, and so the age 

for entering active military service was lowered by a year. After three 

months of intensive military training I became a private in the 169th 

infantry regiment at the Taman Front, the southernmost part of the 

Soviet-German emplacements. Novorossiysk, an important Soviet 

port on the Black Sea, was still in German hands and an offensive was 

planned to liberate it at the end of May. After intensive artillery and air 

bombardment of German positions, three Soviet armies (21 divisions) 

attacked the German “Blue Line” which was defended by 17 German 

divisions and two brigades. We quickly overran the German trenches and 

moved on. Twelve kilometres behind the first line of German defences 

was another line that was better prepared. As a result the Soviet troops 

were stopped and unable to take the city, still 40 km away. We hastily 

dug out individual trenches, which were really nothing more than holes 

in the ground, and stayed put. On the next day we repelled the German 

counterattack but with heavy losses for both sides. My own experience 

of active fighting continued for only one week longer. I was wounded in 

my right foot on June 1st; and our company was reduced to only 20 men. 

Before the attack against German positions there had been 150 men in 

the company. Novorossiysk was finally liberated in October. 

Biology, medicine or agronomy? 

After treatment in three military hospitals my right foot had healed just 

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enough for me to walk without crutches, using a cane, and so I boarded 

the train for Moscow. I arrived in Moscow at the beginning of January 

1944 with an intention to enter Moscow University’s Faculty of Biology. It 

was the middle of the academic year, but I had no choice. 

The Dean of Biology at the University greeted me warmly. He was ready 

to designate me as a “candidate” at the beginning of the academic year in 

October. At that time there were very few male students. A temporary 

rule gave invalids and veterans of the war the right to enter universities 

without entrance examinations or competition. However, because 

the University did not have a hostel for students, it would have been 

necessary for me to rent a room. Finding accommodation in Moscow 

in 1944 was nearly impossible and extremely expensive; my small war 

invalid’s pension was certainly not enough. There was also food rationing 

and because ration cards had to be linked to a permanent address, a 

place at a student hostel turned out to be a necessity. I was therefore 

unable to take up the University place. 

My next destination was the Medical Institute. The Director of the Medical 

Institute was impressed with my knowledge of medical problems and was 

also ready to give me the status of “candidate”. But again there was no 

accommodation for undergraduate students. All student hostels which 

were part of the Institute campus had become military hospitals. 

There was still one possibility for education in biology – the K.A.Timiriazev 

Moscow Agricultural Academy. The programme of the academy included 

botany, zoology, organic chemistry and biochemistry, physics, plant 

physiology, genetics, and microbiology. Since plants and farm animals 

also age, I reasoned that I would be able to study ageing here just as 

well as at the university. The Timiriazev Academy, nearly 100 years old, 

occupied a very large plot of land in a suburb of Moscow and had 25 

buildings, both old and new, as well as several blocks of student hostels, 

a park, ponds, experimental fields, a forest and several animal farms and 

museums. The dean of the main Faculty of Agronomy, Professor Nikolai 

Maisurian, welcomed me as a friend. Like me, he was also born in Tbilisi 

and realised how difficult it was to reach Moscow from there. He 

offered me candidate status, a temporary job at the experimental station 

and a bed in the student hostel (each room there was shared by four


undergraduates). This offer solved all my problems. The academic year 

started on October 1st. There were two hundred undergraduates in the 

first year at the agronomic faculty who attended lectures, but only six of 

them were male. Four were war invalids, one was handicapped, and the 

sixth had tuberculosis. The other faculties were not much different. There 

were five faculties with horticulture the most popular. 

Professor Petr Mikhailovich Zhukovsky 

Different departments of the academy usually welcomed undergraduate 

students to remain at the laboratories and to receive some subject 

tuition or even to take part in some research projects. There was also 

a “Student Science Society”. During the spring of 1945 this Society 

decided to organize a student science conference, a tradition that had 

been interrupted by the war. I did not have any research results to report 

yet but I did submit a handwritten paper anyway. It was a hypothesis 

concerning the question of how the plant vegetative growing point, 

which consists of an apical or primary meristem (the group of rapidly 

dividing embryonic cells), is transformed from the vegetative growing 

point into a flowering shoot under the influence of certain factors such 

as short or long days or cold weather (for winter crops). The problem of 

how the leaf-producing tissues change abruptly to flower-producing ones 

was the main puzzle not yet solved. The chairman of the conference who 

had to read papers or abstracts and select some for oral presentation 

was Professor Petr Zhukovsky, the famous botanist whose lectures for 

first year students were very popular. In 1943 he had been awarded the 

Stalin Prize in science. His textbook on botany was considered to be the 

best. Every week first year students not only had a lecture on botany, 

but also a practical seminar where we used to work with different plants, 

with herbariums, got experience using a microscope, worked in the 

greenhouse etc. Zhukovsky already knew me, since I was the only man in 

a group of 20 students at the practical seminars of different departments. 

After one of the botany seminars I was invited to the professor’s office. 

Zhukovsky greeted me in a very friendly manner. 

Zhukovsky made some positive comments about my paper... “It is 

written with good scientific language. Let’s test your theory together”, he 

suggested, “we have a laboratory of plant embryology at our department. 

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We’ll give you a good microscope. You do need to learn a lot.” The next 

day I came to the laboratory and found it was a large room with different 

microscopes and other equipment and the smell of toluene. 

Two weeks later the war was over. 

The Nikitsky Botanical garden 

While continuing to study a number of subjects, I worked intensively 

at the plant embryology laboratory. I was also given a small space in 

the Department of Organic Chemistry for analytical procedures. At 

the end of 1945, a lot of new laboratory equipment was arriving from 

Germany as “war reparations”, including modern Zeiss microscopes, Jena 

laboratory glass and many chemicals. Professor Zhukovsky was fascinated 

by a 1939 German study of unicellular algae, Chlorella, which showed that 

the male and female cells contained different compositions of carotenoid 

pigments. It was suggested that these pigments, or products of their 

metabolism, might play a role in the sexual differentiation of plant cells. 

It was known that there were several hundred different carotenoids, but 

their role in plant tissues was not well established. Zhukovsky asked me 

to collect all available literature on the problem in English, since he did 

not know the language although he was fluent in French and German. I 

made nearly one hundred translations for him from material I found in 

the main state library and he wrote a review entitled “The role of light 

and carotenoids in the development of asexual and sexual generations 

of plants” (in Russian) which was soon published in an academic journal 

under both our names. It was my first scientific publication. 

At the beginning of 1948 Zhukovsky arranged a six month research 

assignment for me at the laboratory of plant biochemistry of the Nikitsky 

Botanical Garden, near Yalta in Crimea, to study the composition of 

carotenoid pigments in the male and female organs of different plants. It 

had been founded by Tsar Alexander I as an “Imperial” botanical garden 

in 1812. Thanks to the subtropical climate and extensive space, nearly 10 

square kilometers, by 1947 more than 50 000 species and varieties were 

collected in this garden, including different sorts of olive trees, grapes, 

fig trees, palms and decorative trees, such as the Lebanon cedar and 

Ginkgo biloba. When I arrived, at the beginning of April 1948, the head of

Biochemistry was Professor Vasily Nilov, a good friend of Zhukovsky. I was 

given a small room at the laboratory and a single room in a guest house 

for research visitors. A modest salary was also provided in addition to my 

student stipend and invalid pension. 

Since 1946 the Nikitsky Botanical Garden’s biochemistry laboratory was 

focused on the quest for plant extracts with antibiotic activity. Extracts 

and evaporation products from different plant tissues were tested for 

their antibacterial effects. My work was different but extremely absorbing. 

I was collecting samples of male and female parts of different plants and 

analysing their carotenoid 

diversity. There is a great 

variety of sex types among 

plants: hermaphrodite (selfpollinating), 

bisexual and 

heterosexual, with male 

and female plants growing 

separately. To identify 

individual carotenoids I 

used paper and column 

chromatography, at that 

time a new and exciting 

analytical technology. Nearly 

every week I would prepare 

a detailed report of results 

which I mailed to Professor Zhukovsky in Moscow. I also greatly enjoyed 

all the opportunities offered by the Black Sea coast, with the beach only 

a ten minute walk from my house. This idyllic life, however, was suddenly 

interrupted on August 1st, the day when Pravda, Izvestia and other central 

newspapers (distributed throughout the country by air) published a 

lengthy report by Academician Trofim Lysenko entitled “On the Situation 

in Biological Science”. It had been presented at a special session of the 

Lenin Academy of Agricultural Sciences on 31 st July 1948. Lysenko was at 

the time the president of this academy. 

The August coup 



In the entire history of the USSR this was an unprecedented occurrence. 

17

18 


Never before had a scientific report, even by scientists at the highest 

level, been published simultaneously and in its entirety in government 

and Party papers, which amounted approximately to sixty million copies. 

Normally only Reports of Central Committee Secretaries at Communist 

Party Congresses or Plenums would receive this treatment. This meant 

therefore that the Lysenko Report was made on behalf of the Central 

Committee and had been approved by Stalin and the Politburo, which 

were the main policy-making and governing bodies in the USSR. Yet 

the main content of Lysenko’s work was primitive pseudoscience that 

returned biology and all related sciences to the past, going back 150 

years to Lamarckian ideas according to which acquired characteristics 

can be inherited. At the centre of Lysenko’s Report was a declaration 

that theories of heredity, based on discoveries by Mendel, Morgan and 

the ideas of Weismann, were reactionary, idealistic and bourgeois. The 

chromosomal theory of inheritance and the existence of genes and germ 

lines were all rejected. All explanations of the significance of meiosis and 

mitosis were dismissed as irrelevant, and those who continued to believe 

in these theories were now to be regarded as reactionaries, idealists, 

and carriers of a bourgeois influence in Soviet science. Only those who 

accepted, without qualification, the concept of heredity developed by 

Lysenko would be considered to be materialists and representatives of 

progressive science. 

In the next few days the newspapers published shortened versions of 

the debates on the Lysenko report. Most speakers had risen in support 

while some were even more radical, treating Morganists-Mendelists- 

Weismannists as “enemies of the people” serving the interests of 

imperialists. Zhukovsky took part in the debates, presenting the strongest 

criticism of Lysenko’s theories and supporting the chromosomal theory 

of inheritance. He attempted to explain the meaning of the constancy of 

chromosome numbers in different species, meiosis, and the connection 

between chromosomal alterations and mutations. However, on the final 

day of the debates, after Lysenko’s acknowledgment of the fact that his 

report had been considered and approved by the Central Committee 

of the Communist Party, Zhukovsky took the floor again and stated that 

he now understood his errors, rejected Morganism and would work 

according to Michurin’s biological principles. Ivan Michurin was a Russian 

self-educated fruit plant selectionist who considered that vegetative 

hybridization or grafts were the way to change plants. Zhukovsky was

a member of the Communist Party and had little choice but to follow 

party discipline. Two other prominent scientists repented their errors as 

well. 

Professor Petr Zhukovsky 


It was clear that the August session of the Lenin Academy had transformed 

Lysenko into a kind of dictator in biological and agricultural sciences. 

Mass repressions against supporters of traditional genetics inevitably 

would follow. It was also possible that the campaign against geneticists 

was a cover-up for a more general repressive political campaign upon 

which Stalin’s dictatorship was based. Unexpectedly my professor, Petr 

Mikhailovich Zhukovsky arrived at the Nikitsky Botanical Garden, badly 

in need of a rest and the chance to talk to friends. The Nikitsky Garden 

was under his supervision. He embraced me and tears were in his eyes. 

He told me “I made a Brest Treaty with Lysenko, a shameful treaty... But I 

did this for my students.” He was referring to the Treaty of Brest-Litovsk, 

which Lenin signed with Germany in March 1918. It was annulled a few 

months later. 

19

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The transformed Academy 

Vavilov-Lysenko-Stalin 

Courtesy of Roberto Bobrow 

Vavilov repeatedly criticised the non-concepts of Trofim Lysenko. As a result, Vavilov was 

arrested on August 6, 1940 and died of malnutrition in a prison in 1943 

When I returned to Moscow at the end of September 1948, the Timiriazev 

Academy was already a different place. The Rector of the Academy, the 

prominent agrarian economist Professor Vasily Nemchinov had been 

dismissed, and the new rector Vsevolod Stoletov was a trusted assistant 

of Lysenko. Key biological departments were completely reorganised. The 

famous plant geneticist, Professor Anton Zhebrak and nearly all lecturers 

in the Department of Genetics and Selection had been fired. Lysenko 

himself took the chair. Professor Aleksandr Paramonov, Head of Zoology 

and a world famous expert on farm animal parasites and the author of 

two textbooks was also dismissed. He was replaced by Nikolai Nuzhdin, a 

Lysenko supporter who was not even a zoologist. Deans of two faculties 

were also replaced. Both Zhukovsky and Maisurian, who had repented 

their “errors”, retained their positions. For undergraduate students the 

main problem now was the textbooks. Previous textbooks on botany,

zoology, genetics, plant and animal breeding, plant physiology and other 

subjects were withdrawn. But new textbooks were non-existent. Biological 

faculties of universities suffered even more serious reorganizations. There 

were not enough Lysenko cadres for all the key positions therefore one 

of the true Lysenkoists was given several posts. Isai Present, who was a 

Marxist philosopher and Lysenko’s closest colleague since 1930, became 

the dean of biological faculties of Moscow and Leningrad universities 

simultaneously. He would spend one week in Moscow and the next in 

Leningrad. 

The new situation made it extremely problematic for me to stay at the 

academy and to do research for my Ph.D. The new rector of the academy, 

V.N. Stoletov, personally took charge of changing the research topics of 

graduate student projects in many departments. 

Ph.D. degree by surprise 


I decided to extend my undergraduate term, moving from the general 

agronomic faculty to the more specialised smaller faculty of agro-chemistry 

and soil science. Because I now had to study several new disciplines 

(analytical chemistry, physical chemistry, soil chemistry, herbicides) I needed 

two years before graduation, rather than one as before. I calculated that 

the two years would give me enough time, not only to complete my 

diploma work, but also to accumulate enough experimental results for 

a Ph.D. thesis and to prepare for oral examinations. The Soviet Union’s 

manner of awarding scientific degrees was inherited from the old Russian 

tradition. It required an open public defence in front of the “Scientific 

council” either of the faculty or the research institute. All the professors 

of the faculty or heads of laboratories of the institute, between 10 and 20 

men and women, were members of such councils. Two official opponents, 

usually professors, were given the task of evaluation. Anyone else could 

also attend and scrutinise the work. In some rare controversial cases the 

debates could extend to the following day. A decision was then made by 

secret ballot of the council. 

The political situation in the USSR in 1949 was going from bad to 

worse. The Berlin crisis which started in July 1948 along with the conflict 

between the USSR and Yugoslavia made the international situation very 

21

22 


unstable. This tension provided an excuse for a campaign against “agents 

of imperialism” in the Soviet Union, during which several thousand party 

and state officials in Leningrad and Moscow became victims and hundreds 

were sentenced to death. A second terror campaign was anti-semitic. 

Prominent figures of the Jewish Anti-Fascist Committee were arrested 

and the Jewish theatre in Moscow was closed. The death penalty, which 

had been abolished in 1947 in commemoration of the 30th anniversary 

of the October Revolution, was reintroduced. Now it was not only the 

courts that could impose death sentences, but also “Special Committees” 

formed by the Ministry of State Security (MGB) which were given the 

power to condemn people without trial, on the basis of “investigation”. 

During the spring and summer of 1949 I worked in a small botanical 

garden at the Timiriazev Academy. My main project was research into the 

nature of the sexual determination of hemp (Cannabis sativa) which has 

separate male and female plants in variable proportions. With sensitive 

tests based on isoelectric point measurements I was able to discover the 

fact that the pollen of hemp is nearly equally divided into two groups. I 

suggested that half were male and the other half female. Results of this 

study were soon published in the scientific journal Doklady Akademii 

Nauk. The previous year’s results of my carotenoid research were also 

published. From October 1949 I spent long hours in the library reading 

and writing until very late. 

I was known in the academy as a young researcher, but it was also clear 

that Zhores Medvedev, now a chairman of the Student Research Society, 

was not a supporter of “Michurin science”. I decided to submit my work 

not to the Science Council of the Faculty, but to the Institute of Plant 

Physiology of the Academy of Sciences of the USSR. The Director of 

this Institute, Professor and Academician Nikolai Maksimov, was a good 

friend of Zhukovsky and it was he who was submitting our papers for 

publication in Doklady Akademii Nauk. There were 13 voting members of 

the science council at this Institute and only one of them was known as a 

follower of Lysenko. At our faculty the ratio was not as favourable. 

