by Nessa Carey
Praise for The Epigenetics Revolution:
‘A book that would have had Darwin swooning – anyone seriously interested in who we are and how we function should read this book.’
—Guardian
‘[A] splendidly clear explanation’
—The Oldie
‘Fascinating stuff’
—Bookseller
‘Combines an easy style with a textbook’s thoroughness.’
—Nature
Praise for Junk DNA:
‘A cutting-edge, exhaustive guide to the rapidly changing, ever-more mysterious genome’
—New Scientist
CONTENTS
Title Page
Acknowledgements
Dedication
Prologue
1 The Early Days
2 Creating the Toolbox to Hack the Code of Life
3 Feed the World
4 Editing the Animal World
5 Gene Editing Ourselves
6 Safety First
7 Changing the Genome For Ever
8 Shall Man Still Have Dominion?
9 Pick a Question, Any Question
10 Fame and Fortune
Index
About the Author
Also by Nessa Carey
Copyright
ACKNOWLEDGEMENTS
As always, I marvel at my luck in having a great agent in Andrew Lownie, and a supportive publisher in Icon Books. Particular thanks go to Duncan Heath for his remarkable patience.
Encouragement from friends goes a long way when you are trying to juggle too many conflicting demands on your time. Honourable mentions in no particular order to Cheryl Sutton, Julia Cork, Julian Hitchcock, Gosia Woznica, Ellen Donovan, Catherine Winchester and Graham Hamilton.
Just as helpful are those pals who simply accept that you are swamped and don’t give you a hard time for being an antisocial grump. Fen Magnus, Catherine Williamson, Rick Gibbs, Pat O’Toole, Mark Shayle, John Flowerday, Astrid Smart, Joanne Winning and Cliff Sutton are just a few of the people who have given me a much appreciated free pass.
My mother-in-law Lisa Doran always gave me space, time and a never-ending supply of digestive biscuits to encourage me to get on with things. I am very grateful (and a bit heavier than I used to be).
And finally, a huge thank you to my wife Abi Reynolds, who despite knowing what a nightmare I become as deadlines loom, still encourages me to write another book anyway.
For Abi Reynolds, of course.
I’ll get the car.
PROLOGUE
On 28 November 2018 a Chinese scientist announced the birth of twin girls, Lulu and Nana. Unfortunately, this wasn’t the typical case of a happy father telling the world about his daughters. In fact, the identity of Lulu and Nana’s parents is a secret. The reason why He Jiankui from Southern University of Science and Technology in Guangdong Province, China, made the announcement was because there was something very special about these two infants. They were the first children ever born with changes to their genetic material which had been deliberately introduced by scientists. The DNA of the two girls had been through a process called gene editing, and it’s likely that if they have children they will pass on the introduced changes. Their genetic lineage has been changed for ever.1,2,3
Professor He had adapted the techniques of in vitro fertilisation (test-tube babies) for his work. He had edited the DNA of the embryos when they were just a tiny bundle of cells in the laboratory, and then implanted these embryos into their biological mother’s uterus.
The announcement was met with dismay from researchers around the world. The news about the twins was revealed at a conference, not in a peer-reviewed paper, so the amount of data that was shared was not comprehensive. But even from the results that were presented, other scientists could deduce that the gene editing hadn’t been carried out well. It wasn’t clear if all the cells had been edited during the laboratory stages. Because of this these girls may be a mosaic of different cells, only some of which carry the change. It also appears that the change He Jiankui had introduced was a relatively imprecise one. He had inactivated the gene he was targeting, but had used an inelegant methodology that rather clumsily achieved its end, changing the gene in a way that has never occurred in nature.
You might expect that if someone was planning to create edited humans, they would only risk the ire of the scientific community by doing so to save the children from a terrible and inevitably lethal genetic disease. There are, sadly, plenty of these from which to choose. But Professor He didn’t do this. Instead he mutated a gene involved in responses to human immunodeficiency virus-1 (HIV-1).
HIV-1 binds to a specific receptor on human cells, but this binding isn’t enough on its own for the virus to set up an infection. Another human protein called CCR5 also needs to be active for the virus to complete its entry into the cells. About 10% of Caucasians have a DNA variation in CCR5 which prevents the virus from getting in, and these people are resistant to certain strains of HIV-1.
He Jiankui edited the DNA of Lulu and Nana so that their CCR5 gene wouldn’t produce a functional protein, but he didn’t create the same variation as seen in the resistant humans. He told the conference that the reason he chose to edit this gene was because the girls’ father is HIV-positive. This still carries a great deal of stigma in China and he wanted to save the children from being exposed to these negative reactions.
But the problem with this justification is that it’s a bit of a false issue. HIV-1 is usually transmitted via intimate body fluids. With a few simple precautions, it’s relatively easy for fathers to avoid transmitting the disease post-natally to their children. So Lulu and Nana were never at a really high risk of becoming HIV-positive. They may, however, be at increased risk of contracting influenza, as a functional CCR5 protein is important at fighting off this virus. No one knows if the edits that Professor He introduced into the girls will leave them susceptible to this disease, which is common in China and can be very dangerous.
