The ethics of editing humans and the scientist who helped make it easy
Jennifer Doudna co-discovered the Crispr tool that could cure disease and change the human race
Jennifer Doudna: “On the one hand, it sounds very profound and potentially very scary to be editing the human population. But it takes time and it doesn’t happen overnight”
Jennifer Doudna wears her responsibility lightly. The scientist who co-discovered Crispr does not appear to be weighed down by the burden of her creation: the revolutionary gene-editing technology that promises to empower humans to control our own genome. She waves and smiles as she bypasses the hostess stand at Gather, an organic, farm-to-table restaurant in Berkeley. It’s the sort of place that wears its principles on its sleeve – a fitting venue for a discussion of the ethical conundrums that has unleashed.
The 55-year-old appears to have thrown on her blazer in a rush, squashing down one side of her shirt collar. Since news of her scientific breakthrough was published in 2012, she has learnt to toggle between the white coat of her lab work, building on that initial discovery, and her suited-and-booted role pushing politicians and lawmakers to contemplate the consequences of changing the human genome.
She has also found herself at the heart of a maelstrom. Crispr is now the simplest, cheapest and most accurate way to edit our DNA, but its development raises a multitude of moral questions. Fine-tuning our immune systems to fight cancer is one thing - but given how much we have still to discover about the genome, what might be the unintended consequences of altering it? These are not merely speculative questions. In the years since Doudna’s discovery, a Chinese scientist sent shockwaves through the international scientific community when he announced the birth of the first Crispr-modified babies.
“One of the big challenges with gene editing is to think about how we take a very powerful technology that has a lot of potential and make it more widely available
“One of the big challenges with gene editing is to think about how we take a very powerful technology that has a lot of potential and make it more widely available,” says Doudna, as we settle down at a small table in the light-filled room. “I don’t want it to be something that is only available to a few. That’s a big push, a big challenge.
“But also we need to be thinking about these broader implications of a powerful technology and how to develop them responsibly.”
A molecular biologist had noticed the presence of mysterious sequences - Clustered Regularly Interspaced Short Palindromic Repeats - in bacteria’s immune systems in the late 1980s, but hadn’t been able to figure out what purpose they served. When Doudna first started studying these sequences in the mid-2000s, it seemed highly unlikely that the work could lead to patents that could be worth billions. At that time she was a leading specialist in RNA, an essential molecule in the production of proteins.
In collaboration with French microbiologist Emmanuelle Charpentier, she homed in on an enzyme called Cas9. The pair discovered that Crispr segments could be used to guide Cas9 to locations on the genome, where it would then cut like scissors. Together, Crispr and Cas9 could snip out genes or change their function far more precisely than the clunky existing tools. This technology has become known as Crispr.
The years since have seen a frenzy of Crispr-ing. Scientists are developing Crispr-modified tomatoes that are more resistant to disease and Crispr-ed beer that tastes more hoppy.
Meanwhile, researchers are using Crispr to learn more about the human genome, experimenting with what happens when you snip certain genes out. Patients with cancer and blood diseases have been treated by having their blood cells taken out, Crispr-edited and put back in. This year, the first Crispr gene-edits will be done in human cells while they are still in the body, in trials to treat rare diseases in the eye and the liver.
Anyone with basic scientific knowledge and materials bought online can experiment with Crispr in their own garage. Some so-called biohackers are already injecting themselves with genetic material: for example, trying (and thus far failing) to engineer more muscle.
Doudna agrees that there are dangers with these home-brew experiments, but – perhaps surprisingly for a professional scientist – welcomes them as part of the democratisation of science.
It’s a little bit analogous to the internet, where you have people working around the world. They don’t have to have lots of special resources to contribute to the content of the internet
“It’s a little bit analogous to the internet, where you have people working around the world. They don’t have to have lots of special resources to contribute to the content of the internet, or to develop the software that has become widely available,” she says. “It’s kind of the same thing with Crispr. It’s interesting that it’s being adopted widely and globally and now we see really impactful work coming from all sorts of avenues.”
But having failed to create robust international rules for the internet - and won’t regulating Crispr be even harder? Many governments, including those in the EU and China, have made moves to ban the editing of egg and sperm cells - “germline editing” - and in the US, this in effect is the case as the FDA is not allowed to approve germline editing studies. However, there are few rules specific to Crispr and, as with online hackers, it will be challenging to enforce laws on people who use gene editing dangerously.
On the one hand, it sounds very profound and potentially very scary to be editing the human population. But it takes time and it doesn’t happen overnight
“On the one hand, it sounds very profound and potentially very scary to be editing the human population. But it takes time and it doesn’t happen overnight,” she says. “Whereas the internet...things go viral and they’re global almost instantaneously.”
The most disturbing development in Crispr’s history did not happen in a biohacker’s basement. In November 2018, Doudna received an email from Chinese scientist He Jiankui, saying he planned to announce the birth of Crispr-edited twins at an upcoming conference in Hong Kong.
The children were engineered without the knowledge of the international scientific community, whose leading members - among them Doudna - had been pressing for a moratorium on germline editing. Crispr-Cas9 is very good at cutting, but it leaves cells to fix themselves, opening the way for potentially dangerous mutations. Doudna felt it was important to improve the accuracy of these repairs, as well as to discuss the broader repercussions of the technology. He went ahead regardless.
