Battling illness with body proteins; recombinant DNA technology has enabled medical researchers to manufacture several human proteins that can bolster the body's natural defenses against disease

Science News, Jan 17, 1987 by Mary Murray

Battling Illness With Body Proteins

Thirteen years have passed sincemedical researchers Stanley Cohen and Herbert Boyer first pasted frog genes into the plasmids of Escherichia coli bacteria. As hoped, the bacteria were able to manufacture the frog RNA encoded in the genes. It was the first step in learning how to give bacteria the genetic ability to produce animal proteins.

Very quickly, the medical communityrealized that Cohen of Stanford University and Boyer of the University of California at SAn Francisco had come up with the key to a new biological technology -- recombinant DNA -- which could induce bacteria to "clone" large amounts of specific proteins. And almost as quickly, there began widespread, unbridled speculation about the medically useful human proteins that could be cloned. It seemed scientists could make vaccines against diseases ranging from cholera to malaria, brain opiates that could replace artificial painkillers and enough cancer-fighting cells to eradicate many forms of the disease.

It's no wonder that, to date, recombinantDNA technology has not lived up to such lofty expectations. Nevertheless, medical researchers have been able to develop a respectable range of pharmaceuticals using Cohen and Boyer's bacterial technique.

By 1982, the U.S. Food and Drug Administration(FDA) had approved for general use the first gene-cloned medical product: human insulin, which diabetics must take in drug form and which previously came only from cow and pig pancreases. And within the last two years, the FDA has approved recombinant human growth hormone, to treat growth-hormone-deficient children of short stature; alpha interferon, to break down tumors in people with hairy cell leukemia; and a vaccine against hepatitis B.

Medical researchers now are at worktesting other potentially therapeutic human proteins that can be manufactured from recombinant DNA. Clinical trials are under way on new forms of cancer-fighting enzymes, on proteins capable of breaking up blood clots and on hormones that lower blood pressure and reduce water retention. None of these is a cure for any illness, but all promise to be strong defensive weapons that could slow or halt the progress of disease.

Recently, a group of these researchersgathered at Stanford University's medical school to report on their latest work, providing a convenient snapshot of the present state of recombinant pharmaceuticals.

They described, for example, two ofthe new recombinant proteins designed to help heart patients: atrial natriuretic factor (ANF), a hormone capable of reducing blood pressure and water retention in people suffering from congestive heart failure and hypertension; and tissue plasminogen activator (tPA), a clot-dissolving enzyme that can reduce tissue damage after sudden heart attacks.

ANF, normally made by the heart,was cloned in 1983 and is still in the "very preliminary" stages of investigation, Ferid Murad told some 100 scientists at the symposium. Murad, acting chairman of Stanford's Department of Medicine, says that so far the hormone has been tested on only a few dozen patients, but it already has demonstrated its ability to lower blood pressure and reduce water retention. Murad himself has given ANF to 10 patients with congestive heart failure, and most of them benefited, he says.

"We have found it does improve the excretionof salt and water in most cases," Murad told SCIENCE NEWS. "The question is, can it be useful in therapy over the long term?"

Murad recently has found that one ofthe ways ANF operates is by relaxing the muscles in blood vessels, thereby helping to reduce blood pressure. ANF also appears to enhance the movement of water sodium through the body, increasing urine volume and the excretion of salt, he reports.

Murad has observed that ANF also affectsthe kidneys, lungs, liver, brain, intestines and testes. Laboratory experiments have shown, for example, that it can raise or lower levels of the hormone testosterone in men, depending on how much is administered. And it appears ANF may affect the intestines in such a way as to induce diarrhea. Some of these noncardiovascular effects may turn out to be potential new uses for recombinant ANF, Murad says; others may turn out to be serious side effects. "Where this peptide is going is a little bit unpredictable," he says.

Tissue plasminogen activator, aprotein produced in the linings of the heart and blood vessels, is farther along than ANF in clinical trials (SN: 3/10/84, p.151, 4/13/85, p.229). Since it first was cloned in 1983, tPA has shown great promise in tests on some 2,500 heart attack patients worldwide, and it is expected to get FDA approval in 1987.

In most of the trials, tPA has broken upclots significantly faster and more frequently than the traditional clot-busting medicines: streptokinase, a bacterial enzyme; and urokinase, an enzyme found in the urine, Burton E. Sobel reported at the symposium. Sobel has directed tPA trials at the Washington University School of Medicine in St. Louis, where he is director of the cardiovascular division.