November 2001

Adult Stem Cells

Continued from page 2

By Stephen S. Hall

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.