Professional Documents
Culture Documents
Cancer pa g e 1 6
Why do discoveries take
so long to reach the clinic?
When your genes aren’t
to blame, what is?
Is tumor sequencing
ready to ramp up?
plus
Tuning into
protein networks
Biology’s
big tent
Window on Whitehead On the cover
Researchers study
Science for me and YouTube an enormous range
of possible causes
My daughter is studying biology in high school, and her experi- and cures for can-
ence is both amazingly like and amazingly unlike mine at her age. cers—and the early
The amazingly unlike part isn’t hard to figure out. My old biology text- results of more powerful under-
book doesn’t mention recombinant DNA, which had barely been invented. standings are just now filtering into
My daughter lives in a world in which the human genome has always been clinics. Here, a cultured cell with
sequenced, sheep have always been cloned, and a certain number of your structure typical of melanoma or
friends have entered this world via in vitro fertilization. breast cancer. Image by Stone
What’s amazingly like is how she’s learning: teacher, textbook and a lit-
tle time in the lab. Oh, her biology teacher is fond of educational websites,
but those aren’t terribly important in class (yet). Among our contributors
However dramatically medicine has changed
The popularity of in my lifetime, that’s nothing compared to what DAVID CAMERON
she’ll see. As both a medical consumer and citi- manages media rela-
Web videos gives zen, she’ll need to understand the strengths and tions at Whitehead
us new ways limitations of the major advances now lurking Institute. He tells us
just over the horizon. he is secretly biding
to learn about But I don’t think she’ll spend much time his time until he lands a position
today’s biomedical reading about them in print. as staff writer for Jon Stewart’s
We still get print newspapers, news maga- Daily Show.
research zines and science publications delivered at home.
My daughter rarely reads any of them. ALYSSA KNELLER is
What she does, like her friends (and her parents), is spend time on the Whitehead’s Web
Web. Lots of time. The Web will be her main channel for tracking the editor. She has lived
future of biomedicine, as it will be for so many other topics. on three islands and
And when she can, she’ll be watching videos on the Web. worked as an envi-
For years, Whitehead has been filming our principal investigators as ronmental consultant and commu-
they give lectures to our non-scientific staff, and posting those films on our nity journalist.
website (www.whitehead.mit.edu/news/video_gallery).
But, as everyone knows, the popularity of Web videos is soaring now JAMES robert
with the combination of powerful PCs, fast Internet connections, inexpen- O’BRIEN is a nation-
sive digital video hardware and software, and Web video aggregators. ally recognized
That’s excellent news for public understanding of biology. Along with illustrator whose
the extraordinary power and promise of today’s research comes extraordi- work is created using
nary complexity. The popularity of Web videos gives us new ways to dive Adobe Photoshop and Illustrator
through all those details to learn about today’s biomedical research. along with found and hand-made
Enjoy an animation of proteins doing their dances together, and sud- elements. In his rare free time, he
denly you understand the basic concept. Watch a researcher explain what enjoys entertaining his daughter,
her lab studies, and it becomes clear. Show students a postdoc describing running marathons, reading impor-
how he got excited about his field, and you can inspire them too. tant novels and collecting and cre-
What’s really new is that people don’t have to wander across your web- ating music.
site to find this great stuff. Today, for instance, YouTube’s most famous
science video shows the startling results of dropping a Mentos mint into a JAMES YANG has
bottle of Diet Coke. But the video aggregation website also is becoming a received over 200
major resource for high school teachers swapping classroom videos. awards for design
So we at Whitehead and our colleagues at other research institutions and illustration excel-
will be expanding our use of video, along with podcasts and other Web lence. He also has
goodies. It’s another way for our scientists to tell their stories—and some- exhibited sculpture at the Smith
times, my daughter and her peers will tune in. —Eric Bender sonian Institute’s National Museum
of American History and created
the children’s book Joey & Jet.
www.whitehead.mit.edu
paradigm Life sciences at Whitehead Institute for Biomedical Research spring 2007
contents
Cover stories: Questions on cancer
12 A slow saga of success
Ever wondered why the journey from lab discovery to the clinic
takes so long?
21 Out of sequence?
Scientists debate whether it’s time to tackle tumor genomes
and epigenomes
Features 16
5 The RNA connection
Joint projects by David Bartel’s lab highlight the crucial role
of collaborations
8 Mouth to mouth
What can a frog mouth tell us about human birth defects?
