Rock Solid Science

Whether conquering nature in the laboratory or on a mountain, researcher Robert Chow is up for the challenges of achieving scientific and personal goals.

by Lori Oliwenstein

When Robert Chow stands at the bottom of an enormous rock, preparing himself for the ascent to its top, the world around him disappears.

“When I climb, it’s just me and the rock,” he says. “I enter a state in which time is gone and my whole existence is confined to the experience of the climb.”

Chow does not climb for recognition or prestige. Instead, he climbs for much the same reason he is committed to the endeavor of science: because he likes a good brainteaser.

“I climb just for the pleasure of puzzle-solving,” he says. “For the physical and mental challenge of figuring out how to get myself from the bottom of a rock to the top.”

In his laboratory at the Zilkha Neurogenetic Institute, Chow, M.D., Ph.D., and associate professor of physiology and biophysics at the Keck School of Medicine of USC, approaches his studies of insulin and the ways in which pancreatic beta cells control their secretion with much the same sort of attitude. By mentally mapping out the best way to achieve scientific goals, he says, there is a better chance of making steady and significant progress.

And that is precisely what Chow has done. The son of a physician who died when Chow was just eight years old, Chow always knew he would follow in his father’s footsteps. When he was in college, however, he discovered that his interests went beyond clinical medicine. “I still wanted to be a physician, but I realized that I was also very interested in figuring out how things in the body work,” he says. And so he decided on an M.D./Ph.D. degree and entered the Medical Science Training Program at the University of Pennsylvania.

Chow’s scientific journey took him to the Max Planck Institute in Germany, where he worked under and was mentored by Nobel Prize-winning biophysicist Erwin Neher. From there, he journeyed to the University of Edinburgh School of Medicine as a faculty member of the Department of Physiology and, in 1999, to USC and the Keck School of Medicine.

Cellular sleuthing


Chow’s focus through much of his career to date has been on the secretion of various chemicals from cells via vesicles, membrane-bound bubbles that act as a sort of shuttle for a wide variety of molecules that need to traverse a cell.

The typical secretory cell—such as the endocrine cells found in the adrenal gland, which were the focus of Chow’s work in Edinburgh, or the insulin-secreting beta cells found in the pancreas—is filled with tens of thousands of these bubbles. The vesicles form by budding off from the cell’s golgi apparatus, a cellular organ found deep in the cell’s cytoplasm.

In a 2003 study that graced the cover of the highly regarded journal Nature, Chow overturned long-held scientific assumptions when he showed that the vesicle-bound hormones and neurotransmitters are released from cells using age-related criteria, with the youngest vesicles getting first shot at releasing their contents.

“As far as we could tell before,” Chow says, “the vesicles got in line after they were formed, waiting their turn to move forward to the cell membrane, which is where we know that secretion occurs. It was always assumed that they did a sort of orderly forward march where seniority ruled—first made, first out.”

It was only when Chow developed a new technique that allowed him to track fluorescently labeled vesicles in adrenal cells that he was able to see what was really happening in the cellular soup. By labeling vesicles with a protein whose fluorescence changes from green to red over time, he and his colleagues could watch as newly made vesicles headed immediately to the cell membrane, jumping ahead of older vesicles to disgorge themselves of their contents. “I think of it as the brashness of youth,” Chow says.

Although the work was done in adrenal cells, it has implications for any number of cells, including those that Chow now studies: the pancreatic beta cells, on whose success or failure in insulin secretion lies the health of each and every human being.

Critical insulin crystals

Since coming to USC, Chow has shifted his focus from adrenal chromaffin cells to those pancreatic beta cells, looking at what they do to succeed in proper insulin secretion, as well as what happens when they fail. And, as a well-trained physician, he is keeping his eye on the ultimate prize: applying the work he is doing to the actual treatment of patients with diabetes.

It is not as long or disconnected a link as one might think, Chow says. The truth is that the best way to treat diabetes would be to mimic the release of insulin and the processing of sugars by a normal pancreas as closely as possible, instead of using the sort of hit-and-miss methods of insulin pills, shots and pumps that are the only choices available to diabetics today. The problem is that nobody has really detailed the pancreas’s release and processing behaviors.

And that is why the work being done in Chow’s laboratory is so critical. Chow and postdoctoral fellow Darren Michael, Ph.D., have shown in the laboratory that insulin stored in pancreatic beta cells exists as a crystal in the lumen, or middle, of vesicles. They also have noted that this crystalline insulin is surrounded by a lot of dissolved molecules that appear to play a role in insulin’s release.
Perhaps most importantly, they have found that the insulin crystals released from the vesicles dissolve at varying rates. Indeed, the insulin itself seems to come out in different forms: sometimes dissolving in less than a second of its release, and, in other cases, dissolving over many seconds to minutes at a time.

The rapidity with which insulin is used by the body has long plagued diabetes clinicians. It makes keeping a diabetic’s insulin levels stable a real challenge. In recent years, pharmaceutical companies have worked to develop longer-lasting forms of insulin which, when paired with fast-acting insulin, can both process sugars eaten at a recent meal and also attempt to keep sugar levels stable for some time thereafter. Still, diabetes treatments are far from perfect, Chow says, and certainly not anywhere near able to do what the healthy body does naturally.

“It’s humbling to discover that cells have worked out through evolution how to do something that the pharmaceutical industry only discovered in the last century,” Chow notes.

Guiding post

Chow’s scientific fervor is not confined to the laboratory. As the recently named deputy director of the Keck School M.D./Ph.D program, he is now helping to guide students through a complicated course of study that relatively few scientists have traversed before.

The M.D./Ph.D. program, under the direction of Keck School Dean Brian E. Henderson, M.D., is both growing and thriving, Chow reports, with 42 students in the program. One student, Ramzi Azzam, recently published a paper in the journal Science, considered the leading scientific journal in the country.

In addition, the program currently boasts two recipients of the prestigious Fulbright Scholarship, the first to receive such awards in the Keck School’s history. Second-year medical student Jeffrey Friedman is spending a year in Rio de Janiero, studying the biochemistry of dengue virus infection. Sulggi Lee, who has completed her doctoral thesis, is in Uganda studying the genetic variations that may or may not be linked to malarial resistance.

“They are a testament to the spirit of scientific curiosity and achievement that characterizes this program,” Chow says.

Chow says his commitment to these students and their success comes from the support he received as he has grappled his way up the face of his own scientific career.