By March 1950 my thesis manuscript was ready: 260 pages of typewritten 

text. Its title “The Physiological Nature of the Formation of Sexual 

Differentiation in Plants” made it possible to discuss different theories in an

objective way. I brought a copy of my thesis to Professor Zhukovsky who 

was my official supervisor. He was surprised but pleased and relieved. It 

was his achievement as well. 

In March 1950 I finally graduated from the Timiriazev Academy with 

the qualification of “agronomist” specializing in agro-chemistry and 

soil science. The date of my Ph.D. defence was December 1st 1950. 

The secret ballot decision to award the degree was unanimous. Now 

I was free to apply for a position as a research scientist and to select a 

new research problem. I decided to start some experiments on protein 

synthesis and the nature of senescence in plants. The Nikitsky Botanical 

Garden biochemistry laboratory was the first place where I started. 



23

24 

Bringing it all back home: next-generation 

sequencing technology and you 

Mike Gilchrist 

Technological advances in experimental biology are accelerating at such 

a pace that today a California company can propose, for ten thousand 

dollars and given a sample of your DNA, to do something that would 

have cost us three billion dollars a decade ago – sequence a human 

genome. How can they do that? And possibly more importantly, why 

would you want them to do that? What would it tell you about your state 

of health, both now and in the future? What might it tell you about your 

parents’ and your children’s prospects? 

To understand what is really quite a revolution in experimental biology 

we will have to look not only at the architecture and organisation of 

the genome, but also at the methods we have been using to get at the 

information it carries, and how this information is used by the organism 

to grow correctly from an embryo to an adult. We will also need to 

understand how small differences between the genomes of different 

individuals arise, and how these lead to some of the observable differences 

that make each of us unique. Let us start with the genome 

The molecular structure and information content of our 

genome 

The human genome has two primary functions: it carries the coded 

instructions for how to build and run a human being; and it conveys this 

genetic information from generation to generation, while allowing a little 

mixing and small amounts of change so that future generations remain 

robust and can evolve. Since Crick and Watson solved the structure of 

DNA we have understood how the molecular structure of the genome 

allows it do these things. The genome is carried on twenty three long 

molecules of DNA, our chromosomes, and we have two copies of it in 

most of the cells in our body. The genetic information on the chromosomes 

is encoded into the sequence of bases that link the twin helical backbones 

of the DNA molecule (see Figure 1). This genetic code is very simple, 

consisting of just four different bases; adenosine, cytosine, guanine, and 

thymine; which we usually refer to by the letters A, C, G and T. A base on 

one strand of the DNA must bond with its complementary base on the 

other strand, A with T, C with G, and vice versa, so that the two strands 

make exact but complementary copies of each other.

Figure 1 The molecular structure of DNA 

The double helix structure of DNA solved by Crick and Watson in 1953, showing the 

base pair links between the two sugar-phosphate backbone molecules. Although only a 

few turns of the helix are shown, these molecules extend for many millions of base pairs 

to form our chromosomes. 

This is what facilitates the precise replication of the chromosomes 

when cells divide during growth of an organism. Although the basis of 

the genetic code is simple, the sheer length of the DNA - there are 

approximately 100 million base pairs in an average size chromosome - 

provides more than enough variation to build the tens of thousands of 

distinct molecules that are needed for life. 

The international Human Genome Project set out in 1990 to determine 

the sequence of our DNA, involving hundreds of scientists from North 

America, Europe, Asia and the Pacific Rim. It took ten years to produce 

a draft version of the genome and we now know that it contains close 

to 3 x 10 9 , or three thousand million, base pairs, and we know what 

most of its sequence is. Can we get a feel for how much ‘information’ the 

genome contains? In simple terms a good thick airport novel contains 

about a million letters, and so a library of 3,000 such books would hold 

the same amount of ‘text’ as the human genome. This would fit easily 

into bookcases lining one wall of a generously sized living room. If we 

were to devote our leisure time to reading these ‘books’, and could get 

through one a week, it would take sixty years to plough through our 

entire genome – a nice fit with our lifespan, and hopefully a few years left 

to digest what we have read. 

As we read through our genome, however, we would quickly be assailed 

25

26 


by a recurring sense of déjà vu: that we had read this or that bit before, 

possibly many times over. It turns out that not all of the genome ‘text’ is 

unique, and not all of it carries useful information, at least so far as we 

can currently interpret it. We could improve our analogy to take this into 

account. Suppose that our book collection starts off with all the novels of 

(say) Austen, Tolstoy and Zola. This would make up a little under 2% of the 

total of 3,000 books. Then we need to imagine that the balance is made 

up of 2950 copies of Marcel Proust's À la recherche du temps perdu: Du 

côté de chez Swann. Furthermore, these multiple copies are themselves 

cut up into fragments ranging from a few characters to several pages, 

and the resulting mixture, much of which is highly repetitive, is distributed 

randomly amongst the pages of the other books. 

Going back to the real genome what this means is that our genome 

sequence is largely made up of repetitive, or uninformative, sequence, 

which we think of as having little impact on the day to day running of 

our bodies. This material is sometimes called ‘junk’ DNA, and as you 

might guess, it turns out that the repetitive elements have a significant 

adverse impact on our ability to experimentally determine the sequence 

of our genome. Our genes, which do most of the useful work, occupy the 

remaining ‘interesting’ 2% of the genome, and are the key to our biology. 

We have about 20,000 – 25,000 genes, and each is responsible for making 

one of the many smaller molecules (mostly proteins) that we need to 

grow and to function. The recipe for each gene’s product is contained 

in its DNA - think of it as long paragraphs of unique text interspersed 

amongst the junk – and the precise sequence of the gene determines 

the structure and nature of (say) the protein it produces. In addition, the 

sequence around a gene contains signals which, in concert with other 

genes, tell the body where and when to produce that gene’s protein. This 

is the origin of our need as biologists to sequence the genome, as only 

this way can we begin to understand the functioning of all these genes. 

So how do we go about sequencing a genome? 

Sequencing the human genome: old style 

Consider first what we could do ten years ago, at the turn of the 

millennium. The primary method for sequencing DNA then was called

Bringing it all back home: next-generation sequencing technology and you 

Sanger sequencing (after the Nobel Prize winner, Fred Sanger, who 

invented it), and we could routinely sequence sections of DNA for up 

to about 800 bases with high accuracy. This however was as far as we 

could go, and even though we could sequence the ends of quite large 

fragments of DNA, we could not sequence the section in the middle 

(see Figure 2a). Extracting someone’s DNA is easy enough, but how do 

we begin to sequence a whole genome when our technology allows us 

to access only the very end sections of DNA molecules? As the Human 

Genome Project progressed, the methods used to sequence the genome 

changed quite radically. At first it was a methodical sequencing of small 

regions of known sequence to build up larger ones; now the standard 

approach for vertebrate genomes is so-called shotgun sequencing. In very 

simple terms we take the genome and shatter it into many thousands of 

molecular fragments, and then sequence the ends of all the fragments. 

And we do this not just with one copy of the genome, but with millions 

of copies, although this is easy, as our body contains trillions of cells, each 

one containing its own copies of the genome. Then, using a considerable 

amount of computing power, we begin to look for sequenced ends that 

match each other, and gradually we assemble a copy of the genome 

sequence from these overlapping matched ends, not entirely unlike a 

very large jigsaw puzzle (see Figure 2b) with tens of millions of pieces. 

The repetitive nature of the genome is, however, quite a problem for the 

assembly process. By working with DNA fragments that are generally 

larger than most of the repetitive regions we can effectively ‘step over’ 

these regions when assembling the genome pieces in the right order. Then, 

when the overall order is correct the individual repetitive regions are 

easier to assemble. A simple shotgun sequence strategy might combine 

groups of carefully size-selected fragments of 5kb (i.e. 5,000 base pairs), 

20kb and 100kb. This enables the assembly software to handle quite 

large repeat regions, and increases the chances of a robust and accurate 

assembly. 

In many ways it is amazing that we have been able to do this, and we 

have sequenced a few more species with genomes as large and complex 

as ours, but it is prohibitively expensive and it is unlikely there will be any 

more large genome projects like this. 

27

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Figure 2 (a) limitations of DNA sequencing capability 

DNA is sequenced by breaking it up into fragments and sequencing the fragments from 

both ends. There is a limit on the distance from the end that can be sequenced, and this 

often leaves the sequence of the central portions of fragments inaccessible. For older 

style Sanger sequencing this limit is about 800-1000 base pairs. 

(b) de novo shotgun assembly of a genome sequence 

Tens of millions of DNA fragments are sequenced from both ends, and then assembled 

by computers looking for overlapping matching sequence from different fragments. 

Large fragments, and a range of different sizes, enable assembly to take place despite 

the presence of confusing repetitive sequences. The figure shows a partial assembly with 

about 3x average coverage from a mixture of 5kb fragments (blue) and 20kb fragments 

(ochre). Random positioning of fragments means that there are still gaps where the 

sequence is unknown, although the order of the sequenced sections relative to each 

other is known. 

The new sequencing technology 

New sequencing technologies began to emerge during the closing phases 

of the Human Genome Project with the promise of very much higher 

throughput than Sanger sequencing, and these methods quickly became


known generically as massively parallel, next generation sequencing. The 

most widely used system today is owned by the US company Illumina Inc., 

which bought the UK company Solexa that developed the technology. 

The technical details are quite fascinating: it involves the simultaneous 

sequencing of millions of tiny fragments of DNA on the surface of a glass 

slide about the size of a large matchbox, essentially by imaging them as 

they grow. Fragments of DNA to be sequenced are anchored at one end 

to the surface of the glass slide, in an enclosed flow cell through which 

reagents can be passed. The fragments have been transformed into single 

stranded DNA and a second strand can now be re-synthesised using the 

Figure 3. Illumina ‘Genome Analyser’ flow cell (schematic) for high throughput 

sequencing 

(a) Flow cell channels reagents between glass plates with millions of anchored DNA 

fragments for sequencing. (b) Cross section of flow cell showing second strand synthesis 

of anchored template strands. Laser light activates base-specific emission colour from 

modified nucleotides incorporated at the end of each cycle. (c) Imaging the surface of the 

flow cell after each cycle records the base added at each ‘spot’ of DNA. (d) Image analysis 

‘reads out’ the sequence of incorporated second strand bases at each spot. 

29

30 


anchored strand as a template (see Figure 3). Individual building blocks of 

DNA, or nucleotides, are used, which have been modified so that each 

of the four bases (A, C, G or T) emits a different coloured light when 

excited by a laser. When these are washed over the template fragments 

on the glass slide the nucleotide with the next correct base is chemically 

locked in place on the growing second strand. The glass slide is then 

photographed at very high resolution while laser light is shone on it, so 

that each growing fragment shows up as a tiny dot of light, coloured 

depending on which base was just added. The light emitting capability 

is then removed chemically, and the process repeated in cycles until the 

point where it becomes unreliable. The resultant stack of images is then 

analysed by computer, and the DNA sequence of each fragment can be 

easily ‘read out’ according to the sequence of colour changes at each 

dot. 

One of these new technology sequencing machines costs about the same 

as the older sequencing machines to run, but instead of a few hundred 

sequences each time, we generate hundreds of millions of sequences for 

the same effort, and this is why they are so powerful. But there is a catch, 

and in fact there are two catches: first, the sequences are very short, only 

tens of bases, and secondly, the maximum fragment size is limited, in the 

simplest version of the technology, to a few hundred bases. 

Could one assemble a genome sequence with these short reads, if there 

were enough of them? Small microbial genomes can be assembled as 

they lack the great number and size of the repeat sequences found in 

genomes like our own. Even quite small repeat regions of just a few 

thousand bases become impenetrable barriers to assembly when 

the two sequenced ends of your DNA fragments are no more than 

a few hundred bases apart, and so this new technology is unsuitable 

for the complete assembly of human-size genomes. The resolution of 

this apparent problem lay in an unexpected direction – after all why 

assemble the human genome again from scratch when all our genomes 

are very nearly identical? Simply by matching the sequence of these 

short reads against the existing ‘reference’ genome and laying them out 

alongside it we can effectively re-sequence the genome for any individual. 

Furthermore, this works best just where we have the most interest: the 

relatively unique regions containing genes and their control signals.


But why would we want to sequence other humans if we have already 

sequenced one? The answer is that a lot of what makes us different from 

each other is determined by many small differences in our DNA, and 

next-generation sequencing technology gives us a quick and powerful 

way of finding these differences. What we see if we line up all the short 

sequence reads for a given individual against the reference genome is that 

at many positions the individual has a different sequence to the reference, 

often over as little as a single base (see Figure 4). In fact we may see two 

different bases at some positions, and this reflects the inheritance of 

different genomes from our parents. In order to understand why some 

of these differences are so important we need to return to the genome 

sequence and see how signals are encoded in DNA, and how changes 

to the DNA arise. 

Figure 4. Re-sequencing an individual’s genome 

Although the short reads we typically get from next generation sequencing technologies 

are not really good enough for de novo genome assembly, we can effectively re-sequence 

someone’s DNA by aligning their data against our known reference genome. In this way 

we can easily determine the sequence variation for any individual that may underpin 

complex diseases and other inherited traits. 

The genetic code and signals in the DNA sequence 

We have established already that the DNA of our genome is a long and 

variable sequence of the four bases A, C, G and T. The precise sequence 

31

32 


of these bases determines many things: where on a chromosome a 

gene begins and ends, what the nature and structure of the molecule 

it produces is, and when and where the gene is active in the body. We 

can usefully think of the bits of sequence that do these things as signals 

between the genome and the machinery of the cell which has to translate 

the signals into meaningful molecular action. If these signals are changed 

or lost because of damage to our DNA, then our cells may misbehave 

with sometimes unfortunate consequences. 

For example there are two simple signals in the sequence of a protein 

coding gene: an ATG where the cell should start using the sequence 

to build the protein, and TAA, TAG or TGA where it should stop. The 

important point is that if either signal is lost then the gene will not 

produce the right protein. The converse is also true: if the DNA within 

the gene sequence is altered so that a new ‘stop’ signal is gained in the 

wrong place then the protein it produces may be shortened, and in all 

likelihood will not work as it should (see Figure 5a). There are many other 

types of signal in our DNA which control the behaviour of genes; some 

are very precise, and some, to our eyes, look uncomfortably ill-defined, 

but all have in common the property that changes to the DNA sequence 

will have effects on the functioning of our cells and our body. 

Fortunately DNA is quite a robust molecule and can generally be 

repaired by the cell, but it is not immune to alteration. External agents 

like radiation or chemicals can cause breaks in the DNA, which may be 

mis-repaired, or they can cause the base at a given position to change. Of 

course this is damaging the DNA in just one of the body’s many cells. In 

most cases the effect will probably be insignificant, but not if the damage 

occurs in one of the specialised cells from which our offspring derive. 

These germ cells, eggs in women and sperm in men, carry only one copy 

of the genome, and it is from the fusing of a single sperm with a single egg 

that a new human being grows. The critical point, for this story, is that any 

changes which have occurred in the DNA of either of these two parental 

copies of the genome are now copied into every cell of the new body 

as it divides and grows. Changes in the functioning of the altered gene 

may affect any, or all, of the body’s tissues where the protein from that 

gene is required.


Human genetic variation and complex diseases 

When a change in the DNA is created it is called a mutation, but if 

it is passed on to future generations and becomes established in part 

of the population we refer to it as a polymorphism – i.e. a difference 

in the genetic code present in some people at a specific position in 

their genomes. Small pieces of DNA may be lost or inserted, but the 

commonest form of polymorphism is the alteration of a single base, or 

nucleotide, to a different base, and we refer to these as single nucleotide 

polymorphisms, or SNPs (pronounced ‘snips’). We inherit one complete 

copy of the genome from each of our parents, so at the site of each 

known polymorphism we might inherit the ‘normal’ version from one 

parent, and the ‘deleterious’ version from the other parent, or any other 

possible combination depending on which versions of the polymorphism 

our parents had inherited from their parents, and so on (see Figure 5b). 

We refer to the different versions of the sequence in the populations as 

alleles. If one allele is clearly deleterious, we may refer to it as a mutation 

even when established in the population, and we will use this meaning 

here. 

What are the effects on each of us of carrying these polymorphisms 

around in our DNA? Human variation, by which we mean everything 

that distinguishes us as individuals, from hair and eye colour, to height and 

weight, and the ability to play chess or make music, is the combination of 

two things: our genetic inheritance and the environment in which we grow 

up. Some of these, like eye colour, are purely genetic in quite a simple way, 

i.e. the eye colours of our ancestors determines the possible eye colours 

we may be born with. But some characteristics are much more complex, 

and in ways we are only beginning to understand. For example, we know 

that height is a combination of genetic and environmental factors. By 

careful study of family relationships we estimate that well over half of 

human height variation should come from our genes, but even with 

masses of data on this most measurable of traits, we cannot yet identify 

all the genes that are contributing. 

