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MIT’s March on Cancer

A leader in basic cancer research for more than 30 years, MIT is now setting the standard for cross-disciplinary research on the disease.

MIT’s Center for Cancer Research is not much to look at. It’s part of the large nondescript complex on Ames Street where buildings E17 and E18 begin and end with no clear delineation. The glass door of the center’s main entrance is as unremarkable as its basic brick facade. The lobby–which isn’t really a lobby at all but a narrow elevator bay with a set of stairs that lead to the reception area–has the feng shui of a utility closet. The windows leak when it rains and the place is overcrowded. In fact, only 13 of the center’s 33 members have offices in the building. The rest are scattered across campus.

But remarkable things happen here. Since the facility opened in 1974 under the direction of biology professor and Nobel laureate Salvador Luria, it has become a seat of cutting-edge research in molecular biology, genetics, cell biology, and immunology. Here, scientists have helped dispel early views about what triggers cancer; they’ve shone a light on how cells work; they’ve uncovered molecules now used in cancer-fighting drugs; they’ve discovered disease-causing genes; and they’ve developed new tools for cloning cells and sophisticated models for testing gene function. And yet people still seem puzzled when center director Tyler Jacks talks about cancer research at MIT. “We often get blank looks [because] they don’t understand we do biology at all, let alone disease-oriented research, let alone cancer research.”

The nondescript building may be partially to blame, but more likely than not, people overlook the center because it does not treat patients or conduct clinical trials. Instead, it is one of eight centers nationwide designated by the National Cancer Institute (NCI) to do basic cancer research. Over the last 30 years, that research has evolved from the investigation of cells’ molecular components in isolation to the consideration of how those components operate as a system. That broadening of perspective has required, among other things, biological models that imitate cancer growth in living tissue, collaborations that draw on fields outside of biology, and close examinations of the chemical circuitry underlying it all. The researchers at the MIT center are by no means the only ones subjecting the disease to such scrutiny. But, says Dinah Singer, director of the division of cancer biology at NCI, “they have taken a leadership role in this area.” The center’s strengths, Singer notes, are its faculty, the breadth of their expertise, and the level of their interaction with the rest of the university, which puts them in a position to take enormous strides in developing new forms of biotechnology. A sampling of some of the center’s latest research and cross-disciplinary initiatives reflects its progress and points to the path it will follow in its fight against cancer.

A Better Mouse
One would expect that the Institute’s world-renowned engineers could build a better mousetrap, but a better mouse? In fact, scientists at MIT’s cancer center are genetically engineering laboratory mice ideally suited for cancer research. In the fight against cancer, animal models are vital because they allow researchers to pinpoint the genetic sources of the disease, to study cancer cells as they grow within living tissue, and to analyze the effectiveness of treatments–something they cannot do in human beings. In the past, researchers might have cultured cancer cells in a petri dish, implanted them under the skin of a mouse, and then observed their growth. But genetic engineering has made that kind of lab work largely obsolete. Scientists now know that mutations in certain genes can lead to human cancer. But the nature of the mutations–are the genes damaged? turned off? hyperactivated?–is not always well understood. Researchers can begin to answer some of those questions by tweaking one or several genes in mice and then observing whether the animals become more susceptible to cancer. The models are informative because humans and mice are biologically similar. “In the end, we’re big mice, or mice are small people,” says Robert Weinberg ‘64, PhD ‘69, director of the Whitehead Institute for Biomedical Research and a member of the cancer center since its inception.

Weinberg has many “firsts” on his long list of professional accomplishments. He discovered the first human oncogene, a mutated form of a normal gene that can contribute to cancer. He was the first to turn a normal human cell into a cancer cell. And he was the first to clone a tumor suppressor gene, which normally restricts cell growth but when mutated allows cells to proliferate. His lab was also the first to successfully graft human breast tissue into the mammary glands of mice. The tissue produced human milk and in some cases developed tumors similar to those found in humans. For the first time, scientists could study the early stages of breast cancer in human tissue without having to examine a human being.

