The heartbreaking loss of seven astronauts in the shuttle accident earlier this year was a tragedy. But the data and pictures collected before the shuttles demise helped make project Biotechnology Demonstration System-05one of 80 scientific experiments aboard space shuttle Columbia on flight STS-107a success.
In less than one day in space, the prostate cancer cells had started to stick together, forming a tumor more than one inch in diameter. After three days, pictures and data transmitted to Earth showed cancers the size of golf balls. By the time the space shuttle Columbia disintegrated on February 1 after 16 days in space, the tumors had grown to the size of a small fist.
The project was designed to recreate the natural environment in which prostate tumors develop in the presence of bone. Human prostate cancer cells and bone stroma mixed gently together in a zero-gravity "bioreactor"a device so sophisticated that it could carry away waste products generated by the living tissue while continuously replacing nutrients. Samples from these artificial tumors, which the researchers dub "organoids," might have shown the gene activity that results, as well as the cellcell bidirectional "cross talk" that occurs, when tumor cells organize into three-dimensional living bodies that become androgen-independent, metastasize into bone, and proliferate.
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Although the organoids were lost, along with a part of the data that were collected every two days by astronauts Laurel Clark, M.D., and Kalpana Chawla, Ph.D., the experiment produced what appears to be the best three-dimensional model to date of prostate cancerbone cell interaction, Chung said.
The same experiment conducted on Earth as both a back-up and control, using a rotating wall vessel designed to reduce the force of gravity, resulted in tumors that were less than one-eighth of an inch across, he said. Analysis of these organoids revealed their ability to undergo androgen-independent progression and acquire bone metastatic potential, said Chung, showing that three-dimensional microgravity conditions mirrors "the in vivo phenotypes of human cancer progression."
"From a tissue engineering point of view, the shuttle experiment was an unqualified success," said Thomas Goodwin, Ph.D., NASAs manager of the project and a co-investigator. "It did much more than we expected it to do. The overall size and density of the tumors that developed was unexpected, especially in that short of time."
Chungs prostate cancer experiment was scrubbed 18 times before it finally flew, 3 years after its projected date. Now the million-dollar bioreactor is destroyed, and the space shuttle program is on hold. And some scientists are again questioning whether space research is really science, arguing that the research cannot be reproduced and that it is little more than a bid to cement the publics support for the space program.
Both the American Society for Cell Biology and the American Physical Society have published position papers questioning the value of space shuttle science. Although previous NASA research did bring Americans everything from Tang and scratch-resistant coating on sunglasses to dimples on golf balls, space research has not significantly benefited any field of science, these organizations charge. "In my field of research, crystallography, space science has proven to be of no value at all after 8 or 9 years of effort," said Stephen Harrison, Ph.D., a Harvard Medical School professor. "But despite the fact that the research has proven fruitless, and should be discontinued, it is still going on."
"Weightlessness doesnt have fundamental biological consequences, except, perhaps, for astronauts traveling to Mars," he added. "If space health is the goal of these studies, then NASA should say so, instead of couching it as good research, and then we can talk about whether the physiology of beings in space is a research and funding priority at the moment."
Others worry that projects like Chungs could be sapping money from oncologys piece of the federal research pie. "As fascinating as this space science isand Chungs results look to be really interestingI have to ask if it is worth doing when federal funding of biomedical research is under such great constraints," said Leonard Zwelling, M.D., a research administrator at the University of Texas M. D. Anderson Cancer Center, Houston. "Think about how many RO1 grants you could fund with the money it takes to do space research ... thats a real concern to me."
But others say that growing tumor organoids in three dimensions is so much better than producing flat tumor sheets on glass, because weightlessness allows these organoids to assemble naturally. Researchers who have worked with them contend that tumors produced in low gravity look and act more like cancers found inside the body than do the flat, two-dimensional spreading layers grown in petri dishes.
"The first time I worked with a cell line in 3-D, I did it nine times before I could believe the result," said University of South Florida cell biologist Jeanne Becker, Ph.D., who has worked with NASA for a decade. "Now every time I go from 3-D back to 2-D, I wonder if I can believe my 2-D system anymore, because it is so different."
Using a rotating wall vessel, a chamber NASA developed to simulate low gravity, Becker has found that 3-D ovarian cancer organoids she produced were more resistant to chemotherapy drugs than were standard 2-D assays. "Their spatial orientation makes them much more drug resistant, just as ovarian tumors in the body are," Becker said. "They form tumor cakes that are very hard to kill."