We can make a broad distinction between simple traits and complex traits. 

With simple traits we can generally track down the causative gene with 

ease, and indeed some have been known for many years. Complex traits 

are more of a puzzle, and we do not yet have the ability to find all the 

contributing genes. Where this creates difficulties for us is in developing 

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34 


our understanding of the causes of genetically complex diseases, like 

diabetes, asthma, cancer, autism and schizophrenia. 

Figure 5. (a) A mutation becomes a polymorphism 

DNA may be damaged thereby causing a mutation, and if it is in a germ cell it may be 

passed on to a child, and hence into the population. Some mutations are harmful; for 

example in this case the C to A mutation in a gene causes the appearance of a premature 

STOP signal and a truncated protein when the gene is activated. 

(b) The genetics of inheritance 

Once a polymorphism is established in the population the children of heterozygous 

carriers (who have one copy of each allele) may have none, one or two deleterious 

alleles. In the last case this may cause serious illness, while heterozygous offspring can be 

largely unaffected. 

As with other simple traits, the genetic causes of simple or monogenic 

diseases, such as cystic fibrosis and sickle cell anemia, are well known and 

we can identify specific mutations in a given gene as the cause with some 

degree of certainty. If you are unfortunate enough to have inherited such 

a genetic variant you will almost certainly develop the disease at some 

point. With complex diseases we only know enough to say that if any


of your parents or grandparents had the disease, then there is some 

likelihood, greater than in the general population, that you may develop 

the disease yourself. We do know some of the contributory genetic 

variants and affected genes but we have a pretty good idea that, even for 

well studied diseases, there are many we have not found yet. 

Genome wide association studies 

Early attempts to track down the genes involved in complex diseases 

using data from affected families largely failed, probably because we 

underestimated the numbers of genes involved. Now that we have 

catalogued large amounts of human genetic variation we can use a more 

brute force approach. 

Genome wide association studies (GWAS) rely on being able to determine 

the genetic status (i.e which allele they have) for many individuals at many 

known polymorphic sites in the genome, a process we call genotyping. 

Initially we have no idea which polymorphisms, and hence which genes, 

are associated with a disease being investigated, but by studying the 

genotypes of a sufficiently large group of people with the disease, and 

comparing them with a similar size group of healthy people, we can 

begin to track down the genes involved. For polymorphisms that have 

an effect on the likelihood of you getting a disease, one of the alleles 

will predispose you to the disease, and the other will be protective. This 

should show up in a statistically different bias between the two groups 

in the study: i.e. the disease group are more likely to carry the disease 

associated allele than are the control (healthy) group. This both identifies 

the polymorphism as being disease associated, and tells us which allele 

increases our risk of developing the disease. In contrast, polymorphisms 

that are not associated with the disease will show the same allele 

distribution in both groups. The outcome from this type of experiment 

is therefore a list of genomic locations where there are polymorphisms 

whose alleles are to some extent predictive of our disease status. 

The first surprise is that, for a given disease, these lists are quite long; 

recent studies in type-I diabetes and Crohn’s disease have suggested 

more than 30 genetic risk indicators in both cases. The second surprise 

is that although we can estimate the genetic contribution for each 

polymorphism associated with a given disease, adding them all together 

falls some way short of explaining the proportion of that disease we 

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36 


expect to be genetic from a study of its behaviour in families. A pervasive 

concern is that this ‘missing heredity’ may be in very rare alleles, found in 

only a small proportion of the population, and that these polymorphisms 

will, as a consequence of their rarity, be very difficult to find. So the 

picture we have now of complex diseases is that they are the result of 

possibly quite subtle failures in some, but not all, of the genes associated 

with developing the disease; and it is proving quite difficult to track down 

all the genes involved, and even more so to understand precisely what 

functional role they each play. 

Personal genomes 

Let us try and pull these diverse threads together. We have already 

assembled a complete version of the human genome – a reference copy 

– using ‘old fashioned’ long-read sequencing, and this was expensive and 

time consuming. Now we have new sequencing technologies that can 

easily produce many millions of short sequence fragments of our own 

DNA. These cannot be ‘assembled’ in the traditional sense, but they can 

be lined up against the reference genome, to see where our own DNA 

differs from the reference. We note in passing that the reference genome 

is just another person’s genome and is no more ‘right’ than our own, it is 

just the one we sequenced first. We also have an extensive catalogue of 

human polymorphisms. Some of these we know indicate clear causality 

for simple diseases; many are associated, with varying degrees of risk but 

little clear causality, with a steadily growing list of complex diseases. The 

vast majority, however, have a quite unknown effect, even those which are 

clearly likely to affect the functioning of a gene. 

So it is entirely possible to have one’s genome ‘sequenced’. The cost 

would be measured in thousands, rather than tens of millions, of dollars, 

and the data would be ready in just a few weeks. The important stuff will 

be there, as the re-sequencing approach works just where it is needed: 

in the regions of relatively unique sequence where the genes lie and are 

controlled. 

What would we learn from our genome? For each polymorphism that 

was known or suggested to be associated with a disease we could get a 

read-out of the two alleles we have at that position, our genotype, and 

from that an indication of the risk of having or developing that disease. 

For complex disease the excess risk for each polymorphism can be


aggregated to give an estimated overall risk, although our confidence in 

these calculations is not as high as we would like. Some of these pieces of 

information may help us make beneficial adjustments to our lifestyle: for 

example if our genetic profile indicates a 10% additional risk for type-II 

diabetes then we might make extra effort not to put on weight, as that 

is a known aggravating factor that we can control. For known monogenic 

diseases there would probably be no big surprises. These are mostly rare 

and mostly severe, so the likelihood is that you already know you have 

it, or for later onset disease, that it is in your family and you already 

know the chance of developing it. The same might also be true for some 

complex diseases where we have specific genetic tests for some of the 

contributory factors, like breast cancer. 

There is a further twist: although we have made progress in understanding 

the genetic basis for disease, even in those cases where we can pinpoint 

the precise causative mutation in a particular gene it remains an extremely 

challenging problem to figure out how to repair broken genes in vivo. We 

hope that in the future we will be able to use gene therapy, where we 

introduce a new copy of a gene into the genome in the cells where it is 

needed, but just now this is a risky and somewhat controversial approach. 

A more promising short term gain may be in the field of personalised 

medicine, which starts from the observation that the effectiveness of 

some drugs can be quite variable between individuals, and this may have 

a genetic component. Our genotype may lead to more appropriate drug 

treatment. 

We may be curious to know everything that is in our genome, but there 

may be unpleasant surprises that we are not prepared for, and can do 

nothing about. The arguments here are not much different from those 

associated with genetic counseling, where people at known risk of a 

genetic disorder are contemplating taking a test: what is the value of 

knowing? If there are no cures for what you find, are you better off not 

knowing? But what if you are contemplating having a family? This brings 

us to our final point, and that is that in some senses the information 

in your genome is not yours alone. Choices you might make to ‘know’ 

your genetic profile will affect people you share your genes with: your 

parents, your siblings and your children. There are some profound ethical 

issues here, and, at least until we can make more and better use of the 

knowledge gained, it may be best to think carefully whether or not to 

read Pandora’s genome. 

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Harriet Groom 

The Immortal Life of Henrietta 

Lacks is a non-fiction work 

about the life and family of 

a woman from Baltimore 

in the USA. She died in 

hospital in a “coloured ward” 

in 1951 from an aggressive 

form of cervical cancer and 

yet cells from her body 

have continued to grow in 

laboratories since her death. 

These cells have been the 

spring-board to some of the 

greatest advances in medical 

science in recent history but 

their fame in the scientific 

community has far exceeded 

that of their begetter, 

Henrietta Lacks. When 

George Gey, a scientist at 

Johns Hopkins University, 

created an immortal cell line 

from Henrietta Lacks’ tumour 

Courtesy of Pan Macmillan 

he named it HeLa (hee-luh) 

from her first name and 

surname. The HeLa cell line 

was set to change biomedical science forever but the Lacks family would 

only find out 20 years later that cells had been taken from Henrietta 

without her knowledge or permission and were being traded and used 

across the globe. 

This book is simultaneously charming and informative, gripping and 

thought-provoking. It addresses issues as fundamental as trust, racism 

and loss, alongside a detailed and transparent commentary on the science 

that developed from the creation of the first immortal human cell line. 

Rebecca Skloot has penned an engaging description of the journey she 

took to research the life, family and issues relating to Henrietta Lacks and 

her amazing legacy. The people she met on this journey are brought to 

life with great skill and faithfulness to reality, to the extent that you feel

you are accompanying her on her journey of discovery. The book is an 

essential read for anyone using HeLa cells, but is also highly recommended 

for everyone else, scientist or not. One of the many reasons for its broad 

appeal is its resistance to being pigeon-holed into a particular genre. 

Although it is largely a biographical work, the narrative is simultaneously 

popular science, a detective story and, with characters so compelling, you 

could be forgiven for mistaking it for a novel. The book provides an eyeopening 

insight into medical practices at the time, intertwined with the 

impact of class, race and mental health. 

One woman, many lives 

The book begins by introducing us to the title figure but she is by no 

means the only protagonist. The other main character of the book is 

Henrietta’s daughter, Deborah. Abused sexually as a child and physically 

in her first marriage, hers has not been an easy life by any stretch of the 

imagination. Her feisty but vulnerable character is the main focus of the 

story and is part of what makes it so engaging. The third unexpected 

character in the book is Skloot herself. On her website she talks about 

the decision to include herself in the narrative and it is clear that the 

difficult and sometimes dangerous routes she took to find answers are 

indeed part of the story itself. 

Beyond the three main characters I really enjoyed the book’s “tale 

within a tale” nature. Throughout, the reader is introduced to numerous 

characters, be they members of the Lacks family or their neighbours, 

or the scientists who contribute to the HeLa side of the story. For 

each individual Skloot concisely and elegantly gives us an introduction to 

their lives, character and motivations. By the end of the book I felt like 

I had spent time with a huge diversity of people including some of the 

scientists that previously I had only known from textbooks. 

Despite its charm and wit, the book is not a comfortable read. The 

tragedy contained within it is profound, from the blackening of Henrietta’s 

tumour-ridden body during radiation therapy to her burial in an unmarked 

grave. Deborah’s quest to learn more about her sister, Elsie, who was 

committed to a Hospital for the Negro Insane during childhood, is not 

an uplifting one. Indeed it is debatable whether the tale as a whole ends 

happily or not. The book finishes with a brief summary of where its 

39

40 


protagonists are now, a touch gratifying to a naturally curious reader. This 

serves to remind the reader of the biographical nature of the book; a 

reality check at the end of a novel-style read. 

Award-winning writer Rebecca Skloot 

Rebecca Skloot was first inspired to find out more about Henrietta 

Lacks after her community college lecturer, Donald Defler, gave a brief 

introduction to Henrietta and her cellular legacy. 

As the other students filed out of the room, I sat thinking, “That’s 

it? That’s all we get? There has to be more to the story”. I 

followed Defler to his office. “Where was she from?” I asked. 

“Did she know how important her cells were? Did she have 

any children?” He said “I wish I could tell you, but no one knows 

anything about her.” 

This thirst for knowledge and passion for a story, Henrietta’s story in 

particular, stayed with Rebecca Skloot for over 20 years, through high 

school, a biology undergraduate degree, a Master of Fine Arts in creative 

fiction and on into her career as a science writer. This combination 

of scientific and creative training has led to a very accomplished first 

book. The book has received very positive reviews as well as accolades. 

Rebecca Skloot will be a success story to inspire anyone considering the 

“soft science” path of scientific journalism. 

The project to research and write the book took over a decade to 

complete and required a significant financial and emotional investment 

by the author. The effect she had on the family is evident throughout 

and particularly touching in the closing chapters of the book. The 

acknowledgments are a revealing treat in this respect, referring to one of 

the Lacks family members singing hymns into her answerphone on her 

birthday. 

The omnipresent tool 

Before I read this book, I was certainly familiar with HeLa cells and, like 

many other scientists, had used them during my research. However, I 

am ashamed to say that my knowledge of their origin was limited to a


muted recollection of a lecturer referring to the woman from whom they 

were derived. A brief perusal of the index of my undergraduate science 

“bible”, the textbook Molecular Biology of the Cell by Alberts et al., 

satisfyingly reveals an entry for “HeLa, cell line”. The citation refers to the 

establishment of a continuous line of cells derived from a human cervical 

carcinoma in 1952 by Gey and colleagues. Unfortunately, in common 

with many references to the cell line in biology textbooks, the person 

to whom HeLa refers is missing. Now, thanks to “The immortal Life of 

Henrietta Lacks”, the identity of the woman from whom this ubiquitous 

cell line was derived will remain etched in my memory permanently. The 

next time I use them in the lab my thoughts will migrate to her family and 

the author of this book. 

Immortality and legacy 

Rebecca Skloot 

Courtesy of Manda Townsend 

The unique status of the cells derived from Henrietta’s cervical tumour 

was that they were the first immortal human cells grown in culture. 

George Gey’s lab, and many other labs, had tried for years to make human 

cells grow outside of the body but this was the first successful attempt. In 

the chapter “The birth of HeLa”, Skloot describes how Henrietta’s cells 

doubled in number every 24 hours and expanded to fill the space they 

were given. An oft-quoted statistic is that more than 50 million tonnes 

41

42 


of HeLa cells have been grown since their first isolation in 1952. At a 

conservative estimate they feature in more than 60,000 scientific papers 

and thousands of registered patents. Scientists affectionately refer to 

HeLas as weeds due to their ability to out-grow and out-survive other 

cell lines. Their ease of growth is a double-edged sword as it means that 

HeLas easily contaminate other cell cultures (an issue that is covered 

with engaging historical perspective in the chapter “The HeLa Bomb”). 

In my PhD I used HeLa cells to study the properties of a particular 

protein of human immunodeficiency virus (HIV). Like many researchers I 

chose these cells due to their high growth rate, ease of manipulation and 

robustness. Since then I have used HeLa cells to study the infectivity of a 

novel retrovirus xenotropic murine leukaemia-related virus (XMRV). You 

would struggle to find a tissue culture lab in the world that has never had 

HeLa cells growing in it and considering the scale of scientific research 

across the world, this is no small statement. 

So, what makes HeLa cells different from the normal cells in Henrietta’s 

body? Scientists use the word immortal to describe cells that do not 

adhere to the “Hayflick limit”. This is a natural limit on the number of 

times a cell can divide before it undergoes programmed cell death. Cells 

in the body are limited to this number of divisions because the ends 

of chromosomes shorten with every cell division and the cell commits 

suicide before it passes on truncated, damaged chromosomes to 

daughter cells. The portions of DNA at the ends of chromosomes that 

signal this cell death when shortened are called telomeres. Immortal 

cells express an enzyme called telomerase which restores the ends of 

the chromosomes, thereby bypassing this important defence mechanism 

and allowing mutations to be passed on to future generations of cells. 

The accumulation of mutations through a number of avenues can lead to 

the transformation of a cell (see a previous Mill Hill Essay from 2005, “A 

Lottery Ticket and a Packet of Cigarettes, Please”). 

The process of transition from a normal cell to a cancer cell is called 

transformation. In 1984 Harald zur Hausen discovered a new strain of a 

sexually transmitted disease-causing virus, human papilloma virus (HPV). 

To date hundreds of HPVs have been identified but only a small subset 

of these, known as “high risk” types, cause growths on the cervix that can


lead to cancer. Together with collaborators zur Hausen identified HPV- 

16 and HPV-18 in cervical cancers and he believed these viruses could 

cause cancer. He had HeLa cells growing in his lab so he tested these 

and found them to contain HPV-18. He obtained cells from Henrietta’s 

original biopsy and found that the cells had multiple copies of the HPV- 

18 genome. Some viruses show a propensity to insert some of their 

own DNA into a cell’s DNA via the process of integration. In HPV this 

occurs but with a very low frequency. Subsequent research into HPV in 

HeLa cells found that the insertion of some HPV DNA into the cellular 

DNA resulted in disruption to the levels of the cell’s p53 protein. The 

p53 protein regulates the cell cycle and is considered to be an important 

guardian of the genome from mutations. Through interactions with other 

proteins p53 prevents the cell dividing when there is something wrong 

and therefore has a protective effect against cancer. The inactivation 

of p53 will have contributed to the transformation of the cells in 

Henrietta’s cervix. The work on HPV-18 and further studies with HeLa 

cells contributed to the Nobel Prize won by zur Hausen in 2008 for 

his development of a vaccine for cervical cancer, the disease that killed 

Henrietta Lacks. 

