This week's finds: the purpose of health research, the mystery of long distance enhancers, GMO regulations, and more.
Some worthwhile links to start your week.
1. What is the purpose of academic health research?
Our new dean of the school of public health at Washington University in St. Louis, Sandro Galea, lays out the real stakes in the current head-on assault of our health institutions in an editorial he co-authored with UC San Francisco’s Kirsten Bibbins-Domingo. They start out by correctly noting that the Trump administration’s crudely implemented policies, such as the proposed cut of indirect costs to 15%, would be “a near-existential threat to academic health research as we know it.” They also note that it is not clear how much, if any, of the proposed changes will stick. I’m still inclined to think that most of them won’t, but it’s a low-confidence opinion.
One way to think about the value of health research is through a cost-benefit lens. The authors point out that the scale of NIH funding, which is greater than any other funding body in the world enables large-scale projects and research infrastructure that wouldn’t be possible otherwise. Being a country that leads in such large-scale projects brings enormous benefits to the U.S. Publicly funded advances in vaccine technology and public health efforts for routine childhood vaccination prevent tens of thousands of deaths and tens of millions of illness over the lifetime of each year’s birth cohort, saving billions of dollars in societal costs.
But there is more to say in defense of academic health research than cost-benefit analyses. Galea and Bibbins-Domingo ask “How should we consider the value of academic health research, and perhaps, implicitly, of health itself?” Their answer is that the purpose of fostering health among all of our citizens is to give people the opportunity to have more agency over their lives:
The point of this work is to allow people to be healthy so they can live, however they choose to. Hence, in a world of ideological and partisan division, health should be the ultimate nonpartisan good. We do the research we do so that more people can live long, healthy lives, and live them as they wish to live them.
Those of us in academic health research should make it clear to our fellow citizens that we take this purpose seriously. We value the trust we’ve been given, largely through tax-payer dollars, to do work that is ultimately meant to make everyone’s lives better. As health researchers, regardless of what motivated us to go into science, the ultimate purpose of our work is to allow people and democratic society more broadly to thrive by reducing the burden of disease:
If a country sees itself as a robust, vibrant, thriving, and growing country—as certainly the US of myth and nationalistic narrative suggests it to be—it requires a strong academic health research enterprise to allow it to inhabit that vision of itself. That should make academic health research as core to the national identity as our vision of a democratic country that permits and encourages self-determination.
2. The mystery of long distance enhancers deepens.
Most of the functional genome consists of regulatory DNA, but exactly how regulatory DNA works is still one of the biggest mysteries in biology. Distal enhancers, which, in linear genomic sequence, are often located very far away from the genes they regulate, are among the most puzzling functional elements of the genome. We know a few things about them: they are bound by DNA-binding proteins, they are transcribed by RNA polymerase to produce enhancer RNAs (whose function, if any, is unclear), and their chromatin epigenetic state is often distinctly different from the DNA around it.
We also know that distal enhancers are typically very cell type-specific. Their specificity is why the same genome can specify the gene expression programs of the great diversity of cell types in the human body, which include motor neurons that transmit an electrical signal across the ~1 meter distance between the human foot and the base of the spine, and a ~100 µm cardiomyocyte that keeps up an unrelenting rhythmic contraction every moment of our life.
But what exactly happens, biochemically, when an enhancer activates its target genes? This is still mysterious. What does an enhancer deliver to the target gene promoter? How close in 3D space, and for how long, does it need to be to deliver whatever it is that it delivers? Why do enhancers often skip by the nearest gene to target another, more distant one?
One source of clues about enhancers are cases when one long distance enhancer regulates more than one gene. In these cases, two different target genes seem to compete for the enhancer, suggesting that the enhancer can only do whatever it does at one gene at a time.
A new paper in Genes & Development casts doubt on that idea. The paper describes a single enhancer that regulates two functionally unrelated genes, and it can do so without any competition between the target gene promoters.
The study, led by Wouter de Laat of the University Medical Center Utrecht in the Netherlands, describes an impressive series of deletion experiments that tease out the role of this particular enhancer in shaping the local 3D genome structure, thereby allowing its two target genes to come into close proximity.
Those who care about the details should check out the paper, but I’ll just make two comments about this investigation into one of the most critical molecular processes at the foundation of life: First, the enhancer itself, and not just the normal CTCF/Cohesin machinery seems to be important for shaping the compact 3D genomic domain that brings the enhancer and its target genes close together. Not all enhancers do this, as far as we can tell. And second, there seems to be no competition between the enhancer’s target genes, meaning that whatever it is that this enhancer brings to a target gene promoter, there is enough of it to go around. When the investigators inhibited one target gene, there was no effect on the other, which is not what we expect if the gene promoters were competing for the enhancer’s attention.
