By David N. Leff
BOSTON - It was standing-room only - plus many attendees squatting on the floor - at Tuesday morning's BIO Science Symposium, on the theme: "Putting Genes and Cells to Work: Cell-Based Technologies and Regenerative Medicine." The event's No. 1 draw was the keynote address by molecular biologist William Haseltine, founder, chairman and CEO of Rockville, Md.-based Human Genome Sciences Inc.
Haseltine took as his topic, "From Genes to Drugs," and started off by observing, "I would be surprised if less than half of this audience isn't on some kind of chemical drug. But I don't think the past is going to be prologue. I think we're going to see some kind of growth of human complement as medicine, whether those are proteins, antibodies or cells. What is now a small fraction of the pharmaceutical market, in 20 years, I think, will grow, if not to be the majority of new drugs, close to half the next 10 to 20 years - into medicine derived from our own body."
He spelled out his vision of regenerative medicine: "I see it as addressing the needs of an aging population, which is going to dominate the practice of medicine." He cited "the content of ads on television programs - for antacids, arthritis, osteoporosis - a litany of the woes of an aging mankind.
"In my mind," Haseltine said, "regenerative medicine also includes stem cell biology - the use of stem cells to replace aging stem cells, to recreate younger organs."
He pointed to the large difference between human genes and the human genome, now being sequenced, pointing out that only 3 percent of the genome consists of those genes. "As any biologist knows," he offered, "a gene is the philosopher's stone of modern understanding of living systems."
Using his approach of treating gene function anatomically rather than genetically, Haseltine's company has "discovered a new gene that makes a secreted protein on the surface of fetal brain cells, which can probably be cleaved off with a soluble molecule. It has no homology to anything in the human genome. Most of the most interesting genes we discover this way have no homology to anything in the human body.
"When we looked at our collection of genes," Haseltine added, "we found about 14,000 new molecules that have a signal peptide sequence. That's about 10 percent of all human genes. And we can make full-length protein now from 98 percent of them. People ask us, 'What is their biological function and medical utility?'"
Haseltine gave one clinical example, on which he and his colleagues have been working for the past five years: "We're looking for molecules that can cure various diseases. The first thing we have to do is make the protein. So we've engineered for expression, instead of 12,000 human genes, into expression vectors. On the one hand we make the protein in bacteria, so we can raise antibodies to it, and we also make it in animal cells, so we can have active protein to assess its activity."
The medical problem Haseltine described was how to find a "clean" interleukin-2, "free of its well-known side effects. So we hit that button, and our computer answered: 'Here are five genes that meet that criteria.'" The final, narrowed-down gene "stimulates T cells in a very specific way, and has homology to nothing ever seen before. We're developing that as they're doing with IL-2."
Charles Vacanti is director of the Center for Tissue Engineering of the University of Massachusetts in Worcester. He spoke on "Tissue Engineering and the Use of Stem Cells."
"For almost 15 years," Vacanti told the attendees at the BIO symposium, "we've been working with tissue engineering, which means obtaining a number of cells from biopsy, expanding them in culture, attaching them to a 3-dimensional synthetic polymer scaffold, to deliver back into a recipient, and generate new tissue.
"We've done that with several types of tissue," he recounted, "starting with bone and cartilage. More recently we've been focusing on liver, pancreas and nerve.
"We have recently identified what we have termed a 'spore-like cell,'" Vacanti said, "because it's smaller than any previously described cell. It's less than a micron in size, and almost pure nuclear material; very little cytoplasm.
"This cell," Vacanti added, "is present throughout all mammalian tissues. It has an extremely low oxygen consumption, and stays dormant until the patient is injured. It's Mother Nature's own repair cell. In times of injury, this dormant cell is turned on, starts to multiply, and is responsible for the body's attempts to repair.
"Why I say it's very dormant and has low oxygen," Vacanti explained, "is that we've taken tissues out of an animal - for example, spinal cord, liver pancreas, lung - and put them in a refrigerator for more than a week, with no special nutrients. And after that week, we've been able to isolate these cells, which are viable, multiply and differentiate into the tissues from which they were isolated. So for liver, they made mature hepatocytes, which made bile. From pancreas they turned into islets that made insulin. From the lung they turned into alveoli, which secreted surfactant. And from the spinal cord we've isolated these spore-like cells, which turned into neurons, astrocytes and oligodendrites.
"In animals," Vacanti noted, "we've resected 3-millimeter to 4-millimeter portions of the spinal cord, which resulted in total paralysis below the lesion, 100 percent of the time. We've replaced this gap with a hydrogel polymer seeded with these very small immature spore-like cells, and those cells generated new spinal tissue, which integrated above and below the cut, and returned functional recovery to the animal.
"In humans," he said, "it will probably be a while; FDA hurdles are tremendous. We hope, however, to do an injured-dog study. We won't injure the dog, but when people have a pet that's been hurt in some type of accident, we would like to apply this regeneration technology to see if we could help those animals."