“It was around Thanksgiving weekend, the US big holiday weekend,” says Doudna, of the email. “I guess my initial reaction was, ‘I wonder if this is real’, but I had this feeling that it probably was.” She dropped everything and flew to Hong Kong to manage the media fallout. The poor quality of He’s data convinced her his study was real. “If you were going to fake it, you would fake it better than that,” she explained later.
He claimed to have edited the embryos to protect them from HIV, which their father had. Scientists decried it as unnecessary - it is very rare for HIV to pass from father to child - and potentially harmful, as we cannot know the long-term effects of the edit.
“The repair was different in different embryos, so he created changes to the DNA that honestly had probably never been seen in the human population and never even tested in animals,” says Doudna. He thought he would be a “hero”, she believes. But at the end of last year, he was sentenced to three years in jail and fined Rmb3 million ($390,000).
I think it really does make a strong statement to others that might consider doing that kind of work, that this is just not appropriate to do right now and it will not be accepted, will not be tolerated
“One never wants to see that kind of outcome,” she says softly, as our main courses are placed on the table. “I think it’s kind of sad - he has a young family and I feel for them. But I think it really does make a strong statement to others that might consider doing that kind of work, that this is just not appropriate to do right now and it will not be accepted, will not be tolerated.”
Calls for moratorium
Doudna declined to sign another call for a moratorium after the revelation of the Chinese babies, saying that there needs instead to be appropriate regulation of gene editing. In A Crack in Creation, a book she co-authored in 2017, she wondered whether we would ever have the intellectual and moral capacity to make decisions about germline editing. I ask if she still feels that way.
“I would say my feeling today is that, like it or not, we’re going to have to figure it out,” she says.
In 2016, James Clapper, then US director of national intelligence, added genome editing technology such as Crispr to a list of “weapons of mass destruction and proliferation”, pointing to the possibility that it could be used to develop “potentially harmful biological agents or products”. Since then, Doudna had attended national security events to cut the science fiction down to fact: “not get too far down the road with Crispr soldiers and crazy stuff like that”.
I’ve grown up in a capitalist society where you believe that as technologies become more capable, the cost is driven down
She has also made several trips to Congress to speak to senators. “I worried that it would all be about [THE CHINESE]Crispr babies. It actually wasn’t,” she says. Instead, the senators saw Crispr through their own preoccupation with the soaring cost of healthcare.
Existing gene therapies can cost more than $2 million (€1.8 million) for a one-time use. Crispr could allow for new cures that senators feared would place an impossible burden on the healthcare system. Although the first targets of trials in humans are serious diseases that we know are caused by a single gene, such as sickle cell or Huntingdon’s, as we understand more about combinations of genes increasing risk factors for other diseases, Crispr could be used more widely.
“They said, ‘Oh my gosh, if we’re on the verge of a cure for sickle cell disease, and we have 100,000 people in the US [affected by the disease]...how do we cater to that? How do we make sure they all have access to it and they don’t bankrupt the government?’,” she says.
Investors and future innovation
Crispr is already luring investors: Doudna has co-founded several Crispr start-ups including Caribou Biosciences, which is working on editing the immune system’s T-cells for therapies, and Mammoth Biosciences, programming other Cas proteins to detect disease in patients or contamination in food or the environment. She has also joined the board of Johnson & Johnson, a sign that while large pharmaceutical companies appear to be waiting before they invest heavily in Crispr, they are watching closely.
I think they see the writing on the wall. I think they appreciate the importance and the power of the technology for research
“I think they see the writing on the wall. I think they appreciate the importance and the power of the technology for research,” she says. “We’re going to have to rethink how we even define a drug.”
How can she make sure Crispr is not prohibitively expensive? Her answer is simple: with more innovation. “The more efficiently you can do the editing, the more effectively you can deliver editors into cells, whether plant cells or the human brain or anything else, the better it will work, and the more you can control cost,” she says.
“I guess I’ve grown up in a capitalist society where you believe that as technologies become more capable, that it enables more companies to do interesting things and then it drives down cost and we’ve seen this over and over.”
She points to the iPhone as an example of a technology that was once the stuff of sci-fi and is now widely available. Yet it seems wishful thinking to imagine the same will happen for the drug market, with its web of entrenched interests and government-granted monopolies.
As the market begins to take off, lawyers are battling over who owns which Crispr patents. UC Berkeley, where Doudna is based, and the Broad Institute of MIT and Harvard, home of scientist Feng Zhang, are in a drawn-out dispute over when the scientists filed and over the use of the technology in human cells. UC Berkeley is currently ahead with 20 US patents and the European patent office recently cancelled a Crispr patent from the Broad. The Broad has said it wants to reach a resolution with UC Berkeley.
Doudna says the disagreement has been “very disappointing for me, as a scientist and as a person” - whether because of an earnest sense of dismay over the dispute between fellow scientists, or the potentially billions of dollars in licensing fees that are at issue for the discoverers and their universities. “When I get frustrated I try to take the long view,” she says. “I try to imagine how I would feel 50 or 100 years from now, if I came back and I was looking at this whole story. This will be one piece of the story.” – Copyright The Financial Times Limited 2020