Sound of Silence
Peter Laird Has a Lot To Say About The Role Gene Silencing Plays in Cancer.
Peter Laird, Ph.D., is making a lot of noise in a field that is all about silence.
The field is epigenetics, a discipline at the cutting edge of biomedicine
that deals with the ways in which genes are regulated or suppressed—silenced,
in other words.
The noise Laird
is making is a groundbreaking, paradigm-shifting clatter that is attracting
the attention of scientists at USC and around the globe. It has merited collaborations
with literally dozens of other scientists at the Keck School of Medicine and
the USC/Norris Comprehensive Cancer Center. It has earned him a patent—awarded
in December 2001—on a technique called MethyLight that he and his colleagues
at the Keck School created to assess a particular type of epigenetic change
called DNA methylation. It has garnered him the role of chairman and organizer
for a meeting of the Federation of American Societies for Experimental Biology
to be held in 2004, as well as a seat on the Board of Directors of the international
DNA Methylation Society.
And, perhaps most impressively, it has brought Laird a resounding nod of approval
from the National Institutes of Health (NIH), which, last year alone, approved
funding for four different research grants on which he is the principal investigator,
handing him a total of more than $6 million in funding over the next five
years, all to be used for epigenetic research.
“This is an indication of how hot the fields of methylation and epigenetics
are,” says Laird.
Methylation light
Laird, an associate professor of surgery and biochemistry and molecular biology
at the Keck School of Medicine of USC, strides through his laboratory at the
USC/Norris on long, lanky legs. He stops in front of a hooded lab bench where
a robotic arm is dropping a clear liquid into dozens upon dozens of wells
with a near-dizzying speed and efficiency.
“This is MethyLight,” Laird says as the arm softly clicks and whirs.
He explains that this sort of large-volume data-gathering technique is the
single most important tool in doing science in a field where hundreds of thousands
of cells must be examined to come to a single conclusion. “If it weren’t
for this technique, or others like it,” he adds, “I couldn’t
do my job.”
What Laird is looking for in these wells and cells is a pattern of epigenetic
changes that will help him dig up the roots of cancer.
Like the well-investigated field of Mendelian genetics, epigenetics focuses
on the ways in which proteins and enzymes are ultimately produced from genes.
But while genetics is about the sequence of bases in DNA, epigenetics is about
the regulation of those sequences.
The best-understood mechanism for epigenetic gene silencing is a process called
DNA methylation, in which a methyl group—made of one carbon and three
hydrogen atoms—is tacked onto critical stretches of a gene, preventing
it from being replicated or turned on. “DNA methylation marks part of
the DNA as a part that should not be used,” says Laird. “It’s
like a pair of chemical handcuffs. The gene is intact; it’s just been
silenced.”
Under most circumstances, this handcuffing is a good, necessary thing, since
not every gene in every cell is supposed to be on all the time. But sometimes,
methyl groups wind up handcuffing genes that are supposed to remain unshackled.
And that creates problems, says Laird, since some of these genes may be required
to prevent cancer from developing.
Still, Laird says, “It’s been a struggle to convince the scientific
community that epigenetics could play a role in cancer.” What that struggle
needed was someone willing to make a little noise.
Mice and methylation
Peter Laird was born in Groton, Mass., but moved to The Netherlands as a young
man, graduating from high school there, attending the University of Leiden
(where he received both his bachelor’s and master’s degrees in science),
and then moving to the University of Amsterdam, where he received his Ph.D.
in 1988. After a three-year stint as a postdoctoral fellow at The Netherlands
Cancer Institute in Amsterdam, he came back to the U.S. in 1991 to work as
a postdoc at the Whitehead Institute at the Massachusetts Institute of Technology.
It was there that he began thinking and talking about the connections between
methylation and cancer, and it was there that he began working to prove that
such connections existed.
