January 1995
FDA Consumer special report

When the space program was younger, the "out-of-this-world" medical prospects focused on manufacturing scarce products like interferon and pancreatic beta cells in an environment virtually free of gravity.

McDonnell Douglas Corporation, Ortho Pharmaceuticals, and the National Aeronautics and Space Administration were cooperating in the early 1980s on continuous flow electrophoresis experiments. This was a process of separating biological materials from preservative solutions to produce erythropoietin, a hormone important for stimulating human red blood cell production, more efficiently than seemed possible on Earth. Those experiments seemed to point toward large-scale orbiting pharmaceutical factories to produce quantities of insulin, interferon, and other vital substances.

Today, science has a very different view, looking in space for medical breakthroughs difficult to achieve on Earth for conditions ranging from motion sickness to osteoporosis, AIDS and cancer.

Although 1983's experimental technology succeeded, earthborn science and spacecraft experience over the past decade have pushed orbiting drug factories further into the future. In space, the practical problems of prolonged low-gravity exposures, combined with the logistics of working in the limited confines and duration of orbital flight, limited progress. On Earth, the "new biotechnology" based on manipulation of the genetic material of living organisms won the race with space by developing better ways of producing products such as erythropoietin. (A form of erythropoietin, Epogen, has been approved for treating anemia in patients with chronic renal failure and also in patients infected with HIV, the virus that causes AIDS, who are taking Retrovir [zidovudine, also known as AZT].) Workable in theory, space drug factories in practice now seem remote.

Yet, separation of biological substances from the fluids necessary to preserve them remains important. The process used in space can work to separate other biological materials--indeed, almost any natural hormone or enzyme--more readily than on Earth. Additional experience in space has opened stellar new vistas in several fields of medicine.

For the short term, "we're not thinking about factories," says Barbara Ann Hale, formerly of Pennsylvania State University's Center for Cell Research (founded in 1987), one of the original 16 Centers for the Commercial Development of Space that NASA set up after 1985. Of the 16, the Center for Macromolecular Crystallography at the University of Alabama, Birmingham (1985), and the Bioserve Space Technologies Center at the University of Colorado, Boulder (1987), are the two others also cooperating with industry to find medical applications for aerospace research.

Expense a Problem

A principal objection to space manufacturing is the expense of transporting products back to Earth, which limits early options to producing rare compounds now expensive--if not impossible--to produce. Beyond purifying processes, such as continuous flow electrophoresis, that separate substances from their preservative fluids, areas worth exploring include protein crystal growth and tissue culture.

Conditions peculiar to spacecraft may make feasible experiments that are difficult or impossible to achieve in a laboratory subject to the Earth's gravity. Space has become not a factory, but a highly specialized medical laboratory. Some processes happen more slowly in its microgravity. Others speed up. Still others just work differently.

In addition, medical measures to help astronauts' bodies adjust to the stresses of space flight may bring unanticipated benefits for patients on Earth. Astronauts have served, sometimes unwittingly, as human guinea pigs, their experiences suggesting new biomedical inquiries. Weightlessness isn't a restful state. It is extraordinarily stressful on human systems splendidly adapted to Earth's gravity. Thus it can replicate stresses caused by disease.

Speeding Up

Near weightlessness--astronauts never experience "zero gravity"--takes much pressure off human systems well evolved to cope with gravity, causing rapid adjustments in the system. Major weight-bearing muscles quickly atrophy, losing a quarter of their mass in as little as nine days. The left ventricular chamber of the heart decreases, losing a tenth of its mass in 84 days. Red blood cell counts may drop by a third.

The cardiovascular reactions of astronauts have much in common with many earthly clinical problems, including effects of spinal cord lesions, adrenal insufficiency, and diabetes mellitus. Insights useful in conditioning people for weightlessness may be applicable to treatment of those diseases.

Bone material loss offers another rare research opportunity. Sturdy leg bones made needless by microgravity lose up to 0.4 percent of their calcium in a month, becoming quite brittle. Heel bones degenerate as fast as 5 percent a month. Astronauts experience a speeded-up model of osteoporosis, a type of bone erosion particularly debilitating in older women. Although the manner of bone erosion may differ somewhat, the result is similar.

