She has just won the Nobel prize for chemistry – and her discovery of the groundbreaking Crispr is already revolutionising the treatment of disease. But does this brave new world mean a generation of superbabies?
When Jennifer Doudna woke up, she realised her phone had been buzzing on and off for some time. It was still dark outside. In fact, her phone told her that, here in California, it was 3am. More pertinently – she might have thought, but didn't – it was midday in Stockholm.
She answered. In the blurriness of her waking, she says she did not have an inkling why the world was so keen to speak to her at such a strange time on the first Wednesday in October.
"It was a reporter from Nature magazine. 'Sorry to bother you so early,' she said. 'I'd like to ask you your response to the Nobel.'
I thought she was asking me about someone else winning. I said, 'I don't know. I've just woken up.'"
Unlike almost all other scientific prizes, Nobels are only decided on the morning of the prize. If the committee cannot reach the winners in an hour, they announce regardless. In Sweden, the Nobel committee had already read out Doudna's citation. If she had been listening, she would have learnt she had shared the prize with a French scientist and long-time collaborator Emmanuelle Charpentier, "for the development of a method for genome editing".
Another way of describing their work – work that has revolutionised genetics arguably faster than any discovery in history – is that it has given humans the power to control their own evolution.
"Oh my gosh!" said the reporter, realising she'd just broken the news. "You don't know."
What follows is a classic example of a perennial feelgood science story: the newly minted laureate in the wrong time zone.
The first thing that happened was that Doudna's husband, Jamie Cate – also a professor at the University of California, Berkeley – went in to rouse their son. "He said, 'Wake up! Your mother has won the Nobel prize,'" says Doudna, who is 56. "He was very matter of fact." Teenagers, even those whose mothers have been awarded a Nobel, take a while to get into the party atmosphere when forced out of bed before dawn.
"But he did look at me that morning over coffee at 4am and say, 'Mum, I'm really proud of you.' It's not often your 17-year-old says that."
A quarter of an hour later, the TV crews arrived. Because of Covid-19, they conducted the interviews outside. "I felt a little bad because there were lights. And my neighbour at one point texted me and said, 'Either there's a problem in your garden or something very exciting is happening.'"
So far, so standard. There are, though, a few ways in which Doudna's story is slightly different from the usual tale of US west coast laureates. The first is that, unlike other laureates jolted awake by a phone call in the small hours or dazzled by TV lights outside, Doudna was not new to fame. She has a book out, and she has – that ultimate imprimatur of pop-academic success – a TED Talk.
For much of the past decade, she has been the face of a technology that has gone from obscurity to ubiquity faster than any in the history of biology.
The second is that despite receiving the Nobel, the peak academic accolade humanity can give to anyone, she is still not so sure her legacy is assured. Quite the reverse.
"There's always the worry I could be a Dr Frankenstein," she says. "I couldn't really live with myself if I didn't take responsibility for the work that we had done."
The first time I met Doudna was at a talk in 2018 at the Royal Society, Britain's oldest and most prestigious scientific institution.
In the room above her, there was a bust of Charles Darwin, the father of evolution. Below, she talked about humanity's ability to transcend natural selection and control evolution.
She put up a slide of an Economist cover that is now famous in the community. Under the title "Editing humanity", it shows an annotated baby "improved" by science.
"Sprinter," says a label pointing to its legs. "High IQ," says another, pointing to its head.
This cover illustrated the power, the promise and most of all the fears of Crispr cas9, Doudna and Charpentier's genome-editing tool – a tool with the potential to cure genetic disease, to tailor crops to our purposes, but also to fundamentally change our idea of our own humanity.
One day Crispr (pronounced crisper) may indeed make high-IQ, sprinting babies. It may create a Brave New World – for better or worse. But its story begins in microbes. It is difficult to categorise what it is that Doudna and Charpentier have done. Crispr is partly an invention, partly a discovery. It isn't, as a concept at least, new. It was always there, if we knew where to look.
