Biomedicine

Adult Stem Cells

With research on embryonic stem cells mired in controversy, adult stem cells are quietly providing the basis for striking advances toward new therapies.

 The morning began with a first gamy whiff of what lay in store. Shortly after 9 a.m., Bradley Martin, his assistant Jin-Quang Kuang and a researcher named Ellen Flynn marched along a dimly lit, institutional-tiled corridor at the Johns Hopkins Hospital in Baltimore. After pausing to take a deep breath, they pushed through a green door and entered a small room where several robust Yorkshire pigs greeted them with braying squeals and frothing curiosity. Flynn wheeled a heart-imaging echocardiogram machine into the narrow aisle between the cages, and then Martin, a flimsy yellow surgical gown covering his blue jeans and sports shirt, stepped gingerly into one of the cages and gently wrapped an arm around the huge porker, a gesture that wavered between a hug and a headlock. “All those years of graduate school,” Martin grunted over his shoulder, “are finally paying off.”

Spending your morning wrestling a 180-kilogram pig into position and holding it steady, while a colleague rubs a jelly-coated probe over the animal’s chest in search of a good echocardiogram signal, against deafening squeals of porcine protest and the in-your-face odor of big animals kept in close quarters-that’s not exactly how most people imagine the world of cell biology. But then Martin is not interested in ordinary cells-or ordinary biology. His foray into the animal room represents what could be one of the last steps in readying a futuristic form of coronary medicine for testing in humans. If all goes well, those human studies could begin as early as the end of this year.

Martin, a sandy-haired, good-humored senior researcher at Baltimore-based Osiris Therapeutics, has been paying weekly visits to this room for six months. It is a cardiac ward of sorts: all of the pigs in the room have suffered heart attacks. Some of them, however, have subsequently received a highly unusual form of treatment, an injection of stem cells-specifically, an adult form of these versatile progenitor cells isolated from bone marrow. It is Martin’s hope that these special cells, known to biologists as adult mesenchymal stem cells, have grown and transformed themselves within the pigs’ hearts to form new, healthy tissue right at the site of injury.

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Indeed, it is the uncanny ability to zero in on areas of physiological damage and then to organize the process of healing and repair that makes these and other kinds of stem cells so laden with medical possibility. Most of the cells in the body are specialized to perform specific functions in specific tissues, but stem cells-found both in embryos and in various locations in the adult body-can form a number of different tissues and so could in theory be used to treat a vast array of diseases. Rebuilding hearts after heart attacks, regenerating livers ravaged by cirrhosis or viral disease, reconstructing damaged joints, seeding the brain with fresh neurons to reverse the effects of Parkinson’s disease and Lou Gehrig’s disease-those are just some of the fantastic medical promissory notes that doctors predict these remarkably potent cells will ultimately redeem.

Still, a professional rivalry has emerged between researchers who think stem cells derived from embryos have the greatest medical promise and those who are instead betting on cells derived from adult tissues. Embryonic stem cells are able to form more than 200 separate and distinct tissues, while adult stem cells are “multipotent,” able to form just a limited number of tissues; the Osiris cells, for example, have only six possible fates. But because of their controversial origins in embryos left over from in vitro fertilization, embryonic stem cells have met fierce public opposition from religious and political conservatives that has slowed funding and research opportunities. And while President George W. Bush’s August decision to allow limited federal funding for embryonic stem cell research could help open the field, its political future remains murky.

While this public drama has been playing out, embryonic stem cells’ supposedly less potent and seemingly less glamorous biological cousins, the adult stem cells, have quietly been writing a fascinating story of their own-a story that in many ways is more advanced, clinically and commercially, than the embryonic stem cell story. While federal funding bans and policy debates have relegated human embryonic stem cell research to labs at a handful of companies, in the parallel universe of adult stem cell research has come great progress, with both companies and academic scientists publishing one striking finding after another. On the strength of those studies, a number of human trials using adult stem cells have been launched in the past two years, with several more high-profile experimental treatments scheduled to begin human testing within the next year.

