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Faculty Profile: Tom Muir

In science, some challenges are easily met, while others are of a scope and complexity that demand an enormous degree of persistence and ingenuity. When setting research priorities, Tom Muir, the Van Zandt Williams Jr. Class of ’65 Professor of Chemistry, is primarily interested in the latter. Muir and his group at Princeton University are applying the tools and sensibilities of the organic chemist to the study of some of the most complicated and fascinating questions facing the field of molecular biology.

Over the past fifteen years, Muir has developed a menu of highly creative and enormously useful synthetic technologies that allow for the assembly of functional proteins, both in vitro and in living systems. These tools, which are employed throughout the chemical biology community, have greatly facilitated the study of protein function. Muir’s groundbreaking advances in the area of protein engineering have been widely recognized, most recently by the Royal Society of Chemistry, who named him the recipient of the 2012 Jeremy Knowles Award.

Notwithstanding these pioneering achievements in chemical synthesis, research in the Muir group is fundamentally driven by a fascination with exploring biological processes at the molecular level. Muir explains, “We are trying to solve biological questions. It’s not sufficient to merely make the molecule, but we have to do it with a purpose. You hope to apply your methods to problems that biologists really care about.”

Raised in a small town in the west of Scotland and educated at the University of Edinburgh, Muir came to the United States for postdoctoral training in the laboratory of Stephen Kent, at the Scripps Research Institute. In 1996, he joined the faculty of Rockefeller University, where he would remain until coming to the Princeton Chemistry Department in the summer of 2011. Muir, who was trained as a chemist, was drawn to the research environment at Princeton, where the department was expanding dramatically, and opportunities for collaborative interactions in both chemistry and biology were abundant. Says Muir, “I liked the people here a lot and totally bought into what was going on in the department.”

At Princeton, Muir is bringing his unique perspective and considerable expertise to bear on a number of high-profile challenges in molecular biology, including the study of bacterial virulence and the field of epigenetics.

Epigenetics, a burgeoning area of research that touches on virtually every aspect of human development, encompasses the study of heritable changes in gene expression – that is, whether a gene is switched “on” or “off” – that are not linked to mutations in the DNA sequence. Every gene encodes instructions for the synthesis of a protein, but whether or not protein synthesis is initiated within a given cell depends on whether the gene in question is turned “on” or “off”.

Gene expression is regulated through a complex process that begins with the way in which DNA is packaged in the nucleus. As Muir explains, “DNA is not crunched together like a bowl of spaghetti” in the nucleus; rather, DNA strands are carefully wrapped around a series of “spools”, composed predominantly of histone proteins. This highly organized complex of millions of DNA–protein spools, which may be imagined as a series of “beads on a string”, is termed chromatin. Through epigenetic processes, the histone proteins of the “spool” are tagged with small molecules, which Muir likens to “chemical bar codes”. Appendage of these bar codes along the DNA-protein spool can alter the structure of chromatin and flag a gene to be turned “on” or “off” within the cell.

Most fascinating is what can happen when these chemical bar codes get mis-read or mis-installed on the histone proteins. There is growing evidence that this “epigenetic breakdown”, which results in improper protein expression, contributes to a range of diseases, including cancer. Because these “bar code” errors are not caused by mutations in the DNA sequence of the gene, epigenetic breakdown should be a reversible phenomenon. The potential therapeutic implications are enormous, says Muir. “Every pharmaceutical company is trying to develop drugs to fix epigenetic breakdown.”

The challenge, argues Muir, is that there is simply so much about this regulation process that we don’t yet understand. Without a firm grasp on what exactly is happening at the molecular level in the process of epigenetic regulation, Muir suspects it will be prohibitively difficult for researchers to develop effective therapeutic approaches. “The more you understand about a system, the better chance you have of fixing it when it breaks.”

Muir believes that the best way to uncover the secrets of epigenetic regulation and breakdown is by actually building the chromatin complex in the laboratory, and examining how it behaves. Using synthetic methods, researchers in the Muir group have already constructed large portions of chromatin and are beginning to study the ways in which variations in the chemical bar codes may impact chromatin structure and function. The ultimate goal is to understand, on a molecular level, the “black box” of epigenetic regulation and to use that knowledge to treat diseases of epigenetic origin.

If Muir’s programs, which operate at the interface of physical organic chemistry and molecular biology, seem impressively ambitious in their scope, it’s because they are, and that is exactly the point. Muir believes that scientists should seek to “tackle the hard problems; because everything was hard at some level until someone figured it out.” By aiming his sights on fundamental biological questions of enormous import, Tom Muir is demonstrating the growing power of synthetic chemistry to have a meaningful impact on pressing questions in biology.