Ohio State University scientists have shown that one drug prevents bone loss in rats under simulated weightlessness. In October 1992, Penn State's Center for Cell Research and the Merck pharmaceutical firm tested an osteoporosis compound in laboratory rats aboard the space shuttle Columbia. Results may be available in 1995.

Slowing Down

Other phenomena occur more slowly in space than on Earth. One example is the growth of protein crystals from biological cells, which are important in the development of treatments for cancer, AIDS and diabetes. The microgravity environment of a spacecraft allows production of crystals that are better because they form more slowly.

A crystal forming rapidly on Earth may become as irregular as a brick barrier hastily thrown up, like the Berlin Wall. A wall built slowly and carefully will assume the precise shape the builder desires. But protein crystals growing slowly in space will exhibit a greater regularity, allowing researchers to design drugs with a more precise "fit."

Working from these well-formed protein crystals, scientists can design exact antidotes to disease-causing organisms, rendering them ineffective.

Some protein crystals produced in space are larger and more symmetrical than their equivalents produced on Earth, and consequently more useful to scientists. Scientists at the University of Alabama's Center for Macromolecular Crystallography hope that longer flights, or even an orbiting space station, will produce larger and even better-formed crystals. Thus, the microgravity effects that slow some biological processes can be as useful to scientists as those which speed others up. The same is true of those that are just different.

Differing Processes

Human adaptation to the extraordinary stresses of long space voyages, even for limited periods, demands intensive medical investigation.

This research, usually done on Earth, has yielded information helpful to treating patients with certain diseases. For example, one process that is different in space, the radical shifts of bodily fluids that can incapacitate astronauts during takeoff or atmosphere reentry, has implications for patients with circulatory problems.

Claire Lathers, Ph.D., former FDA pharmacologist and consultant to NASA, has been working on the problem of orthostatic intolerance--the body's difficulty in accommodating sudden footward fluid shifts, particularly after prolonged weightlessness. A common result of orthostatic intolerance is that astronauts may faint or become lightheaded from the decreased blood flow to the head when they attempt to stand after their spacecraft reenters Earth's gravity.

Realizing that astronauts' muscular and cardiovascular systems atrophy in ways comparable to those of bedridden long-term hospital patients, Lathers and her associates studied healthy volunteers during periods of prolonged bed rest. "Experimental procedures and equipment are first tested on Earth," Lathers states, adding that in time this research may well directly benefit future hospital patients as much as astronauts.

From volunteers resting in bed for as long as 17 weeks, experiments progressed to NASA's KC-135 aircraft, a plane designed to give brief periods of weightlessness. Finally, astronauts apply the findings in space flight.

Lathers and her associates used a technique, lower body negative pressure (LBNP), common in hospital clinical pharmacology units, to study patients with circulatory problems. LBNP counteracts the tendency of blood and other fluids to pool in the head during takeoff and then rush toward the feet during landing, causing astronauts to exhibit orthostatic intolerance and/or to faint. The researchers conducted numerous bed-rest studies using the cumbersome metal vacuum chambers, similar in design to the old "iron lung," used on the long-term Skylab missions.

Subsequently, the personnel in NASA's Johnson Space Center Cardiovascular Laboratory, directed by John B. Charles, Ph.D., contributed to the development of a new, compact, collapsible LBNP device. It looks like a duffel bag designed for astronauts to stand in, and it is used on the space shuttle. The LBNP device is sealed around the waist. A vacuum draws fluids to the lower body.

In addition to using the LBNP device, Lathers and Charles have considered the effects of various drugs to stabilize blood pressure to prevent orthostatic intolerance. Finally, they have pondered the use of both pharmaceuticals and LBNP devices in combination.

As their work progresses, the goal of keeping humans in space long enough to perform significant medical research moves closer to reality. Their experiments could have important benefits for patients on Earth who experience circulatory problems, including serious high- and low-blood pressure conditions. If researchers can learn to control distribution of bodily fluids in space, they can, in time, do so on Earth. An enhanced understanding of the entire cardiovascular system could result.

Benefits Begin

When will space medical technologies start reaching patients on Earth? Some already have.

