Scientist of the month: Phillip Zamore

Phillip Zamore talks to us about his research into small RNA silencing pathways.

Brief biography

Phillip Zamore, PhD
Phillip Zamore received his undergraduate and PhD degrees in Biochemistry and Molecular Biology from Harvard University before completing postdoctoral studies at MIT and the Whitehead Institute for Biomedical Research. Today, he is the Gretchen Stone Cook Professor of Biomedical Sciences at the Howard Hughes Medical Institute and managing co-director of the RNA Therapeutics Institute, University of Massachusetts Medical School. His lab studies small RNA silencing pathways in eukaryotes and prokaryotes.

In 2014, he was elected a Fellow of the National Academy of Inventors, and in 2015 he received the Chancellor’s Medal for Excellence in Scholarship at the University of Massachusetts Medical School. Nature Biotechnology selected him as one of the Top 20 Translational Researchers of 2014.

Why did you decide to become a scientist and how did you first become interested in RNA silencing pathways?

I decided to become a scientist in high school, after taking a Saturday morning course at Columbia University. The topic was protein synthesis, and the professor’s description of the ribosome was the most amazing thing I’d ever heard. I was hooked by the end of the lecture.

My introduction to RNA silencing began when I presented the 1998 Fire & Mello Nature paper as a journal club in the Bartel lab, where I was a post-doc. Unknown to me, Tom Tuschl was scheduled to present his experimental progress to the group at the same meeting, and he described his strategy to recapitulate RNAi in a cell-free extract. I loved the idea, but not his choice of organism (Ascaris). I advocated that he use fly embryos, and he proposed we do it together!

What has been the most memorable moment for you during your research?

Definitely the day Diane Schwarz, György Hutvágner, Martin Simard, and I figured out how the cell knows the difference between the microRNA strand and the miRNA* strand of a pre-miRNA. It really drove home to me the importance of thinking about data and its meaning in a group of smart people obsessed with the same biological problem.

What are the biggest challenges facing your research at the moment?

First, there are too few hours in a day. Second, genome assembly and annotation is still too time consuming. Third, bioinformatics in general has become the limiting step for most of our experiments. Playing with sequencing data is just much harder than playing with kinetic or biochemical data. The level of skill required can take years for a student or post-doc to attain. Partnerships between experimentalists and computationalists work, but not nearly as well as when the wet and dry experiments are done by the same person.

What would you say are the major questions still to be tackled in the RNA field?

Of the three major classes of small RNAs in animals – siRNAs, miRNAs, and piRNAs –​ we really don’t understand the biological function of miRNAs or piRNAs except for a small number of relatively special miRNAs or classes of piRNAs, and even then in just a few exemplary systems. We all like to pretend we understand, but most of our models remain unproved.

For example, the piRNA biogenesis machinery is concentrated in several different intracellular locations: in a mysterious structure surrounding the germ cell nucleus (nuage) and on the outerface of the mitochondrial membrane. We like to pretend these correspond to “factories” where piRNAs are made by stepwise processing. Yet we don’t even have tools to detect where and when the processing events occur in the cell. Knowing where molecules are abundant is not the same as knowing how they are made in time and space. And we definitely do not understand how a germ cell knows which RNA sequences should become piRNAs and which should not.

Looking at the future, where do you think the field is going over the next 5–10 years

I think the small RNA field will head in two complementary directions: deeper biochemistry and broader use of non-model organisms. Evolution often provides the best clues as to how things work. As we explore small RNA production and function across a broader array of animals, I think we will find recurring themes and molecules. For my lab, this means expanding our work from fruit flies to other non-model insects.

You recently became director of the RNA Therapeutics Institute. What does this institute mean for RNA research?

The RTI is a bit of a social experiment. We are testing the hypothesis that if you put really smart fundamental and applied scientists together in a collegial, well-resourced environment, basic discoveries will be translated into novel research tools, diagnostics, and medicines faster and more effectively than if you insist that people focus on so-called translational science.

If you could specialize in any other field of science (or any other discipline), what would it be, and why?

I’m a huge admirer of the study of the microbiome, particularly how the microbiome influences healthy and dysfunctional metabolism in animals. In a way, the microbiome is the most extreme example of epigenetic regulation: the genetic information that regulates our phenotype is encoded in another living organism distinct from ourselves.

Are there any historic scientists that you draw inspiration from?

Morgan. Not only did he invent the idea of a model organism (flies), but he understood that data always trumps elegant ideas. I’ve read that he hated the idea that chromosomes were the basis of heredity, yet we all know that it was his lab that proved they are. He filled his lab with smart young scientists, which remains the essential ingredient in the modern biology lab.

One thing you could not live without? (inside or outside the lab)

My family.