The role that HeLa cells have played in science since their birth is not 

limited to one vaccine but is fundamental and far-ranging. George Gey’s 

growth of HeLa cells in specially created liquid, or “culture medium”, 

led to the development of standardised techniques for growing cells in 

laboratories. Many concepts that seem second nature to all scientists 

today began in Gey’s lab. Skloot’s description of Gey’s lab is an interesting 

aside into Gey’s character as well as the technical aspects of growing cells 

in culture. Researchers will be interested to read about the introduction 

of sterile technique, a way of preventing bacteria and fungi growing in 

the rich culture medium and killing the cells you are investigating. More 

alien to the modern researcher are the tales of home-made laboratory 

equipment. Even in the current financial climate I don’t think scientists 

would make their own tissue culture rooms by hand or carve sinks out 

of stone from the local quarry! Gey was obviously very committed to 

his quest for immortal human cells. The introduction of standardised 

laboratory techniques developed in his laboratory resulted in the 

biological supplies industry, a multi-million pound industry today, and the 

new idea of biological materials as commodities. 

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44 


The rapid spread of HeLa cells around the world was underpinned by 

the ability to send cells in frozen form, rather than in flasks in the warmth 

of scientists’ pockets. This concept would eventually lead to cryogenics 

including the freezing of human embryos. The technical advances 

associated with HeLa cell culture in the 1950s translated in due course 

to significant leaps including the cloning of Dolly the sheep, the isolation 

of stem cells and in vitro fertilisation. 

The discovery that HeLa cells could be infected with poliovirus was a 

stepping stone to the development of a vaccine for this crippling disease. 

Since their birth HeLa cells have been infected with and subjected to all 

assaults known to man and this has helped us to learn a great deal about 

a variety of diseases. Another significant virus human immunodeficiency 

virus (HIV) was used to infect HeLa cells and this resulted in the discovery 

of the mechanism that the virus uses to enter the cell. HeLa cells have 

also been key in discoveries in tuberculosis and Salmonella research 

amongst many others. 

In addition to the cells themselves, HeLa cell DNA has been used 

to perfect numerous techniques and processes. The cells were used 

to develop genetic tools such as tests for Down syndrome and 

preimplantation genetic screening for in vitro fertilisation. Haematoxylin, a 

stain that allows the visualisation of chromosomes was first used in HeLa 

cells. Being able to visualise chromosomes, containing the code for life, 

was a significant milestone in scientific history. In the book the family are 

presented with a picture of Henrietta’s chromosomes “painted” through 

a technique known as fluorescence in situ hybridisation (FISH). This gift 

was made by a scientist, Christoph Lengauer, whose research at Johns 

Hopkins University relied heavily on HeLa cell research. The effect on 

Deborah’s brother Zak is very touching. 

Who told you you could sell my spleen? 

A less obvious contribution of HeLa cells and Henrietta Lacks to scientific 

research is the effect that her story had on the way we now approach 

medical ethics. At the time that Henrietta’s cells were taken from her, the 

idea of “informed consent”, a concept that forms the backbone of current


guidelines on human tissue research, was virtually non-existent. In the 

chapter “Night Doctors” we read tales of black people being abducted 

by white doctors to be guinea pigs in scientific research. Although 

some of these stories are based in black folk-lore, Skloot summarises 

real historical examples of vulnerable populations being used in research 

without their consent. The images of black bodies shipped in turpentine 

containers and families living in houses laced with lead will certainly shock 

modern readers. 

In addition to the necessary historical references to consent issues in the 

main body of the book, the afterword focuses on the idea of consent 

and the contentious ethical and legal issues surrounding human tissue 

research in modern day America. Those of us not familiar with the current 

situation may be shocked by the opening paragraph of this section: 

When I tell people the story of Henrietta Lacks and her cells, 

their first question is usually “Wasn’t it illegal for doctors to take 

Henrietta’s cells without her knowledge? Don’t doctors have 

to tell you when they use your cells in research?” The answer 

is no – not in 1951, and not in 2009, when this book went to 

press. 

With the caveat that Skloot’s research focuses entirely on legislation and 

practises in the USA, the chapter is informative in considering the two 

prongs of this issue, consent and money. Whilst litigation is normally 

associated with financial motives, this chapter reveals that the issue of 

consent rather than money underlies the greater proportion of lawsuits 

related to human tissue research. I think the author summarises the 

difficulties well when she says “How you should feel about this isn’t at 

all obvious.” Agreeing to give your tissues for a known purpose, such as 

being on an organ donor register or contributing knowingly to a medical 

study, is one thing; your appendix being used after having them removed 

without your prior knowledge is quite another. 

Interestingly, one of my early experiences as a researcher at the MRC 

National Institute for Medical Research, was attending a course devoted 

to the Human Tissue Act, the legal framework for human tissue research 

in the UK. It is clear that we have come a long way since those cells were 

isolated from the cervix of the young woman in Baltimore in the 1950s; 

however, the issues surrounding informed consent are not straightforward 

45

46 


and perhaps never will be. Those of you who are interested in this topic 

and seek further information on this or any other aspect of the story 

will be satisfied by the extensive referencing at the end of the book in 

addition to further information on Rebecca Skloot’s website. 

Henrietta Lacks’ gravestone 

Courtesy of David Kroll 

Closure and the Henrietta Lacks Foundation 

The book is a passionate quest to tell the story of a woman whom 

science has largely forgotten. The tone of the book is not crusading 

but its passion contributes to the emotional involvement of the reader. 

The stress that the investigative journey puts on Henrietta’s remaining 

daughter, Deborah, manifests as troubling ill-health. It is a sad irony that 

the Lacks family struggled to afford good health care. However, we are 

left with a feeling of catharsis as the family come to terms with the loss 

of their mother and her existence as immortal cells in labs across the 

world. This heartwarming resolution peaks with the moving scene of 

Deborah and her troubled brother Zakariyya seeing their mother’s cells 

down a microscope in the very building where she died more than 50 

years previously.


A portion of the revenue from book sales are being donated to the 

Henrietta Lacks Foundation. This foundation was set up by Rebecca 

Skloot and has given out its first grants to members of the Lacks family 

this year to contribute mainly to their access to education. On its board 

of directors sits Dr Roland Pattillo, the doctor who has been a friend of 

the Lacks family throughout their hard times and who helped Rebecca 

Skloot to contact them in the first place after an extended screening 

process. 

Rebecca Skloot and the Lacks family set out to tell a story that needed 

to be told. The author has achieved this in a wonderful book that is 

destined to be a classic. 

The Immortal Life of Henrietta Lacks is published in the UK 

by Pan Macmillan. 

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48 


Marianne Neary 

Francisco Pizarro 

the Spanish Conquistador and 

conqueror of the Incan Empire 

When Francisco Pizarro and his 

Spanish army arrived at the borders 

of the Inca Empire in 1528, they 

faced some of the most mountainous 

terrain on earth. They were not 

viracocha cuna, or ‘gods’, as the Incas 

had initially mistaken them for; they 

had come to forge the collapse of 

one of the most prized empires in 

the world. 

The Conquistadores pursued the 

Incas higher and higher into their lofty 

abode. The Incas were not retreating, 

however. Well aware of the effects of 

altitude on lowlanders, theirs was a 

cunning trick leading the Spanish into 

the gasping jaws of Mother Nature. 

Alas, no great battle is without a 

struggle and, despite the military 

prestige of the Conquistadores, this 

was no exception. Only in 1545 did 

they eventually establish the city of 

Potosi; at 4090m it was the world’s 

highest city. However, Potosi was 

never more than a frontier town: 

due to the altitude Spanish babies 

and cattle all died at birth. The only hope of survival was for pregnant 

women and animals to descend to the lowlands in order to give birth 

and rear their young for the first year of life. 

Five hundred years later, this same dilemma haunts our earthly heights, 

from the Han Chinese population of Tibet to the cattle ranchers of the 

Rocky Mountains. Joseph Neary, a vet in the Rocky Mountain National 

Park, has observed that, unlike those species that have evolved to live 

at high altitude such as llamas and yaks, cattle can develop a condition 

known as High Mountain Disease (HMD). 75% of cattle loss to HMD 

occurs in animals less than 2 years old.

We do not have a scientific explanation of these observations, though 

we do know that a major challenge of living at altitude is the lack of 

oxygen. Since an unborn baby or calf is subject to similar conditions of 

low oxygen in the womb, it is a puzzle why they should struggle at high 

altitude. The answer to this conundrum may shed light not just on the 

problem of fatalities at birth but also on conditions such as Sudden Infant 

Death Syndrome or ‘cot death’. 

Panorama of Potosi, Bolivia 

This picture was taken and modified by Martin St-Amant. This image is distributed under the 

Creative Commons Attribution 3.0 Unported License. http://bit.ly/bLeg1M 

Getting to the heart of the matter may lead us just there. Our heart 

clocks up a whopping 100,000 beats every day and consumes a great 

deal of energy in the process. To generate this energy the heart has 

a choice of fuels: fat, which provides the most energy, or sugar, which 

generates less energy but doesn’t guzzle as much oxygen in the process. 

In the normal adult heart, fat is the fuel of choice. Before we were born 

however, our hearts used sugar; this makes sense considering the relative 

paucity of oxygen in the womb. Following this logic it is no surprise that 

the switch of fuel, back to sugar, happens within a few hours of birth, 

when our heart has to suddenly adapt to deal with larger pressures and 

energy demands. 

We hypothesise that if this switchover in fuel does not occur, the heart 

cannot meet the increased demands and fails to cope: this proves fatal. 

What could happen to prevent this switch occurring? Insights gained from 

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50 


the Spanish conquest suggest that increased oxygen availability could be 

the trigger for the switch. So when oxygen concentration is as low outside 

the womb as it is inside, as it is at high altitude, problems arise. 

The fact that Spanish infants had to be raised in the lowlands for a whole 

year before returning to altitude further suggests that the switch remains 

unstable and liable to change in early life. This may echo a poignant truth 

for cot death, which occurs in the same time frame. Looking at the 

risk factors for cot death, you see that most of them can point to low 

oxygen: prone sleeping position, maternal smoking, bed sharing and head 

covering. 

ENERGY VIA GLYCOSIS 

Fatality 

Birth at 

high 

altitude 

Birth at low altitude 

Cot death risk factors 

=Decrease in [o2] ? 

ENERGY VIA FAT OXYDATION 

[O2] 

The link between metabolic pathways, oxygen and infant mortality 

Exploring this further, we have found that immediately after birth a key 

fat-burning metabolic pathway is turned on in the heart and this pathway 

turns out to be activated by increased oxygen. Yet how come the Inca


babies survived? A scientific report published in May this year revealed 

that populations native to high altitudes have subtle variations in two 

genes. Adding support to the theory, one gene relates to oxygen sensing 

and is the same gene that is found to vary in activity at birth; the other 

induces the same fat-burning pathway we described above. 

The next steps are now to see whether artificially blocking portions of 

this pathway and interfering with the oxygen sensing machinery prevents 

the fuel switchover. 

If the theory is correct, maintaining normal oxygen levels could spare 

the heartache of cot death. Simply ensuring adequate ventilation in an 

infant’s room and cot may achieve this. Dr Joseph Neary, from the Rocky 

Mountain National Park reports that “One ranch I visit gives oxygen to 

calves after they are born at high altitude. So far, this has increased the 

proportion of calves surviving to weaning”. 

Whether this translates into human physiology remains, for the moment, 

‘up in the air’. 

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52 

Is immunotherapy the ultimate solution for 

Alzheimer’s Disease? 

Marina Lynch 

Just over 100 years ago Auguste D, a 51 year-old woman, was admitted 

to the state asylum in Frankfurt under the care of the psychiatrist Alois 

Alzheimer. She was suffering from loss of memory, progressive cognitive 

impairment, hallucinations, delusions and psychosocial incompetence. 

When asked to write her own name, she was unable to and repeated: 

"I have lost myself" (Ich hab mich verloren). This sentiment was echoed, 

perhaps more eloquently, by Abraham Schweid, an academic pathologist 

who was diagnosed with Alzheimer’s Disease in 2003. In 2005 he 

wrote: 

I can’t finish my ideas. 

My words are upside down. 

When I begin an idea, 

It’s not there when I go back to it. 

According to the World Alzheimer's Report, one person is diagnosed 

with Alzheimer’s Disease every 7 seconds and an estimated 35.6 million 

people worldwide are living with dementia in 2010. This number is 

expected to nearly double every 20 years. Because of progressive decline 

across a broad range of cognitive functions, daily living tasks become 

increasingly more difficult and the increasing dependency of the sufferers 

means that the current and projected cost, both in economic terms and 

in societal terms, is huge. 

Auguste D died 5 years after she was hospitalized. Alzheimer, now in the 

medical school in Munich, and his mentor Emil Kraepelin undertook a 

post-mortem examination of her brain. They linked the deterioration 

in cognitive function with histological findings, which are the hallmarks of 

the disease: the presence of abnormal accumulation of fibrous proteins, 

or plaques, around cells and the presence of microscopic fibrous tangles 

within cells, coupled with extensive loss of nerve cells (neurons). These 

findings were published in 1907 and the condition became known as 

Alzheimer’s Disease. 

An insoluble protein called amyloid-b is the main component of plaques. 

In the past two decades or so it has been established that specific forms 

of amyloid-b are capable of causing neuronal death and also capable of 

inducing inflammation. These are well-established features of Alzheimer’s

disease and therefore it was proposed that amyloid-b was a major 

contributory factor in the pathogenesis of Alzheimer’s. This idea was 

formalized with the development of the so-called amyloid hypothesis, 

which proposes that amyloid-b is the causative factor in Alzheimer’s 

disease. 

Auguste Deter. Alois Alzheimer’s patient in November 1901, the first described 

patient with Alzheimer’s Disease 

Cortesy of http://www.flickr.com/photos/vivacomopuder/3051327340/ 

Alzheimer’s disease can be divided broadly into two subtypes, early-onset 

or familial Alzheimer’s, and late-onset Alzheimer’s. There is a strong genetic 

component to familial Alzheimer’s; persons with inherited mutations in 

certain genes have a 50:50 chance of developing the disease. Amyloid-b 

is derived from another protein called amyloid precursor protein. 

Presenilin is a protein involved in the removal of potentially damaging 

proteins. Mutations in the genes that code for amyloid precursor protein 

or presenilin confer a risk of developing familial Alzheimer’s but this form 

of the disease accounts only for about 5% of sufferers. There is, however, 

also a genetic risk factor for people who develop late-onset disease. 

There is a gene that codes for a protein called apolipoprotein E (ApoE), 

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which is involved in the transport of certain fats. The risk of developing 

Alzheimer’s disease is associated with inheriting one particular form of 

the ApoE gene; this is identified as the e4 form (ApoEe4) and the greater 

the number of copies of this gene that are inherited, the greater is the 

risk of developing Alzheimer’s disease. However, only about 40% of those 

with late-onset Alzheimer’s inherit the ApoEe4 gene and so the gene is 

only one of the risk factors. 

Current strategies for the treatment of Alzheimer’s disease are 

only minimally effective. Part of the reason for this is the absence of 

methods to diagnose the disease at an early stage. In many cases it is 

likely that significant neuronal loss has occurred before diagnosis and 

in this scenario, because restoration of function is unlikely, treatments 

focus on limiting further neuronal loss. Prevention of the disease is the 

ultimate goal and it is interesting that the risk of developing Alzheimer’s is 

reduced in individuals who are treated long-term with non-steroidal antiinflammatory 

drugs for conditions such as rheumatoid arthritis. There 

is some evidence indicating that the cholesterol-lowering drugs, statins, 

also offer some protection but the evidence is less compelling. However, 

it is highly unlikely that either strategy will ever be adopted as a means 

of protection against the disease because neither drug offers complete 

protection and, like all drugs, however safe, both have side effects. 

Immunotherapy is perhaps the strategy likely to offer the greatest hope 

for the prevention of Alzheimer’s disease and for the treatment of mild 

or moderate Alzheimer’s, particularly as diagnostic tools to identify early 

disease become more sophisticated. The primary aim of immunotherapy 

is to eliminate amyloid-b, accumulation of which is detrimental to the 

health of neurons, and so it is based on the amyloid hypothesis. There are 

two possible immunotherapy options. The first is active immunotherapy, 

where amyloid-b is injected and triggers activation of specific immune cells, 

T cells. These are lymphocytes, which are a subtype of white blood cells, 

and their activation plays a pivotal role in immunity. A sequence of events 

is set in motion resulting in the production of specific antibodies. The 

second option is passive immunotherapy, where an antibody is injected 

by-passing the need for activation of the immune cells. In both cases, the 

objective is to ensure that the antibody will prevent accumulation of 

amyloid-b and therefore the development of the amyloid-b-containing 

plaque.

