Role models

October 6, 2004

Tags: Genetics + Genomics

CAMBRIDGE, Mass. — When genes work, they stick around. And so do many of the biological processes they create. As Whitehead Member Hazel Sive put it, kicking off Whitehead Symposium XXII, the process of evolution “conserves circuitry.”

Surprisingly similar genes appear in organisms separated by many millions of years of evolution, driving biological activities along comparable pathways. Additionally, each life form makes the most of its suite of built-in tools. The same developmental processes that form embryos “are used by your body even as you are sitting here,” Sive remarked.

In the past decade, studies of everything from yeast to zebrafish to mice have created explosive advances in developmental and evolutionary biology. Now that we are aware of the astonishing similarities between humans and other species, “we’re trying to harness this power in terms of understanding human disorders and treating human diseases,” said Sive.

Held at the Massachusetts Institute of Technology on September 27, this year’s Symposium brought together some of the world’s leading biologists to discuss the topic: “Disease, Development and Darwin: Experimental Models of Human Disorders.”

The event, which drew more than 1000 attendees from the local scientific community, revealed the latest results from seven research efforts that could lead to new therapeutics for diseases ranging from cancer to diabetes to HIV to liver disease. Among them, Harvard’s Douglas Melton reviewed the puzzling case of the missing pancreatic stem cells, and Cynthia Kenyon of the University of California/San Francisco outlined her progress in creating worms that keep wiggling way beyond normal life spans.

Desperately seeking stem cells

Embryonic stem cells can differentiate into almost any kind of cell type and offer hope for tissue replacement for diseases such as diabetes and Parkinsons. But since 2001, U.S. scientists have been prohibited from using federal funds to work with new lines of the cells

Last October, however, Melton began changing the rules of the game when he announced he had developed 17 lines of embryonic stem cells with private funding. Earlier this year he started sharing the lines freely with other scientists.

Melton developed the stem cell lines after years of failing to find adult stem cells in the pancreas that could be used for tissue replacement to cure Type 1 diabetes. That disease wipes out the body’s ability to create insulin and now hits at least one in 300 children.

Co-director of the new Harvard Stem Cell Institute, Melton described his lab’s work that found “no evidence for adult stem cells in the pancreas.” Done on mice, the experiment was simple in concept: Mark the insulin-creating cells in the pancreas in young mice, and wait up to a year (a very long time in mice life) to see if the percentage of marked cells diminished. That’s what you would expect if adult stem cells were present and turning into new insulin-creating cells. But it’s not what happened. Melton saw no signs that such adult stem cells exist—a finding that caused an uproar in the diabetes research community.

His lab is now struggling with the challenge of giving the right biochemical signals to trigger embryonic stem cells to take the first step toward the insulin-creating cell. Once that’s overcome, however, Melton is hopeful for rapid progress in curing the disease. “We have a pretty good idea what happens later on once we have pre-pancreatic cells,” he said.

A fountain of worm youth

Like Melton, Cynthia Kenyon has received much attention in the popular media. It doesn’t hurt that her research—an investigation into the genetic and hormonal pathways that could lead to longer life—appeals to the age-old desire for immortality.

Kenyon is investigating a potential life-extending mechanism found in a mutated variety of the nematode worm C. elegans. In 1993, Kenyon made headlines by showing that suppressing a gene in C. elegans can create a six-fold increase in lifespan. The process not only delayed aging but slowed the aging process, so worms that were the equivalent of 300-year old humans were swimming around like youngsters. Since then Kenyon has found that the mechanism is similar to a mutation effect found in mammals related to changes in insulin levels, so adapting it to humans may be possible.

Kenyon also has developed new techniques to identify and measure traits linked to aging in worms, thus providing evidence to counter skeptics who claimed that while the worms might be dying later there was no proof they were aging later. (Immortality, after all, is far more appealing if you can still wiggle around a bit.)

Over the last few years, Kenyon’s team and researchers at the University of Washington and Mass. General Hospital have identified 29 genes involved in extending life-span. Kenyon’s main focus has been the life-span-extending daf-16 gene and complementary daf-2 braking mechanism, which curtails the DAF-16 protein and thus hastens death.

Even this single set of pathways is fraught with complexity. The researchers recently discovered, for example, that if you destroy the germ line cells of the C. elegans reproductive system, the worms can’t reproduce, but the process also activates the steroid signaling pathway required to launch DAF-16—and thus extend life.

From an evolutionary perspective, Kenyon admitted, there may be good reason why longevity mutations are not more widespread. Once each worms passes on its genes to some 300 progeny, there’s not much use for the oldsters.

Cell migration, gene wars, and prion protections

Also at the Symposium, Denise Montell of Johns Hopkins showed the latest results of her studies on cell migration in embryonic fruit flies. Her research may lead to treatments that might impede cancerous metastasis of carcinoma cells.

Randall Moon of the University of Washington gave a whirlwind tour of his research into the signaling of Wnt proteins, which help to regulate interactions between cells during embryonic development. Variations in Wnt signalling appear to play a role in neural development as well as diseases ranging from melanoma to Alzheimers’.

Markus Grompe of Oregon Health and Sciences University discussed progress toward restoring damaged livers by using liver cell precursors rather than whole-organ transplants.

HIV research was represented by the Salk Institute’s Nathaniel Landau, whose experiments with mice revealed insights into the intracellular Cold War underway between HIV’s VIF gene and a particular mammalian gene that strives to halt HIV replication.

Finally, flying in from University Hospital of Zurich, Adriano Aguzzi shared results of his mouse-based research into prions (a type of infectious protein responsible for Mad Cow) and a potential defense against the diseases they can trigger.

Written by Eric S. Brown, a science and technology writer in Boston.

Doug Melton lecturing

Which stem cells were those? At the 2004 Whitehead Symposium, Doug Melton reported on the case of the missing mouse cells.

Photo: Justin Knight


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