#3 - Interview with Michael Snyder
It wasn’t that long ago that RNAs were regarded as rather static molecules. The information encoded in DNA is transcribed to messenger RNA (mRNA), which squeezes out of the nucleus to ribosomes in the cell, where proteins are made. Transfer RNAs (tRNA) in turn truck amino acids to the ribosomes in the correct order for protein production. These are crucial functions to be sure, but also straightforward. RNA was, to put it bluntly, kind of boring from a research standpoint.
How things have changed. As it turns out, there are many kinds of RNAs performing other vital, often complex functions in cells. And much of our understanding of one of the most intriguing forms — micro RNA (miRNA) — is thanks to the work of V. Narry Kim, Ph.D., who has made many significant contributions to the field since receiving her Ph.D. fewer than 20 years ago. Dr. Kim now directs the Center for RNA Research at the Institute for Basic Science, Seoul National University, and was presented with the Chen Award at the recent Human Genomics Meeting in Barcelona for her outstanding work.
V. Narry Kim, Ph.D., directs the Center for RNA Research at the Institute for Basic Science, Seoul National University.
Over breakfast before the last day of the meeting, Kim discussed her interest in miRNA and the value of understanding biological details.
miRNAs are short [note: usually 21-25 nucleotides in length] RNAs that don’t code for proteins but are nonetheless highly conserved across species. They regulate many targets, such as in mRNA suppression, where they prevent an mRNA from being translated into a protein. miRNAs are in turn regulated by many other parts of the system. We know that they’re very important because they’re conserved, and also experimentally. For example, when we knock them out in mice, the mice get very weird, to be non-technical.
Earlier we developed a model for how miRNAs are made in the cell and how that process is regulated. We’ve now expanded our program into multiple projects. In one, we’re looking at aspects of miRNA function in cells, such as how they help determine how stem cells differentiate into different mature cells and tissues. We’re also researching the structure of miRNAs, both alone and in complex with proteins, and determining how miRNAs are recognized and processed within cells. This project will help with miRNA gene annotation as well, as we can use knowledge of how they’re processed to improve database entries, many of which are currently inaccurate or incomplete. Finally, we’re studying different kinds of RNA modification and post-transcriptional control. RNA-protein interaction is important, and there are many different kinds of interactions, with many functions. We’re developing methods to map out the sites on the molecules that interact and determine the RNA sequences that are recognized by proteins.
We work in mammalian cells (human and mouse) mostly, but because miRNAs are so highly conserved, we use other animal models such as Drosophila and zebra fish to make comparisons and focus on what’s conserved between them.
It’s true that we’re looking at fundamental biology at this time. But the mechanisms can be applied to any biological context: development, disease, cancer, degeneration. RNAs play many roles in many different processes in the cell, and you need to elucidate the basic rules that apply — you need to understand how it actually works — before you can know what happens when it goes wrong. That said, some of my students are interested in developing focused applications for RNA-based research after their work in my lab. So we’re building a foundation, but the knowledge we gain may be very useful for more translational or applied research in the years ahead.
Charles Lee, Ph.D., FACMG, began his term as president of the Human Genome Organisation (HUGO) at the annual Human Genome Meeting in early February in Barcelona, Spain. As genomic data pile up and clinical implementation of genomics becomes a reality, it is important to address many issues associated with genomics and precision medicine now rather than someday in the future. After a meeting packed with impressive science and compelling presentations, Dr. Lee contemplated HUGO’s place in the global research and clinical communities and its value moving forward.
Q: HUGO originally formed in 1988, and for almost three decades its focus has been on sequencing the human genome and providing international standards for genome research findings. Do you foresee changes as HUGO approaches its 30th year?
A: Yes, I do. Sequencing has become relatively commonplace and new capabilities are rapidly emerging. Genomics is entering the clinic, large genomic data sets are being compiled and used for analyses, genome editing is now widely accessible because of CRISPR, and more. As a result, we need to look at genomics through a broader societal lens, and I think HUGO, with its international scope, can play an important role in this.
For example, ELSI (ethical, legal, social implications) issues are critically important. An obvious one that is being discussed a lot is CRISPR and editing human DNA. What sorts of changes are permissible? What should be restricted? What regulatory oversight is appropriate? Even within a single country these are difficult questions, and with different cultures and traditions it is even more challenging to develop a coherent and effective framework for ethical research. With its international scope and members’ broad expertise, HUGO can be a powerful advocate and authoritative voice for broad-based recommendations in the efforts to establish this framework.
Another area of concern is the implementation of precision medicine. So far it’s largely concentrated in large medical centers and most patients who could benefit from it don’t have access. This is the case even within the United States, but when you look at the entire world, it’s apparent that more work needs to be done so that these impressive medical advances can be made available on a wider basis and not just to a select few.
Q: What research areas would you most like to see HUGO support?
A: I would like to expand our outreach and support to more regions around the globe. Supporting the growth of human genomics research internationally is a core piece of HUGO’s mission, and there’s far more to be done in this area.
It’s also of particular importance to expand the populations represented in genomic databases. Currently the data are mostly from populations of European origin, and acquiring large amounts of data from patients and healthy people in Africa, Asia, the Middle East and so on is becoming increasingly vital to correctly assess and annotate disease variants. We’ve seen several examples of a rare genetic variant being incorrectly correlated with disease in one population, only to find out later that it’s relatively common in healthy individuals from another population. Having better representation from a wide range of populations will increase the effectiveness and expand the value of clinical genomics worldwide.
Finally, related to this, HUGO can play a role in helping to bridge some of the data siloes that have already begun to emerge. By bringing genomics researchers together from all corners of the globe, we can help foster collaborative projects and build an environment to encourage data sharing and access. The sequencing of the first human genome was a huge achievement, but a single genome tells us relatively little about human genome diversity, which has long been my personal area of research interest. To get at the difficult questions regarding disease variants, complex disease and more, we need to gather many thousands or even millions of genomes for analysis. There are efforts underway to do just that, but it will certainly take more than a village to make it happen.
--Dr. Lee is an expert on structural variants in genomes and their roles in disease