This is further evidence that not all enhancers work in the same way, and that is what makes these regulatory DNA elements so mysterious. Enzymes aren’t like this - alcohol dehydrogenases all more or less work the same way (to the best of my knowledge). But ‘enhancers’ may not be a natural biophysical category–different regulatory DNA sequences may have evolved to activate their target genes in different ways.
3. Will GMO regulations slow down new therapeutic biotechnologies?
The March 2025 issue of Trends in Biotechnology has several pieces reflecting on the 50-year legacy (or notoriety) of the Asilomar meeting on the then-emerging technology of recombinant DNA. For some scientists, Asilomar is an example of the community showing the ability to regulate itself: the rapidly developing ability to move genes around among species had potentially catastrophic consequences (in the view of some), and so scientists agreed on a moratorium until the issues could be more carefully considered. Others consider Asilomar the epitome of scientific arrogance, because scientists assumed that they, and not legislators, should be the ones to decide how to handle the risks of recombinant DNA. (This is for another day, but I think neither of those positions is correct.)
A piece by Hans-Georg Dederer, a law professor at the University of Passau, Germany, discusses how GMO regulations might inhibit medical advances based on new genetic technologies. He begins with a premise that I agree with (and, again, will discuss another day):
The 1975 Asilomar conference contributed to the misperception that recombinant DNA (rDNA) technology is inherently risky to human health and the environment.
Dederer argues that Asilomar confused the risks of a process–methods and technologies that involve recombinant DNA–with risks of specific products that should be evaluated on their own merits, and not by virtue of the fact that recombinant DNA was used to create them. He writes about how this confusion, a legacy of Asilomar, could obstruct the approval of new therapies based on CRISPR or other gene editing technologies, or pharmaceuticals that are produced by what Europe categorizes GMOs. While Europe has made some modifications to their laws to address concerns like this, Dederer argues that the law has not kept up with the rapid technological progress, and thus may work to hinder the arrival of say, new cancer therapies based on genetically engineered cells.
It’s a thought-provoking article that puts current debates within the larger historical context of post-Asilomar views on genetic engineering.
4. Early origins of the human genome project
Bob Waterston, former chair of the Department of Genetics at Washington University in St. Louis, was one of the early movers and shakers of the Human Genome Project. His insights were crucial to developing many of the important technologies that got the project off the ground, and his role is why we here at Washington University have a Genome Institute today. Waterston later moved from Washington University in St. Louis to the University of Washington in Seattle, where he became chair of the Department of Genome Sciences. (The fact that he was chair at both places does not help the common confusion of the University of Washington with Washington University.)
Waterston has a memoir out in the Annual Review of Genomics and Human Genetics. It’s an insightful and well-told account of how one of the most consequential efforts in biology came to be. If, like me, you’re inspired by frank accounts of how stuff really gets done in science, don’t miss this. Also, for a second perspective, I posted a transcript of a talk by another of our former chairs, Mark Johnston, who was deeply involved in these early days of genomics.
5. A Brief History of Intelligence
I have been a New York Times subscriber since the 90’s. For most of that time, one of my favorite sections was the book review. But something there seems to have changed–these days I rarely find reviews of anything that interests me. Part of the problem is that they’ve turned half of the book review into a listicle section, and the other problem is that they now rarely (not never, just rarely) review serious books on science or intellectual history that connects to science. They also review basically no fiction that interests me. The whole book review section has become boring.
I now get my book review fix from The New York Review of Books, a list of interesting literature posters on X that I follow, and from recommendations on Substack. I found something interesting this week that I’ll pass along here–Max Bennett’s A Brief History of Intelligence. It came out in 2023, but if it was reviewed in the NYT I missed it. (And a search didn’t turn up anything.) I found the book due to a recommendation by Stetson, author of the interesting Substack newsletter Holodoxa, and the economist Jason Furman:
Here is the book’s description:
Artificial intelligence entrepreneur Max Bennett chronicles the five “breakthroughs” in the evolution of human intelligence and reveals what brains of the past can tell us about the AI of tomorrow. In the last decade, capabilities of artificial intelligence that had long been the realm of science fiction have, for the first time, become our reality. AI is now able to produce original art, identify tumors in pictures, and even steer our cars. And yet, large gaps remain in what modern AI systems can achieve—indeed, human brains still easily perform intellectual feats that we can’t replicate in AI systems. How is it possible that AI can beat a grandmaster at chess but can’t effectively load a dishwasher?
Max Bennett, the book’s author, is a tech entrepreneur and not a historian or scientist. I don’t usually buy big think books by people who aren’t scholars in the field, but I’m making an exception for AI. The field is moving really fast, and so much of the innovation is taking place outside of academia. Anyway, I’m on an AI reading binge. While I haven’t read this one yet, I thought the recommendation was worth passing on.