Even if the editing carried out by He Jiankui had been technically perfect, it would almost certainly have caused huge concern anyway. Scientists throughout the world have been debating the power of gene editing and particularly its potential to change the genetic sequence of a human for eternity. Biologists, ethicists, lawyers, regulators and politicians have been working together, trying to explore the implications of these new tools, and to develop frameworks for making sure they are used well, in a responsible way. Groups have been attempting to create international norms, and to ensure that ethics are considered in advance of the implementation of the science. Everyone involved also recognises the necessity of building dialogue with the general populations of their countries and moving forward in a carefully stepped manner.
He Jiankui has shot this measured approach to pieces with his announcement, and now the rest of the scientific community is on the back foot, trying to reassure the public and to create consensus rapidly. Researchers worry about a backlash from politicians, who could introduce new regulations driven more by fear than understanding, and this could have deleterious effects on a field that has enormous potential for good, but that is still being established. Perhaps weirdly, Professor He seemed surprised and somewhat taken aback by the reaction of his peers. So unconcerned was he by the implications of his action that he had already created and implanted a third edited embryo into another woman, so at least one more child is likely to be born with a permanent change in their genetic script.
The condemnation hasn’t been an exclusively western phenomenon. The Chinese authorities have been quick to castigate He Jiankui. Articles about his other achievements have vanished from official websites and the government is aligning itself with the
voices of consternation. This isn’t surprising – China wants to become a valued member of the international scientific community. Professor He’s announcement has simply served to reinforce international concerns around ethical infrastructure and research integrity, and this isn’t a helpful message.
It’s almost hard to resist feeling sorry for He Jiankui. There aren’t that many high-profile scientists who are exposed to universal ire on the triple fronts of scientific competence, ethical integrity and political nous.
But in many ways, the most incredible aspect of this story of spectacular mis-steps is that it was possible in the first place. Six years earlier it would have been almost inconceivable even to dream of carrying out this work, as modifying the human genome in embryos had very little chance of working. But a breakthrough in 2012 ripped open the genetic fabric of every organism on this planet, from humans to ants and from rice to butterflies. It’s giving every biologist in the world the tools to answer in a few months questions that some scientists have spent half their careers trying to address. It’s fuelling new ways to tackle problems in fields as diverse as agriculture and cancer treatments. It’s a story that began with curiosity, accelerated with ambition, will make some individuals and institutions extraordinarily wealthy, and will touch all our lives. We are entering the era of gene editing, and the game of biology is about to change. For ever.
Notes
1. Cyranoski, D., Ledford, H. ‘Genome-edited baby claim provokes international outcry’. Nature (November 2018); 563(7733): 607–608.
2. https://www.nature.com/articles/d41586-018-07607-3
3. https://www.sciencemag.org/news/2018/12/after-last-weeks-shock-scientists-scramble-prevent-more-gene-edited-babies?utm_campaign=news_weekly_2018-12-07&et_rid=49203399&et_cid=2534785
1
THE EARLY DAYS
Homo sapiens.
‘Wise man’.
That’s what we humans have called ourselves since Carl Linnaeus first included us in his scientific classification system of all living things, back in 1758. Even if you can put to one side the obvious sexism of naming our species with reference to the male, is this really the most appropriate way to describe ourselves? After all, the Cambridge English Dictionary defines wisdom as ‘the ability to use your knowledge and experience to make good decisions and judgments’. Look at the world we have created, and the world we are destroying, and we might start to wonder. We have undoubtedly been successful as a species – we can tell that by the disproportionately huge number of us on this planet. But view us through the perspective of most other organisms and we are a pest, a plague. So, maybe we should think of a different name for ourselves. But what?
Perhaps, with apologies to Latin scholars everywhere, we could go for something like ‘Persona hackus’? A human is a person who hacks stuff about. Because this is what we have done throughout our history. See that cave – wouldn’t it look better with a picture of a few bison? Look at this flint – I can knock some sharp edges into it and carve up the bison for dinner. We’ll initially develop computers to break codes and win a global conflict, and sixty years later we’ll use them to show total strangers the imaginative things we have done with a Billy bookcase from Ikea. We hack, we tinker, we design, we change things – we create. We are human, and we just can’t help ourselves.
There’s one way in which this tendency to hack our world has had more impact than any other. That’s food. Current evidence suggests that farming started in the region known as the Fertile Crescent, around 12,000 years ago. Multiple groups of people from different genetic backgrounds seem to have been farming independently in the area that now includes modern Palestine, Iraq, Jordan, Israel, western Iran, south-eastern Turkey, and Syria. The shift from a nomadic hunter-gatherer existence to agricultural settlements was probably a gradual one, but it depended absolutely on the human ability to tinker. Humans began to select the largest grains, the most prolific legumes, and to plant these selectively. Repeating this process over multiple growing seasons led to the development of nutritious harvests, and the selection of many of the crops on which we depend today.
These early farmers didn’t just change the development of plants. They also selectively bred animals for traits that were useful, from the milk and meat production of cattle, sheep and goats to the tractability and companionability of horses and dogs.
