to story and artwork
by Adam Rogers '92
a science, medicine is a wonderful art form. Most of its practitioners
admit that they have more questions than answers about what goes wrong
with the human body and how to fix it. Like us patients, they're waiting
for the day when they can wave that little sparkly salt shaker from Star
Trek, see what's wrong on a Palm Pilot and deliver a cure via a needle-less
injection that makes a shusshing sound. Been to the doctor lately? We
ain't even close.
But we're getting there. Medicine, chemistry, biology, physics, computer
science--a flight of fields called biomedicine when taken together--are
taking hesitant steps toward the sparkly salt shaker. Perhaps more importantly,
biomedical researchers are beginning to see how what they know now might
extend into the future, a sort of daydreamy bootstrapping. Pomona alumni
turn out to be at the forefront of research efforts with the potential
to transform the way physicians heal, from basic research to clinical
medicine to understanding the health of entire populations. The future
The fundamentals have to get worked out first, of course. Every biological
organism is built out of cells. In complicated, multicelled animals like
people, cells are microscopic factories with an array of specialized functions.
Nerve cells conduct information, muscle cells move the body, blood cells
carry oxygen, and so on. Inside just about every animal cell is a nucleus,
and inside that, chromosomes. These are tightly packed coils of deoxyribonucleic
acid--DNA, the storage medium for genetic information. Since DNA was first
described in 1953, figuring out how human beings get from DNA to a miraculously
complicated body, and what can go wrong in the process, has been prime
Today, that's basic research with many possible applications. Jennifer
Doudna '85 didn't initially know that's where she wanted to stake her
claim. As a grad student she got interested in RNA--ribonucleic acid,
the "cheap copy" of DNA that cells actually read and use to make proteins.
In an animal, if it's not bone or fat it's probably a protein. Weirdly,
RNA on its own is also capable of making more RNA. This is software acting
like hardware, as if a copy of Microsoft Word could also make print-outs.
Doudna started her career by working out the structure of self-replicating
RNA, using a technique called X-ray crystallography. If you can figure
out the shape of a biological molecule, you can often figure out what
it does or how it does it. "Just seeing this molecule for the first time,
I almost can't communicate how profound the feeling of discovery was,"
Many of the properties Doudna found for that curl of RNA turn out to hold
true for other functional RNAs, as well. That's where the potential for
new drug therapies comes in. For example, Doudna's research mostly concerns
the virus that causes hepatitis C, which infects people worldwide and
has no known treatment. "Part of the RNA in the virus forms a structure
that is able somehow to hijack the host cell's protein synthesis machinery
and direct it to making viral proteins," Doudna says. Nobody knows how
it works, but if you stop the RNA, you stop the virus. "A number of these
new drug targets are turning out to be RNA," Doudna says. "This hasn't
been a focus until recently of pharmaceutical research." There aren't
chemicals that interfere with RNA pathways the way thousands of so-called
"small molecules" do with proteins. But many natural antibiotics interfere
with RNA's role in protein synthesis, so the potential for new drugs is
Those small molecules, and their interactions with proteins, may yet provide
a pharmacological gold mine. That's the research focus of J. Andrew McCammon
'69. He's a theoretical chemist, but while at Pomona, he started working
with early computers to design drugs. While RNA may have some unusual
functions, the real action in cells, biochemically speaking, centers on
proteins. Genes are fundamentally just lists that describe sequences of
amino acids. Stuck together, those form proteins. But proteins aren't
linear; atomic interactions among the amino acids twist and fold them
into three dimensions, and it's in the pockets and grooves of these structures
that the chemistry of life takes place.
Here's an example: HIV, the human immunodeficiency virus that causes AIDS,
has three enzymes, proteins that have an active biological function. Ten
years ago the only AIDS therapy attacked an enzyme called reverse transcriptase,
a protein that converts the virus' RNA into DNA, ready for inserting into
a human host cell. But another of the enzymes is a protease, which eats
other proteins. McCammon studied the structure of the protease enzyme,
converted it into a computer model and generated potential shapes for
small molecules that would bind to the protease and disrupt its function.
Chemists then synthesized these protease inhibitors, which are now the
basis for the combination therapy that has been most successful at treating
AIDS. "We've learned enough in the last 30 or 40 years about the structure
of enzymes that we can approach the design of small-molecule inhibitors
almost the way somebody would approach the design of a bridge or a building,"
Where does it lead? McCammon's group at the University of California at
San Diego is tackling the third HIV enzyme, which integrates viral genetic
material into the human genome. And more powerful computers mean possible
solutions to basic problems in protein structure. Like: proteins turn
out to be more flexible than biochemists thought. "So you have to take
into account the fact that these molecules might deform somewhat in binding
to one another," McCammon says. In fact, proteins seem to fluctuate through
many possible shapes, with some areas of stability and some that are atomically
"fuzzy." Nobody knows how that works, but it could mean that interactions
between small molecules and proteins rely not just on fitting hand-into-glove
but on electrostatic forces between atoms, or even quantum mechanical
effects. Quantum mechanics is so weird that biomedical researchers tell
stories about it to scare each other, so we'll just move on.
