The new physical therapy
By Philip E. Ross
Red Herring
May 9, 2001
This article is from the May 1 and 15, 2001, issue of Red Herring magazine.
In March 1999, doctors at the University of Pittsburgh drilled a hole in Sylvia Elam's head and injected 6 million neuron-like cells into the basal ganglia of her brain. At lunch the next day she could taste her food for the first time since suffering a stroke six years earlier. Within three months, she regained feeling in her right side, got over a bad stammer, and learned to walk almost normally.
"I am fully convinced that the improvements came from that operation," says Ms. Elam, now 67 -- although deficits from a later stroke oblige her to speak in a whisper. "If I had the chance to have a transplant for the second stroke, I would do it. Yes, sir."
It may seem strange that an era dominated by genomics and rational drug design should see so many drug companies betting on cell therapy, a modern equivalent to the monkey-gland injections that people took 100 years before Viagra. Yet doctors have always yearned for cellular treatments, for the simple reason that cells often do a job better than any chemical could. For example, a diabetic can only roughly control his blood sugar with insulin, even if he injects it often. But if you can get his body to accept a graft of pancreatic islet cells, the cells will react instantly to changes in blood sugar concentration and secrete just enough insulin to keep it within bounds.
So far the cell transplantation procedure performed on Ms. Elam has been tested more for safety than efficacy. But because she was the last of 12 patients to receive the injections, Ms. Elam's doctors were confident enough of the safety to give her the largest dose of cells -- enough living material to cover the heads of three pins. That she had one of the best results hints at a relation between dose and response, one of the things the U.S. Food and Drug Administration looks at when determining the efficacy of a drug. And these cells are a drug -- a living drug -- because, unlike conventional grafts, they are the product of extensive research and manufacturing by Layton BioScience of Sunnyvale, California.
PROBLEM SUPPRESSION
Treatments using cell transplantation had languished for decades because of two problems: immune-system rejection and the shortage of donor tissue. Solutions to both now seem nearly within our grasp. Doctors are getting much better at fending off the patient's immune reaction, by suppressing it with drugs, hiding the transplants from the immune system, or inducing tolerance to the foreign tissue. Meanwhile, potentially unlimited sources of transplantable material seem more easily attainable -- from animal donors; so-called immortalized cell lines; and stem cells, the progenitors of all the cells in our bodies.
The neurons that went into Ms. Elam's head derived from an immortalized line called a teratoma, an ever-dividing, never-aging testicular tumor taken from a patient some 20 years ago. Scientists learned that a properly administered splash of retinoic acid, a chemical cousin of vitamin A, would stop the cells' replication and turn them into a stable, neuron-like form. Layton BioScience purchased an exclusive license to the cells from the University of Pennsylvania in 1991, found ways to increase yield and purity, and started selling the cells for research purposes. Then, around 1995, Layton proposed injecting them into the brains of stroke victims.
"Most neuroscientists thought at the time our plan wouldn't work," says Layton BioScience CEO Gary Snable. "They thought that even if the new cells survived and somehow integrated, the connections would be incorrect and cause more harm than good. But we're finding that the brain is more like random-access memory: the more you add, the more function you can restore."
Exactly how the cells work remains unknown, but at least it is clear that they survive long after the end of the short, initial course of antirejection drugs. At an autopsy of the brain of a patient who died two years after receiving Layton's neurons, doctors found the transplanted cells living where you'd expect to find them, along track lines left by the transplant surgeon's needle.
The cells are partially shielded from rejection by the blood-brain barrier, a natural defense against toxins that also blunts the immune system's response. Because of that shield, and because researchers know how to culture neuronal cells but not other kinds, neurological disorders have become a prime target.
There are other organ systems, besides the brain, that may benefit, because last year James Shapiro, director of the Clinical Islet Transplant Program at the University of Alberta in Edmonton, and his colleagues injected pancreatic islet cells into diabetic patients and got every one of them off insulin.
Dr. Shapiro's main innovation lay in fine-tuning the drug cocktail used to restrain the patient's immune system. Rather than administer the entire panoply of drugs, his team administered a light course -- dubbed the Edmonton protocol -- that left out steroids and other components harmful to delicate islet cells. Even so, Dr. Shapiro cautions that because the antirejection therapy increases patients' exposure to infection and cancer, his treatment is still probably worse than the diabetes itself for all but the minority of patients who simply cannot control their blood sugar by other means. "The hope is that we could do the transplant with even fewer drugs, maybe just a tickle of the drug," he says.
One method of giving islet cells something like the brain's immunologically privileged position is to encapsulate them in an artificial shield, a technique called immunoisolation. Companies like TheraCyte and Neocrin, both in Irvine, California, are working with polymer membranes that have pores large enough to let nutrients in and insulin out, yet small enough to fend off marauding immune cells.
In part because of concerns about the safety of cell lines, which after all originate in cancer, most companies (including Layton BioScience, which is hedging its bets) now plan to get the necessary masses of tissue from stem cells. These primordial cells have what is called plasticity: they have not yet accepted the fate of being skin, bone, brain, or heart, but can become any of those things. With a culture of stem cells, you ought to be able to produce any cell in quantity, including more stem cells.
