Brave New Cells

It's the kind of scene you'd expect in a thriller by Michael Crichton or Robin Cook. A scientist throws some nondescript cells into a lab dish, leaves them alone for a bit and returns to find a disembodied heart thumping away.

That's not quite what's happening in Roger Pedersen's lab at the University of California in San Francisco at least not yet. But he has managed to turn a group of carefully tended progenitor cells into a patch of thriving, beating cardiac muscle. "It's amazing," Pedersen says, "when you put unspecialized cells away, come back after the weekend and there's a clump of heartlike cells beating before your eyes in a dish."

And that's just the beginning. Someday, scientists hope to use cells like these to cure diabetes, Parkinson's disease and multiple sclerosis, as well as to reverse congestive heart failure and heal spinal-cord injuries. But there are some aspects of this story that are brave new worldish. Known scientifically as stem cells, Pedersen's marvelously pliable cells are derived from seven-day-old human embryos, which are destroyed in the process. Although not all stem cells are produced this way, embryonic stem cells seem for now to have the greatest potential for medical miracles.

Pedersen and the handful of other scientists working with human embryonic stem cells uses embryos left over from fertility attempts that would otherwise be thrown away. Still, treating human embryos like so many tissue factories seems straight out of Huxley. It certainly doesn't sit well with antiabortion activists or, in many cases, with U.S. lawmakers. In 1996 Congress banned human-embryo research by federally supported scientists, forcing researchers like Pedersen to seek private funding (most of which has been provided by Geron, a Menlo Park, Calif., biotech company).

A lot has changed in the past couple of years, however, that might persuade Congress to reconsider. Last September the National Bioethics Advisory Commission concluded that harvesting stem cells from discarded embryos is morally akin to removing organs from dead people for transplant. Also, the National Institutes of Health has seized on a possible loophole. In their view, federally funded scientists can do research on stem cells as long as someone else say, in the private sector actually dismantles the embryos. Most important, a small but influential group of Republicans and Democrats on Capitol Hill has started pushing for a relaxation of federal policy.

Senator Arlen Specter of Pennsylvania, who has called stem cells "a veritable fountain of youth," has convened a hearing on Capitol Hill to review both the science and the ethics of the research. "Finally there is a very possible solution to conquering diseases that were always thought incurable," says actor Christopher Reeve, who has been paralyzed since his spinal cord was crushed in a fall from a horse in 1995, and who, along with former Senator Bob Dole and others, is scheduled to testify. "This research should go forward as fast as possible," Reeve says. To that end, Senators Specter, a Republican, and Tom Harkin of Iowa, a Democrat, have introduced a bill to lift the ban. Just how far they'll get in an election year is anyone's guess.

To critics, anything that requires the destruction of human embryos no matter what the reason is abhorrent. Calling that "worse than abortion," Richard Doerflinger, a director of policy for the National Conference of Catholic Bishops, says, "If [the embryo] is a member of the human family, you cannot destroy that being for the sake of others."

The ethical considerations aside, researchers have so far offered promises aplenty about what stem cells can do but very little proof. Scientists acknowledge that many "nontrivial" technical obstacles remain to be overcome, and they are worried that stem-cell therapy has been so overhyped that it can't help but disappoint. There has even been one death from a related treatment.

To complicate matters, adults have stem cells too. Lurking in the microscopic nooks and crannies of the brain, bone marrow and other organs, these stem cells live in a state of perpetual readiness. Then when, say, the lining of the intestine becomes worn, the body signals the appropriate stem cells to start a process called differentiation, in which they divide and give rise to lots of mature, fully functioning intestinal cells.

These adult stem cells appear to be fairly restricted in what they can become. (Stem cells in the bone marrow usually give rise to different types of blood cells; stem cells in the muscles generally give rise to muscle.) Otherwise, Kafkaesque as it may seem, you could wake up one morning to find that your foot had turned itself into a liver. In any case, while there's no controversy over the use of adult stem cells, their potential benefit as a therapy seems limited.

