3 Takeaways - Editing Life Itself: A Conversation with David Liu, the Scientist Who’s Rewriting DNA and the Future (#253)

Episode Date: June 10, 2025

What if we could rewrite the code of life—just like editing a Word doc?Gene-editing pioneer David Liu takes us behind the scenes of the revolutionary tools transforming medicine. He’s the Harvard scientist who invented base editing—a breakthrough that lets scientists fix a single DNA letter to correct genetic disease at its root.This is science fiction come to life—and it's happening now. He edits DNA like we edit text. Come meet the man who's changing lives, one letter at a time. 

What if we could fix the mistakes in our DNA that cause thousands of human diseases, just like editing a document? That's now possible thanks to powerful new gene editing tools that rewrite genetic code with pinpoint accuracy. Unlike older methods that disrupt genes by cutting DNA, these next generation techniques can make precise substitutions, insertions, and deletions. This means that we can now repair, not just silence, faulty genes. These tools are already being used in experimental treatments with life-changing results.

Could we soon cure most genetic diseases? And if so, what are the limits and risks of rewriting life? Hi, everyone. I'm Lynn Toman, and this is Three Takeaways. On Three Takeaways, I talk with some of the world's best thinkers, business leaders, writers, politicians, newsmakers, and scientists. Each episode ends with three key takeaways

to help us understand the world and maybe even ourselves a little better. Today, I'm excited to be joined by one of the most influential scientists in the field of gene editing. David Liu is vice chair of the faculty at the Broad Institute of MIT and Harvard, a professor at Harvard, an investigator at the Howard Hughes

Medical Institute, and the founder of over 10 companies with valuations in the billions of dollars. He has authored over 275 scientific papers, holds more than 110 U.S. patents, and has been elected to the National Academies of Science and Medicine. He is also the 2025 Breakthrough Prize Laureate in Life Sciences. Perhaps most notably, he's the inventor of base editing and prime editing, powerful tools he compares to a pencil and a word processor for rewriting our DNA. I'm excited to find out how these tools are already being used to correct genetic diseases

and what the limits and risks are of rewriting life. Welcome David, and thank you so much for joining Three Takeaways today. Thank you for having me. It is my pleasure. David, let's talk about DNA. When do mistakes in DNA occur? The structure of pretty much all DNA in all living systems

known is the same. The fundamental unit of A's, C's, G's, and T's have a certain chemical structure. That chemical structure is not perfectly stable. And so, mutations in our DNA occur ultimately because DNA is chemically not perfectly stable. For example, each of your cells have roughly one and a half billion C's, the letter C in DNA in it, cytosine. About 300 of them every day will spontaneously change into a U, which is a base that pairs like T instead of C, which can cause mutations.

In fact, that's the most common single letter mutation that causes genetic disease. The most common is caused by the instability of C. And then there are other ways the DNA can become damaged as well. Certainly, if you smoke, if you eat a lot of barbecued meat, if you expose yourself to carcinogens, if you expose yourself to sunlight, maybe most important, those are all sources of DNA damage as well. So our genomes are constantly being mutated by factors both within our control, but largely out of our control as well.

And of course, that can have profound impact on our lives if those changes happen to occur in just the wrong place. A baby was recently in the news for being treated with your gene editing tools. Can you talk about that? Sure, so the baby is KJ Muldoon, treated with your gene editing tools. Can you talk about that? Sure. So the baby is KJ Mulderne. And this is work that was co-led by Kieran Musunuru and Rebecca

Arens-Nicholas, both at Children's Hospital of Philadelphia and UPenn, and involved many, many researchers. So it's very important to give credit where credit is due. It's the definition of a village effort. Our lab developed the base editing technology that was used to correct KJ's mutation. But many labs contributed to identifying which flavor of base editor was the best to use,

manufacturing it, making the cells, and the animal model, the mouse model, and doing the monkey studies that were needed to de-risk to the extent possible the treatment. This is a very special case because the disease that KJ suffered from was a single letter change in a gene called CPS1 that has as a consequence that ammonia levels are elevated and can't get cleared through the normal mechanism. And that can be very toxic. It can be fatal. About 50% of patients with this disease don't survive past infancy. And it can cause constant long-term brain damage if levels of ammonia