Is immunotherapy the ultimate solution for Alzheimer’s Disease? 

Studies into the possibility of using immunotherapy to treat Alzheimer’s 

disease began in 1995, after the creation of a mouse model of the 

disease which developed amyloid-b-containing plaques and showed a 

deterioration in cognitive function with age. The mouse was engineered 

to produce increased amounts of a mutant form of a human amyloid 

precursor protein that was isolated from a Swedish family with the 

inherited form of the disease. The first trial of active immunotherapy was 

conducted in 1999 and the authors reported that repeated immunization 

of these mice with amyloid-b prevented plaque formation in young 

animals, and reduced the plaque burden and prevented cognitive decline 

in older animals. It was concluded that this active immunization protocol 

stimulated the production of anti-amyloid-b antibodies and initiated 

the removal of amyloid-b by microglia, which are the cells in the brain 

responsible for removing cell debris by a process called phagocytosis. A 

short time later, another group undertook a similar experiment in a nonhuman 

primate, the Caribbean vervet, with a similar outcome. In this case, 

the clearance of amyloid-b from the brain was linked with a decrease in 

the amount of amyloid-b in the cerebrospinal fluid, the protective fluid 

that circulates around the brain and spinal cord of the central nervous 

system, and an increase in the amount of amyloid-b in the plasma. These 

studies identified two methods whereby amyloid-b-containing plaques 

can be cleared from the brain: antibody-mediated removal of amyloid-b 

by phagocytosis, or transport of amyloid-b from the brain. A third 

possible method is chemical modification of amyloid-b leading to the 

dissolution of plaques. Theoretically, approaches to stimulate any of these 

mechanisms should be beneficial; immunotherapy focuses on the first. 

The promising preclinical results led the drug companies Elan and Wyeth 

to initiate in 1999 the first Phase I clinical trial with their amyloid-b vaccine, 

called AN-1792. This trial involved 80 patients with mild to moderate 

Alzheimer’s disease. The vaccine consisted of a synthetic amyloid-b 

peptide and another substance, called QS-21. This is an “adjuvant”, which 

is necessary to activate the immune response that leads to antibody 

production in the immunized individuals. There were no apparent sideeffects 

following the four intramuscular injections over a six-month period 

but few of the patients developed antibodies. As a result, the vaccine was 

modified by the addition of a substance called polysorbate 80, which was 

designed to boost the immune response and therefore increase antibody 

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production. This modified vaccine was used in the Phase IIa clinical trial 

which began in 2001, with an enrolment of 372 patients, but the trial 

was aborted when a small number of vaccinated patients developed 

meningoencephalitis, an inflammatory condition of the meninges and 

brain. The cause of the excessive inflammatory response leading to the 

meningoencephalitis has been the subject of intense research and debate. 

One possibility is that it resulted from the addition of polysorbate 80 

to the vaccine, which led to unacceptable activation of immune cells, 

specifically T cells. In 2001, this solubilizing agent was considered to be 

inert, but it is now known that it can induce extreme allergic reactions. It 

was initially suggested that patients who developed meningoencephalitis 

might be those who exhibited the most profound immune reaction 

to the injected amyloid-b (and therefore who produced the greatest 

amount of antibody). However antibody levels did not correlate with 

the development of meningoencephalitis. 

Despite these setbacks, some important findings have been reported and 

follow-up analysis is still ongoing. Of the 80 patients enrolled in the Phase 

1 trial, 42 died before or during follow-up. Post-mortem examination 

of eight of these individuals who had been vaccinated with AN-1792 

indicated that vaccination markedly reduced the number of plaques in the 

brain. Plaque clearance was correlated with antibody level but not with 

cognitive performance because all eight individuals showed symptoms 

of severe dementia before death. The most likely explanation for the 

persistent dementia is that the neuronal damage was too advanced by 

the time of vaccination but these individuals also did not complete the 

trial and received only one or two vaccinations. 

Neuropathological analysis has also been completed on three of the 18 

individuals who developed meningoencephalitis in the Phase II trial. This 

revealed that few plaques were observed in these patients, indicating 

efficient clearance, but there was evidence that cells which are normally 

found in the circulation, but not in the brain tissue, had infiltrated the 

brains of the patients. In contrast, while plaque clearance occurred in the 

brains of vaccinated patients who did not develop meningoencephalitis, 

there was no significant infiltration of T cells and this led researchers 

to conclude that the presence of these cells was likely to be the cause 

of the excessive inflammation. Studies on another 14 individuals have


confirmed that vaccination does indeed cause a marked reduction in the 

number of plaques, but the persistence of some of the other pathological 

features of Alzheimer’s disease like the presence of microscopic fibrous 

tangles within cells and amyloid-b accumulation in cerebral blood vessels 

(another of the effects of the disease) appears to resolve over time. Initial 

indications were that plaque clearance was accompanied by a slower 

rate of cognitive decline but the most recent follow-up data suggest that 

this improvement is confined to a subgroup of patients where antibodies 

persisted. At this point, the conclusion is that immunization is likely to be 

beneficial in a specific cohort of individuals but it should be emphasized 

that, although other trials have been completed, the only comprehensive 

set of data published is from the AN-1792 trial. 

Efforts are currently focused on engineering vaccines that avoid the 

adverse side effects and this is being done by immunizing with specific 

fragments of amyloid-b, rather than using the whole protein or by linking 

amyloid-b with proteins that control cell activation. In theory, either 

approach should prevent the unwanted side effects observed to date 

but the results of the ongoing clinical trials will not be available for at 

least 12 months. 

Passive immunotherapy, i.e. when anti-amyloid-b antibodies are 

administered directly, is the second major immunotherapeutic approach 

to Alzheimer’s. In this case, because the patient’s own immune system 

is not activated, the effects of the therapy are short-lived. However, this 

approach avoids the risk of T cell-mediated inflammation of the meninges 

and brain, and it also eliminates the problem of a poor response to 

antibody (which can be a problem in older individuals because the 

efficiency of the immune system decreases with age). Animal studies 

indicated that weekly immunization for six months resulted in a decrease 

in the number of amyloid-b plaques and an improvement in memory, 

but microhaemorrhages were observed in some animals. Initial Phase I 

trials generally showed good safety and tolerability with some evidence 

of improved cognitive function. An additional encouraging finding was 

reported at the International Conference on Alzheimer's Disease in 

July 2010. The results of one clinical study have found that appropriate 

screening of patients by magnetic resonance is likely to avoid the side effects 

of a potentially powerful passive immunotherapy drug, apineuzumab. 

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Meanwhile, another passive immunotherapy drug, bapineuzumab, is being 

evaluated in two Phase II trials and seven Phase III trials, several of which 

are actively recruiting participants. 

Amyloid b, plaque formation and immunotherapy 

Intravenous immunoglobulin (IVIG) treatment is injection of a cocktail 

of natural human immunoglobulins that includes amyloid-b antibodies. 

It is also being considered as a possible treatment for Alzheimer’s. This 

has been used since 1982 as a treatment for autoimmune neurological 

diseases like myasthenia gravis. More recently IVIG has been shown to 

promote amyloid-b clearance from the brain and protect neurons from 

the neurotoxicity induced by amyloid-b. The reports of a pilot study,


published in 2004, suggested that amyloid-b was decreased in the fluid 

which bathes the brain, the cerebral spinal fluid, and increased in blood 

serum. This indicates that amyloid-b is being removed from the brain 

and, importantly, this was accompanied by a stabilization of cognitive 

function in some patients. It has since been established that the changes 

in amyloid-b distribution were maintained only during treatment, and 

not after treatment was stopped. Results of a Phase II trial by Baxter 

International have suggested that there is reduced cell loss and improved 

cognition, over an 18 month period, in patients given their IVIG therapy, 

Gammagard, compared with placebo-treated patients. A Phase III trial 

is currently underway and is due to be completed in July 2011. The 

potential of IVIG treatment is also being evaluated by other companies. 

Immunotherapy is designed to eliminate amyloid-b accumulation and 

therefore presupposes that the causative agent in Alzheimer’s disease 

is amyloid-b. However this view continues to be challenged by some 

researchers, although research in the area continues apace. Perhaps 

we should not overlook the convincing epidemiological evidence which 

indicates that preventing inflammation reduces the risk of developing 

Alzheimer’s and consider the combination of anti-inflammatory therapy 

and immunotherapy. Huge strides have been taken in the development 

of immunotherapies for the treatment of Alzheimer’s since the initial 

Elan clinical trial in 2001 and the optimism that this will offer the first 

truly beneficial therapeutic after 100 years is palpable. More important, 

perhaps, is the prospect that further development and research will, at last, 

result in a vaccine that will eradicate this most devastating of diseases. 

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Qiling Xu 

A survey of the prevalence of treated and untreated mental disorders 

in the adult population aged 16 and over in England was carried out in 

2007. It found that nearly one person in four had at least one mental 

disorder and that one person in eighteen reported having attempted 

suicide. Depression is one of the commonest mental disorders and it has 

been predicted that by the year 2020 depression will form the second 

greatest contribution to the worldwide burden of disease. The illness 

is characterised by sadness, loss of interest in activities and decreased 

energy. Depression is different from normal mood changes that are part 

of our daily life. 

A severe form is manic depression - also called bipolar disorder – in 

which the mood swings from exaggerated elation (“mania”) to feeling 

low or irritable (“depressed”). Depressive disorders and schizophrenia 

are responsible for sixty percent of suicides, with manic depression the 

third leading cause of death in 15-24 year olds. The causes of depression 

are complex and include psychological, social and genetic factors. 

First-line treatments for depression are medication, psychotherapy, or 

a combination of both, together with support groups for vulnerable 

individuals. 

Remarkably, a simple chemical compound – lithium salt – is highly effective 

in the treatment of bipolar disorder. Lithium is a naturally occurring 

element, in the same group of alkali metals as sodium and potassium 

in the chemical periodic table. On its own lithium is a highly reactive 

metal, but it is normally found as a salt, a chemical compound in which 

the positively charged lithium ion is associated with a negatively charged 

cation; it is the lithium ion that is the therapeutically active component. 

The use of lithium salts for treating mental illness such as manic disorder 

was known in the 19 th century but rediscovered in the mid-20 th century 

by an Australian psychiatrist, John Cade. As described in his seminal study 

“Lithium salts in the treatment of psychotic excitement”, published in the 

Medical Journal of Australia in 1949, he first experimented with guinea pigs 

to analyse the toxicity and protective effect of lithium salts and found that 

the treated animals became lethargic. He then presented in detail the 

results of treatment of ten manic patients. This is an excerpt from case I:

“a male, aged fifty-one years, who had been in a state of chronic 

manic excitement for five years, restless, dirty, destructive, 

mischievous and interfering, …His response was highly 

gratifying. …with lithium citrate he steadily settled down and 

in three weeks was enjoying the unaccustomed surroundings of 

the convalescent ward. …He was soon back working happily 

at his old job.” 

The patient was readmitted several months later due to not taking 

the lithium medication and was treated again. He was soon better, and 

returned to home and work. John Cade also reported the sedative effect 

of lithium treatment on six patients with dementia: 

“Although there was no fundamental improvement in dementia, 

three patients, who were usually restless, noisy and shouting 

nonsensical abuse, lost their excitement and restlessness and 

became quiet and amenable for the first time for years.” 

Based on these findings, John Cade suggested that lithium salts should 

be used for treatment as an alternative to involuntary confinement of 

psychopathic mental patients. 

Following these pioneering studies, Mogens Schou and co-workers 

carried out the first rigorously-controlled clinical trials of lithium that 

firmly established that it has a mood stabilising effect. In the 1970s the 

U.S. Food and Drug Administration approved its use in treating bipolar 

disorder. Today, lithium is used mainly to help patients by reducing both 

the number and the severity of manic and depression states, giving them 

more emotional control and greater capability in coping with problems. 

John Cade’s work has thus been hailed as the beginning of the modern 

psychopharmacological era, and it opened the door to treatment that 

has saved many lives and improved the quality of life of millions with 

manic depression. 

The finding that lithium is highly effective for the treatment of manic 

depression raises the question of how it exerts its therapeutic effects. 

Lithium has been found to alter the amount of many different biochemical 

components of the functioning brain, including substances that relay (or 

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“signal”) information between nerves. These alterations could in turn 

underlie the changes in mood. It can be difficult to guarantee effective 

treatment as it is necessary to achieve the appropriate level of lithium in 

the body: if the dose is too low, it won’t work; if too high, it has unwanted 

side-effects, or toxicity. Lithium toxicity often leads to poor compliance 

in patients, who need to have regular blood tests to make sure they are 

getting the right dose. Alcohol use is discouraged because it interferes 

with the efficacy of the lithium medication. 

It is therefore important to uncover whether the beneficial effects of 

lithium are due to it acting on one specific target that has several roles 

in the brain, or instead are due to it acting on many targets. If just one 

or a small number of targets of lithium are responsible for the beneficial 

effects, then new drugs could be devised that are more specific for these 

targets. There is emerging evidence that one particular target of lithium 

underlies many of its effects on mood. Before discussing this, the stage 

will be set by a brief summary of key aspects of brain development and 

maintenance, as many psychiatric diseases, including bipolar disorder, have 

their origins in foetal development. 

The adult human nervous system is very complex and consists of over 

one hundred billion neurons (nerve cells) of hundreds of different types, 

and five to ten times as many other cells (glial cells). The nervous system 

is formed progressively during development, starting from the induction 

of a simple sheet of neural cells that are the progenitors, or ‘stem 

cells’, that give rise to all of the different types of nerve and glial cells. 

These progenitors proliferate and differentiate in a highly orchestrated 

manner to generate appropriate cell types at the correct time and place. 

During their differentiation, cells will migrate to specific locations, and 

each neuron extends long branches that form connections with specific 

neurons, and in some cases with other cell types. During the process of 

making connections brain cells are linked through specialised junctions 

called synapses. A synapse is the club-shaped tip of a nerve branch which 

almost touches another cell and thereby allows the transmission of signals, 

and hence information, between the two nerve cells. The signals can be 

electrical or chemical. The chemical signals carried by molecules are 

called neurotransmitters and many antidepressant drugs act to increase 

the amount of neurotransmitters in the brain.


Until recently, it was believed that once the mature nervous system is 

formed, no new neurons can be generated. We now know that in specific 

regions of the adult brain, stem cells are present which differentiate to 

form neurons and may have important roles in specific functions such 

as learning and memory. In addition, the existing neural stem cells may 

enable some replacement of cells that have been lost due to injury or 

disease. Some of the factors that regulate nervous system development 

may thus have continued roles that maintain the functionality of the 

mature brain. 

During the development of many animal species, including humans, 

there is an overproduction of neurons that compete with each other to 

make connections to the appropriate target, and the excess neurons are 

eliminated by a process of programmed cell death, termed apoptosis. This 

elimination occurs because neurotrophic factors - signaling proteins that 

are required for the survival and growth of nerve cells - are present only 

in small amounts. Consequently, during normal development not all nerve 

cells are able to receive sufficient neurotrophic support, and the others 

undergo cell death. An abnormally low level of neurotrophic factors leads 

to increased apoptosis and loss of nerve cells in the developing or mature 

nervous system, and this is one of the common pathologies underlying 

many neurodegenerative diseases. 

Brain Derived Neurotrophic Factor (BDNF) is one of the neurotrophic 

factors with important roles in the developing and mature nervous system. 

It helps to support the survival and growth of existing neurons and the 

differentiation of new neurons from stem cells. BDNF is present in areas 

of the brain that are crucial for learning, memory, emotion and higherorder 

thinking. Defects in the BDNF gene and its regulators are associated 

with a milieu of mental disorders such as depression, schizophrenia and 

dementia, as well as neurodegenerative diseases including Alzheimer’s 

disease and Huntington’s disease. 

Studies of the postmortem brain from bipolar patients have shown 

that in the prefrontal cortex - an area associated with judgement and 

executive function - there is a significant increase in the levels of proteins 

that affect apoptotic cell death. Intriguingly, several lines of evidence show 

that lithium treatment leads to increased production of BDNF in the 

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brains of patients with bipolar disorder. Lithium may therefore exert its 

effect in part by activating neurotrophic signalling that protects cells from 

apoptosis. Bipolar patients have different levels of response to lithium 

treatment, with around one third of them seeing total remission of 

symptoms. Comparative studies have revealed that plasma BDNF levels 

in these patients were higher than in the patients who respond less well 

to lithium, but the same as those of healthy controls. Excellent responders 

may constitute a specific subgroup of bipolar patients for whom longterm 

lithium administration can produce complete normality. 