Sprinkled in tissues throughout the body, from just below the surface of the skin to deep redoubts like the liver and bone marrow, adult stem cells are not, critics say, the answer to every ill. “For certain diseases, adult cells appear very promising, for hepatic and cardiac diseases in particular,” says Ronald McKay, a researcher at the National Institutes of Health. “However, if you’re asking for a solution to Parkinson’s disease or diabetes, I would say the cells that offer the best way are fetal and embryonic.” Still, in the unforgiving crucible of clinical studies, where medical potential meets the fickle realities of the human body, adult stem cells are already being tested, while the initial use of embryonic stem cells in humans is perhaps three to five years away.

While a number of biotech companies have adult stem cell research programs, Osiris has been especially aggressive about taking the cells into human trials. Since 1999, for example, doctors working with the company have been testing the ability of mesenchymal stem cells derived from bone marrow to help patients with cancer more quickly rebuild their blood and immune systems, which can be damaged by chemotherapy. In these studies, the mesenchymal stem cells were intended to enhance traditional bone marrow or umbilical-cord-blood transplants. “What we can say so far,” says University of Minnesota professor of pediatrics John E. Wagner, who heads one of the studies, “is that we have seen no negative side effects, and we have the impression that it’s faster.”

Recent animal studies emerging from academic labs have underscored the major take-home lesson about adult stem cells in the past year or so: these cells are much more biologically versatile, and capable of adopting many more cellular fates, than anyone previously thought. Last May, pathologist Neil Theise of New York University and stem cell biologist Diane Krause of Yale University and their colleagues published a report in the journal Cell claiming that an adult stem cell from the bone marrow of mice had the capacity to form multiple tissues-blood, lung, liver, stomach, esophagus, intestines and skin. Theise believes these adult stem cells are as flexible as the embryonic kind, and he refers to them as the “ultimate adult stem cell.” And a team led by Freda Miller of McGill University in Montral recently published work showing that adult stem cells plucked out of the skin, an easily accessible site for harvest, can develop into fat, muscle and neural cells.

Another similarly surprising wrinkle in the adult stem cell story has emerged in the last year in research at Stanford University and the National Institutes of Health. The lab of Eva Mezey at the National Institute of Neurological Disorders and Stroke, for example, has shown that, in mice, transplanted bone-marrow-derived stem cells can migrate to the brain and develop into cells with characteristics of neurons and other types of brain cells. It is part of a string of intriguing, but far from definitive, experiments suggesting that the fate of adult stem cells is determined to an enormous degree by the local environment in which they are placed.

Skeptics warn that stem cell experiments in mice don’t automatically translate into human biology. Still, all these studies reinforce the notion that the adult body maintains a reserve of stem cells, certainly in the bone marrow and probably in many other tissues as well-although the supplies seem to dwindle with age. “They seem to be part of a natural repair system, so that when you damage a tissue, they come from the marrow in large numbers,” says Darwin J. Prockop, director of Tulane University’s Center for Gene Therapy in New Orleans, LA. In other words, adult stem cells appear to act as the body’s on-call, 24-hour-a-day microscopic medical dispensary for wound repair.

As a body part, the bone marrow has never inspired the kind of rapturous Shakespearean prosody lavished on, say, the heart, liver, brain or even spleen; for the better part of recorded history, it’s been of greater value in a soup pot than in the clinic. But this spongy matrix of tissue, encased as in a safe by bone, is increasingly being recognized as a guarded physiological repository for some of the body’s most precious jewels-namely, cells that can differentiate into many other tissues. Indeed, adult stem cells from bone marrow have actually been a prominent and respectable feature of medicine for about four decades. It’s just that for much of that time, no one referred to the use of them as “adult stem cell therapy.”

Human bone marrow transplants, first attempted as a treatment for blood cancers, achieved routine success by the 1970s. That success occurred, it is clear now, because the recipients received, in the slurry of donor marrow infused into their bodies, “hematopoietic” stem cells-that is, progenitor cells that possess the ability to specialize into all the various cell types of a healthy and whole blood system. In this case, one mother hen of a blood cell gives rise to red blood cells, different types of white blood cells with immunological function, platelets and all the other components of blood.