Until now, scientists have gotten stem cells either from early-stage embryos or from specially manipulated adult cells. The use of embryos poses ethical problems and, in the United States, regulatory ones as well. Adult cells manipulated by nuclear transfer -- in which an egg cell is emptied of its nucleus and filled with that of an adult cell -- face a number of technical problems. Dolly the sheep, for instance, was cloned by such means only after hundreds of failed attempts.
PPL Therapeutics (London: PTH), which had a hand in Dolly's cloning, says that it plans to produce batches of stem cells with the goal of turning them into insulin-secreting tissue -- either entire pancreatic islets or just the beta cells that make the insulin. So far, however, nobody can do that.
"First we must learn to grow them in an inexhaustible supply," says Ron James, PPL's managing director. "Later on we can look at the more difficult job of matching them to tissue types." He envisages producing islet cells in varieties compatible with different patients' immune systems, so as to minimize the immunosuppression that they would need.
PPL has also announced that it has developed a method of creating stem cells without first creating an embryo or resorting to nuclear transfer into human eggs. Mr. James declines to discuss the technique until patent rights are nailed down, but he says that it will prove valuable even in the United Kingdom, where the use of human embryos in research has just been legalized, because the new method should allow for greater yields, greater standardization, and greater control.
Elliot Lebowitz, CEO and president of BioTransplant (Nasdaq: BTRN), in Charlestown, Massachusetts, says his company is also working on a way to make stem cells without embryos, which it, too, will not discuss. He cautioned, however, that no single line of research can be dubbed a winner in a field as new as this one. "A high-tech company in a fast-moving field has to diversify its risks," he says. Indeed, fetal-cell therapy suffered a setback in March, when it was reported to cause serious overdoses in some patients treated for Parkinson's disease. Therefore, in addition to a portfolio of work on stem cells, BioTransplant is trying to get cells and whole organs from an entirely different source: pigs. In a joint venture with Novartis (NYSE: NVS), called Immerge BioTherapeutics, it plans to genetically modify a herd of highly inbred miniature pigs to optimize the animals' organs for human transplantation.
At first this would seem impossible: as hard as it is to transplant human tissue into humans (allotransplantation), it is far more difficult to transplant across species (xenotransplantation). "Put a human kidney into a patient without immunosuppression, and it will die in a couple of weeks," says Julia Greenstein, CEO and president of Immerge. "Put a pig's kidney in, and it begins to go in 30 seconds; in two minutes it is black and necrotic." Such "hyperacute" rejection focuses in large part on a sugar that appears on the surface of pig cells, but not on human ones. The sugar also appears on the bacteria that populate our large intestines, so we have all been vaccinated against it, as it were. Ms. Greenstein's goal is to breed a genetically modified pig that lacks that sugar, perhaps by next year.
DECEPTIVE IMMUNITY
To cope with other aspects of the immune system's assault on pig tissue, Immerge is also working with a new immunotherapeutic technique called tolerization, whereby the body of the patient is fooled into regarding the implanted material as if it were native tissue. This strategy, which is being pursued by many groups, works by combining the immune systems of the patient and the tissue donor.
Tolerization was first noted in patients who had received transplants of the liver, an organ intimately involved in the immune system. "A few years into a liver transplant, 60 percent of the patients need no immune suppression at all, something weird and wonderful," says Alan Colman, research director at PPL Therapeutics. Some researchers attempt to induce tolerance by including a bit of the donor's liver along with anything else they may be transplanting. Others, including Immerge, take a bit of thymus, a gland that helps an infant's immune system learn to distinguish its own tissue from foreign matter. Dr. Lebowitz says that in a pilot trial, a kidney-transplant patient thus tolerized has had normal kidney function since September 1998, even though no immunosuppressive drugs were administered after day 70.
Such techniques need not be confined to teaching a patient's immune system to live and let live; they can also teach it to fight harder against true enemies, like tumors or infectious organisms. In preliminary trials BioTransplant has participated in at Massachusetts General Hospital, one out of four lymphoma patients on whom all other treatments had failed are showing remission. Aastrom Biosciences (Nasdaq: ASTM), in Ann Arbor, Michigan, has produced kits that enable hospitals to create antitumor vaccines from the patient's own dendritic cells, a component of blood. Aastrom CEO and president Doug Armstrong says early trials of the vaccine show 30 to 40 percent remission rates in patients whose renal cancer or melanoma had resisted conventional treatment.
It is not yet clear whether a mixed immune system can be assembled from human and nonhuman elements. If it can, and the problem of rejection is solved along with the organ shortage, BioTransplant and Immerge may enjoy a competitive advantage, because they own a line of miniature pigs whose cells seem to be incapable of infecting human cells with porcine retroviruses -- a health concern, given that HIV originated as a primate retrovirus.
Supplies of transplantable tissue would at last allow doctors to repair what have been regarded as permanent disabilities, one of the heaviest -- and costliest -- burdens of old age. "There are about 3 million patients in the U.S. who believe that they're permanently paralyzed as a result of their stroke, and we'd like to show them that they're not," declares Mr. Snable.
What would be left to dream of in a world with usable tissue and practical antirejection schemes? One day we could clone tissues and organs from cells of the transplant recipient, producing material as compatible as that from an identical twin. It would snap on and hold fast without the slightest difficulty, as if it had been designed for that patient alone. Indeed, it would have been.
Write to philip.ross@redherring.com. |
