LOS ANGELES — Francis Collins stepped down from his position as head of the National Institutes of Health at the end of last year — but he’s been staying plenty busy in 2022, serving until recently as acting science adviser to President Biden.
STAT spoke with the trailblazing genetics researcher at this year’s annual meeting of the American Society of Human Genetics in Los Angeles. Read on to learn more about Collins’ latest projects, progress at his lab in the Center for Precision Health Research at the NIH, and his thoughts on where genetic research may be heading next.
Here’s the full conversation, lightly edited for brevity and clarity.
Dr. Collins, thank you so much for speaking with me. Can you tell me what you’re up to these days?
It’s been an interesting year. I thought I’d be spending most of my time in my lab, working on some writing projects, maybe taking a little mini-sabbatical here and there, but then I got asked by the president to be acting science adviser back in February. So that was all-consuming for the next seven months. I’m not complaining. It was incredibly interesting and significant, and I got to learn about a lot of things that go well beyond my own expertise — things like semiconductors and fusion energy and technology to fight wildfires.
Then Arati Prabhakar got confirmed by the Senate as the science adviser and [Office of Science and Technology Policy] director and was sworn in three weeks ago. But the president asked me to stay on for a few months more to work on a few projects — the main one is hepatitis C. This is the opportunity to take a disease that’s killing tens of thousands of people every year and for which there is a cure, but it’s not getting to the people who need it. That seems like something worth trying to fix.
And what is your lab up to?
The lab happily has been up and running consistently since 1993 when I arrived at NIH from Michigan and asked permission to keep my hand in research. We’ve been pushing in two areas. One is diabetes, trying to understand the genetic factors and how they work. That has turned into a stem cell-driven enterprise, which is exciting. The other is this rare disease called progeria, the most dramatic form of premature aging, for which my lab found the cause almost 20 years ago. We now have an FDA-approved drug, but it’s not a cure. We are aiming for a cure with in-vivo gene editing, and that’s a big leap but going pretty well.
Your lab co-discovered the cystic fibrosis gene in 1989 amid hopes a cure would come soon. What lessons can we take from the journey to find a treatment?
I think the expectation was that CF would be a good candidate for gene therapy — it seemed simple, you would just package up the necessary gene and get a virus to deliver it and everything would be fine. That thinking was naive and massively underestimated the immune system’s ability to discover what you are doing and upend your plans. What followed was a decade of real frustration. The gene therapy approach just wasn’t giving a big success story. That frustration then led to, particularly because the CF Foundation was willing to take a big risk, taking a small molecule approach. Most people in the ’90s would have said that would not work. Now here we are with Trikafta, an amazing advance for 90% of CF patients.
What about other, rarer genetic diseases that don’t have such investment and backing? Or diseases that have been so difficult to treat, like Huntington’s.
I’m more optimistic now that we might get to them by the ability to do in-vivo gene editing because that’s scalable. If you have an appropriate menu of delivery systems to go to the tissue where you want to send your CRISPR-Cas, and you have base editors that are precisely able to change almost anything in the genome that needs to be fixed, then you’ve got an approach that ought to be applicable across many diseases, including Huntington’s. For Huntington’s obviously you’re going to need a delivery system that gets to the right part of the brain, and is capable of snipping out or somehow inactivating the triplet repeat expansion that creates this toxic protein, but with gene editing that’s actually imaginable. There are an estimated 6,400 human genetic diseases where the DNA mutation is known. Those ought to be candidates for this kind of in-vivo gene editing strategy.
What about sickle cell disease? That was another one that seemed so simple to cure on a whiteboard.
Right, we’ve known how simple it was supposed to be for a long time. And now it’s finally happening. I’m enormously excited about sickle cell because, at least in small numbers, we are curing people, both with bone marrow transplants and now with gene therapy. That’s all ex-vivo, which is incredibly demanding in terms of resources and somewhat risky because you’re having to use bone marrow ablation to make room for the corrected cells. If you want to see that approach extended to the 100,000 people in the U.S. who have sickle cell or the roughly 5 million in sub-Saharan Africa, it can’t be done this way. I think what we need is an in-vivo gene editing approach where you would utilize some kind of delivery system that homes just to the hematopoietic stem cells in the bone marrow, and then delivers the payload — a gene editor to fix the sickle mutation or turn on fetal hemoglobin. NIH and the Gates Foundation are committed to pursuing this as a 10-year project, seeking a cure for sickle cell disease that could be done on an outpatient basis in a low-income setting.