10 Network news 6
Hui Ge sifts through oceans of data to explore how genes collaborate
Departments
2 Science digest 26
Cracking open the black box of autoimmune disease, and a gene that
shuts itself off
22 Whiteboard
The link between epigenetics and cancer
28 Fast FAQs
For all the controversies, it’s still early days for stem cell science
29 On the Web
Twenty-five years ago, Jack Whitehead signed the agreement creating
the Institute that bears his name
29
prevent biological “friendly fire” by ensuring that the discover the molecular mechanisms that drive these
T cells do not attack the body’s own tissues. Failure of conditions, we can migrate from treating symptoms to
the regulatory T cells to control the frontline fighters developing treatments for the disease itself.”
give rise to each 21U are identical. MIT professor and Nobel laureate Phillip Sharp, who was
“Using the sequence pattern, we can predict where not part of the research team.
MicroRNA genomics
and targets in flies
Lee Lim, Rosetta
Inpharmatics
(Merck)
MicroRNA target
recognition in
human cells
Harvey Lodish,
Michael Hemann, Whitehead Craig Mello,
MIT MicroRNAs in University of
MicroRNAs blood cell Massachusetts/
involved in development Worcester
cancer Small RNAs in worms
The RNA
More than a third of the human genome is partially
regulated by microRNAs—tiny snippets of RNA that can
disable a gene’s ability to create proteins.
So it’s no surprise that the lab of Whitehead Member
connection
David Bartel, the first to report this surprisingly widespread
role for microRNAs, has found many colleagues happy to
collaborate. At the same time, “as our lab looks at the par-
ticular targets of particular microRNAs, then we become
A snapshot of joint projects by interested in what’s going on in other labs that specialize in
those targets,” Bartel says.
David Bartel’s lab highlights the Here’s a glimpse at some current connections for the 20-
person lab—and it is just a glimpse. It shows only the prin-
crucial role of collaborations cipal investigators, not the postdocs and students who do all
the bench work, let alone the ongoing streams of informal
discussions.
»
By David Cameron
Gregory Stephanopoulos,
Hal Alper and Gerald Fink
celebrate their success in
illustration: tom dicesare; photo: donna coveney/mit
Here’s how
ethanol fuel is Enzyme Enzyme Yeast
created from
corn. Yeast
does all the
heavy lifting in
the fermenta-
tion process. Corn Grind Cook Turn Convert Ferment Distill Ethanol
to liquid to sugar
“At around the same time, the two New genetic analyses tie into other formation in frogs and shed light on
layers begin to mix, which is truly work in the Sive lab on the extreme the interactions between genes and
remarkable,” says Dickinson. “It’s as anterior region of embryos. proteins in humans. And the Sive lab’s
if you shuffled two decks of playing Postdoc Shuhong Li concentrates studies highlight how basic research on
cards.” on the genes and proteins that control seemingly esoteric organs or systems
As endoderm and ectoderm cells a much simpler organ—the cement can yield information that aids human
mix, some of them begin to die. The gland, which sits just below the pri- biomedical research.
mixed mass grows thinner and thin- mary mouth. Sive likens this organ
ner until it’s just a single layer of cells. to an underwater Post-it note, which David Cameron contributed to this
Finally, this layer, which is stretched secrets mucus to help frog embryos story.
Network news
»
Hui Ge sifts through oceans of data to explore
how genes collaborate By Eric Bender
starts with the components of a system, can study how the organism works,
hermaphrodites). and studies how those components not just by studying individual genes
But C. elegans also has about work together to achieve a certain but understanding what a lot of genes
function, such as protein synthesis do at a time,” she says.
19,000 genes—almost as many or protein degradation. “It’s impor- In a homework assignment for
genes as humans. And just as in tant to know not just the individual a class taught by Harvard’s George
components of a cell but how they Church, Ge came up with a computa-
humans, no gene does its work are mapped together,” Ge notes. “It’s tional strategy that eventually turned
alone. Instead, tasks are accom- like a subway system; if you remove into a paper in Nature Genetics.
a station, the effect on the system will The strategy was about correlating
plished through highly complex depend on its position.” data from large-scale studies of genes
networks of protein interactions. “These are data-driven approaches with large-scale studies of protein
In a 2005 Nature paper, Ge and colleagues Next, the researchers filtered out a network When the researchers zeroed in on “sub-
combined maps of protein interactions (blue), “backbone” that grouped proteins shown to networks,” they found that proteins whose
gene expression (red) and loss-of-function be interacting by at least two sets of data. functions were already known helped to char-
profiling from RNA interference studies (red). acterize unknown proteins nearby.
