The Johns Hopkins Gazette: September 11, 2000
September 11, 2000
VOL. 30, NO. 2


Studies of Life's Starter Cells Net Pew Scholar's Award

By Michael Purdy
Johns Hopkins Gazette Online Edition

All flesh is grass, wrote the prophet Isaiah, but he had no way of knowing about germ cells.

The sperm and the egg are the parts of every animal that keep on ticking after the rest of the body has had its licking, and are, in some respects, immortal. In the transition from one generation to the next, they are the essence of everything that goes on.

"That's what got me interested in germ cells in the first place--these are the cells that are going to survive," says Mark Van Doren, who joined the faculty of the Biology Department of the Krieger School of Arts and Sciences last November. "They can give rise to an entire new organism--we consider them 'totipotent' for that reason, because they have to somehow retain the potential to give rise to all the new cell types that would be used in constructing the new individual."

Mark Van Doren

Van Doren's research into the early development of germ cells recently won him a prestigious Pew Scholar's Award in the Biomedical Sciences, which includes a four-year grant that annually will provide Van Doren with $60,000 in research funding. The new funds will help him prime the pump at his new Hopkins labs, allowing him to obtain the preliminary data he needs to "seed new research directives."

Van Doren's efforts, and those of other germ cell researchers, may one day help open up new avenues to treatments for developmental disorders and fertility problems.

"A newly conceived organism has to remake the germ lineage anew at the same time that it is segregating off the cell lines that make up the rest of the body, which we call the somatic lineages," Van Doren says.

Based on his research in fruit flies, Van Doren theorizes that cues both within a prospective germ cell and outside shape this selection process. The push toward life as a germ cell appears to start with the inheritance of a specialized cytoplasm, the fluid and structures inside the cell but outside the nucleus; continues with exposure to molecular signals from the rest of the embryo; and culminates as the germ cells interact with the somatic cells that make up the gonads, or reproductive organs, and start to take on male or female germ cell characteristics.

Strangely, germ cells do not develop in or near the area where the gonad develops; instead, they first show up some distance away from it.

"The germ cells solve that problem by effectively picking up and walking," Van Doren says. "They migrate individually, with some communication between each other, but predominantly as individual cells navigating through the embryo, wandering, to search out the gonads. Once there, they can then populate the gonad and find the environment that's going to be appropriate for their development."

The initial separation of germ cells, the trek they take and the signals that lead them on their journey are the among the major foci of Van Doren's research.

Much of the research is conducted in the fruit fly drosophila. Because of the wealth of data available on it, Van Doren says, "You can effectively 'ask' the organism to tell you what genes are important for a particular process, and that allows you to work in a much less biased manner."

Van Doren cites HMG CoA reductase, an enzyme he linked to germ cell migration, as a prime example. Studies in fruit flies brought the enzyme to his attention, and he found that if he stimulated increased production of it in an unusual part of the embryo, the germ cells would start to migrate for that part of the embryo instead of the areas where the gonads were forming.

"Much to our surprise, we later found out this protein we were looking at was already being studied for its role in producing and regulating cholesterol in the body," he recalls. "We would never have predicted in a million years that a general metabolic enzyme was providing spatial information in this process."

The enzyme itself probably isn't the signal, Van Doren notes. Flies lack the ability to make their own cholesterol, so they can't be using HMG CoA reductase in that way. Many enzymes get used in a variety of different ways, though, and Van Doren suspects that HMG CoA reductase has other, as yet unidentified uses, which scientists call "pathways." One of these pathways may produce a compound that serves as the signal.

At that point, Van Doren suddenly found his work proving a point well-known to scientists but little recognized elsewhere: Basic science may have finding an answer to a question as its only priority, but the mystery of an unanswered question sometimes hides potentially fruitful connections to applied problems in science.

"Medical researchers are currently testing the use of a class of drugs known as statins to lower cholesterol levels by inhibiting the creation of HMG CoA reductase," he explains. "They're finding that these cholesterol inhibitors are affecting disease states without affecting cholesterol levels in some cases, or having the effect be independent from cholesterol levels, so it very well may be that these other pathways are critical to human disease as well."