Figure 1 Lithium decreases GSK-3 activity in several ways 

GSK-3 is inactivated by specific enzymes that add a phosphate, and this can be reversed 

by dephosphorylating enzymes. Lithium inhibits the dephosphorylation, and consequently 

GSK-3 is less active. Magnesium ions (Mg 2+ ) are required for activated GSK-3 to 

phosphorylate substrates required in a diverse array of biological functions. By competing 

with Mg 2+ , lithium ions block the function of activated GSK-3. As a consequence of these 

inhibitory effects, GSK-3 can no longer regulate many important biological processes.


The emerging links between lithium and neurotrophic factors are 

encouraging advances but they do not address the direct mechanism 

by which lithium acts. Chemically, lithium exerts its action by competing 

with magnesium (another metal ion) for binding, thus inhibiting various 

magnesium-dependent enzymes. Many of these enzymes are involved in 

the propagation of chemical signals required for cell survival, proliferation 

and differentiation. Some of them are implicated in neurological 

functions. 

Lithium can also inhibit some metabolic enzymes, including one called 

glycogen synthase kinase 3 (GSK-3) (see figure 1). GSK-3 is an enzyme 

initially discovered to be involved in the regulation of glucose metabolism 

but is also found to be a component of several pathways that relay 

chemical signals from outside cells (extracellular) to the cell nucleus. In the 

mid 1990s, researchers found that lithium administration to developing 

frog embryos had the same effect as did loss of function of GSK-3. This 

led them to the discovery that GSK-3 was directly inhibited by lithium. 

Since then, GSK-3 has emerged as a key target that is central to the 

effects of lithium treatment. 

GSK-3 is involved in several diverse cellular processes and it is likely that 

several of these contribute to the therapeutic effects of lithium. One of 

these processes is regulation of the activity of specific transcription factors, 

proteins that act as molecular switches to turn particular genes on or off. 

An important and well-understood example is the Wnt signaling pathway. 

The Wnt pathway came to light in studies of embryo development and 

was found to have essential roles in promoting the survival, proliferation, 

differentiation and migration of cells in many different tissues including 

nerve tissue, as well as in synapse formation in the nervous system. In 

essence, the Wnt pathway involves the inhibition of an inhibitor, leading 

to activation of a transcription factor. In the absence of Wnt signals, GSK- 

3 comes together with other proteins and causes a critical mediator 

of the pathway, a protein called beta-catenin, to be rapidly removed by 

degradation. The binding of Wnt signaling molecules to receptors on the 

cell surface leads to blocking of the function of GSK-3. Consequently, betacatenin 

can now accumulate, move into the cell nucleus and assemble 

with other proteins to switch on specific target genes. The mode of 

action of lithium on the Wnt pathway is illustrated in Figure 2. 

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Figure 2 Effect of lithium on the wnt pathway 

In the absence of wnt signals, GSK-3 causes destruction of beta-catenin. Wnt proteins 

bind to their receptors on the cell membrane and activate the pathway. This leads to 

inhibition of GSK-3, such that beta-catenin is no longer destroyed, and can now move 

into the nucleus and activate specific genes. Since lithium inhibits GSK-3, it has the same 

effect as activation of wnt pathway. 

Lithium is a potent inhibitor of GSK-3, and consequently it activates the 

Wnt pathway which in turn promotes cell survival. Activation of the Wnt 

pathway may also affect manic depression through additional mechanisms, 

for example the increased production of BDNF and an increased number 

of synapses. Indeed, a recent report demonstrates that beta-catenin can 

directly bind and activate the BDNF gene. 

In addition to its relationship with the treatment of bipolar disorder, there 

is emerging evidence for links between the Wnt pathway and other 

neurological disorders. For example, GSK-3 and potential targets of the 

Wnt pathway have been linked to schizophrenia and autism. A search 

for genes switched on by beta-catenin has identified some of the known


susceptibility genes for schizophrenia, autism and bipolar disorder. 

Recently a gene called Disrupted in Schizophrenia-1 was discovered. When 

defective this gene increases the risk of having psychiatric disorders, and 

is an essential regulator of the proliferation of neural progenitor cells. 

A recent report reveals that this gene acts via inhibition of GSK-3 and 

modulation of the Wnt signaling pathway. Furthermore, several studies 

have identified GSK-3 as a mediator of the pathological effects of alcohol, 

and lithium is used in treating alcohol abuse. It is therefore not surprising 

that GSK-3 has emerged as a therapeutic target for the design of novel 

drugs for the treatment of bipolar disorder and other neurological 

diseases. 

A major difficulty in devising new treatments for manic depression is that 

the underlying causes of the disorder are not yet understood. Emerging 

lines of evidence paint a multifaceted picture of causes and effects. The 

risk of bipolar disorder has been associated with viral infection and pre- 

or perinatal stress. Mood switches in bipolar patients have been linked to 

impaired control of rhythmic activities such as the sleep/awake cycle in the 

brain. Genetic predisposition is also a major risk factor in the pathogenesis 

of bipolar disorder. Gene discovery efforts have been hampered by the 

complex mode of inheritance and the involvement of multiple genes. 

Genome-wide association studies aided by large-scale DNA sequencing 

(a separate topic in this volume) are a powerful approach to uncovering 

the secrets of genetic mutations and variations in bipolar patients. 

Genetic variation may also contribute to different responses to lithium 

treatment and other antidepressant drugs. Investigating the genetics of 

lithium sensitivity has identified new molecules that modulate lithium 

sensitivity and thus offer new therapeutic targets for the treatment 

of manic depression and other mental disorders. Furthermore, the 

identification of risk genes for manic depression may provide a better 

understanding of the nature of pathogenesis and in turn may lead to 

a better therapeutic target. Many of the genes associated with bipolar 

disorder have also been associated with schizophrenia. These overlapping 

candidate genes may help to determine some of the common features 

such as psychosis, mania and suicidal feelings, and interestingly lithium is 

effective in reducing the frequency of suicide attempts in both diseases. 

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There are reports of defects in the glial support cells in the brain in manic 

depression and schizophrenia, suggesting that these rather than nerve 

cells may be the affected cell type in some cases. 

The multi-causal nature of bipolar disorder remains a major challenge 

for the diagnosis and treatment of this illness. Animal models have been 

developed to enable a better understanding of its pathology, and to identify 

therapeutic targets and better drugs for bipolar disorders. Investigating the 

genetics of lithium sensitivity has identified new molecules that modulate 

lithium sensitivity and thus offer new therapeutic targets. 

Another important tool is the use of functional magnetic resonance 

imaging (fMRI), a brain scan technique that maps areas of brain activated 

by, for example, tasks or questions to the conscious person. This has 

enabled meaningful comparisons of brain images, which define the 

affected regions and provide a neurophysiological basis for understanding 

mental disorders such as bipolar disorder. A number of imaging studies 

suggest that structural abnormalities in the amygdala, basal ganglia and 

prefrontal cortex occur in patients with bipolar disorder. These are the 

brain areas associated with a variety of functions, including motor control, 

learning and emotion. 

fMRI will also have a great impact on investigating a wide array of 

other brain lesions and aspects of mental health. A recent example 

is a study showing that fMRI could help doctors diagnose adults with 

autism by identifying structural differences in their brain, though it is not 

clear whether the regional differences are the cause or effect of the 

pathogenesis. Extension of this study to younger people will help to shed 

light and allow the identification of at-risk children more rapidly. 

The discovery that lithium inhibits GSK-3 has paved the way to establishing 

that many mood disorders involve the activity of GSK-3 or GSK-3 

regulated functions. Disruptions of these intricate regulating systems may 

contribute to the heterogeneity of the disorder. As a mood stabiliser, 

lithium will remain popular in treating bipolar disorder, although the side 

effects and toxicity remain a problem. Further research is needed to 

discover new drugs and ways of controlling GSK-3 activity in a tissuespecific 

manner to avoid unwanted effects of inhibition outside the 

nervous system.


Stephen Fry 

Courtesy of Lotte D’Hulster 

Stephen Fry, the actor, comedian and author, has spoken publicly about his 

experience with bipolar disorder, which was also depicted in the documentary 

Stephen Fry: The Secret Life of the Manic-Depressive. 

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Translation: beating scientific swords 

into medical ploughshares 

John Galloway 

Science: use or ornament? 

What is science for? Sir JJ Thomson is credited with the proof of the 

existence of the electron; he won the Nobel Prize for it in 1906. It is 

alleged that at an annual dinner of the Cavendish Laboratory, one of his 

colleagues proposed a toast. “To the electron - may it never be of any use 

to anybody!” Even if no more than apocryphal, those few words crystallise 

the answer to the question. They suggest that science ought to be above 

mere utility which is a bit ‘trade’. At the same time they strongly imply 

that there are those who, rather regrettably, think otherwise. 

So, perhaps depending on your point of view, on the one hand science 

is there to find out interesting things about the world: its purpose is to 

be enlightening. Or, on the other, science ought to be useful: keeping the 

streets clean, making us live longer, paying the national bills. Five years 

ago the UK government’s Economic Impact Group asked the Research 

Councils, the main funders of research in the UK, to: 

“…provide views on how they could deliver and demonstrate a 

significant increase in the economic impact of their investments, 

and also to provide information on each council’s strategy for 

the allocation of funding.” 

The Warry Report was the Research Councils’ response. It didn’t hold 

back: 

“The economic benefits too will be diverse, extending beyond 

productivity gains to conceptions such as value created through 

better healthcare, better public services at national and local 

level, through law and policy making and cultural benefits.” 

That’s quite a claim. It is difficult to know what else there is that could 

benefit! 

The two views about the purpose of science appear to be diametrically 

opposed, even mutually contradictory. One is a romantic adventure to 

discover the truth about the world and is pursued only for its own sake; 

the other, chasing the dragon of the mastery and exploitation of nature;

ultimately attaining the utopian state of physical, mental and social well 

being. Scientists have spotted that it would be a good thing for them 

to argue that you cannot have the second without the first. Scientists 

of necessity have to be ‘free-range’, able to follow their own, however 

idiosyncratic, inclinations, if what they find is to be of any real use to the 

world outside science. Only in this way will they attract ever-greater 

bounty from government. 

Consider this for instance: 

“Practical and economic benefits arise from scientific discoveries. 

Science has economic impact precisely because curiosity-driven 

research reveals patterns and features of the natural world 

that we did not know and did not expect.” 

It is taken from a recent website aimed at recruiting disaffected scientists 

to petition the government for a reversal, or at least a change, of policy.: 

“A policy now being applied by the UK Research Councils…. 

directs funds to projects whose outcomes are specified in 

advance….” the UK taxpayer should not support investigations 

with foregone conclusions.” 

The sentiments it expressed were echoed last year by a letter to the 

Financial Times signed by any number of UK Nobel Prize winners. 

What is the source of this tension between scientists and their government 

paymasters? In relation to medical research the editor of The Lancet, 

Richard Horton, wrote of: 

“…the huge gap between theory and practice, between the 

burgeoning scientific basis of medicine and the relatively slow 

progress of clinical practice and preventive public health… the 

discontinuity is all too well recognised today with the debates 

about how to translate research into practice and how best to 

use the mass of information we already have.” 

In other words, governments that hold science’s purse strings have made 

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it clearer that they wish to see something more than exponentially 

growing quantities of increasingly recondite and largely incomprehensible 

information, however interesting to scientists it might be. They wanted to 

see some practical benefits coming out of science, preferably benefits that 

attracted votes. Notice, by the way, that Horton was writing in 1993. 

Where and when did the problem start? It is apt as well as convenient to 

look at the UK Medical Research Committee, forerunner of the Medical 

Research Council (MRC), set up in 1913. In his history of the MRC Sir 

Landsborough Thomson wrote: 

“Thus began a policy of the concerted funding of medical 

research from the public purse.…it had functions not previously 

discharged on the public behalf to more than a slight extent; 

and it had potentially a scope as wide as the farthest limits of 

medical science.” 

There was of course a difficulty. It wasn’t seen back in 1913 but it is 

seen clearly enough now. Whereas more scientific knowledge and better 

understanding are necessary for progress, it turns out they are far from 

sufficient. However wonderful the biology being created, it still has to be 

turned into practical, safe and reliable forms of treatment or diagnosis; 

worthwhile clinical outcomes in other words. And this is far easier to 

promise than to deliver. Indeed, the history of the funding of research 

from the public purse over pretty much the whole of the last century 

has been one of governments attempting, though largely failing, to direct 

or channel the money towards the ‘practical’ problems and priorities of 

government ministries, rather than merely leaving scientists to get on 

with it. The famous, or infamous, 1971 Rothschild Report proposed that 

the Department of Health should commission research from the MRC. 

Years later a member of the MRC Council at that time commented “The 

effect was nil.” 

Spreading the word 

Horton used an interesting word, translate, to describe research being 

transformed into practice. It is a sense not given by the Oxford English 

Dictionary, although it has been in the Oxford Dictionary of English since

1998, for example: 

Translation: beating scientific swords into medical ploughshares 

“the translation of research findings into clinical practice.” 

Its first use in this sense may have been by McKinney and Stavely in 

1966: 

“Anti-inflammatory screening suffers from the fact that animal 

models of laboratory inflammation have not provided ideal 

counterparts of human arthridites and the translation of results 

from the laboratory to the clinic has not always been fruitful”. 

Then there seems to have been something of a gap of nearly 30 years 

until 1994, when Kelley and Randolph wrote: 

“The opportunities for translation of information gained from 

molecular biology to health care delivery have never been 

greater.” 

It is worth noticing that the House of Lords Select Committee on 

Science and Technology did not use the word in their 1988 report called 

‘Priorities for Medical Research’. 

As we move closer to the present day, however, this shift in sense for 

translation has gained a great deal of ground. It is now the second most 

common current use of the word. The press have got hold of it: 

“The report will also highlight the need for more translational 

research – studies that get from the laboratory to the patient” 

This appeared in The Times on 15 March 2010 MRC itself called its 

2003/04 annual review, ‘Translating Research’. The 2006 Department 

of Health strategy paper, ‘Research for Better Health’ set up Biomedical 

Research Centres specifically to ‘spearhead translation’. The MRC created 

a ‘Translational Research Overview Group’ covering its four research 

boards. Dozens (perhaps hundreds) of translational research institutes 

and centres have been set up world-wide. And, possibly, the final proof 

that the word and its meaning are now seriously entrenched was the 

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2009 launch by the publishers of Science magazine of a sister journal 

called Science Translational Medicine. 

But what does ‘translation’ mean in concrete terms? Just what 

demonstrable benefits (and for whom) follow from particular scientific 

discoveries? And who exactly does the ‘translating’? The second half of 

this essay attempts to provide some sort of answers. It looks briefly at 

two current clinical problems in the broad field of transmissible disease 

covering between them, prevention, treatment and screening, and the 

part that research at NIMR has contributed to their eventual solution. 

The MRC 2003/04 annual review, Translating Research

Present day pestilences 

Malaria, and influenza (flu) are two scourges of which the Horsemen 

of the Apocalypse would be proud. The World Health Organisation 

estimates that there are 3-500 million clinical cases of malaria a year, and 

growing, and one to three million deaths, including 2000 children every 

day. Even these figures may be gross underestimates and indeed have just 

been challenged in The Lancet. And then there is influenza. 

Just geometry 


As ‘seasonal flu’ the threat of relatively mild infection is, like the poor, 

always with us. It occurs each year here in the UK, as in many places. But 

there is also the possibility of far more infectious and lethal strains of 

the virus emerging. The outbreak of ‘Spanish’ flu immediately following 

WWI killed between 30 and 40 million people world-wide. Though 

decidedly milder in its effects, ‘Asian’ flu which appeared in 1957, was 

highly infectious and 2 million people may have died from it. In the last 

few years, the threats posed by both avian and swine flu have forced 

the country and the wider world on to public health ‘red-alerts’. Like 

terrorism, these threats may oblige governments to engage in expensive 

and socially dislocating plans of prevention and treatment irrespective of 

whether they actually materialise or not. 

The flu virus was identified at NIMR in 1933 where its changeable 

tendency was also noticed. Underlying its capricious and potentially deadly 

behaviour is simply a viral genome with the potential for a lot of variation. 

The resulting variety in the structures of the proteins that the genome 

prescribes creates strains of virus that are difficult to vaccinate against or 

treat. Their potential mildness or lethality as well as their demographic 

targets (the old and weak, the young and strong, the middle-aged) are 

impossible to predict reliably. 

A flu protein which drew the attention of the drug industry is 

Neuraminidase (NA). An enzyme, it breaks the virus out of the cells 

where it has been multiplying. While not in itself sufficient, therefore, NA 

is certainly necessary for the spread of infection. And whatever the viral 

strain, NA’s substrate is always the same, sialic acid on the cell surface. It 

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was argued perhaps 40 years ago that a drug whose molecular structure 

closely mimicked sialic acid would not only be a good bet but also 

effective against all strains of the virus. Not only that, but any evolving 

resistance to such a drug would necessarily also render the virus ‘unfit’ 

in an evolutionary sense. In other words, a drug-resistant virus would, 

rather conveniently, also be relatively harmless. 

