initial skepticism of the defect-toleration hypothesis has proved correct.
The young embryo indeed monitors for damaged nuclei and expels them,
thus assuring the integrity of its constituents. It does not, as had
been suggested, allow sloppiness early and wait until stage fourteen
"Bill doesn't let the prevailing dogma affect his
thinking at all," says Doug Kellogg, of the University of California,
Santa Cruz. "He's not really bound by the way the rest of the scientific
community looks at things."
Sullivan's unconventional approach resonates with
other aspects of his life. When he began working at UCSC as an assistant
professor, his home was a boat. And as an undergraduate at the University
of California, San Diego, he slept in his car for several years. "I
think he didn't get around to making arrangements for living in campus
housing," says Sullivan's sister Jeannie Sullivan. " It was easier to
just buy a parking permit."
At UCSD, Sullivan already knew he wanted to study
science. He had become fascinated with the natural world as a child.
Every week he tuned in the family TV to "The Undersea World of Jacques
"At the end, the narrator would say something like
'and he solved the mystery of the Red Sea,' and I thought, 'By the time
I'm old enough [to work as a scientist], Cousteau's going to have everything
figured out,'" Sullivan recalls. "There got to be a point when I couldn't
watch any more. At twelve, I was already worried about being scooped."
In his office on the University of California, Santa
Cruz campus, Sullivan sits at a desk with its drawers ajar. Piles of
folders, a large glass flask, a box of computer disks, and a sweater
litter his floor. A paper coffee cup and muffin wrapper lie on a tabletop
supported by two sawhorses next to his desk. A thick black binder holds
his scientific papers, neatly ordered and numbered.
Sullivan, with the reds and blues of his different
shirt arms peeking out from under one another, says he likes the formalism
"You have the analysis on paper and then do something
simple like count the number of flies with a certain eye color, and
you can learn something really profound," he says. "It's pretty amazing
that Mendel got it all right--just by counting peas."
More than 100 years ago, Gregor Mendel figured out
the rules that govern the inheritance of many traits by mating plants
of different colors and pea shapes.
Sullivan sits up in his chair, nods his head, and
leans forward as he talks. His eyes brighten. He seems a bit like a
child, talking about his new Lego set.
Anxious to get back to the lab, Sullivan glances
at his watch, which is attached to its band with a strip of bright green
found out what happens to damaged nuclei in fly embryos, he dove deeper
into the question of how they usually manage to divide correctly. He
thought the answer would lie in the molecules that push and pull DNA,
and package it into new nuclei. So he set out to find the embryonic
components that shepherd the chromosomes.
As his first step, he created strains of flies whose
nuclei make more than the usual number of mistakes. These strains, he
reasoned, should contain altered versions of molecules that normally
make nuclei behave properly.
This approach is similar to learning about how cars
function by tying the hands of different workers in an automobile factory,
Sullivan explains. The flawed cars that roll off the assembly line provide
information not only about each person's job, but also about how the
car works. When cars emerge without the round plastic devices on their
front left-hand sides, one suspects that the incapacitated person installs
steering wheels. And when those same cars are driven to the parking
lot and fail to make the first turn in the road, one might conclude
that the round plastic devices steer the car.
In principle, by tying every worker's hands on different
days and studying the emerging cars, one can match people with their
jobs in the factory, and discover what the different components of the
car do. In flies, each strain (or day in the factory) contains a defective
gene (or worker with tied hands).
"What's nice about [fruit flies] is that if there's
a defect, you detect it because the nuclei are no longer evenly spaced
in the embryo," says Kellogg. "There's an easy read-out."
Sullivan looked at 76 strains of mutant flies. He
found several that display an irregular pattern of too few nuclei on
the embryonic surface and contain excess nuclei on the interior.
His scheme succeeded, but, like many research projects,
it easily could have failed. Daring experiments, however, don't daunt
Sullivan, reports Kellogg. One Friday night about eight or nine years
ago, Kellogg and Sullivan were walking up Tank Hill in San Francisco.
