Here's major news these days, for those of us teetering on the edge of geezerhood, our memories fading and our vital organs wheezing. Now it appears that things don't have to be that way. All our lives we have been told, for example, that the human brain cannot regenerate lost neurons: it really is downhill all the way. Late last year, however, undeterred researchers found that, at least under some conditions, the brain does indeed grow new cells. Not only that, but the day may be coming when we will be able to have new neurons injected into our brains.
November of last year brought the extraordinary news that teams of scientists at the University of Wisconsin at Madison and the Johns Hopkins University School of Medicine in Baltimore had succeeded in growing human embryonic stem (ES) cells in their laboratories. These are cells, usually formed early in an embryo's development, that have the potential to become any kind of cell but have not yet begun to differentiate. More about how they work in a minute, but for now the news is that the possibilities they represent are staggering. The researchers expect someday to take some of those stem cells and grow them into heart muscle cells, for example, and then inject those cells directly into the hearts of patients whose cardiac function has been weakened by heart attacks. Congestive heart failure could become a reversible condition. Or conceivably, stem cells could be induced to become pancreatic islet cells, manufacturing more insulin for patients who had been diabetic as a result of cell damage.
Any research on human embryos sets off alarms. The few-days-old cluster of cells that are taken apart to obtain stem cells are potential precursors of human beings. For some, any work that prevents them from becoming so is murder whether, as the spokeswoman for one group said, "it's done in the womb or a petri dish." Current federal law prohibiting the use of federal money for research on human embryos was restated just last October in the appropriations bill.
President Clinton took notice when a small company in Massachusetts claimed that it could induce human cells to revert to the undifferentiated embryonic state by fusing them with cow eggs, whose nuclei have been removed, to produce hybrid cells. He asked the National Bioethics Advisory Commission to consider the implications and report back to him "as soon as possible." And recently Senate hearings were held to examine the ethical issues.
When a human egg is fertilized, it begins to multiply. After about five days, it has become a blastocyst, a fluid-filled sphere made up of cells that will become the placenta, and 15 to 20 cells clinging together and to the inside of the blastocyst wall that will become the embryo. These inner cells will give rise to embryonic stem cells, each identical to the others, and each able to become any kind of cell in the human body. One of the goals of cell biology is to find out how each cell "decides" what to become — what it is that causes one to become a liver cell while another becomes bone.
What the Wisconsin and Johns Hopkins groups have done is to grow embryonic stem cells in a special medium that prevents them from specializing. Raised that way, they will grow and divide forever. When the cells are transferred to a nutrient bath that allows them to differentiate, they do so. Thus far the scientists cannot dictate what the cells will become. They can only passively separate them by their function once they have differentiated: ultimately, those that have become heart cells into this culture dish, say, or liver cells into that one. (The differentiation of these ES cells into neurons has already been documented.) They hope, however, to be able in the not-too-distant future to direct the process, to make the cells turn into whatever they want. At the same time they would genetically alter the cells to prevent rejection by the body. Finally, they would simply inject the new cells into the organ that needs them.
The Wisconsin group, led by James A. Thomson, published its work in the November 6 issue of Science. The Johns Hopkins group, led by John Gearhart, followed four days later in the Proceedings of the National Academy of Sciences. In an unusual twist, Gearhart offered an appreciation of Thomson's work in the same issue of Science in which Thomson's paper appeared. The "research and clinical potential for human ES cells is enormous," he writes. They will be used for studies of normal and abnormal human embryo development (birth defects), to test new drugs and especially "as a renewable source of cells for tissue transplantation, cell replacement and gene therapies."
Gearhart ends his discussion by pointing to the legal problems involved in such research. Both the Thomson and Gearhart teams operated in laboratories wholly separate from their regular labs, places where not even an extension cord had been bought with federal money. Thomson used blastocysts left over from in vitro fertilizations that would have been discarded. The donors of the blastocysts gave permission for them to be used in research. Gearhart cultured human ES cells from primordial germ cells (undifferentiated cells that would have become eggs or sperm cells) that he had extracted from aborted fetuses. Federally funded research on fetal tissue is legal, but Gearhart, too, avoided using any federal funds. Instead, money for the research was put up in large part by the Geron Corporation in Menlo Park, California, a biotechnology company that specializes in antiaging research. In return, the company receives essentially exclusive licenses to use the technologies.
Thomas B. Okarma, vice president for research at Geron, said his company does view the cells as different from others, as having "moral authority." But, he adds, because the blastocysts would have been discarded, he believes it is justified to use them to develop lifesaving treatments.
The possibilities of embryonic stem cells represent a huge leap for science and medicine. The news is more than enough for any day, week, month or year. Yet there is more — possibilities so extraordinary that I hesitate to mention them. Briefly, they have to do with cell immortality. The idea goes something like this. The ends of chromosomes are sections of DNA called telomeres. They get a little shorter each time a cell divides until finally they hit a critical length that signals the cell to stop dividing.
In January 1998, Geron biologists reported that an enzyme called telomerase can keep the telomeres from shrinking, allowing cells to live and divide indefinitely. (Something like this is apparently what happens with cancer cells.) Telomerase is active in embryonic stem cells, which as noted above can live and divide forever. When those cells start to differentiate into specific cells for specific organs, the telomerase disappears. The company is trying to find ways to make it reappear so it will work against the deterioration associated with aging. It is also looking for ways to block telomerase in treating cancer. (One more piece of the puzzle appeared in November, when scientists at Rockefeller University announced that an enzyme called tankyrase seems to control telomerase functioning.)
It may be possible, according to Geron scientists, to manipulate human embryonic stem cells so that they retain the ability to divide indefinitely even as they turn into the specialized cells of all the body organs. To put that another way, it may not only be possible to inject a failing heart with new heart cells, but to do so with immortal heart cells. That's the sort of thing that's best to think about for only a few minutes at a time, especially with neurons that are already badly worn.
By John P. Wiley, Jr.