THE WALL above Bill Sullivan's file cabinet hangs a winged tennis
shoe. Trapezoid-shaped Plexiglas panels splay out from the side of
the shoe, attached with metal hinges. Sullivan invented this contraption
to help him negotiate a trail in Big Sur that meanders back and forth
across a river. It's hard to swim wearing tennis shoes, he says, and
he didn't want to take them off and put them on every ten minutes.
The panels fold up for walking and down when he needs flippers.
Sullivan's knack for solving problems many people
never even ponder gives him a unique approach to scientific puzzles.
His radically fresh perspective has led him to challenge and overturn
some widely held assumptions in his field.
Sullivan has applied this approach to ask how a
fruit fly develops from a fertilized egg into the complex insect that
makes a nuisance of itself in fruit bowls on hot summer days. In particular,
Sullivan is asking how the fly's embryo grows at seemingly reckless
speeds during the early stages of its development, and yet manage
to produce an animal with exactly four wings, six legs, and two eyes,
all of which function properly.
The flies use unexpected methods to assure quality
control during their initial growth period, Sullivan has found. These
include techniques that organisms such as humans use later in life
to protect themselves from cancer. His findings have opened up a new
avenue for studying how cells normally behave as good citizens in
the bodies of a wide variety of animals.
of self-correcting development starts with a tiny fruit fly egg. After
fertilization, the resulting cell duplicates its genetic blueprint.
The two copies separate from each other, and each is sequestered in
its own pouch, or nucleus, inside the cell. This process repeats as
the fly embryo grows, to produce increasing numbers of nuclei.
The nuclei synchronously zip through the first
thirteen reproductive cycles at some of the fastest reproductive rates
known. During this period, the duplicating nuclei inhabit one large
sac. After seven initial divisions in the interior of the embryo,
most of the nuclei begin to migrate to the surface. There they continue
to double in concert, coordinating their movements as well as the
timing of their divisions with choreography that resembles a Busby
Berkeley dance scene in an MGM musical comedy. The appearance of the
embryo reflects this precision: the nuclei that dot the ellipsoid
sac are evenly spaced over the surface. Because so many nuclei are
dividing quickly, simultaneously, and with scripted movements, young
fly embryos lend themselves especially well to the study of regulated
At the fourteenth division, membranes form to separate
the nuclei into distinct cells. Sullivan is asking some critical questions
about this process. For example, until this point, how do the nuclei
duplicate without bumping into one another? How do the embryos contend
with defective nuclei that arise? These questions snagged Sullivan's
curiosity because the nuclei divide at breakneck speed, closely packed,
with no cell membranes to confine them to their own spaces.
In most mature plants and animals, dividing cells
ensure quality by inspecting their work at every step before they
proceed. This process counteracts the defects that inevitably arise
from slightly imperfect cellular machinery as well as harmful outside
influences, such as environmental toxins. If a cell finds errors,
it pauses to correct them. Cells check, for example, that they've
finished copying their entire genetic blueprint before they split
in two. That way, both offspring cells contain a complete set of plans.
Young embryonic fly nuclei, in contrast, seem more
focused on speed than accuracy. If they fail to copy their genetic
blueprint completely in the time allotted, the nucleus divides anyway,
without a full set of instructions for each resultant nucleus. Delays
in individual nuclear divisions would disrupt the synchrony of the
mass cycling and throw the process into chaos. "It's like in a race
with thousands of people," Sullivan says. "If someone stops to tie
his shoe, it'd be nice if everyone stopped--but that's not what happens."
Like the person with an untied shoe, the disabled nuclei must stumble
along with the crowd.
But animals that accumulate flawed nuclei risk
developmental problems and, after birth, cancer, so scientists reasoned
that there must be some way for the embryo to correct its mistakes.
Leaders in the field suggested that growing fly embryos tolerate imperfections
until division fourteen. At that point, when nuclear duplication slows
down, the embryo begins acting like an adult. Its cells then scrutinize
nuclei and mend injuries, according to the theory.
This idea bothered Sullivan. "They thought there
was no mechanism to deal with damage [early during embryonic growth],
but that didn't make sense," he says. " That's the most important
time in development, so you'd think that it might be important to
do it right."
Sullivan wanted to see for himself what happened
to faulty nuclei in developing embryos. He devised a way to look at
chromosomes within dividing nuclei. Normal chromosomes pair up to
form rows, which facilitate their organization during division. Sullivan
was particularly interested in nuclei with jumbled, instead of neatly
ordered, chromosomes. The nuclei containing these unruly chromosomes
didn't divide properly, and lagged behind their neighbors.
Sullivan saw a ruthless world, where nuclei that
don't keep up get thrown out. Instead of stopping to fix problems,
the embryo tosses defective nuclei into its middle, the "garbage can
of the developing animal," he says, and there they die. "The fly makes
a whole lot of nuclei and just throws out the bad ones," says Sullivan.
In this way, the embryo maintains standards.
A fruit fly embryo can lose as many as half its
nuclei and still turn out right, Sullivan found. "The embryo has a
tremendous ability to compensate," says Sullivan. "You can eliminate
huge numbers of nuclei and somehow the embryo can keep track and replace
what it got rid of."
Beginning at stage fourteen, the animal seems to
value each individual more, and rehabilitates misbehaving cells rather
than sentencing them to death.
Sullivan likens the initial stages of fly development
to a basketball factory. "It's OK if two percent are messed up and
you throw them out," he says. "But if you're making a Mercedes, you
want to make each one perfect. It's too valuable to afford to lose
one." Early on, when the nuclei are interchangeable, they are dispensable.
Later, however, when they commit to futures as wing or antennae components,
their worth increases.
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 to inspect.
"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 lab tape.
Sullivan 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
"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."
the 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
is 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
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 yeast.
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.
familiar to Sullivan to start out with a general goal, but find himself
in a place he never would have anticipated. It's the same approach
he takes when he goes hiking in a new area. While some people pore
over maps and meticulously plan their hikes, he just finds a trail
head and starts walking, he says. "I've never been to any of the places
and I'm sure they'll all be nice. The people who agonize over maps--they'll
end up in a nice place too, but never where they hadn't planned. There
are some types of science where you pick a trail and continue along
that. If anything tries to lead you away, you don't let yourself detour."
Jeannie Sullivan says she's surprised her brother
wound up in the lab. "He never seemed to be a precision type of guy,"
she said. "He's not someone who would take apart an alarm clock and
put it back together. He'd just take it apart."
One day a few years ago, however, she started seeing
the adult Bill in a different light. They had stopped to pick blackberries
at the side of the road. "My brother was never neat, ever," she says.
"We finished picking blackberries and my hands looked like I'd been
mashing them. But his were completely clean. He somehow picked them
so precisely that his hands didn't get dirty.
At the same time, she says, "his socks don't match.
"It has to do with putting your energy where it