remain high. There's an initial period, a sort of grace period where the infants appear to do better than after that grace period is over. And so, Kieran and Rebecca decided that baby KJ would be the first or they would make an all-out effort, a race really, to identify the genetic mutation causing the disease, to make a mouse model of that disease, that is a mouse with that genetic mutation in it, which itself is a significant undertaking, to test a variety of base editors, including some recommended from our lab that ended up being the one that was used in the treatment, performing off-target editing analyses to really try to understand what are all the different ways that the base editor could make the intended change,

but also what are all the possible ways it might make an unintended change, and try to quantify those and assess whether they cause any significant medical risk to the baby. Manufacture the base editor as a messenger RNA complex with an LMP, something that's sort of conceptually similar to the COVID vaccines that many of us got.

Submit all of this data to the FDA for approval to start a clinical trial. Somewhere along the way, do a toxicity study in monkeys as well, which is also a very significant undertaking. And then dose the patient. And the remarkable thing about this study is that it took less than seven months from the genetic diagnosis to the time the patient. And the remarkable thing about this study is that it took less than seven months

from the genetic diagnosis to the time the patient was dosed. And that list of milestones I just went through would normally take on the order of seven years, not seven months. So it was really a perfect storm where Karen and Rebecca and all of the participants, highly motivated by the urgency of the disease by the ticking clock that KJ faced, and I think also excited about, motivated by the fact

that when we looked at the individual components required, I think everybody thought, you know, this might be possible. This doesn't require us to invent anything else. I think all of the difficult stuff has really been invented, but it would require an unprecedented, at that time, coordination and synergy of many different groups' efforts to try to save baby KJ. And fortunately, the effort appears to be successful.

I think doctors are always hesitant to call something a cure until much more time has passed. But the result of receiving base editor injections that corrected the single letter misspelling back to the normal DNA sequence in KJ's liver is that KJ's blood ammonia levels have now dropped to around the high end of what would be considered normalish in an infant.

KJ can tolerate protein in their diet, which is normally a major source of ammonia being elevated, and so is normally a danger for patients with this disease, and is meeting developmental milestones that patients with this disease normally don't meet. So everything looks quite promising for baby KJ, and I think that's why it's been such a celebration for the communities involved, for KJ's family foremost,

for Kira and Rebecca's teams, and for everybody involved in this, I think, triumph of science. And it really is a triumph because KJ's prospects were really dire. And there were no other possible treatment options. And now, after this treatment, he's been released from the hospital. That's right.

That just happened today, supposedly. So. And what are some of the other genetic diseases that prime editing and base editing will help to treat or cure? Yeah, the list is extensive of the trials that are underway. They include liver disorders like alpha one antitrypsin deficiency.

There are blood diseases. Sickle cell disease has been treated in multiple clinical trials by base editing, installing mutations in fetal hemoglobin genes to reawaken them to compensate for mutated adult hemoglobin genes that cause sickle cell disease. So there are many, many other examples within these base editing and prime editing clinical trials that have been announced. How about leukemia or Alzheimer's or some of the diseases that have massive numbers of sufferers? Yeah, so the highlight of the Breakthrough Prize ceremony for me was being able to meet Alyssa Tapley. Now she's a 16-year-old incredible young lady in the UK who was and will always be the very first patient treated with a base-edited therapeutic. At the time, she was a 13-year-old

T-cell leukemia patient, cancer patient. If you have T-cell leukemia, the only two options before this point were getting a bone marrow transplant or chemotherapy and doctors tried both of those treatments on Alyssa and unfortunately neither resolved her T cell leukemia. So she was given the opportunity to participate in a then groundbreaking experimental clinical trial led by Dr. Waseem Quaseem at the University College London and Great Ormond Street Hospital, Ghosh. And that treatment was to take CAR T cells, install three base edits in those CAR T cells that allow those CAR T cells to attack Alyssa's cancer,

but not her healthy cells and not each other, because after all, CAR T cells are T cells, just like Alyssa's cancers are T cells so you have to figure out clever mechanisms to distinguish them. And then Alyssa was given these Tripoli base edited CAR T cells. They cleared her cancer very quickly so within the first month there was no detected cancer and she's remained cancer free now for I think a little more than three years. That is wonderful.