The more precisely known the structures of proteins are, the easier it
will be to create drugs that act on them. But protein structures are determined
by genes, which in a nutshell is why the Human Genome Project seemed like
such a good idea. "You don't discover genes anymore," says Sean Tavtigian
'84. "You just associate them with their function." He should know. He
bailed on a Harvard postdoc to go to work for an upstart company called
Myriad Genetics, which gave him a front-row seat for the discoveries of
the breast cancer genes BRCA 1 and 2 in the mid-1990s. Today he's Myriad's
head of cancer research.
The problem Tavtigian's talking about is: What do you do with genes once
you've got them? Endless lists of As, Ts, Gs and Cs, the basic alphabet
of the genetic sequence, don't tell you anything about how genes go wrong.
Sure, for simpler diseases like the rarer forms of breast cancer associated
with the BRCA genes, researchers were able to develop diagnostic tests.
But "diagnostics are traditionally a very low-profit industry," says Tavtigian,
"and pharmaceuticals are traditionally a very high-profit industry." As
a result, many genetics firms--Myriad included--are transforming themselves
into drug discovery companies, trying to figure out how to do what McCammon
does but faster, cheaper and for thousands of potential targets.
One reason genetics start-ups think they can be drug companies has to
do with a field of study called pharmacogenomics. Basically, everyone
responds to a given drug differently. While most people respond normally,
some people will metabolize it so quickly that it has no effect, and a
few others will have intolerable side effects. Those responses are genetic.
"One can find drug response associations which would lead to genotyping
tests where a patient could basically know how they'll respond to a drug,"
says Tavtigian. Now, that's not necessarily as great as it sounds. Drug
companies may not want to know if some segment of their market can't take
the drugs targeted to them. On the other hand, knowing who can take what
might also allow drug companies to find markets for drugs that are dangerous
to some people but help others. Either way, setting up a program to figure
it out would cost big money--$500 million by Tavtigian's estimation. And
nobody's sure who's going to pay.
Another way to go at the problem of what to do with the nearly complete
human genome is to look at proteins. The 34,000 or so genes in a person
make up the genome; so too do the million or so proteins those genes encode
make up a "proteome." Proteomics, the science of studying them, is wicked
complicated. Every gene isn't turned on, making protein, all the time.
Time of day, temperature, mood, nutrition and a host of other environmental
and biological factors regulate the process. Some proteins are combinations
of subunits made by different genes, and those subunits can be put together
in different ways. But those variations, those genetic-environmental interactions,
are at the heart of just about every disease that isn't caused by a germ.
That's especially true for the ones that affect human beings more as they
age, like heart disease or Alzheimer's.
Large-scale proteomics is too new to have medical success stories, but
the concepts behind it are leading researchers in interesting directions.
Grover Bagby '64 directs the Oregon Cancer Institute at Oregon Health
Sciences University. His leukemia research deals with a family of genes
called Fanconi anemia genes. They show up in stem cells, the cells in
bone marrow that make blood cells, and when mutated they lead to leukemia.
His lab is examining the proteins these genes make, both mutated and normal,
to figure out the differences that can lead to leukemia later on.
Bagby is looking toward microarray technologies. Developed to do high-speed
genetics work, a microarray is essentially a silicon chip with millions
of strands of DNA attached, each a perfect match for part of a human gene.
By passing a sample of genetic material across the chip's surface and
seeing where it sticks, a researcher can get a very fast read on which
mutations are present in specific genes and which genes are switched on
or off. "I'd say 10 years from now a patient with leukemia might come
into a specialty treatment center and have their bone marrow looked at
under a microscope," Bagby says. "A microarray would then tell the hemotologist
what specific kind of leukemia that patient had, which chromosomal abnormalities
it mapped to, and which form of treatment would be best."
That's not the only way to treat leukemia, of course. Cladd Stevens '63,
Bagby's classmate in medical school, has a different approach. She's the
medical director of the Placental Blood Program at the New York Blood
Center, where they collect blood from the umbilical cords of newborn babies.
That blood contains hematopoetic stem cells, the precursor cells to red
blood cells, white blood cells and platelets --the cellular components
Leukemia is blood cancer, basically, so treatment often involves the destruction
of a person's bone marrow, where blood is made. But replacing that diseased
bone marrow with a transplant is a dicey proposition. The marrow has to
be very precisely matched to the recipient's immune system. "Apparently
the cord blood, because it's coming from a baby, is not well-educated,
immunologically," Stevens says. "We've done transplants that are mismatched
for tissue type and that wouldn't even be dreamed of with bone marrow."
