Study of Growth Factor Hormone Seen as Key to Many Mysteries

“FGF does everything,” declared the research poster at a recent international scientific meeting in San Diego.

Tongue-in-cheek, it listed how this hormone--its structure unraveled at the Salk Institute just six years ago--can remove wrinkles, improve a car’s gas mileage and bolster male fertility.

While this graduate student’s prank drew laughs from colleagues who saw it, its underlying premise was not so far-fetched.

“Here’s a molecule which was first structurally characterized six years ago, and after six years already some groups are in late-phase clinical trials for diabetic wound healing,” said San Diego researcher Andrew Baird. “I’m impressed by that. That really brings home the importance of this molecule.”

Baird heads a research group at the Whittier Institute for Diabetes and Endocrinology, at Scripps Memorial Hospital in La Jolla.

He was part of the Salk Institute lab of Nobel laureate Roger Guillemin that, six years ago, first identified the protein’s structure.

Since moving with Guillemin to Scripps-La Jolla and setting up his own lab, Baird has gained an international reputation for basic research into the intricacies of FGF, or fibroblast growth factors, in the body.

His group has investigated FGF’s basic role in diabetes, wound healing, reproduction, heart disease, brain cell degeneration, inflammatory processes and cancer, among others. The group recently received a $7.9-million, five-year federal research grant to pursue those studies.

The seven related FGF molecules constitute one of several families of “growth factors,” which have been discovered over the last decade as keys to cell proliferation.

They are difficult molecules to study. Not only do FGFs exist in several slightly different forms, but they also don’t float freely in the blood, and instead seem to hide inside and around cells until needed.

Baird notes that studies of FGF in his and other labs have yielded several surprises so far:

* Heparin, a standard blood-thinner given to heart attack victims to ease the load on their hearts, may actually be helping to repair the damaged heart muscle. Heparin somehow makes more FGF available to promote tissue repair, studies have shown.

* A tradition of treating gastric ulcers by cutting down on excess stomach acid turns out to have been aimed at only an incidental villain, says Dr. Judah Folkman, a Harvard Medical School researcher. He is a folk hero to FGF researchers because he widely proclaimed his belief in growth factors for many years before their existence was proved.

Folkman has conducted studies indicating that, rather than acid initiating the ulcer by damaging the gastric lining, its damage comes from decreasing the supply of available FGF.

* Studies in animals show that FGF can actually prevent degeneration of retinal cells to prevent blindness.

* Fatty plaques that stop up blood vessels are full of FGF molecules, suggesting that an excess of this protein promotes growth of cells involved in atherosclerosis.

* FGF also is seen at elevated levels in the tangles of dead brain cells seen in Alzheimer’s disease patients, suggesting that FGF plays a role in this neural degeneration. FGF also is suspected of playing a role in Parkinson’s disease.

* Cancerous tumors secrete FGF, in a process that FGF researchers believe is responsible for tumors being highly vascularized. Blocking the FGF release might be a way to slow or stop tumor growth, they say.

* Herpes simplex I, the virus that causes cold sores, enters human cells through the FGF receptor--that is, through the keyhole-like opening in the cell wall to which FGF attaches to do its work. The study, done by Baird and colleagues at Scripps Memorial, suggests that blocking the receptor with FGF might be a way to thwart herpes.

But FGF’s first appearance in pharmacies will likely be as a lotion or ointment to heal chronic wounds such as bedsores and diabetic ulcers.

Two companies are testing one type of FGF, with results that they say are promising. One of them, California Biotechnology of Mountain View, expects that, if early indications of effectiveness in humans are borne out, the medication could be available by 1994 or 1995.

These were among research areas addressed at the La Jolla conference last month, sponsored by the New York Academy of Sciences and co-chaired by Baird.

It was the first meeting ever called to try to pull together the emerging multitude of suspected roles for FGF. A second meeting is planned in Colorado in April.

The fever of activity represented at the meeting reflected the need to pull together basic-research findings about FGF and move them into clinical experiments, Baird says.

“What we saw at that meeting was really where things are right now,” he said. “Hopefully, the clever cardiologists, the clever clinical scientists, will look at those results and say, ‘There’s something in there I should be looking at.’ ”

One example of that need is heparin, the anti-clotting drug given to heart attack patients. Heparin is given to prevent further clotting in obstructed arteries from cutting off oxygen to the heart muscle.

But it now is apparent that heparin chemically binds to available FGFs and somehow makes them more readily available to cells, researchers at the meeting agreed.

So, perhaps heparin is also helping by making FGF available to promote growth of tiny new blood vessels to nourish the remaining heart muscle, FGF researchers suggest.

Furthermore, the fact that some types of heparin don’t bind to FGF at all could account for studies that have found it sometimes ineffective in heart attacks, Baird said.

“Some brave clinician is going to have to devise a clinical trial to evaluate the effects of different types of heparin in conjunction with FGF,” Baird said. “And I suppose at some point there’s going to be a need for some kind of biological standards for heparin, and maybe to go back and do a retrospective analysis of the data in heparin studies.”

But unraveling the FGF-heparin mystery won’t be simple. The same FGF that might aid the heart muscle also is suspected of helping fat-filled cells clog up arteries.

“I think it reflects the potential two-edged sword of the problem,” Baird said. “In some instances, you’re going to want to have more of this molecule, and there may be instances in which there’s inherently too much.”

So, while administering a little FGF to animals does prevent blindness in deteriorating retinas, it may be too much FGF that causes blindness in diabetics after many years.

“You can look at the complications of diabetes as being a wound response,” Baird said. “You’ve got cells that have to respond to elevated glucose, that have to respond to injections of insulin which aren’t physiological.

“This is a sort of wounding of the cell. And in response to that wound, the cell will respond in a wound-healing way. There may be too much FGF floating around because the cells are being wounded over and over.”

Likewise, in a few animal studies FGF has been shown to maintain and stimulate new growth in neurons--raising the possibility of using FGF to salvage neurons deteriorating in patients with Parkinson’s or Alzheimer’s disease, said Fred Gage, professor of neurosciences at UC San Diego.

But there are also hints that, in Alzheimer’s, FGF may be causing certain neurons to extend fingerlike projections into pools of toxins that end up killing them, he said.

Gage is studying FGF as a way to make possible brain-cell transplants, a field in which he is a national leader. Still, he is cautious about all the enthusiasm about the hormone in basic-science labs.

“You might wonder why all of a sudden there’s so much interest in this molecule,” Gage said. “In part it’s because, frankly, (it is one of the first such molecules for which) tools are available to explore it in detail.”

These tools include the chemical sequencing of the protein itself and the cloning of a gene for it, to produce significant quantities of the protein in the lab.

“This is to some extent like the analogy of losing your keys at night. Do you look under the lamp pole where the light is, because that’s the only place you can see anything?” Gage said.

Gage also is concerned that scientists need to know more basic information about how FGF works before they do clinical studies of its usefulness. Unwanted cell growth, even cancer, could be a side effect, he suggested.

“One of the concerns is that, with the dose level that you’re going to need to have a biological effect,” he said, “Will you have a down side of some sort of (overgrowth of blood vessels), or a proliferation of other cells that you don’t necessarily want proliferating?”

But, like Baird, Gage remains excited about the positive possibilities in this molecule--a protein whose actions in the body were only a distant dream a decade ago.

“When we first started, these molecules were not even thought to exist,” Baird said. “And there was considerable argument over whether or not specific proteins could have the kind of activities we are talking about now.”

“We’re just at the beginning,” Gage said, “just at the very beginning.”