authors. (The worm was the likely total of around 19,000 genes, she says, these projects.”
target because it was the first multi-cel- and she suggests that it’s because genes Today’s attempts at detailed molec-
lular organism to be sequenced com- can back up each other’s functions. ular modeling are “still first draft,
pletely, in 1998.) “We are combining the protein still relatively fuzzy—just like genome
Next, Ge and colleagues tackled interaction map with the genetic inter- sequencing once was,” acknowledges
very early embryogenesis—the process action map to predict these pairs that Ge’s mentor Vidal. “But they are really
by which the worm divides twice, into give you a synthetic phenotype,” Ge shaping up.”
A slow
with chronic myelog-
enous leukemia (CML) ous methods for infecting healthy
have a unique chro- blood cells in culture. Then, in
mosome, soon 1975, she published her success,
saga of
named the Philadel- using the Abelson virus to induce
phia chromosome.
success leukemia in mouse blood cells. “For the first time we had
If you’ve ever won- a way to study in a controlled environment how this virus
dered why the journey interacts with its target,” she says.
What Rosenberg didn’t know at the time was that this
from lab discovery to postdoctoral success was one link in a profound—and
the clinic takes so long, unsuspected—chain of events that three decades later would
culminate in a spectacular cancer drug: Gleevec.
follow the decades- Gleevec treats chronic myelogenous leukemia (CML),
which strikes about one-fifth of all leukemia patients—
long story of Gleevec roughly 1.5 cases per 100,000 people. Before Gleevec, the
fatality rate of this disease was 100 percent.
By David Cameron
Brought to market in 2002, Gleevec represents a revo-
lution in cancer treatment. Rather than carpet-bombing
the body with toxins that wipe out the cancer but incite a
range of devastating side-effects, and very often fail any-
way, Gleevec targets a specific molecular abnormality of
CML. Although the drug doesn’t eliminate the cancer, for
the majority of patients it knocks it into a kind of perma-
nent remission. As long as patients take Gleevec daily, CML
becomes a chronic, and manageable, disease.
Gleevec points to the future of cancer treatment, but it
also typifies the serendipitous nature of basic research—and
the agonizingly long road that even the most dramatic suc-
cess stories must follow.
“The journey from the lab bench to the clinic is a slow
process,” says Whitehead Member Robert Weinberg. “Most
people fail to appreciate the time it takes for a discovery to
result in a drug. It would be wonderful if these things turned
around quickly. But this process always has—and probably
always will—take time.”
to demonstrate that it, and it alone, could initiate CML in drugs that blocked kinases, Druker
1998
Clinical trials begin for
an animal.” was convinced that CML could
this compound, which
Many research labs were trying to do this, mostly respond to such a novel approach.
is named Gleevec.
through incorporating BCR/Abl into the animals’ germ “It was a well-defined disorder that
lines. But the BCR/Abl gene was toxic to germ cells, and we knew resulted from an acti-
most of these mice died in utero. vated kinase,” he says. “Block the
Daley tried a different route. kinase, and you’d topple the disease. Plain and simple.”
Using the methods that then-Whitehead Member Rich- In 1993 Druker left Dana-Farber and took a position
ard Mulligan had developed for transferring genes into at Oregon Health & Science University. “I had one goal at
blood stem cells, Daley transferred the BCR/Abl gene into the time: to find a company that had an inhibitor for BCR/
the bone marrow of mice. Abl and to bring it into the clinic.”
He then took that bone marrow and transplanted it Druker contacted Nick Lydon, a scientist at Ciba-
into a second group of mice whose own marrow had been Geigy. Lydon had developed a number of small kinase-
destroyed by radiation. blocking compounds that Druker wanted to test. Since
And the second group of mice developed CML. kinases pass their phosphate messages by physically inter-
“If you think about it,” jokes Daley, “this was really acting with other proteins, almost like two Lego pieces
gene anti-therapy.” This experiment proved that the BCR/ snapping together, the hope was to find a tiny molecule
Abl gene was sufficient to cause CML. “We now knew that that could wedge itself inside the exact spot where the two
for this disease, BCR/Abl was the fundamental drug target,” proteins fit, thus obstructing the message. The caveat was
he says. that such a molecule must be so specific that it could only
disrupt BCR/Abl. And while kinases are not as uniform as a
Killing with kinase box of Legos, they are similar enough to make this a daunt-
kim furnald for furnald/gray
Back in 1980, when Owen Witte first discovered the Abel- ing challenge.
son virus fusion protein, he also found that it belonged to a While Druker was screening Lydon’s compounds in
family of proteins called kinases. A kinase sends messages human bone marrow cells, one named STI571 stood out. By
through the cell by adding a phosphate to other proteins, targeting a section of the BCR/Able protein called the “cata-
which in turn affects those proteins’ activity. lytic cleft,” this compound immobilized its ability to transfer
What distinguished the over-sized BCR/Abl protein that phosphates to other proteins. Healthy cells were unaffected.