But the bone marrow, it turns out, also contains another important type of adult stem cell that can meet distinctly different cellular fates-one that has the potential for turning into far more than various types of blood cells. In early 1990, a developmental biologist at Cleveland, OH’s Case Western Reserve University named Arnold Caplan, his colleague Victor Goldberg and his then postdoc Stephen Haynesworth isolated a surprisingly versatile stem cell from the bone marrow. The mesenchymal stem cell, so called because it arises out of an embryonic layer of tissue known as the mesenchyme, possesses the ability to form, not only bone and cartilage, but also muscle, tendon, fat and stroma, the weblike matrix of tissue inside bones. In 1993, Caplan and Goldberg helped form Osiris (Caplan is no longer associated with the company).

Osiris relocated to Baltimore in 1995, and its headquarters is now located in a low-slung, renovated brick warehouse in the Fell’s Point section of the city that abuts the busy harbor. By patenting and working on the technology in the early 1990s, Osiris got a head start in reducing the harvesting and culturing of stem cells to practice and now is shipping bags of the cells to more than a dozen clinical centers. The process basically works like this: A doctor draws about 25 milliliters of marrow through a needle from a donor’s bone, typically the pelvic bone. The desired mesenchymal stem cells are not exactly plentiful-by Osiris’s estimates there’s only one of them in every 10 million marrow cells-but they can be plucked out by a combination of centrifugation and proprietary cell-sorting technology. Once isolated, these cells are prodded to divide in cell culture flasks to produce about 500 million stem cells per intravenous dose and then frozen in liquid nitrogen.

Osiris scientists have learned that, by altering the culture conditions, they can nudge these stem cells toward various fates-as, for instance, muscle or cartilage or bone. (For clinical use, the stem cells are shipped in an undifferentiated form.) Interestingly, the cells don’t just respond to biochemical cues but decide their fates based on physical cues as well, including the three-dimensional environment and even mechanical forces, such as the tension and flexion of joints during walking-which helps explain why the same cells can form such different tissues, depending on where and how they’re implanted in the body. “We just put them in the right place, and the body sends the signals,” said company president Annemarie B. Moseley.

When Osiris first began human tests in 1999, patients donated their own marrow, and then company scientists would isolate stem cells and culture them for about eight weeks before injecting them back into the patients. Now, it’s beginning to look as though cells harvested from unrelated donors might work in all patients, opening the door to a universal cell supply that would not create problems of immune rejection.

In the course of assessing the cells in animal trials, Osiris stumbled upon a totally unexpected phenomenon. According to company scientists, these mesenchymal stem cells are conspicuously denuded of several molecular markings that typically provoke an immune response or even trigger transplant rejection. What’s more, the cells may secrete a factor that actively inhibits the immune system. The cells, in other words, seem to deploy a biological stealth technology to remain immunologically invisible.

This observation stunned Osiris researchers. “We were flabbergasted,” says senior scientist Frank Barry. “We still are.” Many scientists remain unconvinced the phenomenon is real. One prominent stem cell researcher, who asked to remain anonymous, says, “I think all of that is hugely exaggerated.” But a clinician using the cells who has seen Osiris’s in-house data on them told Technology Review “it appears to be true.” If so, it not only means patients could avoid the painful extraction of immunologically compatible bone marrow, but that the commercial preparation of universal cells would be much more economically attractive to a company. Two large groups of patients who potentially stand to benefit are heart attack victims and people whose joints are worn down with osteoarthritis.

Heart disease is the leading killer in the United States, and there are more than one million heart attacks a year in the United States alone. As a result, heart disease has been one of the most intense-and impressive-areas of adult stem cell research in the past year.

Last spring, two separate groups, one at Columbia University and the other a collaboration between New York Medical College in Valhalla, NY, and the National Institutes of Health, published studies showing that heart attacks in rats and mice could be repaired by injecting adult stem cells in or near the injury. Now Osiris is trying to do the same with pigs. In the first round of experiments, veterinary surgeons at Johns Hopkins performed open-heart surgery on the animals and tied off the left anterior descending coronary artery, which feeds the main pumping chamber of the heart, for one hour, triggering a heart attack. After two weeks, Osiris researchers then injected about 50 million mesenchymal stem cells directly into the hearts of five test animals. The cells were genetically tagged with a marker so they could be traced in the body, and these pigs, as well as half a dozen control animals, were closely followed for up to six months.