To do this, he needed a mouse model in which methylation patterns could be
easily toyed with. To start, he looked at a knockout mouse a colleague had
created, in which the gene for an enzyme called DNA methyltransferase—which
allows methyl groups to be attached to DNA—was silenced. “But we
found that when you knock out this gene entirely, the mice don’t survive,”
he recalls.
So Laird and his colleagues created heterozygous mice—mice with one DNA
methyltransferase gene knocked out, but the other intact. They then used a
drug to further inhibit the enzyme in both types of mice. With this advance,
says Laird, he and his colleagues realized they could create mice with different
methylation levels.
They then began to examine how cancer might or might not develop in strains
of mice bred to be susceptible to developing precancerous polyps in their
intestines. They found that control, or “normal,” mice had intestines
stuffed with an average of 113 polyps, while heterozygous mice had an average
of 46 polyps. Normal mice treated with the methyltransferase inhibitor had
about 20 polyps apiece while heterozygous mice that also got the methyltransferase
inhibitor had an average of just two polyps in their purportedly polyp-prone
intestines. “And in most of these mice,” says Laird, “there
were zero polyps. In other words, we had cured these mice of their genetic
predisposition to polyps.”
This work was published in the journal Cell in 1995. “It created a tool
to study how DNA methylation affects the cancer process,” Laird says.
“And it opened avenues for thinking about new therapies as well.”
The human factor
Having conquered the realm of mouse methylation, Laird was looking for a larger
challenge—the chance to look at the relevance of methylation in human
cancer. He found that chance at USC.
“USC is a center of excellence in this area,” he explains. “I
was attracted here by the opportunity to work alongside clinicians and epidemiologists,
and to do translational research.”
And so, in 1996, accompanied by his wife, Ite Laird-Offringa, Ph.D., assistant
professor of surgery and biochemistry, and their two daughters, he left Cambridge,
Mass., and moved to Los Angeles.
Since then, he has been working at the speed of sound. He is doing further
work to follow up on the Cell mouse studies, with a five-year, $1.8 million
renewal grant. He is collaborating with Keck School researchers Kimberly Siegmund,
Ph.D., assistant professor of preventive medicine, Peter Jones, Ph.D., director
of the USC/Norris Cancer Center and Louis Dubeau, M.D., Ph.D., professor of
pathology, as well as Martin Wiedschwendter of the University of Innsbruck
in Austria, in an NIH-sponsored study of DNA methylation and early detection
of ovarian cancer (a new, five-year, $1.65 million grant). In association
with Siegmund, Anna H.Wu, Ph.D., professor of preventive medicine, and Leslie
Bernstein, Ph.D., the AFLAC Chair in Cancer Research, Laird is conducting
a new five-year, $1.8 million study of DNA methylation markers in esophageal
adenocarcinoma.
And in collaboration with Frank Gilliland, M.D., Ph.D., M.P.H., professor
of preventive medicine, he is embarking on a major project, funded by the
NIH’s National Institute of Environmental Health Sciences, to create
a Center for Environmental Epigenomics, which will look at the ways in which
methylation patterns and other epigenomic changes are affected by environmental
influences.
“DNA methylation is a perfect medium to study the way the environment
influences the human genome,” Laird explains. “Methylation patterns
can be changed throughout our lifetime; they can easily be influenced by our
environment.”
That, says Laird, is why he is particularly excited about the Center for Environmental
Epigenomics. “We’ll be looking at things like how smoking affects
DNA methylation,” Laird says. “We’ll be looking at methylation
and nutritional exposures—how diet affects methylation.”
Laird’s excitement is contagious, almost palpable. And no wonder. He
is convinced that the key to understanding and curing cancer lies in the very
phenomenon he is studying, a field in which he is a pioneer.
“Every single human cell on earth has a unique methylation profile,”
says Laird. “If we can tap into that information, we will learn a lot
about the past history of a tumor—and about its future, as well.”
When it comes to epigenetics, Peter Laird will not be silenced.
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