David, your lab is a chemistry lab, and your lab was most interested in DNA. And you and your lab discovered the gene editing tools that you're talking about, base editing and prime editing. Can you please explain in simple layman's terms what these are? First of all, consistent with everything we've talked about, science advances, even significant ones, that open up new capabilities all build on past science and ultimately on basic science. So I think everybody in your podcast

has probably heard of CRISPR. This is really a bacterial defense system to protect against viruses infecting bacterial cells, CRISPR was discovered first from realizing that there are repetitive DNA sequences interspersed with non-repetitive sequences over and over in bacteria. The R in CRISPR stands for repeats, repeating sequences, and the I is interspersed. So CRISPR is a pair of molecular scissors programmed by a piece of RNA to cut at a DNA sequence that matches the sequence of letters in the RNA called the guide RNA.

And CRISPR scissors naturally are used to disrupt, to mess up the genes of viruses so they can no longer propagate in bacteria. That's what Nature Evolved CRISPR to do. And then humans started to use CRISPR, in part catapulted by the really foundational paper by Martin Genick, Jennifer Doudna, Emmanuel Charpentier, and others in 2012, that showed you could reprogram these CRISPR scissors to cut DNA sequences of our choosing. That's really where we came in because cutting DNA,

cutting the DNA double helix into two pieces, literally, is very useful for disrupting genes, which can be used in a therapeutic setting in some cases where you have a gene that's misbehaving or a gene that you want to shut off. But for the vast majority of genetic diseases like those we've talked about today, the simplest way to treat a patient is to fix their already mutated gene, their already broken gene, to fix it back to the normal sequence. And so, base editors are machines that use the targeting mechanism, that beautiful RNA programmed homing mechanism of CRISPR. But we've actually disabled the ability of

base editors to cut DNA because we don't want them to cut and mess up the gene. It's already messed up. We want to fix the gene. So instead, we evolved proteins in the laboratory that we've added to the disabled CRISPR scissors so that they can find the DNA, but instead of cutting the DNA, these evolved laboratory proteins rearrange the atoms in one DNA letter to become a different DNA letter. And that's a way to directly do chemistry on the genome, ideally on just one place in your six billion letter genome. And that's a very powerful capability because about half of all known couple hundred thousand different mutations that cause genetic diseases, about half of them are simple single

letter swaps. Base editors can correct four of those major kinds of single letter swaps. Prime editors work through a different mechanism. They also use the targeting mechanism of CRISPR, that beautiful RNA guided DNA homing mechanism to find the target DNA site. But instead of cutting the DNA, like naturally occurring CRISPR,

and instead of rewriting the structure of one DNA letter like a base editor, a prime editor actually makes a new flap of DNA that contains the new sequence that you wish to edit. And that sequence, importantly, can be anything you type in. You can make a sequence that has any combination of letters in any order that you want. And then the prime editor guides the cell through a process by which that newly synthesized

flap of DNA replaces the original DNA on both DNA strands. And so the result is you can do what we call search and replace gene editing. You can insert missing letters, you can delete extra letters, and that's really the strength of prime editing is its versatility. And it also is extremely precise. What are the ethical issues that you see? It's been interesting.

I teach a class on gene editing. And I've taught it for quite a few years now. And early on, so 10 plus years ago, when I would pull the class during a lecture on the ethics of gene editing, I pulled them about all sorts of case studies. I tried to walk them down a slippery slope of cases like correcting the single letter misspelling that causes progeria, the devastating rapid aging disease. These progeria patients are most wonderful people. Almost everybody in the class,

they raise their hand when I ask if using base editing to correct progeria and treat progeria patients would be ethical. You know, then I ask about genetic hearing losses, where some people don't even consider deafness to be a disease. It's a very interesting and complicated debate that ultimately will boil down to how people feel about what it is to be human and whether humans should hold some level of sacredness about the, quote, original state of their genome. Although, as I point out, our genomes are constantly changing. So the, quote, native state of our genome itself may sort of not really exist. My perspective on it is that I appreciate arguments

from all sides of the spectrum. But I also like to point out that, to me, the ability to use our resources, our creativity, taxpayer money to improve the lives of our children, to give them a better shot at not being so beholden to the misspellings in their DNA, for example, I can't think of a trait that's more defining of humanity than that. So somewhere in the debate, I hope, is the consideration that, to me, it's a very human, a uniquely human characteristic to be