The consequences of creating food sources that allowed populations to remain in one place were profound. Settlements grew in size, and complexity. Social hierarchies were reinforced and maintained, and systems such as writing developed multiple times, as rulers sought to monitor and control systems and populations. The increase in production, and the ability to store surplus food in times of plenty, allowed societies to develop where individuals could specialise and with this came a huge increase in the production of cultural artefacts.
It’s remarkable to consider that almost all human activity – glorious or disastrous and everything in between – has been built because we have learnt how to hack the genetic material of other organisms. By selecting individuals with traits we considered useful or appealing, we changed the evolutionary paths of living species. We bent them to our will, hacking the genetic lottery, and changing irrevocably the genes that survived and were passed on in everything from rice to roosters and from sorghum to Siamese cats.
Of course no one, from the early farmers to the breeders of fancy pigeons that so inspired Darwin, had any idea they were skewing the genetics of other organisms. They selected individuals for breeding based on physical characteristics they could see, hear, smell, taste or appreciate in some other way. They hoped the characteristic they were interested in ‘bred true’, in other words that it showed up in the offspring, or even was better in the next generation. But they had no idea how these characteristics were passed on from parents.
The first step in formalising a data-based theory for this came from the Augustinian friar Gregor Mendel, working in Saint Thomas’s Abbey in Brno, in what is today the Czech Republic. Mendel crossed different strains of peas very systematically and examined the offspring, counting characteristics such as smoothness or wrinkling of the peas. He determined that particular characteristics were passed on in a specific ratio, and to explain his findings he referred to invisible factors that governed the physical appearance. These invisible factors were the fundamental units of heredity.
Mendel published his work in 1866 and hardly anyone realised its significance. It was only in 1900 that his findings were rediscovered and his conclusions began to receive attention. In 1909 the Danish botanist Wilhelm Johannsen first used the word ‘gene’ to describe these invisible fundamental units of heredity. Johannsen didn’t speculate on what a gene was made from, and it wasn’t until 1944 that this question was settled by a New York-based Canadian scientist called Oswald Avery. He showed that Mendel’s invisible factors were made from DNA (see page 13), and with this Avery created the bedrock on which all subsequent genetic research is built. Astonishingly, he never received the Nobel Prize for his work.
After that, the pace picked up. Less than ten years after Avery’s paper, the brash British scientist Francis Crick and his even brasher American colleague James Watson announced that they had solved the riddle of the structure of DNA. Their famous double helix model relied heavily on data generated by Rosalind Franklin, who worked in a department at King’s College London headed by Maurice Wilkins. The Nobel Prize followed quickly on this occasion, and was awarded to the three men in 1962. Rosalind Franklin had died from ovarian cancer at the heart-breakingly early age of 37 in 1958 and the Nobel Prize is never awarded posthumously.
The first break in the genetic wall
In 1973, twenty years after the famous Watson-Crick DNA structure was published, two scientists who had each started out as small-town boys collaborated on a set of now legendary experiments. Stanley Cohen was born in Perth Amboy in New Jersey, and was encouraged by his father to develop a love of learning.1 Herbert Boyer was born
a year later in the Pennsylvania town of Derry, into a family with little knowledge or interest in science.2 Both found themselves drawn into the world of genetic research, and by the 1970s were working in prestigious Californian institutes, Cohen at Stanford University and Boyer at the University of California, San Francisco (UCSF).
The amazing achievement of Cohen and Boyer was that they developed ways of moving genetic material from one organism to another. They were able to select the genetic material they wanted to move and transfer it in a way that meant it still did its job in its new host. Their initial experiments transferred DNA from one species of bacteria to another. Their next breakthrough was even more spectacular. They were able to move DNA from a bacterium into the cells of a frog, and to show that the DNA was able to function in its new home.
Cohen and Boyer had done nothing less than break down the barriers that have separated individuals and species for millennia. The implications were tremendous. From 1973 onwards, no organism could be considered inherently genetically inviolate. Scientists now had the ability to tinker directly with the most fundamental basis of every organism on the planet – its DNA. Genetic engineering had arrived.
Most of us are familiar with the trope of game-changers who are not appreciated in their lifetimes. They achieve no recognition, and maybe even die penniless. Vincent van Gogh is perhaps the perfect exemplar of this but there are plenty of others, such as Mozart or Edgar Allan Poe. And as we’ve already seen in the examples of Mendel and Franklin, science isn’t immune to this phenomenon.
Absolutely nothing like this happened to Cohen and Boyer. Fame and fortune very definitely followed them. True, they didn’t win a Nobel Prize,* but they have won just about every other major scientific award. Their two employers worked together to protect Cohen and Boyer’s work by patenting their findings, a decision that resulted in UCSF and Stanford making hundreds of millions of dollars. The inventors usually receive a share of the income. As if that wasn’t impressive enough, Herbert Boyer went on to found Genentech, one of the most successful biotechnology companies ever created, and one which has produced life-changing and life-saving drugs.