"Bill stops in front of this big poison oak bush and tells me how he
used to get these really bad cases of poison oak and he doesn't anymore
and he's pretty sure he's become immune," says Kellogg. Sullivan reached
out, grabbed the plant, and rubbed it on to the back of his hand.
"Monday I come into work and Bill is sitting at the
microscope. His eyes are nearly swollen shut, and he has big patches
of poison oak all over his hands, his face, his arms," Kellogg says.
"Bill really isn't afraid of trying radical experiments."
fly genes Sullivan has found, one encodes a relative of a protein scientists
already knew about. This protein resides in yeast cells, and gives them
time to repair damaged DNA. When other molecules report problems, the
protein pulls the brakes on cell division. Like mature animal cells,
yeast correct errors, presumably because serious blunders are a matter
of life and death for each of these single-celled organisms.
Fly embryos containing a defective version of this
gene contain clustered--instead of evenly spaced--nuclei. Because of
the clumpy appearance, Sullivan named the gene "grapes."
Embryos with a defective grapes gene contain higher
than normal levels of DNA damage, Sullivan showed. A string of unbroken
DNA usually composes each chromosome in a healthy cell. Although the
chromosome is copied in small segments, the cellular machinery patches
the resulting pieces together. Within the mutant embryos, almost five
times the normal number of loose DNA ends exist. This result indicates
that the nuclei don't have enough time to complete DNA replication before
they start trying to divide, Sullivan says. Such DNA doesn't line up
so it can divide properly, and these fragments of DNA pose a hazard
to cells that contain them.
Reasoning from these results and the resemblance
of grapes to the yeast gene that suspends cell division, Sullivan proposed
that the protein product of the grapes gene generates a pause that allows
fly nuclei time to finish duplicating their chromosomes.
"What's surprising is that the same genes are used
[in yeast and flies]--just in different ways," Sullivan says. Yeast
use their protein to counteract mistakes, while fly embryos use theirs
as a normal part of nuclear division. The fly embryos don't really need
the Grapes protein until cycle 11 because earlier, DNA replication occurs
slightly more quickly and can keep up with the pace of nuclear division.
In both yeast and flies, the relevant proteins generate a pause so the
nucleus can ready the DNA for division.
Once Sullivan decoded the fly grapes gene, Stephen
Elledge's group at Baylor College of Medicine in Houston used the information
to find its human counterpart. Although scientists had isolated the
yeast gene four years earlier, their previous attempts to uncover the
human version had failed because the two are too distantly related.
"People have been looking for it [the human version] for a long time,
but they couldn't pull it out," says Sullivan. Because humans genetically
resemble flies more closely than yeast, Sullivan's gene provided the
missing link that allowed scientists to nab the human gene.
one of two genes in yeast, flies, and humans that ensures that one portion
of cell division is finished before the next one begins, says Sullivan.
This means that scientists may be able to exploit flies to learn about
humans. No one knows whether the grapes gene carries out similar jobs
during human and fly development, but divisions early during embryonic
development tend to differ from later ones in all higher organisms,
so Sullivan's work may hold relevance for human pregnancy.
In addition to informing scientists about embryonic
growth, the grapes gene may provide information about the basic mechanisms
of growth and tumor formation in a wide range of organisms. Genes such
as grapes, which control the order and timing of events during cell
division, have been implicated in the transformation of healthy cells
into cancerous ones. "Cancer is a case of cells [growing] out of control,"
says Kent Golic, a geneticist at the University of Utah in Salt Lake
City. "The cells don't know that they're not supposed to be dividing."
The grapes gene may provide a powerful tool with
which to investigate this process. Like yeast, flies are amenable to
manipulation and experimentation. But their bodies, like those of mammals,
are composed of specialized cells that carry out different jobs. Using
flies to probe the function of grapes may well convey scientists to
an understanding of humans that would not be possible by studying only
Although Sullivan began this project searching for
the components that shove DNA from one place to another within the cell,
he wound up with a gene that plays a role in growth control.
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