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illiam Haseltine, one of the founders and the CEO of Genome Sciences, was recently quoted as saying, "If you were to think of scientists as coal miners of the mind, you'd have it about right."

In Sandra Schmid's mind, first come the wildcatters, individual explorers who set out to discover scientifically rich deposits and then move on, content to let someone else do the heavy lifting while they head off over the next hill. Like the rest of the scientific community, they know that you get the Nobel Prize not for digging but for those single, startling discoveries that make the front page of The New York Times.

After that come the strip miners, scientists who tackle broad areas of science but who go only so deep, who define themselves by sweep, not depth. Then there are the deep pit miners, the ones who, as they say in the current parlance, like to drill down. That description with its connotations of determination and practicality fits Sandra Schmid perfectly.

"I consider myself to be a deep pit miner," she says. "As an undergraduate at the University of British Columbia (Schmid is Canadian) I developed an interest in how proteins are transported in small packages or vesicles into, out of and across cells. I staked my claim as a graduate student in biochemistry at Stanford University focusing on one class of transport vesicles. My laboratory at Scripps continues to dig for a deeper understanding of how these vesicles form and fill with cargo. Our mining continues to produce insights of significant value." As any good miner knows, the deeper you dig the more likely you are to find diamonds.

DIGGING IN AT TSRI

Schmid joined the faculty of The Scripps Research Institute 11 years ago. She was recruited immediately after completing her postdoctoral training in cell biology at Yale, which was supported sequentially by two of the most prestigious awards for young investigators; a Helen Hay Whitney Fellowship and a Lucille P. Markey Scholarship. The latter also helped finance her first five years as an independent assistant professor.

She might have been a freshman at TSRI but she knew precisely where she wanted to dig, had known since she was a graduate student: She wanted to study endocytosis, a process that lies at the heart of human cell metabolism.

EYING THE PROCESS

Basically, endocytosis (or receptor-mediated endocytosis) is an uptake mechanism that allows cells to ingest various substances including nutrients, growth factors, even viruses and toxins. Small pieces of membrane from the cell surface are pulled inward by a protein "coat" that assembles into a lattice-like structure forming a depression, called a "coated pit," that protrudes, almost like a reverse blister, into the interior of the cell. Receptors that attract nutrients and growth factors are concentrated in coated pits as they continue to deepen. Finally, the neck of the basket is pinched off releasing a small "coated vesicle," first described as a "vesicle in a basket," that carries its cargo into the cell.

The process is trickier than it sounds, because the environment outside of our cells -- the bloodstream, really -- is vastly different from the one inside our cells. The bloodstream is similar to seawater, high in free-floating sodium and calcium. But within our cells, there is little sodium and hardly any calcium to speak of. For our cells to survive, these two environments must be kept separate, even though they exchange chemical information on a regular basis. How they do that exactly is still something of a mystery; think of it this way. The cell is a balloon. Now select a small section of the balloon, fill it with a nutrient, inject it into the center of the balloon but don't break the balloon and don't leave a hole.

Morever, cells don't let strangers into their basket party, at least not on purpose. Like any well-run establishment, they have an entrance policy and they discriminate -- only those molecules with specific tickets can get into the club (or the basket) and when it gets full, the door closes and the basket takes off. The protein molecules that end up in these baskets are thousands of times more concentrated within the basket than anywhere else in the body.

Occasionally, though, the doorman gets handed a stolen ticket and the wrong kind of customers -- viruses and toxins -- get inside. The surfaces of both substances are littered with proteins. Using the proteins as masks, they attach themselves to those molecules with the appropriate receptors and are accidentally carried into the cell. If that sounds vaguely sinister, Schmid has a theory: Viruses have been studying cell biology for hundreds of millions of years, we've only been doing it for a century. They're way ahead of us.

DIGGING FOR GOLD

Thanks to Schmid and the work of her laboratory fellows, we're starting to catch up. "I've been studying endocytosis for almost twenty years," she said, and her efforts have produced some rich ores. As a graduate student she determined how clathrin, the major coat protein, assembles into baskets and purified a cell protein that releases clathrin from coated vesicles after they have formed. "The coat has to be recycled and the vesicle has to be naked to deliver its contents to the endosome, a repository and sorting depot for incoming cargo." As a postdoctoral fellow, Schmid developed new methods to isolate endosomes and defined them biochemically. Her laboratory at TSRI has developed the technology to recreate each of the steps leading to endocytosis in the test tube, allowing them to identify the cellular machinery that carries them out and to reveal how it works.