But, “Seek simplicity…and mistrust it” is good advice. Two drugs were 

developed: Tamiflu (Oseltamivir) and Relenza (Zanamivir), both mimicking 

the structure of sialic acid. Awkwardly, though, for this optimistic outlook, 

some mutants resistant to Oseltamivir but still infective were soon 

reported. On the other hand they continued to be blocked by Zanamivir. 

In other words they were mutants that could distinguish between the 

two drugs. It took research by Steve Gamblin’s protein crystallography 

group at NIMR to explain this singular behaviour. The changes in structure 

shown, contrive to deny Oseltamivir, but not Zanamivir, the necessary 

close stereoscopic fit with the active site necessary to block its role in 

breaking down sialic acid. 

Neuraminidase 

In the active site of neuraminidase (blue), oseltamivir fits next to the glutamine amino 

acid in the structure. In the oseltamivir-resistant neuraminidase (red), the mutation of 

histidine to tyrosine pushes the glutamine towards the oseltamivir, so that the drug can 

no longer occupy the active site well. This does not occur with zanamivir because it is 

a different shape, such that the drug is well placed to interact with the glutamine when 

either histidine or tyrosine are present. 

It is a finding that opens up a rational way to design some new drugs, or 

at least sensible variations on the existing ones, with potential benefits 

for both health and the economy. Over to Big Pharma! It also suggests a


good theoretical basis for a UK government strategy for stockpiling antivirals 

against future epidemics: 

“It would be prudent for pandemic stockpiles of oseltamivir 

(tamiflu) to be augmented by additional antiviral drugs, 

including zanamavir (relenza).” 

The two anti-flu drugs (and the research to improve them) illustrate very 

nicely the goal that translation ought to aim for, what might be called a 

‘technological fix’. In other words they are a concrete expression of the 

cause-effect relationship which links the problem to its solution. The aim 

may seem self-evident, but a lot of innovation in medicine falls far short 

of achieving it. 

Telling the one from the other 

Whereas flu poses an ever-present threat of a major public health 

problem in the UK, these days malaria certainly does not; though that 

does not mean it poses no problems at all. Ironically, one of them arises 

from our possession of a successful health service. Like some other 

diseases, malaria can be transmitted by blood transfusion, something first 

recorded in 1911. Hundreds of thousands of people give blood. Hundreds 

of thousands travel to places where malaria is endemic. Some tens of 

thousands do both. Nevertheless, although several hundred cases of 

malaria are ‘imported’ into Britain every year, only 5 cases of transmission 

by transfusion were recorded in the 20 years to 2004. Success followed a 

policy of simply refusing (or deferring) donations from travellers exposed 

to infection. Success had to be paid for of course. Its cost was counted in 

safe donations that were lost. 

What was needed was a ‘marker’ to discriminate between those infected 

and those not. The successful candidate presented itself in a nice instance 

of ‘serendipity’. The vehicle for this happy chance was research into the 

possibility of creating a malaria vaccine started by Tony Holder some years 

before he came to NIMR’s Division of Parasitology. Vaccines provide the 

paradigm for ‘technological fixes’ in their embodiment of the cause-effect 

relationship. It is a relationship relying on the remarkable discriminatory 

power of antigens in selecting for antibodies. It follows that considerable 

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research effort goes into finding antigens that provoke a measurable 

harvest of antibodies. The exclusivity of the antibody-antigen relationship 

also provides a basis for the extremely reliable identification of proteins 

as markers for any number of medical conditions through technology like 

ELISA (Enzyme Linked Immunosorbent Assay). 

Knowing what the antigen actually does is not necessary for its value as 

a marker any more than its utility as the basis of a vaccine. It needs only 

a unique relationship with its source; preferably that there is a lot of it 

and that it is accessible. Around 1980 Tony Holder found a protein that 

satisfied all three needs: Merozoite Surface Protein 1 (MSP1). MSP1 is a 

protein common on the surface of the merozoite, one of the forms the 

malarial parasite assumes in blood. It was a reasonable bet as the basis of 

a vaccine and trials are underway. Medical Research Council Technology 

(MRCT), the Council’s technology transfer arm, negotiated MSP1’s 

use as a marker to test blood donors for the results of their possible 

exposure to malaria. In harness with a close molecular relation, MSP2, 

it now underpins an ELISA-based kit marketed by Lab 21, a company 

who supply it to blood transfusion services. Last year NHS Blood and 

Transplant used it to test 66,500 potential donors for malaria. 1425 

tested positive for antibody with only 346 ultimately confirmed, 0.61% 

of those at risk. For NHS Blood and Transplant, at least, something has 

been found in translation. 

Methods and motives 

Science is characterised not by the ‘scientific method’ which seems to 

be a myth, but as the few examples here illustrate, by its methods. As 

Barnes and Dupré’s book Genomes and What to Make of Them, published 

earlier this year reminds us, any science is not just a body of knowledge, 

made up of models and theories, concepts and ideas, maps, graphs and 

diagrams, but also a methodology embodied in technology of some sort. 

Knowing is not separable from doing. The thing being studied can only 

be conceptualised in terms of the technology. Protein crystallography is 

a vivid illustration of this dependency. It seems that science grows first 

by devising new methods and then by expanding their scope into new 

territory. That’s one important lesson about translation.

In principle, protein crystallography can answer any question that involves 

the three-dimensional fit between a protein and another molecule. But 

its medical and social usefulness lies in the particular causes to which it 

is harnessed, the questions it is chosen to answer, and the way society 

chooses to use the answers. Bob Edwards has just received the Nobel 

Prize for research begun 50 years ago at NIMR into the treatment of 

human infertility. But the translation of that research into producing 

babies has turned on two very different sides to the human character: 

the willingness of some women to let other women have their eggs for 

nothing; and the readiness of some doctors to make huge profits out of 

those free eggs. The success of translation does not lie with scientists, 

however good their science, but with human motives, individual and 

corporate, selfish and unselfish, which underpin health care markets and 

drive market traders. That is the other important lesson. It is one that 

scientists and governments alike should learn. 

Acknowledgements 


I could not have attempted this essay without a lot of help, particularly 

from: Margot Charlton, Steve Gamblin, Tony Holder, Frank Norman, Lois 

Reynolds, Tilli Tansey. I am grateful to all of them. 

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What makes bone marrow such a versatile 

resource for curing human diseases? 

Thomas Elliott 

Marrow is not the most exciting of tissues. Soft and fatty, hidden away 

within lifeless bones, it is easy to overlook. Yet bone marrow is at the 

cutting edge of a remarkable and growing list of disease therapies ranging 

from the treatment of cancer to the repair of damaged hearts. What, 

then, lies beneath this surprisingly versatile tissue and its applications in 

modern medicine? 

Belying its dull appearance, bone marrow is a thriving hub of new life. 

Indeed, the clinical use of bone marrow reflects its astonishing role as 

a vehicle for regeneration in the healthy body. Cell death is a natural 

occurrence and because it happens in the body at a ferocious rate it 

must of course be balanced by an equally prodigious rate of cell birth. 

Red blood cells, for example, die at a rate of 2 million every second 

and are replaced precisely by the creation of new cells within the bone 

marrow. This requirement for renewal on a massive scale is true of most 

blood cells; the neutrophils of the immune system are produced at a rate 

of about 100,000 million per day. At the heart of this renewal process is 

the stem cell. During repeated rounds of cell division not only is the stem 

cell population replaced, but any of a variety of different types of cell, each 

with significantly different functions, may be produced: red blood cells, 

white blood cells and platelets. It is thus both the number and diversity 

of cells produced by the bone marrow that forms the basis of its broad 

medical application. 

There are two basic forms of bone marrow transplant. An autologous 

transplant is one in which cells are removed from a patient and returned 

later. This is often necessary where blood cells are likely to be damaged 

during a medical treatment such as chemotherapy or radiotherapy. By 

replacing healthy bone marrow after the treatment is finished, a speedy 

recovery is ensured. In contrast, allogeneic bone marrow transplants are 

those in which marrow is donated from one person to another. While 

the procedure is much the same, a number of criteria must be met to 

keep the procedure safe. For example, the tissue type of the donor must 

match that of the patient. Whilst tissue matching is normally required to 

prevent rejection of a graft, in the case of bone marrow there is also the 

risk that, unless the match is good, donor immune cells attack the new 

host in a condition known as graft-versus-host disease, which can have 

very serious consequences. Bone marrow transplantation is a dangerous

and complicated task, but the benefits often outweigh the risks. 

Leukaemia, a cancer of the blood or bone marrow caused by uncontrolled 

division of white blood cells, is one of the most common diseases treated by 

bone marrow transplantation. High dose chemotherapy or radiotherapy 

is first applied to kill rapidly multiplying cancer cells, but this inevitably 

also destroys a large proportion of the patient’s healthy immune system 

and stem cells, leaving the patient anaemic and vulnerable to infection. 

Bone marrow is therefore transplanted from a healthy donor, leaving the 

stem cells within the graft to divide and repopulate the patient’s supply 

of blood cells. For example, multiple myeloma is a cancer of antibodyproducing 

cells of the immune system and is at present incurable, but 

survival can be extended using bone marrow transplants. Other cancers 

may be treated in a similar manner due to the plasticity of bone marrow 

stem cells, including myelogenous leukaemias of cells that usually give rise 

to red blood cells. Allogeneic transplants have the potential to be curative 

as the bone marrow is entirely healthy; hence they can be used as rescue 

treatments where bone marrow has already been destroyed, by cancer 

or otherwise. 

Bone marrow transplantation is clearly beneficial for conditions in which 

cell growth is excessive, abnormal and uncontrollable, yet it is equally 

applicable for illnesses in which our bone marrow does not produce 

enough of a desired cell type. Sickle cell anaemia is a disease in which red 

blood cells are abnormally curved; it is potentially fatal. One recent study 

reported a high success rate when treating adult sickle cell patients with 

bone marrow transplants as donor marrow is able to produce healthy, 

disc-shaped red blood cells. Similarly, patients with thalassaemia suffer 

from disproportionate destruction of red blood cells, leading to anaemia. 

In these cases, particularly among children, a transplant can lead to a huge 

increase in the quality of life. The same is true of aplastic anaemia, a rare 

bone marrow disease characterised by insufficient production of mature 

red and white blood cells. 

These well-established procedures just scratch the surface of the exciting 

capacities of bone marrow stem cells to produce blood cells and other 

tissues, as we have only recently begun to discover. Take the example 

of Claudia Castillo, who in March 2008 was the world’s first recipient 

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of a windpipe transplant partially constructed from her own cells. This 

was achieved by combining stem cells extracted from her bone marrow 

with a section of donor windpipe stripped of its cells using digestive 

enzymes. Indeed, the use of adult stem cells for organ regeneration and 

repair is a key area of development. In April this year, it was reported at 

the American Heart Association conference that a team had grown full, 

working blood vessels from bone marrow stem cells, presenting new 

opportunities in bypass surgery where no suitable vessels are available. 

The potential of bone marrow stem cells in medicine is immense; the great 

expansion in research and interest over the past decade suggests that 

developments will continue to emerge. Unlike foetal stem cells, plagued 

by problems of availability, rejection and ethics, adult stem cells found 

in bone marrow are fast emerging as the most versatile and effective 

responses to human disease – to rescue, recover and regenerate.


Life Ascending reviewed by Michael Sargent 

Nick Lane, Profile Books, 2009 

Reviewed by members of NIMR staff 

Life ascending is a wonderful chronicle of momentous occasions in 

evolution. The first three chapters concern the circumstances that allowed 

the “Tree of Life” to germinate. Rejecting the old idea of a “primordial 

soup” Lane argues that life first emerged in alkaline hydrothermal vents 

on the ocean floors, an extraordinary environment where RNA and then 

DNA came into existence. The second chapter, about the birth of selfreplicating 

molecules, is a plausible reconstruction of molecular biology 

as we know it. The third momentous innovation that made Planet Earth 

a suitable habitat for life to flourish was an oxygen-rich atmosphere. The 

key to this was a process that could split water into hydrogen and oxygen. 

This is a reaction that no human chemist has yet accomplished without 

using more energy than is released, but plant cells manage it with the aid 

of a molecule called chlorophyll. Two more primitive versions, known to 

exist in contemporary blue-green algae, fused and entered plant cells to 

become chlorophyll-containing chloroplasts. Crucially, oxygen production 

outpaced respiration because it could not recycle to carbon dioxide fast 

enough, allowing dead plant matter to accumulate. The new oxygenrich 

atmosphere drove oxidative reactions that could create immensely 

strong architectural polymers, such as lignin and collagen, that facilitated 

the evolution of large organisms. 

The most unlikely of evolutionary turning points is the emergence of 

the complex cell. Lane argues this came about when an Archaebacteria 

(an ancient group of microbes with eukaryotic foibles) engulfed a 

Eubacterium. Infested with so called “jumping genes” or transposons, the 

archaebacterial genome multiplied willy-nilly and created a much bigger 

genome in which modern genes were distributed in a vast expanse of 

non-coding DNA. 

Three of nature’s most extravagant initiatives are explored in chapters 

on sexuality, movement and vision. Sex imposed a ruthless discipline on 

the unruly jumping genes and later had a crucial role as a mechanism 

for shedding parasites. A wonderful evolutionary trail links the evolution 

of muscle from an intracellular house-keeping activity in motionless 

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primordial cells to its iconic involvement in the confrontation of predator 

and prey. Vision gave organisms a capacity for appreciating and exploiting 

their environment; an advance so important that most extant animals 

have sight. 

Lane considers the emergence of hot-bloodedness to be the start of 

eco-hooliganism; thermostats jammed at 37°C and food requirements 

ten times that of a solar-powered lizard. It created unprecedented 

opportunities, conferring on mammals and birds extraordinary stamina, 

adaptability to climatic extremes, ability to exploit the dark hours and 

spare energy to develop the brain. The penultimate chapter is a brilliant 

exposition of the emergence of consciousness. The book ends by 

reflecting on the importance of death, arguably a default arising from 

failed maintenance, but without which selective evolutionary pressure 

could not exist. In parallel, programmed cell death became an important 

tool for embryo formation, the immune response and overcoming cellular 

malfunction. 

Some may dispute Lane’s choice of the top ten evolutionary inventions 

but they will certainly enjoy this enterprising survey and the entertaining 

debate it ought to provoke. The book won the 2010 Royal Society prize 

for science books. 

Living with Enza: The Forgotten Story of Britain and the 

Great Flu Pandemic of 1918 reviewed by Michael Sargent 

Mark Honigsbaum, Palgrave Macmillan, 2008. 

The Spanish Influenza pandemic of 1918 was the severest test that public 

health administrations had faced in their first fifty years. The arrival of this 

strain of influenza was dramatic and frightening. In some communities, 

one-third caught flu in a short period and five percent died; those who 

died went purple, drowned by fluid in their lungs. Two days after the 

Armistice, as the pandemic peaked, the British Chief Medical Officer had 

to admit that “he knew of no measure that could resist the influenza”. 

Mark Honigsbaum’s book is a vivid account of the pandemic in Britain 

and a reflection on what could have been done to ameliorate the disaster. 

Face masks and restrictions on public congregation might have helped

ut were scarcely credible as the army began to demobilise. Lessons 

were learnt, though, and eventually a profound knowledge of the disease 

emerged. 

This book went to press before last year’s Swine flu outbreak, with 

Honigsbaum thinking Britain might not manage any better than it did 

eighty years ago in a pandemic of equivalent severity. He suspects 

the huge demand for medical services would be crippling and that 

absenteeism from work would disrupt the economy disastrously because 

of our dependence on remote providers of power, food, transport and 

communications. Gloomily, he supposes modern Britain would lack the 

grace and stoicism that helped people through the crisis of 1918. 

Considering progress since 1918, he grudgingly recognises that our 

knowledge of the virus is an important advantage. He also acknowledges 

the effectiveness of the international surveillance system that did so well 

during the 2003 epidemic of severe acute respiratory syndrome (SARS). 

Today we have antibiotics that will cure secondary bacterial infections 

and anti-flu drugs that can reduce the intensity of the disease if taken 

early. He recognises the need for more research; for drugs to control 

infection and severe reactions to influenza and for the development of 

better vaccines and mass immunisation procedures. 

The title of this very readable book reminds us how British children of 

the 1920s extracted a little gaiety from unpromising circumstances with 

a skipping rhyme: 

I had a little bird 

its name was Enza 

I opened the window 

and in-flu-enza. 