Stem cells derived from embryos, on the other hand, can become just about anything from teeth to muscle to neurons. In fact, they're so strongly primed to differentiate that scientists have a tough time keeping them in their original state. James Thomson of the University of Wisconsin was the first to pull off the feat in 1998. He now has an entire tissue bank of stem cells that he hopes one day to turn into specialized tissue almost at will eliminating the need for fresh embryos.

Stem cells can also be obtained from aborted fetuses in a process developed two years ago by John Gearhart at the Johns Hopkins School of Medicine in Baltimore. Gearhart harvested cells from the region that gives rise to the testes or ovaries. Such fetal stem cells appear to be as malleable as embryonic ones.

One feature that all stem cells share is an urge to travel. Evan Snyder, a neurologist at Harvard Medical School in Boston, has found that stem cells are attracted to injured tissues, perhaps because of biological cues released by dying or diseased cells. Indeed, one of Snyder's lab colleagues found that a batch of stem cells had migrated from one side of a rat's brain to the other to infiltrate a tumor.

Stem cells are also highly responsive to their surroundings. Researchers have taken adult stem cells from the brains of rats and put them in bone marrow and watched, in astonishment, as they spewed out blood cells. True, they did not form all the different blood-cell types, just a few. But until then no one had known that adult stem cells could adapt even that much to their environment.

And the extraordinary thing is that it's the specialized cells surrounding them their older brothers and sisters, if you will that provide the directions. Not in words but in biological signals, like growth factors and surface proteins, and by simply touching them.

David Anderson and his colleagues at Cal Tech have, for example, identified many environmental triggers that get the nervous system's stem cells to turn into neurons or into their supporting glial cells. They've also gone inside stem cells to isolate the genes responsible for the transformations. As with most adult stem cells, these cells appear, so far, to be limited in the types of tissue into which they can differentiate. Yet they still give rise to many different kinds of neurons from sensory cells in your nose to touch receptors on your fingertips. The next step, Anderson says, is to figure out how that happens.

Pretty heady stuff, especially for neurologists who have spent most of their professional lives believing that even if the adult brain had stem cells, they'd never yield new neurons. Now the scientists have at least two options to consider. They can train stem cells to produce nerve tissue in a petri dish and then implant the new tissue in an ailing brain. Or, as Fred Gage at the Salk Institute in La Jolla, Calif., suggests, they can tweak the brain's stem cells to start churning out new neurons. If you could do that, Gage says, "it would take away the controversy over embryonic research."

There's still much more to learn, of course, and many pitfalls to avoid. Consider the case of a 52-year-old American athlete with Parkinson's disease, who in 1989 before human stem cells had been isolated from the brain traveled to China for a fetal-cell transplant. The goal was to replace some of the diseased neurons in his brain with newly differentiated fetal nerve tissue. While that approach has been at least partly successful in hundreds of other cases, something went dreadfully wrong this time. About two years later, the man suddenly developed trouble breathing and died.

An autopsy uncovered a hard mass of tissue pressing on his brain stem, which controls breathing, among other things. Apparently, the surgeons had scooped up a few extra fetal cells that then migrated and became cartilage, skin and hair cells.

Clearly, researchers don't know enough to start injecting stem cells into humans anytime soon, despite predictions that the first human trials could begin in the next couple of years. Just don't expect to hear a lot about what's going on behind closed lab doors, if the current congressional ban continues and stem-cell research remains almost entirely in the hands of biotech companies.

"That's actually the worst-case scenario because now the public has no input," says Larry Goldstein, a cell biologist at University of California at San Diego. "Companies have to be motivated by profit, so they aren't necessarily going to tell us what they're doing."

With or without federal funding, stem-cell research will continue. Scientists may even sidestep the abortion issue by figuring out how to make adult cells act more like embryonic ones. But the private sector isn't going to wait to find out if that's feasible. Tens of thousands of embryos are created in in-vitro fertilization clinics each year and never implanted. If the U.S. Federal Government wants to have a say in how they get used, it will have to pay for the privilege.

Reported by Dan Cray/Los Angeles and Dick Thompson/Washington