The Past Is Prologue

Extraterrestrial Meets Intramural: NASA Director Daniel Goldin and NIH Director Harold Varmus share a pleasant view at NIH Research Festival.

I remember a Sunday dinner at my grandmother's house when I was young, some time well before July 1969, at which the adults were discussing the seemingly impossible task of putting men [sic] on the moon. Also at the table was the elderly gentleman we knew as "Jimmy," a jeweler, barber, and repairer of watches, from Naples, Italy. Still not comfortable with English, he typically remained quiet during these dinners, keeping his attention focused on his plate and the jug of wine on the floor at his side. That Sunday, the topic of conversation apparently piqued his interest and after a few minutes, Jimmy, in a Chianti-fueled outburst of aerospace theory, earnestly weighed in on how to accomplish the lunar mission. It would take a "big, big cannone" (cannon), he explained, stretching very far into space, aimed squarely at the moon. The astronaut, fired from the cannon's barrel, would go "Boom! Straight to the moon!" It's unlikely that NASA engineers ever grappled with the logistics of Jimmy's approach; when Apollo 11 astronauts did reach the moon a few years later, it was by alternative, though perhaps no less fantastic, means.

Listening to NASA director Daniel Goldin's plenary address that kicked off the 1998 NIH Research Festival on October 7, I couldn't help but recall those pre-moonshot, pre-shuttle wonder years. In broad techno-evangelical terms, Goldin outlined his agency's vision for the future of space exploration, spelling out some of the developments in materials science, computing, and medicine that must necessarily precede any attempts to move beyond near-Earth missions. Central to all of these emerging and anticipated technologies, according to Goldin, is marrying NASA's traditional strengths in physics and engineering to that which is near and dear to us at NIH: biology. "My biggest concern," he said, citing the rapid pace of progress in biotechnology in the last 20 years or so, "is that NASA has been locked out of the biological revolution. . . . We have to integrate what we are doing in the physical sciences with the biological sciences."

Goldin used the term "biomimetics" to describe materials and processes born of a biology-physics merger. For example, obtaining high-resolution images of planets perhaps dozens of light years away will require, as Jimmy might have put it, a "big, big" telescope, positioned in distant space. The NASA director envisions a lens that would span several football fields, made not of glass but of a biomembrane that weighs only about 100 grams per square meter. Such technology "hasn't been invented yet," he noted, "which is one of the reasons I'm here—to get the collaboration going with you folks."

Also on Goldin's wish list is the development of suits that incorporate biomimetic "skins" capable of sensing and adapting to different atmospheres that would permit humans to work in space more comfortably and safely. Robots, too, figure in future efforts, but would need an intelligence and adaptive capabilities that far surpass those of the boulder-bumping Rover that patrolled Mars last summer. Goldin advocates revolutionary developments in computing, invoking the need for nondeterministic algorithms and low-power requirements to carry out high-performance operations intelligently and efficiently. He believes we need to learn more about the best hardware-software combination on the market—the human brain—which, he remarked, "operates a million times faster than a teraflop [10¹² floating point operations/second] computer, but takes only a few watts of power," compared to the megawatt needs of today's best supercomputers.

Not the least of the challenges facing space missions is coping with the physiological stress to humans. Prolonged stays in zero gravity are known to induce bone loss, muscle atrophy, immunosuppression, and perhaps a host of other metabolic disturbances. NASA needs to know how to keep people in good physical and mental condition and how to administer general health care as well as surgical and trauma care, according to Goldin—another reason for closer ties to the biological-biomedical community.

The NASA-NIH Partnership

Goldin's wish for close connections to NIH and its resources has been fulfilled in part by the establishment, four years ago, of the NASA-NIH Center for Three-Dimensional Tissue Culture, directed by NICHD's Joshua Zimmerberg (1). However, the Center's purpose is not necessarily to further NASA's mission, but rather to promote a technique of three-dimensional tissue culture using a specially designed bioreactor, developed by NASA, within the biomedical research community. According to the Center's deputy director, Leonid Margolis, the facility is "open to all groups at NIH. Anybody can come and do their pilot experiments if they think the use of three-dimensional tissue or cell culture would be useful. If the pilot experiments turn out to be promising researchers can enter a competitive stage II process, which includes application for the NASA-NIH intramural grant to continue the study" (2).