The hematopoetic stem cells seem to be more forgiving, and even more amazing,
they home right in on the bone marrow, where they're most needed. And
cord blood may have other uses. For example, it also contains osteoclasts,
cells that break down old bone to make room for new tissue. Babies with
a rare genetic disorder called osteopetrosis keep developing new bone
without tearing down the old, so eventually, they die of severe brain
damage caused by the abnormal growth. A cord blood transplant cures these
At the same time that biomedical researchers are hoping genetic and proteomics
work might lead to new treatments for specific patients, they're also
learning how to apply this knowledge to entire populations. In banking
cord blood, Stevens is creating a library of tissue with ultimate uses
that aren't yet totally understood. At a practical level, population research
helps parse out what actually goes wrong in human beings, and why. "Why
is it that some people get heart disease and other people don't? Is it
their stress level, something they eat, where they live?" asks Julie Buring
'71. She heads the Physicians' Health Study and the Women's Health Study
at Harvard Medical School, which follow thousands of participants for
decades, looking at genes and lifestyles. "As much as we're making progress
on treating people, it would be far better if we could prevent disease
from ever occurring," Buring says. It's cheaper, and ultimately improves
quality of life.
There's a continuum among these techniques. In classic genetics, researchers
try to look at families with some inherited condition, and then look at
their chromosomes to try to find similarities, to narrow down the location
of the genes that might be the cause. In the old days of biochemistry,
researchers could look at rising and falling levels of various proteins
in the blood, but there was no way to tell whether those changing numbers
caused a disease or were its consequences. Today, population-based research
methods look at health trends among thousands of people, analyze their
proteins to find differences among the sick and the healthy and then find
the genes that underlie the proteins. "We took a blood specimen from everybody
at the beginning of our study, not even knowing what to look for," says
Buring. "Now we are beginning to know."
Michael Gorin '74 has roughly the same idea. An ophthalmologist and geneticist
at the University of Pittsburgh, Gorin works with smaller populations
trying to track down the causes of age-related macular degeneration, a
progressive blindness. "The goal of my research is to look at what environmental
or therapeutic interventions can reduce the risk," Gorin says. It's not
a well-understood disease--lots of genes are involved, and so are environmental
factors. A combination of genetics and population methods promises to
tease them apart.
But for all this to work, researchers will need more powerful statistics.
Laurel Beckett '68 heads the Division of Biostatistics at the University
of California at Davis' medical school. She's collaborating with neurologists
at Rush-Presbyterian St. Luke's Medical Center in Chicago on a study of
Alzheimer's Disease among 900 Catholic priests, brothers and nuns. The
subjects get annual neurological and physical exams, including extensive
cognitive testing, and, when they die, they donate their brains for pathologists
to count neurons, brain proteins and, if they're present, the classic
plaques and tangles of the disease. Beckett's job is to figure out how
to tell the difference between what's genetic, what's environmental and
what's related to the disease's progress. "People have this idea of statistics
as driven by means and averages, and it's really not true," she says.
"The action is in variability, and trying to understand it."
The new biomedical landscape is covered in a torrent of data. Long-term,
prospective studies like the ones Buring works on generate gigabytes of
numbers. Geneticists looking for individual differences use sample sizes
of only a few dozen people, but look at thousands of genes. With a database
that size, it's easy to get misled by artifacts. "How much of that is
the result of, when you look at ten thousand anything, something's going
to pop up?" says Beckett. "We have to think of how to find pattern and
meaning in a great deal of data." Eventually new statistical methods capable
of handling huge streams of data will help set public health policy. Those
stats will be the only way to tell if population-based preventive measures
actually make a difference.
These futures aren't that far off--10 years, maybe 25. At greater distances
it's possible to imagine replacement organs grown from spare cells, genetically
engineered to avoid rejection by the immune system. Miniaturization technologies
could mean pinhead-sized robots that can sweep clean a congested artery.
Amid all these sci-fi images, however, there is one cautionary note. Ironically,
at the dawn of what promises to be a revolution in biomedical marvels,
nearly half of all Americans today have turned, at least on occasion,
to some kind of alternative medicine--acupuncture, chiropractics, herbalism--even
though Western medicine usually works better. They turn to alternatives
because of the skyrocketing cost and complexity of high-tech medicine,
because they don't get any face-time with their doctor and because they
like the feeling of being taken care of, not merely treated. It's a lesson
Western medicine is struggling to assimilate. And it's a reminder that
there's more to our medical future than that sparkly salt shaker.
That's something Grover Bagby, the leukemia researcher from Oregon, has
known since medical school. On a hematology residency, he treated a woman
who came to the hospital with acute leukemia. She had a 26-year-old husband
and three children, and she was dead in 10 days. "I became almost a monk
devoted to going after this disease," Bagby says. "The idea that the best
doctor is the one that's most removed? That's crap. It's a way that some
protect themselves. But the patients I've followed for many years, I feel
like they're my brothers and sisters."
--Adam Rogers '92 is a reporter, sometimes focusing
on science, for Newsweek.