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The Age of Wonder: How the Romantic Generation 

Discovered the Beauty and Terror of Science reviewed by 

Frank Norman 

Richard Holmes, HarperPress, 2008. 

This book is a multiple biography, about some key scientific figures of 

the late 18 th and early 19 th centuries: Joseph Banks, William Herschel, 

Mungo Park and Humphrey Davy. Many other men of science and men 

of letters also populate the book. One of the interesting things that 

Holmes highlights is the interconnection between science and letters in 

that period. He analyses the scientific imagery used by some poets of 

the time and includes poems written by some scientists. I confess that I 

was not really won over by his characterization of the era as a “transition 

from Enlightenment to Romantic science” and felt he rather laboured 

this point. 

Nonetheless, I enjoyed the book because it is a fact-filled and vivid 

account of the lives of these men and their discoveries. They opened 

our eyes to new cultures, as Banks travelled with Captain Cook to the 

South Seas and Park explored in Africa; to the vastness of the heavens, as 

William Herschel and his sister Caroline built ever-larger telescopes and 

catalogued the stars they found in the skies; and they explored the new 

science of chemistry, as Davy unraveled its secrets. I began to realize the 

enormous imaginative and intellectual leaps that these pioneers made in 

challenging the state of knowledge (or we should perhaps say ignorance, 

or even prejudice) at that time. It really did give me a sense of wonder 

at their achievements. 

I was also fascinated by the accounts given of some of our great UK 

scientific institutions: the Royal Society, the Royal Institution and the 

British Association. Joseph Banks was President of the Royal Society 

for much of his career, steering the nation’s scientific life wisely. William 

Herschel’s son John Herschel was later to become President, ushering in 

a new era of scientific professionalism. Humphrey Davy and his protégé 

Michael Faraday both had long associations with the Royal Institution. 

Towards the end of the period the birth of the British Association for the 

Advancement of Science saw a very different kind of institution arrive on


the scene. It was interesting to see how some issues still alive today had 

their origins in controversies that date back to this period. 

The book, like its title, is very interesting but it is rather wordy and a 

bit longer than I would have wished. It has extensive footnotes and 

bibliographies, and is perhaps more scholarly than truly popular, but the 

author’s eye for detail and lively style has won the book much praise. 

It won the Royal Society book prize in 2009, won the USA National 

Academies’ book prize in 2010 and has deservedly featured on many lists 

of best books for 2009. 

Mismatch: Why Our World No Longer Fits Our Bodies 

reviewed by Michael Sargent 

Peter Gluckman & Mark Hanson, Oxford University Press: 2006. 

Will people born in the 1990s in the developed world live as long as 

those born 60 years ago? The upward trend in life expectancy of the last 

century is set to reverse unless the lifestyle of young people dramatically 

improves according to the authors of this thought-provoking book. With 

the epidemic of obesity in mind, the authors condemn the mismatch 

between intrinsic physiological capacities programmed in the womb and 

lifestyles that encourage consumption of excess calories without the 

physical demands of former times. Like Old Testament patriarchs, they 

urge us to “return to a different way of life” and condemn the modern 

habitat, to which they say we are poorly adapted. 

The heart of the book is predicated on David Barker’s well known idea 

that nutritional and other kinds of stress experienced by the foetus in 

the womb affect its developmental trajectory even after birth. Extensive 

investigations of laboratory mammals and human epidemiology indicate 

that the response to nutritional stress is a Faustian bargain. Protecting 

the development of the brain and reproductive behaviour can only be 

achieved at the expense of underdeveloped viscera that compromise 

health in later life, especially if the child’s nutritional experiences are better 

than the mother’s during pregnancy. The outcome is likely to be premature 

onset of type 2 diabetes, coronary heart disease and more. The embryo 

also responds to high maternal blood sugar and psychological stress 

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through epigenetic modifications of genomic function that are expressed 

after birth. These ultimately cause premature age-related diseases. 

The authors apply their “mismatch paradigm” to a range of situations 

where cultural developments create new problems. These include the 

emergence of a long post-reproductive life and the tricky interval between 

sexual maturity and the time when adolescents are considered mature 

enough to hire a car. Other issues include breast-feeding, the effect of 

reproductive customs on cancer of the reproductive organs, the possibility 

of diets deficient in micronutrients and the advance of myopia provoked 

by excessive reading at an early age. This book conveys admirably for a 

non-specialist reader the implications to human biology of an interesting 

idea, although it does suffer from that unrelieved sententiousness that 

makes Old Testament patriarchs so tiresome. 

50 Genetics Ideas You Really Need to Know reviewed by 

Frank Norman 

Mark Henderson, Quercus, 2008. 

Mark Henderson is the science correspondent of The Times and one of 

the most respected science journalists. Though not himself a scientist 

he has taken a particular interest in biomedical topics and especially 

genetics. He is therefore well qualified to explain the field to a general 

audience. Early on he explains why we should be interested: “The double 

helix…was the harbinger of a new genetic age in which it was to become 

possible to use DNA to diagnose disease, to develop drugs, to catch 

criminals and even to modify life.” Genetics is a relatively young science 

but it is changing the way that we understand life and, to an extent, the 

way we live. 

The book is arranged in 50 four-page chapters, each a pithy and lucid 

explanation of one topic. Henderson does not take a narrow view of 

genetics. His topics range from evolution and classical genetics through 

molecular biology, genomics, genetic technology, sex, genetic modification 

(GM), forensic science, stem cells, ethics, patents, science fiction, evo-devo 

and synthetic biology. The chapters are carefully ordered; several times I 

got to the end of a chapter and found a question forming in my mind

“what about …?” only to discover that the next chapter was devoted to 

answering that question. 

There is a liberal use of quotations from leading scientists such as 

Francis Crick, John Sulston and Alex Jeffreys, as well as quotations from 

figures outside science, such as Bill Clinton, Virginia Woolf, Karl Marx and 

Christopher Reeve. I liked the use of different typefaces and of boxes 

for related points. Some may find this visual diversity a distraction. It can 

make it hard to read through everything in sequence, but it makes the 

book easy to dip into and browse. Occasional illustrations are included 

where this aids understanding. Each chapter also has a timeline, giving 

the dates of major developments for that topic, and a final summary of 

the topic in three to seven words, “the condensed idea”. The book also 

includes a short glossary and an index. 

I think the book works well on many levels and provides a very readable 

introduction to this topic. 

The immortal life of Henrietta Lacks reviewed by Vicky 

Millins 

Rebecca Skloot, Macmillan, 2010. 


HeLa cells came originally from the cancerous cervix of a woman 

who died long ago. She was Henrietta Lacks and her cells live on still. 

This book takes you on a massive journey and paints a picture of the 

desperate attempts of its author to tell the story of Henrietta Lacks, and 

the desperate attempts of Henrietta’s family to close the door on the 

story. Rebecca Skloot took ten years to research this book; a testament 

to how seriously she took her work. She manages to talk the family 

round, but you get the impression it is because they know that the story 

must be told, and they finally have found a woman who is willing to tell 

it to the world. 

The story is not just about the cells or their ‘owner’ but also about 

her family. Far from being a distraction, this adds to the story, and the 

breathtaking honesty of the storytelling makes it linger in the memory. 

It will most probably make you cry; it is incredibly moving in places. One 

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moment that sticks in my mind is where the gruff and rather unstable 

family member is given a photograph of the DNA from within some of 

Henrietta’s cells. His response was touching, and was the first time we 

saw him express grace. This family went through a very tough time even 

without the added burden of the extensive and very public use of their 

family member’s cells. The cells were taken from Henrietta as the result 

of a biopsy and at the time there was no rule against doing so, but you 

come away from the book knowing that an injustice was done. It was 

hard for Henrietta and her family to know the implications of what giving 

away her cells would have meant. The family were wonderful throughout 

though; they say Henrietta would have wanted to do good, and that she 

would be happy to know her cells had saved lives. 

I read the book in the space of only a few days it was so addictive and 

well written. Friends I have lent the book to all say how wonderful they 

found it and how addictive it was. The book won the 2010 Wellcome 

Trust Book Prize. 

Invisible Frontiers: The Race to Synthesize a Human Gene 

reviewed by Paul Driscoll 

Stephen S. Hall, Atlantic Monthly Press, 1987. 

This book describes, in rather a ‘thriller’ style, the origins of the exploitation 

of molecular biology methods for recombinant protein expression. No 

other book I know quite conveys the mixture of hard slog and excitement 

that the pursuit of a practical goal brings, at least not within a field so close 

to my own. On top of the ‘eating pizza at the bench’ aspect to the race to 

synthesize a human gene, the book describes the socio-political-scientific 

concerns that were around in the early 1980s about recombinant DNA 

and protein engineering. In rifling through the pages of the book again it is 

intriguing to recall how ‘dangerous’ some of the procedures that we now 

do routinely every day in category 1 or 2 laboratories were anticipated 

to be back then. 

The book describes the early days of the pioneering biotech company 

Genentech and other aspects of the exploitation of cloning methods for

therapeutic agents (specifically insulin). The book was very well received 

at the time it was published, but it may now come across as dated in its 

description of molecular biology methods: the phrase ‘synthesizing a gene’ 

does not have quite the same meaning as it would now, for example. That 

could perhaps increase the interest of the book to younger readers. It 

is unfortunately out-of-print now but secondhand copies are available 

through the usual channels. 

The Billion Dollar Molecule: One Company’s Quest for 

the Perfect Drug reviewed by Paul Driscoll 

Barry Werth, Simon and Schuster, 1995. 

This book is a mixture of medicinal chemistry, biotechnology, drug discovery 

and high-stakes competition in structural biology research. It is also 

about scientific intrigue, including attempts to manipulate the publication 

process in a top journal, and business development. Characters featured 

include the star synthetic chemist Stuart Schreiber, a phalanx of go-ahead 

US business types, and stuck-in-the-mud Japanese Pharma corporations. 

I like the book partly because it features (albeit briefly) people who at 

various times were my close competitors in structural biology. In the 

past I was involved in a major collaboration with a Japanese company 


2009 

and experienced the culture shock that that entails (first class flights to 

Tokyo complete with in-flight massage, obligatory exchanges of gifts and 

business cards, protocols at business meetings) as well as being part of 

a university team that raised the finance to start a small biotechnology 

company. The book describes these off-shoot aspects of an academic life 

all too clearly. Eight out of eight reviewers on Amazon gave this book a 

top rating. 

God’s Philosophers: How the Medieval World Laid the 

Foundations of Modern Science reviewed by Alessandro 

Pandini and Jose Saldanha 

James Hannam, Icon Books, 2009. 


God’s Philosophers presents historical evidence aimed at correcting our 

misconceptions about the Medieval era. The book is interesting particularly 

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as this period is otherwise poorly documented. When we think of the socalled 

‘Dark Ages’ we tend to conjure up visions of an unenlightened time 

when there was conflict between science and religion, with the Church 

holding back scientific progress. Some myths about that time prevail, for 

instance that people were burnt at the stake for scientific ideas or that 

the Church supported the idea that the earth is flat. In reality, however, 

the middle ages laid the foundations for modern science. James Hannam, 

who has a physics degree from the University of Oxford and a PhD in 

the History and Philosophy of Science from the University of Cambridge, 

argues in this informative and engaging book that the Middle Ages were 

a period of great technological change and cultural advance. 

The Church founded universities in the 12th century where the subject 

of theology encouraged the study of the natural world because it was 

God’s creation. The Church supported natural philosophy (science), 

as long as the philosophical speculations did not impinge on theology. 

This was beneficial since it kept science focused on nature, instead of 

metaphysics. 

In his conclusion Hannam suggests: “It would be wrong to romanticise 

the period and we should be very grateful that we do not have to live 

in it. But the hard life that people had to bear only makes their progress 

in science and many other fields all the more impressive. We should not 

write them off as superstitious primitives.” 

The book is written in a humorous tone, with sections suitable for 

bedtime reading; but as it was based on the author’s doctoral research, it 

includes extensive academic references to back its claims. 

Heart of a Dog reviewed by Frank Norman 

Mikhail Bulgakov, Vintage Classics, 2009. 

Mikhail Bulgakov trained as a doctor but switched to writing after just a 

few years of medical practice. This background is reflected in some of his 

fiction. Heart of a dog is one of his earliest works, written in 1925 though 

not published until much later. It has elements of farce, political satire, and 

science fiction, though it is not entirely any one of these.


The humorous aspects dominate the early part of the book, which is 

narrated by the dog. It reminded me of the very funny short radio series 

About a Dog, scripted by Graeme Garden and starring Alan Davies as a 

dog. Bulgakov’s dog is a street dog who has just suffered a bad scalding 

thanks to an angry cook who caught him scavenging. He is rescued from 

the street by a kind gentleman who brings him to his home. Professor 

Philip Philipovich, the rescuer, is a doctor who specialises in reproductive 

health and rejuvenation including some rather experimental treatments. 

Philipovich has done well for himself; his talents have earned him privileges 

and he knows how to play the system to his advantage. He has no patience 

with the political mores of the day, observing that speaking of Bolshevism 

at the dinner table is the best way to ruin your appetite. This brings him 

into conflict with the chairman of the management committee of his 

apartment complex, Comrade Shvonder, who insists that the doctor give 

up some of his rooms. 

The dog, nicknamed Sharikov, is taken to the doctor’s luxurious consulting 

rooms in Moscow. Sharikov cannot believe his luck: he has warmth, good 

food and comfort. He slowly regains his health and strength until one day 

he finds himself in the doctor’s consulting room, lying on the operating 

table. Philipovich proceeds to remove the dog’s testicles and pituitary 

gland and replaces them with those of a recently dead man. The doctor’s 

notebook records Sharikov’s post-operative recovery and subsequent 

development as the transplants begin to affect him. 

The rest of the book works out the consequences of Sharikov’s 

transformation and Shvonder’s interventions in the doctor’s affairs. The 

book has been turned into a film and more recently into an opera, 

recently performed in London. 

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About the authors 

Peter Coombs is a postdoc researcher in the Division of Virology. 

Zhores Medvedev worked at NIMR in the Division of Genetics from 

1973 until his retirement in 1991. In addition to his scientific publications, 

concerned with genetics and ageing, he has published several books on 

Soviet science and politics. 

Mike Gilchrist is programme leader in the Division of Systems Biology. 

Harriet Groom is a postdoc researcher in the Division of Virology. 

Marianne Neary is a PhD student in the Division of Developmental 

Biology. 

Marina Lynch, now at the Trinity College Institute of Neuroscience in 

Dublin, worked at NIMR in the Division of Neurophysiology and Neuropharmacology 

from 1983-93. 

Qiling Xu is a Senior Investigative Scientist in the Division of Developmental 

Neurobiology. 

John Galloway is Head of the Dental Team Studies Unit at the Eastman 

Dental Hospital. He was Senior Administrative Officer at the Medical 

Research Council. 

Thomas Elliott is a student at Queen Elizabeths Boys School.

Thirteen previous volumes of Mill Hill Essays have been published: 

1995 (gene patenting, gene therapy, obesity, malaria, TB, spinal injury, muscles) 

1996 (memory, AIDS, risk, morphogens, MRI) 

1997 (cloning, GM food, Alzheimer’s, xenotransplantation, SAD, endosymbiosis) 

1998 (TB, ethics, influenza, consciousness, MMR vaccination, diabetes) 

1999 (2000 on cover) (growth hormone, meningitis, health information, warts, 

multiple sclerosis, salmon anaemia, handedness) 

2000 (Millennium edition on cover) (microbiology, frogs, immunology, 

neuroscience, influenza, malaria) 

2001 (transgenesis, stem cells, antimicrobial resistance, ageing, endosymbiosis) 

2002 (drug addiction, limb development, Rosalind Franklin, TB, infertility, malaria, 

obesity) 

2003 (science and citizenship, Alexandre Yersin, genetics, molecular drug design, 

RNA interference) 

2004 (epigenetics, Drosophila, bacterial biofilms, self improvement, allergy and 

asthma, chemistry) 

2005 (African health, cancer, systems biology, heart disease, philanthropy) 

2008 (developmental biology, public health, statistical relevance, laboratory 

robotics, medical diagnosis, saviour siblings) 

2009 (ageing, tuberculosis, Peter Medawar, stem cell therapy, biological imaging, 

John Eccleston, apoptosis, measles eradication) 

Please note that no volume was published in 2006 or 2007. 

All Mill Hill Essays published from 1995 to present are available on 

the NIMR website: http://www.nimr.mrc.ac.uk/millhillessays/ 

Audio versions of some recent essays will be made available during 2011. 

ISBN 978-0-9546302-8-9 

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Computer-generated images of the proposed building for UKCMRI 

http://www.ukcmri.ac.uk

MRC National Institute for Medical Research Mill Hill Essays 2010

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