The 2024 Nobel Prize in Physiology or Medicine goes to Victor Ambros and Gary Ruvkun for their discovery of microRNA, small biological molecules that tell the cells in your body what kind of cell they should be by turning certain genes on and off.
The Conversation Weekly podcast spoke with Victor Ambros from his lab at UMass Chan Medical School to learn more about the Nobel Prize-winning research and what comes next. Below are edited excerpts from the podcast.
How did you start thinking about this fundamental question underlying the discovery of microRNA, about how cells are instructed to do what they do?
The paper describing this discovery was published in 1993. In the late 1980s we were working and studying in the field of developmental biology C. elegans as a model organism for animal development. We used genetic approaches, where mutations that caused developmental abnormalities were then tracked to try to understand what was the gene that was mutated and what was the gene product.
It was well known that proteins could mediate changes in gene expression as cells differentiate and divide.
We were not looking for the involvement of any kind of unexpected molecular mechanisms. The fact that the microRNA was the product of this gene regulating this other gene in this context was a complete surprise.
There was no reason to suppose that there should be such regulators of gene expression. This is one of those examples where the expectation is that you will discover more about the complexity and nuance of mechanisms that we already know about.
But sometimes surprises emerge, and in fact surprises may be surprisingly common.
This C. elegans worms, nematodes, is there something about them that makes it easier to work with their genetic material? Why are they so important for this kind of science?
C. elegans was developed as an experimental organism that allowed people to easily identify mutants and then study their development.
It has only about a thousand cells, and all of those cells can easily be seen through a microscope in the living animal. Yet it contains all the different parts that are important to all animals: intestines, skin, muscles, brain, sensory systems and complex behavior. So it’s a pretty amazing system to really study developmental processes and mechanisms at the level of individual cells and what those cells do as they divide and differentiate during development.
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You looked at this lin-4 gene. What was your surprising discovery that led to this Nobel Prize?
In our laboratory, Rosalind Lee and Rhonda Feinbaum had been working on this project for several years. This is a very labor-intensive process that involves trying to detect a gene.
And all we had to rely on was a mutation to guide us as we gradually delved into the DNA sequence that contained the gene. The surprises started to emerge when we discovered that the stretches of DNA sufficient to transfer this gene’s function and rescue a mutant were very small, just 800 base pairs.
And that suggested: the gene is small, so the product of this gene will be quite small. And then Rosalind worked to further reduce the sequence and mutate potential protein-coding sequences in that small piece of DNA. By a process of elimination, she eventually showed that there was no protein that could be expressed from this gene.
And at the same time we identified this very, very small transcript of only 22 nucleotides. So I would say there was probably a period of a week or two where these realizations emerged and we knew we had something new.
You mentioned Rosalind, she is your wife.
Yes, we’ve been together since 1976. And we started working together in the mid-’80s. And so we still work together today.
And she was the first author on that paper.
That’s right. It is difficult to express how wonderful it is to receive such confirmation of this work we have done together. That is simply priceless.
As if it’s a Nobel Prize for her too?
Yes, every Nobel Prize has this clear limitation on the number of people it awards the prize to. But behind that, of course, are the people who worked in the laboratory; the teams that are actually behind the discoveries are sometimes surprisingly large. In this case, two people in my lab and several people in Gary Ruvkun’s lab.
In a way, they really are the heroes behind this. Our job – mine and Gary’s – is to act as representatives of this entire science enterprise, which is so dependent on teams, collaborations, brainstorming between multiple people, communication of ideas and crucial data, you know, all of this is supposed to be of the process underlying successful science.
Did you expect that first week of discoveries at that time that this could be such a big step for our understanding of genes?
Until other examples of something new are found, it is very difficult to know how peculiar that particular phenomenon might be.
We are always aware that evolution is amazingly innovative. And so it could be that this particular small RNA base-pairs with this mRNA lin-14 gene and switching off the production of the protein lin-14 messenger RNA, that could be a strange evolutionary innovation.
The second microRNA was identified in Gary Ruvkun’s laboratory in 1999, so it took more than six years for the second one to be found, also in C. elegans. The discovery of the turning point occurred when Ruvkun demonstrated it late-7the other microRNA, was actually preserved in perfect order among all bilateral animals. So that’s what that meant late-7 microRNA existed for about 500 million years?
And so it was immediately clear to the field that there had to be other microRNAs – this wasn’t just any one C. elegans thing. There must be more, and that soon turned out to be the case.
You and Gary Ruvkun were postdoctoral fellows at MIT at the same time, but by the time you made your respective discoveries, you had both set up your own laboratories. Would you call them rival labs in the same city?
No, I certainly wouldn’t call them rival labs. We actually worked together as postdocs on this development timing problem in Bob Horvitz’s lab.
We actually divided the work informally. The understanding was: okay, what the Ambros lab will focus on lin-4 gene, and the Ruvkun lab will focus on this lin-14and we expected that there would come a point where we would come together and share information about what we learned, and see if we could come to a synthesis.
That was the informal plan. It wasn’t really a collaboration. It certainly wasn’t a rivalry. The expectation was that we would divide the work and then communicate when the time came. There was an expectation in this community of this C. elegans researchers that you should share data freely.
Your lab is still working on microRNA. What are you researching? What questions do you still have?
One that I find very interesting is a project in which we collaborated with a doctor, a geneticist who researches intellectual disabilities. She had discovered that her patients, children with intellectual disabilities, in certain families carried a mutation that neither of their parents had – a spontaneous mutation – in the protein associated with microRNAs in humans, called the Argonaute protein.
Each of our genomes contains four genes for Argonautes that are the partners of microRNAs. In fact, this is the effector protein that is directed by the microRNA to its target messenger RNAs. This Argonaute carries out the regulatory processes that take place once it finds its target.
So-called Argonaute syndromes have been discovered, in which mutations occur in Argonautes, point mutations in which only one amino acid changes into another amino acid. They have a very profound and extensive effect on the development of the individual.
And by working with these geneticists, our laboratory and other laboratories adopted those mutations that were essentially donated to us by the patient. And then we put those mutations into our system, in our case C. elegans‘Argonaut.
I am excited about the highly organized, active collaboration between the Argonaute Alliance of families with Argonaute syndromes and the basic scientists who study Argonaute.
How can this collaboration possibly help these patients?
What we’ve learned is that the mutant protein is a kind of rogue Argonaute. It basically ruins the normal process that these four Argonauts usually perform in the body. And so this rogue Argonaute could basically be eliminated from the system by trying to use some of the technology that humans are developing for gene knockout or RNA interference of genes.
This is promising and I am hopeful that results for patients will emerge in the coming years.
This article is republished from The Conversation, an independent nonprofit organization providing facts and trusted analysis to help you understand our complex world. It was written by: Victor Ambros, UMass Chan Medical School
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Victor Ambros receives funding from the US National Institutes of Health.