Matthew Shair imitates, improves on nature:

Matthew Shair takes his inspiration from nature. The recently tenured professor of chemistry and chemical biology tries to solve nature’s mysteries and learn enough in the process to improve upon the mother of life. His work is called “biomimetic synthesis,” mimicking the way that life works by mixing chemicals in a laboratory.

“We test our ideas about how nature builds molecules by trying to make those molecules in the laboratory,” Shair explains. “The work we’ve done so far shows us that this is not only possible, but that we can modify the molecules to give them new properties. In another words, we can improve on nature not only by bettering what it does but by discovering molecules with entirely new properties.”

“The breadth, scope, and impact of Matthew Shair’s research is truly impressive,” comments Stuart Schreiber, chairman of the department of chemistry and chemical biology and Morris Loeb Professor of Chemistry. “His work is original and powerful, the type that will inspire many followers in the future.”

One of the areas Shair and his students are working in is called “protein trafficking.” Genes in all living cells carry instructions for making a variety of proteins essential to life. These proteins have to get from place to place in the cells and to destinations outside the cells. It’s like traffic on a busy freeway, and other proteins do the work of directing such traffic.

The problem Shair set for himself was to find such traffic “cops.” The process of searching for them should lead to new discoveries about basic biology. In addition, molecules found to perturb protein traffficking can be involved in disease. Studying them could be the first step in finding better treatments.

Using biomimetic synthesis, two graduate students in his lab, Henry Pelish and Nick Westwood, made a library of about 3,000 molecules that they guessed might be the types that cause protein traffic jams. There was no proof, of course, that any of these compounds were involved in trafficking; they were only suspects because of their chemical structures. These molecules then were tested with the help of a screen developed by Tom Kirchhausen and Fen Feng at Harvard’s Institute for Chemistry and Cell Biology. The screen serves as a sort of radar that can spot cell-traffic violators by allowing researchers to see, with the help of a microscope, what is actually going on in a cell.

The team actually found one of the 3,000 molecules that interrupted the normal flow of protein traffic. They call the molecule secramine. Stationary proteins in the cell control the flow of moving proteins with something similar to traffic lights; secramine appears to foul these signals.

It might work something like this: The normal activity of cells, such as nerve cells, depends on the movement of proteins to send messages from one cell to another. A protein secreted by one cell passes a signal to the next cell, and so on.

“It’s the way many cells communicate with each other,” Shair points out. Cells rouse each other to fight infections this way, and to operate muscles when an organism is threatened with danger. The more scientists can learn about the trafficking of such signals, the more they will know about some of life’s most vital processes. Also, the better they will be prepared to fix such signals when they fail to work properly.

“Protein trafficking is only one exciting area that might be impacted by biomimetic synthesis,” Shair points out. “In all the areas, we’re most interested in what we can learn about basic cell biology, about how humans and other organisms function. Of course, we stay well aware that many times this information will also teach us something about medicine, about the cause of abnormalities, and eventually, perhaps, about how to better treat them.”

Shapes intrigue him

Shair, now 34, “fell in love” with chemistry during his first year at the University of Rochester. “I had taken advanced chemistry in high school,” he recalls, “but I didn’t really get hooked on it until I started doing experiments in organic chemistry. I was most intrigued by the shapes of the molecules, how they twisted and moved and fit together.”

The decision didn’t make his parents happy; they hoped he would be a physician. When he went to Yale to do graduate work in chemistry in 1990, they wanted to know if that meant he wouldn’t be going to medical school.

When his chemistry adviser, Samuel Danishefsky, moved to Columbia University three years later, Shair moved with him. By the time he earned his Ph.D. from Columbia in 1995, he had done enough research in how chemistry influences biology to know that was where his future was.

One of the highest-regarded people in that field is Stuart Schreiber, now head of that department at Harvard. Shair applied for a postdoctoral fellowship with Schreiber in 1995 and was accepted. He has never regretted the choice. “Usually, when you are brought up in one type of chemistry, you think about things one way,” Shair says. “Stuart approaches science with a much broader perspective. Working with him has had a liberating effect on me.”

In 1998, the Department of Chemistry and Chemical Biology and the Harvard Medical School established the Institute for Chemistry and Cell Biology to provide both intellectual and laboratory equipment for chemists and biologists to work together. “I was an assistant professor then,” Shair remembers, “and I could not have discovered secramine without the resources provided by ICCB.”

Shair went on to become an associate professor in 2001 and a full professor this year. One of the things he most appreciates about Harvard is being “surrounded by such dedicated and intelligent students. Chemistry graduate students here are second to none, and I am lucky to be able to work with them.”

On his first day at Yale, Shair met Karoline Mosny, who he fell for as hard as he would for a nicely shaped organic molecule. They were married in 1994. After he left Yale, she stayed on to get a Ph.D. in chemistry. She now works as a patent attorney.

Shair has accumulated an impressive list of awards, including making Massachusetts Institute of Technology’s list of the 100 top innovators in science under 35 years of age in 1999. The award of which he is most proud is the American Chemical Society’s Cope Scholar Award, given to distinguished chemists under age 35.

But his parents still wonder if all this means that he won’t be going to medical school.