able to develop molecular machines that can rearrange the atoms of DNA to fix mutations that cause terrible diseases. Would it not also be a very fundamentally human thing to use them? And while it's easy to pontificate about the ethics when you're an outsider, I think if you become connected with patient disease communities,

you will quickly get a perspective that causes you to rethink just how much pontification versus in the trenches connecting with patients should shape your perspective. Interesting. David, all life is based on DNA. What are the possibilities of gene editing beyond humans? Gene editing is being used in animals and in plants

already with effect. You can buy gene editing produce in some restaurants and stores. You can use base editing and prime editing and the crisper scissors to make crops that are more nutritious, that are disease resistant, that are convenient, that can grow in climates that would otherwise be difficult to grow in, that are more productive,

that have a bigger harvest. You can use them to generate animals that also have characteristics that would benefit society and perhaps would benefit the animals as well. I think the opportunities have not been explored as much as maybe they should be, given that without the regulatory hurdles of drugs that end up in human patients, there is usually

a much shorter path to using gene editing to impact society through agriculture, for example. What are the risks of gene editing? Well, these are designs to be permanent changes in the genome. So first, you have to have a good understanding of what is the likelihood of making the desired change and what is the likelihood of making undesired changes.

I think we have a responsibility to minimize the likelihood that gene editing would initiate cancer, which is primarily the major risk of off-target editing. If an off-target edit is rare, as they almost always are, and causes a cell to die, frankly, if it's a 1% or 0.1% occurrence in most tissues, you'd never notice. But if it initiates cancer at a 0.1% frequency, you would definitely notice. So those are the kinds of risks that the field has been devoting enormous effort to understanding. And thus far, there hasn't been evidence

that editing has initiated a serious side effect in a patient, at least not one that I'm aware of. But as clinical trials for gene editing become more and more common, as more and more patients, there are now hundreds of patients that have been treated in these trials collectively. As that number grows, there will be patients who end up with unfortunate medical outcomes.

And then the question is whether their unfortunate medical outcome is the result of their gene editing or not. And that can be a difficult detective work, but is important to do so that we can continue to improve and maximize the chance that these medicines benefit patients and continue to minimize the risk that we expose them to. David, what are the three takeaways

you'd like to leave the audience with today? The first takeaway I would say is humans now have the ability, in some cases, to correct misspellings in our DNA that cause terrible disease, or perhaps to install changes in our DNA that prevent disease. And those are profound capabilities that society needs to be aware of, to, I think, support and to think about. That the science isn't science fiction anymore, it's science reality. Second, I would say that even though there's enormous benefit and therefore value to patients who suffer from these genetic diseases, to having their disease treated effectively by

correcting the root cause of the disease, that does not guarantee that there is an economically viable path to bring these new medicines to patients. And so we really need to decide how to invest as a public, as a government, as a society, so that we can connect this science with the millions of patients who urgently need and would benefit from these treatments. Finally, I'll say that pretty much everything that we've talked about came from public investment in basic science. Nobody could have guessed that studying repetitive DNA sequences in bacteria, in yogurt, could eventually lead to laboratory evolved molecular machines that rearrange the atoms in a DNA misspelling that cause a grievous life-threatening disease in order

to rescue a baby from that disease. But that's what's happened. And that's just one of many examples where public U.S. federal investment in basic science has returned manyfold gains, not just in our ability to save patients, but also economic gains. So from just about every perspective, all of this, I think, points to the same conclusion, which is we have to be doubling down

on US support of basic science. David, thank you. Thank you for joining Three Takeaways today. And thank you for your research and your discoveries that will lead so many people to lead healthier and better lives. Thank you so much for your interest. It was a pleasure. If you're enjoying the podcast, and I really hope you are, please review us on Apple podcasts or Spotify or wherever you get your podcasts. It really helps get the

word out. If you're interested you can also sign up for the Three Takeaways newsletter at ThreeTakeaways.com where you can also listen to previous episodes. You can also follow us on LinkedIn, X, Instagram and Facebook. I'm Lynn Toman and this is Three Takeaways. Thanks for listening.