All the pigs that did not receive stem cells died within a month or two of their heart attacks. Autopsies showed that their hearts developed extensive scarring at the sites of injury, and that the organs had become excessively large and distorted in an attempt to compensate for diminished pumping capacity. Eventually, the wall of the heart thinned and heart failure ensued. For the pigs that received stem cells, however, it was a different story. The stem cells zeroed in on the injured cardiac muscle, took up residence in and around the scar tissue and literally remodeled the damaged heart. They seemed, in fact, to interrupt the typical progression toward a lopsided (and prognostically grim) cardiac architecture.

Here are the caveats: the stem cells that take up residence in the scar tissue have the markers of cardiomyocytes, the muscle cells unique to the heart, but they do not appear to be organized in the same way and do not exhibit the typical contractile properties of heart muscle. Still, says Martin, “we’ve seen such good results in terms of function that we didn’t care if they were myocytes or not.”

As a result of that first study, completed last December (and still unpublished), Osiris quickly initiated a second round of trials in pigs-the same pigs that Martin visited that morning in May-and the results appear to confirm the initial tests. This second trial uses universal donor cells, rather than cells extracted from each pig’s own marrow, that are injected immediately after the heart attack. Echocardiograms, including the ones Martin and his colleagues gathered during the May visit, have shown a statistically significant improvement in the pumping capacity of the heart. The company is now exploring the possibility of delivering these cells to precisely the right spot in a damaged heart through a catheter similar to the type used in angiograms or angioplasties.

The ultimate aim, Martin explains, is to manufacture “a universal [human] cell, cryopreserved, which could be in the emergency room of every hospital in the country, and used in emergent situations with heart attack patients.” The hope is that initiating cellular therapy as soon as possible after a heart attack could significantly reduce permanent damage to the heart. Two days after Martin visited the pigs last May, Osiris officials met with U.S. Food and Drug Administration scientists, and they hope that, if all lingering regulatory and safety concerns can be satisfactorily resolved, a preliminary safety study of adult stem cells in humans with heart disease could feasibly be launched by the end of the year.

Another barnyard animal is providing further promising results for treating a condition that afflicts more than half of all Americans over the age of 65: osteoarthritis. At a farm north of Baltimore, Osiris scientists have been putting a dozen or so goats through their paces on treadmills. What’s unusual about these goats is that each has sustained severe damage to one knee. To simulate conditions that commonly cause osteoarthritis, veterinary surgeons sever a ligament in the knee and remove the inner half of the meniscus, a resilient patch of cartilage that forms a cushioning pad between the thighbone and the larger of two bones that form the lower leg. The goats then spend several weeks on an exercise program using this wobbly, unstable joint-a regimen that literally rubs and erodes the remaining cartilage off the ends of the long bones. This activity creates a harrowingly accurate model of osteoarthritis.

Osiris researchers have been using an ordinary syringe to inject approximately five to ten million adult mesenchymal stem cells into a little purse of tissue inside the knee, and the results have been encouraging. Although tested in only a handful of animals, the stem cells have not only restored the surgically removed meniscus but within 12 weeks have recarpeted the eroded, bony surface of the thigh and calf bones with new cartilage. “These cells respond to mechanical forces,” Osiris’s Barry explains, “and the fact that the animal is putting weight on the joint means the cells experience these dynamic forces. The second thing is that they respond to the local wound environment.” Encouraged by the results in animal experiments, Osiris hopes to launch initial safety studies in humans before the end of the year.

One of the hottest areas of stem cell research would seem to be beyond the reach of adult stem cells: the brain. The problem, as Harvard Medical School researcher Evan Snyder bluntly puts it, is, “If you’re talking about the brain, where would the adult stem cells come from?”

Fred Gage, a neuroscientist at the Salk Institute for Biological Studies in La Jolla, CA, whose group was the first to find adult neural stem cells in the mammalian brain, has offered a potential rejoinder. Earlier this year, Gage’s team extracted what he calls adult neural progenitor cells from cadavers-leading to the possibility of harvesting the cells from fresh cadavers for medical use, much as hearts, livers and kidneys are harvested from accident victims for organ transplants.