The first time we did look was in 1987, when a Japanese scientist spotted an oddity in the genome of a bacterium. There was a repeating sequence of genetic code, roughly palindromic, that seemed to act as a bookend. This code would appear, then there would be an incomprehensible sequence of genetic letters – actggtcag – then it would appear again, and so on. The discovery was filed as an oddity, and largely forgotten.
Over the next two years, investigations into this obscure mystery made (very) slow, but steady, progress. One group of scientists realised that the incomprehensible sequences of code were not so incomprehensible. They were seen somewhere else: in viruses that attack bacteria.
Why would a bacteria store the genetic code of a virus that attacks it? Only one answer made sense. The bacteria must have saved bits of viral genetic code, so that when those dangerous viruses came into view it could spot them – and defeat them.
The code was part of the bacterial immune system, a library of dangerous pathogens. And the library, in turn, was a catalogue of targets. It used this code to build a molecular machine, an atomic-scale weapon that would seek out that particular string of DNA in the attacking virus. Then when it found it, having locked on to the threat, it snipped it up: shredding its attacker.
Suddenly, the oddity spotted in 1987 became something more profound. This, scientists thought, had the potential to be useful.
Then one day in 2012, in her office overlooking the Golden Gate Bridge, Doudna became the scientist who completed this quarter-century puzzle – and found a use for Crispr.
She and her colleagues took the molecular machine the bacteria used to snip out viral DNA, and reprogrammed it. In their hands, it could instead snip out any DNA they chose – and replace it with a different set of DNA. It was a cut-and-paste function for the code of life. It allowed us to control our own evolution.
Crispr is not the first system for editing genetic code. But it is, by some distance, the best. Genome edits that once took a whole PhD to complete can be done in an afternoon – by a lab technician. Crispr is now ubiquitous. As a research tool, it can be used to understand what genes do, to make laboratory animals to investigate specific diseases, to engineer plants to survive climate change and drought.
In the week of our interview, there is a study published into using Crispr in fighting cancer by targeting the DNA inside tumour cells. There is another about stopping the progression of muscular dystrophy.
None of these, though, is what concerns Doudna. Ethically, they are little different from a drug. What concerns her is what happens if we make the changes not as a targeted intervention in the bodies of sick people, but instead at the point of fertilisation – changing every cell in a baby, and every cell in any babies that baby grows up to have. What happens if we make a designer baby?
When we spoke in early 2018, Doudna considered such a development – with what now seems like sweet naivety – a distant dystopian prospect, but one worth considering nevertheless. Neither of us had any inkling at the time that, in the very month we were speaking, the world's first full designer baby was already conceived.
After her Royal Society talk, we had met over the finger buffet. When did her thoughts move from the utility of Crispr in the laboratory to its potential for making superbabies? When did she realise she would spend much of her career talking about ethics?
"At the very end of 2012 I had my family over for dinner. It should have been a happy occasion, a holiday dinner, but I felt really down. I was sitting by myself in the room, and my sister came in. She said, 'You're looking unhappy.' I said, 'I feel this great weight. We're doing this thing in the lab. I'm excited about it; I can see it's a really powerful technology. I'm also feeling great anxiety.' My mother was very ill and I was caring for her, and I thought, 'How can I do everything I need to do? How can I be a daughter, a mum, a wife, and run my lab?' It felt really intense."
It only got worse. "Around mid-2013, I started talking to my spouse about human embryo editing. Initially my reaction was, 'I don't want to go there. I don't want to talk about it. I don't want these crazy people emailing me.' I eventually realised it was going to go there whether I talked or not. I could see the tsunami coming."
There's always the worry I could be a Dr Frankenstein.
Today, in a pandemic world, we are meeting over Zoom – with the Golden Gate Bridge as her digital background. Nine months after her Royal Society talk, she tells me, she received another email – and whether it was from a crazy person or not was a matter of opinion. But she knew that with it, far sooner than expected, the tsunami had arrived.