The NASA-designed bioreactor consists of a rotating, horizontally mounted cylindrical growth chamber completely filled with culture medium (also known as a rotating wall vessel, or RWV).

Jean-Charles Grivel (Left) and Leanid Margolis

Gases are efficiently exchanged through special membranes incorporated into the design of the growth chamber. Together, these features make for a very cell- and tissue-friendly environment that is virtually free of turbulence and shear forces and conducive to the culture of tissue explants and co-culture of mixed cell types. (A review article profiling the bioreactor appeared recently in Nature Medicine 4: 901­907, 1998).

Wendy Fitzgerald

A widely publicized additional feature of the bioreactor is that cells growing in the RWV experience "microgravity"or something that resembles it, according to Wendy Fitzgerald and Jean-Charles Grivel, two members of the Margolis group. As Fitz-gerald puts it, there's "a randomization of the gravitational vector" within the RWV, which leads to a microgravity-like condition. Grivel says the force in a chamber rotating at 15 rpm is estimated to be about 0.01g. Margolis explains further, "The whole thing rotates as a solid body. The cells do not move relative to the medium or to each other. If you stop [the rotation], then they will fall to the bottom of the vessel."

Microgravity and Immune Response

Although microgravity effects are not the focus of the group's research, Fitzgerald and Grivel were inadvertently led to explore the bioreactor's influence on immune response in vitro in the course of experiments assessing HIV infectivity and tropism within tonsil tissue blocks. Previous work by the lab showed that tonsil explants, growing either on a collagen support in a normal tissue culture dish or in the RWV, support productive infection by several HIV strains showing different tropism. When tonsils are grown on collagen in dishes, T-tropic viruses also suppress antibody recall.

Says Grivel, 'The virus does replicate nicely in in the bioreactor, so we wanted to look at immune responses in this systembut we never got any." That is, uninfected tonsil blocks grown in the RWV did not make antibodies upon challenge with recall antigens, though such responses are readily made by their counterparts grown under normal gravity conditions. He and Fitzgerald did further experiments to see whether the microgravity conditions of the RWV were responsible for this observation. Their results, presented in a poster at the Research Festival, suggest that, indeed, microgravity transiently impairs the ability of lymphoid tissues to become activated upon exposure to antigens or mitogens. Not too surprisingly, these results are consistent with the observations made for shuttle astronauts, who, Grivel notes, become immunosuppressed under the near-zero gravity conditions experienced during their missions, but attain normal function after returning to Earth.

Although it is not a full-time pursuit, Grivel says they hope to understand the basis for microgravity-induced immunosuppression. He adds that NASA biologists have made similar observations of lymphocytes grown in the bioreactor, and that there has been discussion with NASA of including their tonsil culture experiment on a future Shuttle mission.

Wendy Fitzgerald is no stranger to microgravity experiments. She hails from Houston, where her employer, Wyle Laboratories, a NASA-contracted firm, developed the RWV bioreactor in collaboration with NASA and provided staffing to help establish the Tissue Culture Center at NIH. She was sent here to offer her bioreactor know-how to the NIH community. Several years ago, while still in Houston, Fitzgerald engaged in what could be termed "extreme field biology," conducting microgravity experiments on cell morphology in parabolic flight. Strapped with bungee cords into NASA's KC-135 Zero Gravity Training turbojet aircraft, simply yet graphically nicknamed the "Vomit Comet" (3), she did videomicrography of cells as the pilot guided the plane through some 40 successive sharply arcing ascents and descents. At the top portion of each arc, weightlessness is achieved for a period of 20­25 seconds. She flew several of these missions. When asked what she learned, she jokingly replied, "Make sure your bungee cords are secure." On one flight, she recalled, she wound up on the plane's ceiling after a cord dislodged. As for the cells, they did indeed respond to the flight by changing from a spherical morphology in microgravity to ellipsoid in hypergravity.

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