One NASA spinoff comes from work on the motion sickness astronauts experience. Drug injections are impractical, since the medications may froth under weightlessness. Vomiting can make the use of oral medications also unworkable. Drug administration through a patch placed on the skin provided the answer for space voyages. Now the drug scopolamine is approved in transdermal patch dosage (Transderm Scop) to relieve motion sickness on Earth. Similar delivery systems with the ability to deliver steady concentrations work in nicotine patches, helping smokers to kick the tobacco habit, and in nitroglycerin patches relieving angina pectoris (chest pain).

Wireless telemetry NASA developed to communicate with its space vehicles in orbit now monitors patients in hospital coronary care units. Programmable implantable medication systems designed for astronauts later went into clinical trials, and companies are investigating such a pump to deliver precise, preprogrammed concentrations of insulin to diabetics over a long period.

The work goes on. One important field is bioproducts bioprocessing, or use of the microgravity environment to form and manipulate biological materials. Macromolecules used for artificial tendons, blood vessels, and even corneas are among potential products.

Investigation continues, exploring whether certain products could be cheaper, faster and easier to produce or of greater purity when produced in space. These include: pancreatic beta cells capable of curing juvenile diabetes patients in a single injection; an interferon to give resistance to viral infections and possibly to treat some cancers; and epidermal growth factor to stimulate healing of burn victims' skin. In addition, as many as 50 approved products seem candidates for superior production in space. The confines of a spacecraft don't allow much experimental equipment. Worthy medical experiments of different kinds have to compete with one another for inclusion on each flight, in addition to competing with those of other scientific disciplines. Juries of NASA scientists rank proposed experiments by their promise and significance.

It is too early to declare with certainty what FDA's policy will be toward any future consumer products or technologies produced in, or unique to, orbiting pharmaceutical plants. The last time FDA confronted a novel means of production, in the products of the new biotechnology appearing during the last decade, the agency decided to judge the safety and efficacy of all products equally, regardless of their means of production. Whether any visionary space-made "wonder drugs" will present unique issues requiring a different approach, only time will tell.

S.J. Ackerman is a writer in Washington, D.C.

"I'm used to coaxing these cultures along," says Principato, an immunologist with the center's division of virulence assessment. "But to have something shot up at forces greater than any centrifuge spin, well, I just hoped and prayed that I'd get something back to work with."

Her experiment was sent on the shuttle to find out how T-cells from mouse bone marrow respond to the bacteria staphylococcal enterotoxin B in zero gravity. On Earth, the first time T-cells meet staphylococcal enterotoxin B they proliferate. But scientists had questions about whether bacteria or their products activate T-cells in space. Principato's experiment suggests they do.

Principato set up bone marrow feeder cultures and scaled down the experiment from "Earth size" culture dishes to a miniature size that would fit in the tiny wells allotted to her in the specially designed mini-lab.

Principato decided that, even though NASA didn't require it, she wanted to set up the experiment at Cape Canaveral herself. She drove for 14 straight hours on April 3 to get to Cape Canaveral by the newly scheduled launch date. She set up her experiment on Sunday, and Monday was a whirlwind of press briefings and VIP tours. "I was running nonstop, but I never felt tired," she says. She was in the viewing stands as the countdown began, shortly after 1 a.m. on April 6.

T minus 13. T minus 12. When the launch stopped at T minus 11, "my heart sank down into my feet," says Principato. "Then panic ensued because my T-cells were locked up in the shuttle."

It turned out that a bad computer circuit had indicated an unclosed fuel vent valve when the valve had, in fact, closed.

Principato was allowed to check her cells and found they were still alive. She gave them back to the shuttle technicians and crossed her fingers.

The launch was rescheduled for early morning April 8. When the countdown reached T minus 10, "there was a loud cheer," she says.

Discovery lifted off at 1:29 a.m. "It was a glorious sight to see the shuttle go up," she recalls. "It was a moment I'll never forget."

Later that morning, she was able to listen in on the control room's radio as the astronauts worked. She wanted to be sure that they had "thrown the switch" that would turn on the machinery and mix the staphylococcal enterotoxin B with the T-cells.

"You think you've come up with the perfect answer to all problems and then have to hope that a fuse doesn't blow or something doesn't overheat."

John E. Vanderveen, Ph.D., director of FDA's Office of Plant and Dairy Foods and Beverages (which contains the division in which Principato works), says that, "It's always important for government agencies to cooperate, especially when resources are limited. The unique techniques that were employed may be valuable to us in the future."

--Dori Stehlin