Witte had identified from ordinary kinases—and from the “At that point I knew we had a potential drug,” says
normal Abl protein—was that because of its mutant struc- Druker.
M
By Alyssa Kneller
this medical mystery by taking a closer look at tists had already shown that methyl groups block
the VHL gene in patients with the non-hereditary access to DNA, preventing it from being read out,
form of this cancer. so this was a logical conclusion.
the study one step further by setting new methyl marks tumors exhibit epigenetic changes regardless of their origin.
randomly on the DNA of the tumor-prone mice—a gain- So epigenetic patterns could be used to diagnose particular
of-function study as opposed to the many loss-of-function types of cancer, even those caused by genetic mutations. But
studies done previously. scientists caution against losing sight of the big picture.
In most tumor cells, DNA is unusually short on methyl “Although methylation changes can be just as important
groups. Yet the same cells often contain short sequences as mutations in particular cases, epigenetics is just one very
replete with methyl groups, hot spots that typically fall on narrow part of the broad cancer research field,” Weinberg
the regulatory regions of genes. After Linhart and Moran explains.
Health Study, for example, showed that that people have underestimated the lot of layers of epigenetic modification
women who take a multivitamin pill plasticity of epigenomes,” says Emma (beyond methylation), and some will be
containing folate (a form of vitamin B9) Whitelaw, who studies epigenetics in more stable than others,” she says.
and 2003 but is now dropping in real spend 0.5 percent of the budget on by which time we should know more
dollars each year. Whitehead Member cancer genome sequencing, because about what to look for and where to
Robert Weinberg suggests that grant it would make the other 99.5 percent look for it.”
maternal
chromosome
Enhancer
helps turn on
the H19 gene.
H19 gene
Interaction results in
H19 gene product
lgf2 gene
Enhancer
helps turn on
the lgf2 gene.
Interaction results in
lgf2 gene product H19 gene
maternal
chromosome Insulator protein can no
longer bind to the region
between the two genes.
Enhancer
helps turn on
the lgf2 gene.
H19 gene
lgf2 gene Interaction results in
lgf2 gene product
Enhancer
helps turn on
the lgf2 gene.
lgf2 gene
Interaction results in
lgf2 gene product H19 gene
paternal
Methyl groups block access to the
chromosome DNA between the two genes, pre-
venting the insulator protein and
enhancer from binding.
Age: 30 his best chance to bridge the Age: 30 Engineers and biologists
gap. From the perspective of think differently. “In engineer-
Bachelor’s degree: Chemistry, Bachelor’s degree: Chemical
University of Virginia a surface chemist, immunol- engineering, MIT ing, you start with physical
ogy seemed the easiest entry laws you know are irrefutable,
When Christopher Love started point. “I knew there was a lot In a recent meeting of the and if the data don’t support
his postdoctoral fellowship of contact between cells and Harvey Lodish lab, discussion them, you know that the data
in the immunology research that it involved surface interac- turned to the evolution of red are wrong,” Eshghi says. “In
group of Whitehead Member tions—something familiar,” blood cells: Why does a red biology, you don’t have that
Hidde Ploegh, he had not Love says. “It took me a year blood cell lack a nucleus? starting point. It’s very empiri-
taken a biology class since to understand the terminology. “The first thing I thought cal. Classical biology papers
high school. It’s a different language from of was the mechanical proper- use a lot of inductive reason-
Love knew how to make even other areas of biology.” ties of the cell,” says Shawdee ing: ‘This is our hypothesis.
magnetic nanoparticles orga- He needed even more Eshghi, who is just finishing Here are some data to support
nize themselves into micro- time to understand how biolo- her doctoral work in biological it. Maybe this is what’s going
scale structures and how to gists think. “Biology has an engineering under the joint on. We did another experiment
kim furnald for furnald/gray
create nanometer-thin crystal- extra level of complexity from oversight of Lodish and Linda to show this isn’t it.’ They
line coatings of molecules on materials science, physics and Griffith in the MIT biological present all the hypotheses and
metals. He wanted to apply chemistry,” Love comments. engineering division. “The knock them down.”
such tools from the physical “I’m amazed at the types of nucleus is stiff and cannot She adds that engineers
sciences to advance medical insights biologists can draw bend. The hallmark of the have a versatile common
knowledge and public health. from experiments, where it red blood cell is its flexibility. language: mathematics. But
Jumping feet-first into a tends to be difficult to control That’s not what comes to the biological systems need more
biology lab, he figured, was the variables.” minds of most biologists.” levels of explanation.