“We’re becoming increasingly refined in our ability to model human disease [in mice],” says Jacks. “We can produce in a specific way the kind of mutations that occur in human cancer.” Last December, for example, one of his teams announced that it had developed two mouse models that, with only slight genetic differences between them, resulted in two distinct forms of female reproductive disease. In the first model, the researchers mutated a known cancer-causing gene called K-ras, which caused the animals to develop endometriosis–a gynecologic disease that afflicts about five million women in the United States. In the second model, the researchers combined the mutated K-ras gene with an altered form of a gene known as Pten, which normally works to suppress cancer. The result was a mouse that developed a specific type of ovarian cancer. These mice represented the first animal models of the two diseases. “The end result is two models that are very powerful in how they might be used for two important diseases of the female reproductive organs,” says Jacks.

How they might be used depends on who’s interested. Jacks’s team, for example, uses its mouse models to study the effects of genetic mutation on tumor development, extracting cells from the animals’ tissue and examining how genes within the cells function. But people outside of MIT can request the animal models for use in their own research, including tests of potential anticancer drugs. That’s because almost all of the mouse strains developed in Jacks’s lab–and in anyone else’s lab at the Center for Cancer Research, for that matter–are placed in repositories such as the Mouse Models of Human Cancers Consortium Repository in Frederick, MD. Funded by the NCI, the repository makes models available for free to researchers at other institutions. It also manages a database that contains information relevant to each mouse strain. “The NCI has been aggressive in building [repositories] to make it easier for groups to share data,” says Jacks. This is important, he says, because it can take a lab a year or two to develop a specific genetic cancer model, including six months to breed mice that embody it. Singer says that MIT stands out among members of the consortium, not only for developing useful models but for “setting a new paradigm in how we need to be doing collaborative science.”

Following the Pathway
But research at MIT’s cancer center extends beyond mice. Plenty of work still continues at the molecular level, with scientists trying to understand how genes and proteins work together to keep cells functioning properly and cancer free. For the most part, scientists are just beginning to understand the biochemical-signal pathways that control cell function. What they’ve learned so far could serve as the foundation for new means of cancer detection and treatment.

Biologist Angelika Amon, for example, studies how chromosomes organize and duplicate within a cell before it divides. Because chromosomes carry genetic information, any flaws in their duplication can lead to cancer, birth defects, or miscarriages. Researchers in Amon’s lab are studying cell division in baker’s yeast, which is similar to that in humans. In fact, says Amon, if a baker’s-yeast cell lacks the gene responsible for a certain process, the corresponding human gene can substitute for it. Amon has identified a key protein that comes into play after the chromosomes in a cell have segregated but before the cell has divided into daughter cells. This protein appears to control the final stages of the process. “The hope is that by learning about the basic mechanisms that control chromosome segmentation, eventually we can learn and understand what goes wrong during cancer,” she says. Amon’s work recently earned her the National Science Foundation’s prestigious $500,000 Waterman award; the stipend will fund further research on the signaling pathways that contribute to cell division.

Some of Amon’s colleagues at the center study the roles of signaling pathways in processes other than cell division. Biologist Michael Yaffe and his group concentrate on the multitude of pathways cells use to communicate information about their growth conditions, their environments, and the integrity of their DNA. When these mechanisms malfunction, they can contribute to cancer by allowing mutant cells with damaged DNA to proliferate. Yaffe’s work in cell signaling after DNA damage has recently uncovered a pathway that could be exploited to make cancer treatments more effective. In January, the group reported that a molecule previously thought to be involved solely in inflammation also affects a pathway used by cells with DNA damage.

In normal circumstances, damage to a cell’s DNA engages several pathways that prevent the cell from dividing while the DNA is being repaired. But the signals in cancerous cells are malfunctioning slightly, so tumors can continue to grow even when their DNA is damaged. Yaffe’s lab showed that disrupting the DNA damage signals still further, by blocking the inflammatory molecule, caused the tumor cells to die. A number of pharmaceutical companies are developing drugs to inhibit the molecule as part of their efforts to combat diseases such as arthritis. “Those anti-inflammatory drugs in development may now have second lives as chemo-sensitizing agents by making cancers much more susceptible to commonly used chemotherapy,” says Yaffe. Experiments to test this hypothesis in animals are already under way.

One of the most exciting new research areas in biology has to do with DNA’s cousin, RNA. One form of RNA, messenger RNA, copies genes’ genetic blueprints and delivers them to cellular structures called ribosomes. Ribosomes in turn use the blueprints to build proteins that do everything from digesting food to forming hair and fingernails to controlling which substances pass through cell membranes.