But rotating wall vessels do not allow large organoids to grow, because the shearing forces produced by the carousel-like 20 to 30 revolutions per minute needed to keep the cells in suspension prevent tumors from adhering and organizing together into a bulky clump.
Last year Becker was able to fly one of her ovarian cancer experiments in zero gravity with no spinning on the International Space Station for two weeks. She is now processing the samples, looking for oncogenic expression.
Becker was in her Tampa laboratory early on Saturday, February 1, expecting to see Columbia zoom overhead to land at the Kennedy Space Center. She had been a graduate student at the same campus when she looked up to see Challenger explode. Columbias demise, along with Chungs project, "was very devastating to me," she said. "It would be a loss if this kind of experimentation was not done again.
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J. Milburn Jessup, M.D., a professor of oncology and surgery at Georgetown University Medical Center, agreed, saying space experimentation "is research for its own sakenot just for earth applications and the specific care of patients."
Jessup had colon cancer experiments on two different shuttle flights, and plans another based on a finding that mitochondria in cell bodies are displaced when exposed to zero gravity, and therefore tissue function may be impaired. This may be important to the health of astronauts, and may even help explain muscle wasting in bed-bound patients, but, mostly "it is an exciting basic finding," said Jessup, who is a member of several external advisory committees to NASAs Office of Biological and Physical Research. "Most of us who are involved in cancer research see ourselves as investigating biological phenomena or mechanisms that are of interest for themselves and maybut not necessarilyhave application to cancer biology."
With or without the use of microgravity ground chambers, or shuttles and space stations, 3-D modeling of cancer development is "one of the hottest areas of research now," said Suresh Mohla, Ph.D., chief of the Tumor Biology and Metastasis Branch at the National Cancer Institute. "The NCI is very interested in understanding how tumor cells interact with their host environment because that gets to the heart of cancer," he said. A growing number of investigators agree, and short of fancy machines, they have learned to use tools such as soft gels, which allow tumors to grow naturally in a 1G laboratory setting.
The idea that cancer is not a single cell disease, but one that involves cooperation with surrounding cells and tissues, is an emerging paradigm shift in cancer research, said Donald Ingber, M.D., Ph.D., a professor of pathology at Harvard Medical School and Childrens Hospital in Boston. In the 1980s and 1990s, "the molecular biology perspective of cancer ruled," with the notion that oncogenes and tumor suppressor genes led to cancers uncontrolled growth. Now, realizing that genetics is an insufficient explanation, investigators began to focus on cancers physicalityits relationship to stromal tissue, which dictates tissue patterns, blood capillaries and physical interactions between cells and the tissue matrix, Ingber said.
Many credit researcher Mina Bissell, Ph.D., director of the Life Sciences Division at Lawrence Berkeley National Laboratory, for making initial strides in understanding the importance of cancers growth environment. She identified the extracellular matrix (ECM), or basement membrane, which is a network of fibrous and globular proteins that surround and support breast cells, as a crucial regulator of normal and malignant breast cell functions.
To do such investigation, Bissell and others use "designer microenvironments," such as a material like gelatin that has a malleable basement membrane on which tissue can grow, as well as hormones and growth factors. "If you put breast cells in standard culture and give them everything they need, they completely forget what they are," Bissell said. "But if you give them basement membranes, they produce beautiful cells, full of milk.
"You dont need microgravity at all to do these experiments," Bissell added. "You make a thick gel, put cells on top of it, and if they metastasize, they move down into the gel."
"I was intimidated by 3-D research until I started to do it, and then you see so many differences in the way that cells behave when they are not constrained on plastic," said Joan Brugge, Ph.D., a professor of cell biology at Harvard Medical School. She said her 3-D epithelial cell experiments reveal biological activities of oncogenes that cannot be examined in vitro in standard assays.
Dozens of laboratories now have the equipment to do 3-D gel research, which is admittedly harder to do and requires, among other things, expensive and finicky microscopes to look deeper into the cultures, said Rakesh Jain, Ph.D., in the department of radiation oncology at Massachusetts General Hospital, Boston.
Although he works exclusively in gels, Jain added that he appreciates the "additional insights that zero gravity adds" and hopes that space science continues. "We need to do both, not one to the exclusion of the other," said Jain. "The beauty of science is serendipityfinding something unexpected that has relevance for all of us."
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