If cells didn’t stick to each other, multicellular organisms from blades of grass to human beings would not exist.
What holds our cells together? The answer to that seemingly simple question — and its implications for disease, including cancer — arose in part from key discoveries by Richard Hynes, a biology professor in MIT’s Koch Institute for Integrative Cancer Research.
“What has been learned over the last 30 years is that cells, most of them, can’t function without being attached,” says Hynes, who is also a Howard Hughes Medical Institute investigator and former head of the MIT Department of Biology.
His and others’ research has shown that the “extracellular matrix” — the molecular glue that binds cells — also transmits signals to and from cells. Those signals work in concert with growth factors to govern cell formation, organization, and migration. The extracellular matrix helps guide, for example, infection-fighting white blood cells to the site of a bacterial attack in the body. And when it malfunctions, cells can lose their way and turn against the body. Chronic inflammation — caused when white blood cells swarm and attack healthy tissue — is a relatively straightforward example of this, while cancer involves a complex series of cell-adhesion phenomena.
The son of a freshwater ecologist and a physics teacher, Hynes took an interest in science at a young age while growing up in Liverpool, England. His three siblings also became scientists. “We were thoroughly brainwashed,” he jokes.
After earning his Ph.D. in biology from MIT in 1971, Hynes pioneered his chosen field while a postdoctoral fellow at the Imperial Cancer Research Fund in London. There, he discovered a protein, fibronectin, on the surface of healthy cells that enabled them to bind together. At the same time, he found that fibronectin was absent from the surface of tumor cells. These revelations sparked further studies that helped establish cell adhesion as its own field of investigation. “I never intended to study cell adhesion. But, having found it, it was fascinating. I never got away from it,” he says.
Later, at MIT’s Center for Cancer Research (now the Koch Institute) , where Hynes arrived as a founding member in 1974 and which he directed from 1991 to 2001, he was among the discoverers of integrins. A class of receptors that makes cells sticky by binding with fibronectin and other adhesion molecules, integrins play a key role in migration, helping cells to propel themselves through masses of their neighbors and the extracellular matrix.
Hynes’ work has helped enable new drugs, already in use, for diseases arising from defects in cell adhesion. Those diseases include thrombosis, characterized by potentially fatal blood clots, and inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, asthma, and psoriasis.
“White blood cells use adhesion receptors a lot to get where they’re going, and if you can stop them from doing that, you can cut down the inflammation,” says Hynes. Adhesion molecules, he adds, “are very ‘druggable’ molecules. They’re on the outside of the cells. You can get at them. You can block them.” Other drugs that similarly target adhesion receptors are under development to block blood-vessel formation in tumors.
Building on this foundation of therapeutic manipulation of adhesion molecules, Hynes’ laboratory is working toward untangling the adhesion factors involved in tumor formation and metastasis, or the migration of cancer cells from the primary tumor to other parts of the body. “Ninety percent of cancer deaths are due to metastasis. And metastasis is clearly a problem with changes in cell adhesion,” he says.
Enabled by genome-sequencing and imaging technology that emerged in the past decade, as well as advanced mouse models developed in his laboratory, Hynes is investigating “what changes when cells become metastatic. They have to lose adhesion from home base in order to wander. They have to gain ability to walk through the extracellular matrix. They have to get into the blood vessels. They have to stop when they get to a distant site, and get out of the blood vessels. A lot of those tricks are things that white blood cells use as well.”
Hynes’ laboratory has already identified many of the adhesion proteins in a tumor’s extracellular matrix and is working to tease out which ones are key to metastasis. To do this, Hynes is embarking on a collaboration with Massachusetts General Hospital to study how human colon tumors progress. He hopes that, within a few years’ time, he will have identified some candidate proteins promising enough to target with molecular therapies.
When Hynes isn’t investigating how tumor cells behave, he regularly visits his native England to perform duties as a board member of the Wellcome Trust, which is second only to the Gates Foundation in biomedical research funding worldwide. He also helped author the National Academy of Sciences’ guidelines for stem-cell research, and even lobbied Congress alongside celebrity advocates Mary Tyler Moore and Michael J. Fox in favor of federal funding for stem-cell research.
Hynes marvels at how far molecular and genetic technologies have advanced the field of biology over the course of his career. “Almost everything we teach has happened in the last 40 or 50 years. And it changes every five years, or more often,” he says. “All those questions I thought about as a graduate student are getting answered, and new ones are coming up. It’s just wonderful.”