"I was about to leave for Hong Kong for the second international summit on human genome editing," she says. This was a conference where, among other things, scientists were looking to build a consensus on an ethical framework for using her technology. The expectation was that they would call for a moratorium on its use in human embryos until more was known about how it worked, and until society had had time to consider the momentous moral ramifications.
The email was from one of the conference attendees, He Jiankui. He wanted Doudna to know about some research he was going to announce. He had edited the genomes of twin girls, Lulu and Nana, to give them resistance to HIV. The girls had been born a month earlier.
The conference had been worried about making Crispr embryos for research purposes that would then be aborted. These were Crispr babies breathing among us.
He Jiankui had expected congratulations. He didn't get it. "You know, it's quite a shock. Can you imagine receiving that?" says Doudna. It wasn't, and still isn't, completely clear how successful the edit he made to the girls was, or what the knock-on consequences might be. It was also a strange gene to change. If you want to confer resistance to HIV, far better to tell someone to use a condom. He is now in prison.
"That changed the whole focus of that meeting," she says. "It went from being discussions about theoretically what might happen and how to deal with it to how to manage it now it had happened, and what do we do now?" And how much responsibility went to the creators of the technology – to Doudna and Charpentier?
On the campus of UC Berkeley, the roads are named after famous alumni. If you leave Doudna's office and turn left at a row of sparsely filled parking spaces ("Reserved for Nobel laureates," the notice explains), you find yourself on Oppenheimer Way, in honour of Robert Oppenheimer, head of the Manhattan Project's Los Alamos Laboratory – the top-secret facility that developed the bombs for Hiroshima and Nagasaki.
Just before Doudna received the email from He Jiankui, back when she was still jostling with the non-laureates for parking, she says she was reading the classic account of the work of Oppenheimer, The Making of the Atomic Bomb.
In 1945, as the blinding flash of the Trinity test faded to reveal a grey mushroom cloud, Oppenheimer famously claimed he recalled the words from Hindu scripture, "Now I am become Death, the destroyer of worlds."
Like the atomic scientists before her, Doudna confesses she had felt a terrible responsibility on creating Crispr: "It was horrifying to know there was almost nobody in government that had any awareness of this." And there was so much they needed to know.
Sometimes the dilemmas created by easy gene editing can feel a little like an undergraduate philosophy paper or an autogenerated list of Oxford Union debates. "This house believes that it is wrong to change the human genome to cure disease." "This house believes it is wrong not to change the human genome to cure disease." "This house believes we have a duty to make mosquitoes extinct." "This house believes we should take control of human evolution – to make us faster, stronger and happier."
No simple answers are available to these questions. You can set clear red lines – do use it to cure diseases; don't enhance humans – but the closer you get to them, the less clear they become.
The case for the proposition, when arguing against those who would forbid its use, begins strongly. In fact, it arrives in Doudna's inbox regularly with emails from desperate parents wanting to know if she can cure their children. She can't, and she hates receiving the emails, but one day scientists might. Should they?
Let us start with something easy. You may remember sickle cell anaemia from biology classes. There is a gene mutation that affects blood cell production. If you have one copy, you are fine. If you have two copies, you have seriously misshapen blood cells and a life-changing illness that means you get easily tired and are prone to infection, heart injury, ulcers and eye damage.
A team has now developed a Crispr treatment to cure it, by fixing the sickle mutation in the bone marrow cells that make blood. It is still very expensive, but it works.
A disease that blights the lives of millions is fixed. And who could seriously object to that? That's ethical line No 1 happily crossed.
But what if you could go further and ensure that these people never pass the condition to their children? What if you could make what is called a "germline" modification to their eggs or sperm, to remove the mutation at source? If it is right to change it in one person, surely it is right to change it in their offspring?
Doudna has a practical example of this. "My mother's family has Alzheimer's all through the family," she says. None have had their DNA sequenced, but given the family history it seems at least plausible that they have a particular gene variant, ApoE4, that significantly raises the risk of dementia.
