The Glue of Life

By DICK THOMPSON LA JOLLA

If living cells didn't have a fondness for sticking together, we would all be colorful gobs of jelly oozing all over the floor. Fortunately, cells hold to a basic biological premise that stickiness is desirable for form and essential for function. They violate this premise at our peril. When cells become either too sticky or too slippery, arteries can get clogged, cancer cells can skate around the body, and inflammation can turn subversive. Researchers have long believed that if they could somehow manipulate stickiness, they would have a formidable new set of tools for healing.

Now, after decades of frustration and obscurity, the world of adhesion science is beginning to fulfill its promise. Researchers who look at many diseases as a failure of stickiness are designing both antisticky drugs and Super Glue-like drugs to treat a range of disorders, including heart disease, transplant rejection, stroke, arthritis, shock and cancer. Michael Gimbrone Jr., head of vascular research at Harvard Medical School, predicts "a whole new generation of therapeutic interventions." Several drugs are now being tried on humans, and early next year the first of them -- a gel that spurs wound healing -- will enter the final U.S. government approval process.

Stickiness is central to almost all biological processes. Cells are able to form organs and function as a unit thanks to a fascinating category of complex glues they secrete known as extracellular matrix. Securing cells in their matrix are Velcro-like patches called cellular-adhesion molecules (CAMs), which are present on every cell except red blood cells. These cellular glues not only hold things together but also play a vital role in growth, fetal development, repair of damaged tissue and elimination of noxious invaders.

But when cellular glues become too sticky or fail to hold, the outcome is often disastrous. In cancer, for instance, advancing tumors often secrete an enzyme that chews up their matrix, freeing malignant cells to leak into the bloodstream. Some inevitably stick and proliferate at sites elsewhere in the body. Thus the lethal process of metastasis may be viewed as a breakdown in stickiness.

At the opposite end of the spectrum are inflammatory diseases like arthritis and multiple sclerosis, in which things have got a bit too sticky. Normally, inflammation is part of the healing process. At a wound site, for example, chemical signals prompt the cells of nearby blood vessels to produce more CAMs, turning the vessels into a kind of biological flypaper that attracts platelets, leukocytes and other repair cells to the scene of destruction. Once healing is under way, the signals subside so the vessels lose their stickiness and inflammation recedes. But in a disease like arthritis, the chemical signal is always present. Vessels remain sticky, and repair cells pile up, causing pain, swelling and other symptoms of chronic inflammation.

Still, too much inflammation is probably better than none at all. The latter is the peculiar plight of Brooke Blanton, a 13-year-old Dallas girl who has taught researchers much of what they know about cell adhesion and wound healing. Brooke first came to doctors' attention as an infant, when her umbilicus and teething sores failed to close and became infected. Strangely, Brooke's lesions contained no pus -- the carcasses of millions of white cells that pile up at infection sites -- even though her bloodstream was teeming with infection-fighting white cells, or leukocytes.

Mystified, Baylor University physician Donald Anderson and Harvard pathologist Timothy Springer decided to test the child's white cells to see how sticky they were. "There was absolutely no binding at all," says Anderson. A new disease had been discovered: leukocyte-adhesion deficiency. Unable to produce the CAMs that enable leukocytes to stick where they are needed, these rescue cells were sliding past Brooke's wounds like a convoy of ambulances with no brakes. "This child can't heal a paper cut," says Brooke's mother Bonnie. For now, her daughter's life remains a continuous battle against infection, though gene therapists at Baylor hope to cure Brooke by inserting into her white cells a gene for the missing CAM.

Researchers have similar dreams of manipulating stickiness in more commonplace ailments, including cancer. "Cellular-adhesion research isn't going to cure cancer, but it might stop metastasis," says Massachusetts Institute of Technology scientist Richard Hynes. At the La Jolla Cancer Research Foundation in California, genetic scientists have succeeded in inserting a CAM gene inside a tumor cell. Once the cell starts manufacturing patches of biological Velcro, it is essentially "glued in place. It becomes incapable of metastasizing," says Erkki Ruoslahti, president of the foundation. A second approach to controlling cancer is known as "walking on ice." Here the goal is to deny tumor cells traction so they can't grip the walls of blood vessels to implant elsewhere in the body. This may be accomplished by using drugs to block certain CAMs on malignant cells.

While such therapies remain theoretical, reducing stickiness is already proving useful in heart disease, specifically in combatting a dangerous side effect of clot-busting drugs like streptokinase or TPA. Doctors have found that after such drugs are used, lingering pieces of broken-up clots (consisting mainly of platelets) look to surveillance cells like a flood of damaged tissue. Instantly, the inflammation process kicks in: the affected region of the heart becomes sticky and therefore prone to further clotting. Adhesion research has produced a drug now being tested on heart patients that keeps the scattering clot fragments from sticking.

Another antiadhesion drug is being developed for the treatment of traumatic shock. Here too the goal is to prevent the body's own healing process from going awry. Traumatic shock can occur when accident victims lose large quantities of blood, causing cells in vital organs to starve for oxygen. The starving tissues trigger a distress signal that summons leukocytes and other members of the body's damage-control team, which begin to destroy distressed cells. Alas, if the signal stays on too long, cells are killed at a phenomenal rate and major organs begin to die even while hospital trauma teams are rushing to the rescue. Each year 25% of the shock victims who make it to the emergency room are revived only to die later. "It seems evolution never intended for someone to be resuscitated after shock," says John Harlan, head of hematology at the University of Washington in Seattle. Harlan and his colleagues hope to outfox evolution with a CAM-blocking drug that keeps white cells from sticking after shock. In a series of animal studies, the drug saved 75% from certain death.

Furthest along of the new adhesion drugs is an "artificial matrix" designed to promote wound healing. Normally, a wound site looks like the Grand Canyon to arriving rescue cells. But this biodegradable gel, produced by Telios Pharmaceuticals, is peppered with synthesized CAM molecules so that cells arriving at a wound site will have plenty of places to get a grip. With the new gel filling in the gap, repairing wounds, including severe burns or skin ulcers, takes 30% less time and leaves less of a scar, claims company scientific director Michael Pierschbacher.

All this is coming from a science that nearly became extinct. Following some excitement during the war on cancer in the early 1970s, many scientists abandoned the field in frustration for the more glamorous search for the genes of disease. Yet a handful pressed on, captives of their own curiosity. Many, like Harvard's Martin Hemler, had their research proposals regularly sent back from the U.S. National Institutes of Health stamped IRRELEVANT. Without a group to call their own, with no papers circulating, with no annual meetings, sticky cellsters worked in isolation, unaware that anyone else was keeping the faith.

Two events saved the field. The first, in 1976, was the discovery of hybridoma technology. This allowed scientists to build exquisitely precise probes to explore cell surfaces and search for CAMs. The second boost came in the mid-1980s, when M.I.T.'s Hynes noticed a resemblance between research coming from obscure labs working on cancer, immunology, developmental biology and hematology. Hynes began to see that these researchers were all exploring aspects of cell adhesion. In 1987 he drew together these separate lines of research and published a landmark paper in the journal Cell that finally connected the dots. "All of a sudden, these fields fused; they were one," says Hynes.

Since then the pace has swiftly accelerated. Biotech companies are scrambling to capitalize on sticky science. "Thousands of papers are coming out. It's crazy, absolutely crazy," exults Jean Paul Thiery, director of research for the French National Center of Scientific Research. The excitement serves as a reminder that the best guidepost for research may be what it has always been: the persistent pull of curiosity and the tenacity of scientists who ignore fashion and stick with it.