But other RNAs regulate genes. In just the last five years, biologists have discovered a process called “RNA interference,” in which short strands of RNA target and destroy messenger RNA. What’s more, researchers can chemically synthesize these strands in the lab. “They can be designed to any gene,” says Institute Professor and Nobel laureate Phillip Sharp HM, who is trying to explain the mechanism behind RNA interference. “What the discovery means,” says Sharp, “is that we now have a tool to silence any gene in any cell.” Silencing a defective gene known to be associated with cancer, for example, could prove an effective means of preventing or treating the disease. In 2002, Sharp cofounded the Cambridge, MA-based biotech company Alnylam Pharmaceuticals, which is working to commercialize RNA interference.

One of the biggest challenges Alnylam and other biotech companies face is delivering the chemically synthesized RNA strands to target cells. RNA molecules commonly degrade in the bloodstream before they can reach the desired cells. But last fall, Alnylam reported a new delivery system that could solve this problem. Company researchers were able to trick mice cells into accepting RNA strands by attaching them to cholesterol molecules. When the RNA got inside the cells, it silenced a gene responsible for producing cholesterol, lowering the mice’s cholesterol levels by 35 percent. “The exciting part of this is that if it is real for one gene, it will be real for all of them,” says Sharp.

Beyond Biology
Over the past decades, biomedical researchers have amassed a heap of data about the different parts of a cell and how they function individually. The next step is figure out how they work as a system. “The more we do, the more we realize the complexity of the situation,” says Jacks. There are somewhere between 20,000 and 30,000 genes in a normal cell, many of which can contribute in one way or another to cancer. Determining the combination of biochemical signals that renders a cell malignant requires tools beyond those that biologists usually have in their labs. “Bringing in other disciplines is important because the biological perspective, while critical, is not sufficient,” says Jacks.

Since coming on board as the center’s director in 2001, Jacks has been working to increase collaboration among its members and to recruit new members from disciplines outside biology, including computer science, chemistry, and materials science. Scientists become members by invitation. They are asked to give presentations on their work, which is discussed first among a large group of members and then again among Jacks, Sharp, associate director Jacqueline Lees, and former cancer center director Richard Hynes, PhD ‘71. “There is tremendous talent across this campus in a wide variety of disciplines, many of which impact on cancer or cancer research,” says Jacks.

A recent initiative marks a big step in the direction of cross-disciplinary collaboration. Last October, the National Cancer Institute awarded MIT $12.6 million to unite cancer biologists with computational scientists in an attempt to explain at the systemic level how cancer develops and spreads. “MIT is a great place to do this because the pieces are there,” says Hynes. Thirteen investigators, including principal investigators Hynes and Doug Lauffenburger, will contribute to the so-called integrative cancer biology program. They will focus on three areas of research: cell proliferation, DNA repair, and cell migration. The goal of the program is to “try to monitor many events simultaneously in the same type of cancer so that we get a much bigger picture of how this information is flowing,” says Yaffe, who is one of the 13 investigators. The program has just gotten under way, but as the groups begin collecting data, they will make it available on local websites connected to a shared database managed by the National Cancer Institute.

For all its past successes and future promise, the cancer center lacks one thing: an adequate facility. Buildings E17 and E18 are overcrowded and out of date. “We need a new building,” says Amon. “This place is falling apart.” When it rains hard, puddles accumulate on her windowsill. “Water drips into my fancy, expensive microscopes. I’m not happy,” she says. Though it’s been a home to cutting-edge research for 30 years, E18, where part of the center resides, was originally a chocolate factory. “The cancer center clearly needs new physical facilities,” agrees Weinberg.

It may soon get them. Last year, the MIT Building Committee designated a site for a new facility–the empty lot and parking area adjacent to the biology building and across Main Street from both the Whitehead Institute and the Broad Institute, which is still under construction. The site is also only a stone’s throw from the brain and cognitive-sciences center now being built on Vassar Street. “This is a tremendous corridor of bioscience here,” says Jacks. No date has been set yet for breaking ground, nor have fund-raising goals been determined. “We hope to get to these milestones in the coming months,” says Provost Robert Brown, a member of the building committee. But Jacks and his colleagues are looking forward to the day when they can carry out their world-renowned cancer research under one roof. Not only will it solidify the new collaborations they’re now working to establish, but it will anchor the cancer center within the MIT community.

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