Role models
From the search for mouse stem cells to studies
of long-lived worms, this year’s Whitehead Symposium
highlighted what we’re learning from the development
of model organisms.
CAMBRIDGE, Mass. (October 6, 2004) — 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. |