"Let's say it's ApoE4. I saw the suffering of family members, including my own mother. And, you know, if I knew there was a technology to avoid that, and it was safe, it's hard to say that I wouldn't want to use it."
It seems barely even a question – of course, surely, she should tweak the genomes of her future grandchildren. Why stop at ApoE4? There's the BRCA1 gene for breast cancer, and a host of genes linked to heart disease. There are non-Crispr ways of ensuring that you don't get one gene mutation; there are no such ways of ensuring you remove a whole suite, to give your child the very best start in life. And who could object to that kind of designer baby?
Yet Doudna is not so sure. Suddenly you are considering deep time – not just your children, but their children and their descendants until the end of humanity itself. You are removing a human trait that evolved for a reason, for ever more. Is that a responsibility you want?
"Why is that variant maintained in the human population?" she asks. A common gene variant is rarely a mistake. Sickle cell, for instance, is not all bad. It persists because those with just one copy of the mutation have protection against malaria. ApoE4 may confer an advantage we don't understand. So should we remove it? "I struggle with it, honestly."
OK, next stage. You've decided as a society that the ApoE4 variant and a whole host of similar genes are so pernicious it is indeed worth removing them from the human germline. But you don't "remove" a gene – you change it. So what do you change the gene to?
What if, in making the change, you altered it to a variant that doesn't just lower the risk of Alzheimer's, it actively protects against it? Does that, in your red lines, count as cure or enhancement? Or what if you discovered there were a version of the gene that also increased intelligence? Would it be wrong, given you are changing it anyway, to pick that one? Would it, in fact, be perverse not to?
Doudna does not, she says, have the answers. Nor would she want to give them if she did. What she wants is not for her to take control, but for us to take control – for society to take on the burden of considering the problems, so that she can return to the laboratory.
The day before Doudna was woken in her bed, Roger Penrose, 89, received a call from Stockholm while he was, in his words, "stark naked in the shower". In Nobel week, Tuesday is physics day, and on the other side of the Atlantic the British mathematician had just won the prize for his work in the Sixties on black holes – a discipline with notably fewer ethical conundrums than gene editing.
Eighty-nine was, he declared, a "good age" to receive a Nobel. "If you've got grand ambitions it's bad to get a Nobel too early," he said, arguing it "gets in the way of your science".
At 56, Doudna still has a lot of science she wants to do. When the pandemic struck, she and her colleagues switched to testing – becoming part of the network of laboratories that sprung up around the world to get ahead of the virus.
Now that that lab is running on its own, she has returned to Crispr, but with a pandemic theme. What if your Crispr machine was tweaked to seek out coronavirus? And what if, when it snipped out its DNA, it released a fluorescent particle to let you know? That's what she and her colleagues have made – a test that glows if coronavirus is present. They will be trialling it at Berkeley soon.
But how much involvement she will have is hard to tell. The second time we met, in her office, the world's first Crispr babies were entering their second trimester. As our interview ended, I had asked her the question I knew she was waiting for and to which there was – both of us knew – no dignified answer.
When would she get the Nobel? Was she expecting it? Would it happen in 2019? In 2020? She batted it off, as she had to. Then, as we were shaking hands to leave, she added conspiratorially, "You know the best thing? It's two women too – isn't that great?"
Doudna has already become the face of Crispr. Now, with the Nobel – the first Nobel chemistry award to be shared solely between two women – she and Charpentier have also become the face of women in science. A lot more of her already squeezed time must be spent, she says, as "an ambassador for science".
If this means less science, there are other compensations – as has already been pointed out to her. "The chancellor said, 'You know, there's this little prize, but really what we're giving you is a parking space.'"
Below Doudna's laboratory, on the corner of Oppenheimer Way, there is at last a section of pavement reserved just for her. Whether her car spends much time occupying it, though, is another matter.
Written by: Tom Whipple
© The Times of London