In animal experiments, the researchers have shown that transplanted neural stem cells-much like the bone-marrow-derived stem cells in Mezey’s experiments at the National Institute of Neurological Disorders and Stroke-can migrate to the zone in the brain where new neurological cells are formed and to areas of injury. The cells typically take on the shape and function of other cells in those spots. “Not only are new cells born, but they undergo synaptogenesis,” or create the ability to connect with other nerve cells, Gage said at a meeting on stem cell biology at Cold Spring Harbor Laboratory last March.

One of the most surprising findings in the area, though-from Mezey’s experiments and from a recent rat study conducted by Helen Blau’s group at Stanford-is that it might not be necessary to start with stem cells taken from the brain, since stem cells from bone marrow may be able to repair neurological damage. “If we could learn what the signals are and learn how to make it more robust,” Blau said at the Cold Spring Harbor meeting, “if we could get function [in these cells], and see if the cells migrate to damage, it might have great utility in the treatment of Parkinson’s disease, stroke and trauma.”

All those ifs reflect that scientists are in the early stages of research in a field rife with uncertainty-and peril. The research community received a sobering reality check last March when neuroscientist Curt Freed and colleagues at the University of Colorado reported in the New England Journal of Medicine mixed results in a clinical trial in which embryonic neural cells (but not specifically stem cells) were implanted in the brains of patients with Parkinson’s disease. Some of the patients experienced a small degree of improvement, but others developed severe and disabling side effects-constant, jerky motions-that were described as worse than the original symptoms of the disease. While the experiments did not specifically involve stem cells, the results served as a reminder that any cells, once implanted, can have not only unwanted but irreversible side effects.

The limited ability of adult stem cells to form many tissues, however, may be an advantage. “Adult stem cells have been used for years without side effects of that type,” said Daniel Marshak, vice president of bioscience research and development for East Rutherford, NJ-based Cambrex, which provides services to stem cell scientists. “The adult stem cell has somewhat less capacity to do what it wants, but it may be somewhat more programmed to do the right thing.”

Side effects and other clinical issues will need to be addressed as adult stem cell research progresses and more human trials are launched. Those studies will go a long way to eventually determining the real medical potential of these remarkable cells. But for now, the future of adult stem cells remains closely linked to the political and ethical debates surrounding their embryonic cousins.

Among many researchers, it has become almost politically incorrect to speak with unguarded enthusiasm about adult stem cell research-not because the research isn’t exciting, but because such praise has inevitably provided ammunition to opponents of embryonic stem cell research. U.S. senator Sam Brownback of Kansas, for example, used recent results from Prockop’s group at Tulane and Edwin M. Horwitz’s group at St. Jude’s Children’s Research Hospital in Memphis, TN, to argue that adult stem cells are so potent and versatile that there’s no need to destroy embryos to get their stem cells, and thus no need for the government to provide funding for embryonic-stem-cell research. But Prockop reflects the views of most scientists when he says, “We can learn from both groups of cells. We have too much to learn to stop any of this work.”

There are, in fact, substantive scientific questions remaining to be answered before the relative merits of embryonic and adult stem cells can be determined. Some scientists claim embryonic stem cells are easier to grow in culture, and they are unquestionably capable of more cellular fates, but they also pose a small but theoretical risk of developing into cancerous tissues. Adult stem cells may not be as potent as embryonic stem cells, but preliminary clinical results suggest they are safe in humans. Yet they have many academic critics. Stanford biologist Irving Weissman argues that, almost without exception, adult cells have not been characterized rigorously enough, and he dismisses the politicians and religious figures who tout the virtues of adult stem cells, saying, “Those who have made the claim that human adult stem cells can do everything and anything that we want seem to know something that the experts don’t know.”

Nonetheless, virtually all the researchers who’ve laid their hands on adult and embryonic stem cells see them ushering in a new kind of medicine in the 21st century, where the healing wisdom of these powerful biological agents provides a kind of in situ doctoring, where repair and regeneration are startlingly real possibilities, where the drugstore of the future is as likely to dispense bags of cells as bottles of pills. The question, as much political as scientific, is how quickly we are going to get there.

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