When I was reporting in D.C., you were racing against Craig Venter to sequence the first human genome. So much has happened since then. Which advances in gene sequencing are you most excited about?
People tend to think of sequencing as the application to whole DNA genomes. But in reality, sequencing has opened a whole lot of other doors. Now almost every lab that is interested in biology doesn’t just do DNA sequencing, they do RNA sequencing, and sometimes even in single cells. That’s dramatic, and something that a lot of people haven’t absorbed — that you can ask a single cell what it’s doing. It’s just mind-blowing that this is possible. That’s what we are doing in the diabetes project in my lab, trying to understand what’s going on in the pancreatic islet, cell by cell by cell. The results are very different from what you might have guessed by just looking at chunks of tissue. For clinical applications, the whole genome sequence is incredibly powerful for newborns who have some clear sign that something is wrong, but no one can figure out what it is. You can save weeks, months of investigation by simply getting the DNA sequence.
Then of course, cancer has just been turned upside down by the ability to do cheap and accurate sequencing in a timetable that enables a choice about therapy. Taking that approach to early detection, screening blood samples for cell-free DNA may turn out to be the way we can find very early cancers in the body, while they are completely curable. But we have to be careful not to assume that the paradigm is already established. The reignited Cancer Moonshot includes a rigorous assessment of whether this actually changes the outcome. If all you are finding with cell-free DNA is stage 4 disease that would have been discovered soon anyway, that’s not that helpful. The real question is whether you are finding stage 1 that can lead to a cure.
Let’s talk about the scientific workforce. I see people saying they can’t attract postdocs, in part because so many candidates are being lured to biotech companies. Do you see this as a problem for science?
Yes and no. There’s an active market in biotech and pharma for recently minted Ph.D.s. But at the same time the demand for academic postdocs is not being met. A lot of young scientists are less willing to go from graduate school to a postdoc when they have competitive opportunities in industry that might be more compatible with work-life balance and pay a better wage.
Is this good for those students? I’m not sure it always is. I am a big fan of skipping the postdoc if it’s not needed to become an independent investigator — I started an NIH training program for those exceptionally well-prepared Ph.D.s. But for a lot of young scientists, an academic postdoc is an opportunity to mature your capabilities. I do worry about Ph.D.s for whom a postdoc would have been a good intellectual scientific experience, but instead landed in a biotech company that may or may not encourage their independence.
A big problem is there are not enough tenure-track academic jobs opening up. I wish academic institutions would make a higher priority of figuring out how they can open up new slots for more scientists.
As director of the NIH, you publicly apologized last year for structural racism and inequities in funding to researchers in groups underrepresented in science. What kind of change have you seen since?
The change at NIH has been profound. It was really initiated across the board in the summer of 2020 in the wake of the killing of George Floyd, and the realization of many of us that NIH is part of a culture of systemic racism that’s been there all along. All of the data was in front of us already about the lack of diversity of the workforce, and the lower success rate of African American applicants for NIH grant support. But we had to look at this unflinchingly in a way that was not just “admiring the problem” (as we were sometimes accused of), but figuring out what we were going to do about it.
That led to the founding of the UNITE program, which has become the framework for a whole host of actions NIH is absolutely committed to. That includes doing something more substantial about the diversity of the workforce, doing something about the discrepancy in funding, and doing something about our health disparities research, which seemed to be mostly about cataloging problems rather than initiating pilot interventions to see if those disparities could be modified. We did a lot of listening, and we are not going back to where we were before this.
What are you most excited about at this meeting?
I’m doing a lot of schmoozing — it’s been so good to see people I haven’t seen in three years. I am spending a lot of time with young people at this meeting because they’re the future. I’m, I guess, recognizable, so a lot of trainees come up and tell me what they’re working on, and I love that. I’m in a lot of selfies. So I’m just dabbling in all of the sessions, and soaking it up.
My own research interests are in epigenomics, and anything where someone’s coming forward with therapeutics. I do think genetics has come to the point where we have the chance to do more than diagnostics, and actually figure out how to cure people. We’re at this remarkable scientific moment with the opportunity to learn how life works and how disease happens and what to do about it — at a pace that’s unprecedented. It’s really exhilarating. I know there are lots of other problems in the world, but science is just rocketing forward.