In addition to the coat proteins, clathrin and adaptors, that form the lattice of the basket, Schmid and her colleagues discovered that another rather large protein, dynamin, plays a key role in releasing the baskets or vesicles from the cell membrane. For endocytosis to work correctly, it obviously requires a mechanism that can separate the vesicle membranes from that of the cell without breaking the surface of either. Dynamin's chemical structure allows it to assemble itself into rings and spirals. During endocytosis, dynamin molecules form a ring around the top of the basket, like a purse-string to seal off the neck. In other words, the budding vesicle's coat has a collar. Schmid discovered that dynamin could be manipulated to control the rate at which vesicles pinch off. With that discovery, they soon created mutant forms of dynamin that could either speed up or bring the entire process of endocytosis to a complete stop.

At this point, she says, they have discovered the master regulator molecule and are learning the hierarchy of interactions in what is a remarkably complex machine. It is, she points out, as though they had gathered together all the parts needed to build an automobile engine but aren't quite certain how they work together. Their ability to reassemble this cellular machinery in the test tube will eventually allow them to piece together the entire puzzle.

An important next phase is to understand precisely how the transference between cell surface and the cell interior is made. The most acceptable candidate is the thin bilayer of lipids or fat that covers the surface of each cell.

"There has to be some kind of rearrangement of this lipid bilayer," she said. "We think the mechanism will end up looking something like the airlocks on a space ship in that at least one lipid layer is always closed." Indeed, Schmid's laboratory has recently shown that a rare lipid species is required both to initiate coat assembly and to release the vesicle. They are currently digging to discover how this lipid is made and what it does.

The practical possibilities of controlling cellular uptake through dynamin seem phenomenal. Once understood completely, it might be possible to block the uptake of viruses and toxins into the cell. Speeding up endocytosis helps to turn off signalling receptors that trigger uncontrolled cell growth, as occurs in cancer. Alternatively, after a procedure such as angioplasty, it might be possible to slow down the regeneration of smooth muscle cells in the arterial wall by clearing signalling receptors from the cell surface.

"There are a number of ways we think this process might eventually have some practical value," she says. "We're studying a basic mechanism and the better we understand it, the better we can intercede with viruses and toxins or to selectively target cancer cells with specific cytotoxic drugs. It is an essential process but one that can lead to so many applications."

AN EMINENTLY PRACTICAL PERSON

TSRI encourages this kind of practical thinking. In terms of scientific mining, it has always been a stubbornly independent operation.

"People here think about novel therapeutics and new ideas and you get sucked up into that excitement," she points out. "I think in practical terms -- so I can explain to my mom and dad and my children what it is that I do. So when I'm digging in the dark, I try to shine my light in the corners."

A great many of the young women on her staff who were attracted to the laboratory for the scientific opportunities it presented, found her a role model -- an eminently practical woman who has managed to have both a family and a career without short-changing either. She makes it clear that there is no serious reason that being a good mother and having a competitive career in science are incompatible goals. The secret, she claims, is not to spread yourself too thin -- either personally or scientifically -- and to have a very clear understanding of your priorities when you start out.

With her husband -- William Balch, Ph.D., Professor, Department of Cell Biology, who also works at TSRI -- they run a staggered shift. Her husband goes to work early and leaves his laboratory at five so that he's home in time to cook dinner and have it ready when she gets home around seven. "My kids complain, however, when we only talk science at dinner."

"There are two things that are important to me, family and science. What drops off the end are leisure activities that don't include my family. For example, I can't tell you what's playing at the symphony or the local multiplex. I haven't seen a movie in years that wasn't a Disney movie. By the same token, my research is very rewarding and I'm proud of the scientific reputation I have built, both at TSRI and in the international community." Schmid's accomplishments have been recognized by a Career Recognition Award from the American Society for Cell Biology and she was named an Established Investigator of the American Heart Association. She is founding co-editor of a new journal on intracellular transport, named Traffic, that will be based at TSRI. Finally, she says, "I am most proud of the quality of postdoctoral fellows who want to train and work in my lab. Their contributions are immeasurable."