Age: 28 properties of the stretchy stalk Age: 28 inquiries. Recently, Farh and
that affixes the tiny pond crit- collaborator Andrew Grimson
Bachelor’s degree: Biomedical Bachelor’s degree: Computer
engineering, Washington Univ. ter to a rock or crustacean. science, Rice University found that mammalian genes
When she publishes papers, have evolved to avoid target-
A biologist can be hard to find she considers which commu- Kyle Farh’s computer science ing by microRNAs that would
in the Whitehead lab of Paul nity she wants to reach, either training brings much-needed otherwise reduce or compro-
Matsudaira. And the lab’s cell biologists for the subject expertise to the Whitehead lab mise the genes’ function.
expertise ranges from simulat- matter or biophysicists for the of David Bartel. But it did not For all the differences, Farh
ing colliding stars on super- underlying imaging. “People help during his first two years has found a lot of common
computers to building joints either peg you as a biologist or at Harvard Medical School. ground between computa-
for robotic arms. an engineer,” she says. “I probably went to medi- tional and experimental biol-
“I wish we could get a France, whose mom is a cal school knowing the least ogy. “The thing that biologists
biology graduate student to math teacher, set her sights on molecular biology of all my are really good at, compared
work on Vorticella,” a genus of engineering earlier than most classmates,” remarks Farh, to other scientists, is doing
protozoa, muses Danielle Cook girls. “I see a lot of future in who initially joined a dot.com controls, because there is so
France. “There are tons of using the biology we know to startup company after college. much you don’t know about
open questions.” In the mean- engineer new things, such as At Whitehead, Farh’s the system, which is so com-
time, lab technicians provide building materials from basic bench work remains limited plex,” Farh comments. “You
the biological expertise and biological components,” she to occasional and relatively really have to be as rigorous
tutoring in protein purification. notes. “MIT has given me more simple procedures. He has about controls in computa-
France, a biological engi- confidence about starting my surrounded himself with tion.” In the end, he says, test
neering graduate student, own company. That spirit is in experimentalists who inform results can be equally enlight-
studies the rubber-band-like the air.” and inspire his computational ening or enigmatic.
Targeting the
spreading through South Africa.
Scientists are working on many
fronts to unravel the basic biology of
dangerous microbes.
agents of disease
But funding for these research
»
efforts is a major bottleneck.
Fauci points out that existing
resources are being directed at emerg-
In the war on infectious disease, are we ing and re-emerging infections in the
context of global health and security.
spending enough—in the right places? He believes that the intense concern
about a possible bird-flu pandemic is
By Richard Saltus an opportunity to reduce the toll of
ordinary seasonal influenza with better
Megan Murray, an epidemiologist at the Harvard School of Pub- vaccines and therapies. Spending on
influenza has been ratcheted up 10-
lic Health, is very worried about where her next research dollars fold to $222 million, says Fauci. Other
will come from. At times, she thinks she may have to fall back on NIAID priorities include developing an
effective HIV/AIDS vaccine, prevent-
being a practicing physician to make ends meet. ing mother-to-child HIV infections and
The co-leader of a large study in Peru aimed at identifying attacking the worrisome emergence of
drug-resistant TB.
risk factors for drug-resistant tuberculosis, Murray has published Though controversial, the infusion
important papers in the field. But she’s finding that it has become of $1.2 billion in new federal funding
kent dayton
chromosomal aberrations quite eas- son’s, Alzheimer’s and diabetes. some way that redirects it back to
ily. All these issues we can handle in [In SCNT, an egg’s DNA would be an ES-cell-like cell. Nuclear transfer
the mouse. replaced with DNA from a patient, shows that the egg can do it.
Office of Communications
and Public Affairs
Whitehead
2007
In this seven-minute video
Whitehead Institute for overview, Whitehead scien-
Biomedical Research tists describe a research envi-
Five Cambridge Center ronment that inspires
Cambridge, MA creativity and collaboration.
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