http://www.nytimes.com/2001/12/18/health/genetics/18ALTE.html?pagewanted=print

December 18, 2001
By ANDREW POLLACK

Human embryonic stem cells may not be the only source of tissue needed to repair damaged organs. Alternative approaches from the mundane to the exotic are being explored to avoid the ethical controversy surrounding embryonic stem cells. Those cells are obtained by destroying human embryos, which some people view as human life.

Still, it may be hard for the alternative approaches to measure up to the potential of embryonic stem cells, which have two attributes that make them attractive for regenerative medicine. They are versatile, in that they can be turned into any other type of tissue or cell in the body, at least in theory. And they can be easily multiplied in culture, providing an ample supply of cells.

What follows is an assessment of the other possibilities.

ADULT STEM CELLS These are the most frequently mentioned alternative. Certain tissues, like the bone marrow and brain, harbor small reservoirs of stem cells that the body uses to replenish its tissues.

These stem cells may be more limited in their repertoire than embryonic stem cells. A neural stem cell, for instance, may be able to turn into brain cells, but not into heart or liver cells. One type of adult stem cell is already being used to treat diseases. Bone marrow transplants are really transplants of hematopoietic stem cells, which give rise to the various types of blood cells and regenerate an immune system.

Still, many scientists doubt that adult stem cells will be as useful as embryonic ones. Adult stem cells are extremely rare, and hard to isolate and purify. They may not exist for all tissues. Moreover, scientists have not yet figured out how to grow large numbers of adult stem cells in culture.

Still, some adult stem cells are available in large quantities. Blood from umbilical cords, which is rich in adult hematopoietic stem cells, is already being banked and used for patients who need bone marrow transplants. Fat may also yield stem cells: Artecel Sciences in Durham, N.C., says it can extract stem cells from fat removed by liposuction. These cells can turn into fat, bone and cartilage and possibly into neural cells, the company says.

OTHER CELLS Other types of cells may be obtained in larger quantities than adult stem cells. Anthrogenesis Corporation, a New Jersey biotechnology company, says it has isolated stem cells from human placentas. The company claims these cells are as versatile as embryonic stem cells. But it has not published any of its data and declines to identify its collaborators.

Several companies already make artificial skin for wound repair using not stem cells, but cells obtained from foreskins from circumcisions.

Animal cells could be easily obtained, though they might transmit animal viruses to people. Diacrin, a Massachusetts company, is already testing in people neurons obtained from pig fetuses as a treatment for people with brain diseases like Parkinson's.

DRUGS If the body contains adult stem cells to help regenerate tissues, it might be possible to give people a drug that would activate those cells and let the body repair itself. Drugs, unlike transplanted cells or tissues, will not be rejected by a patient's immune system.

"It completely avoids the problem of foreign tissue, completely avoids injuring the brain to get cells in," said Dr. William C. Mobley, a professor of neurology at Stanford, who is experimenting with a drug that can cause nerves to grow.

The use of drugs has already had some success. The biotechnology industry's best- selling drug, erythropoietin, is a human protein that, when injected, prompts the body to create new red blood cells. But attempts to use proteins known as growth factors to spur the body to sprout new brain cells or blood vessels have failed.

In many cases, it seems, tissue growth requires not just one growth factor but a carefully orchestrated combination of them. Duplicating that with drugs may be difficult. Skeptics also say that the reservoir of stem cells inside the body may be too small to do major repairs, even if stimulated by a drug. If brains and hearts really have the innate ability to repair themselves, critics ask, why don't they do it?

PARTHENOGENESIS In certain animal species, females do not need males to reproduce. Their eggs can turn into embryos without being fertilized by sperm. Such reproduction, known as parthenogenesis after the Greek word for virgin birth, does not happen in mammals. But some scientists are trying to use chemicals to turn unfertilized human eggs into embryos from which stem cells can be extracted.

Scientists believe that such embryos, known as parthenotes, could never become babies, even if implanted into a womb. So destruction of parthenotes to make stem cells may not raise the same moral issues as destruction of embryos. Moreover, tissue derived from parthenotes would be very similar to that of the egg donor. So a woman might donate her own eggs to make tissue for herself that her body would not reject.

Advanced Cell Technology, the Massachusetts company that recently claimed to have cloned human embryos, reported the first human parthenotes in the same scientific paper. None developed enough to yield stem cells. But the company says it has obtained stem cells from monkey parthenotes.

Some opponents of embryonic stem cell research say that destroying parthenotes may not be any more acceptable than destroying embryos. Moreover, parthenotes, lacking paternal chromosomes, may develop incorrectly and produce abnormal tissue. And using parthenotes to make customized tissue will not work for half the population — men.

DE-DIFFERENTIATION This idea, also called cellular reprogramming, aims at getting specialized body cells, like skin cells, to revert to a primordial state, like stem cells, so they can be turned into various types of tissues.

This reprogramming happens in cloning, when the nucleus of a skin cell is put into an egg that has had its own nucleus removed. Material in the egg cell, known as the cytoplasm, can reprogram adult cells.

Cloning, however, creates an embryo, raising ethical objections. But some scientist are trying to use the egg cytoplasm to reprogram adult cells without creating embryos. Imagine, for instance, pouring the contents of an egg onto a skin cell to reprogram that cell. An egg would be destroyed, but not an embryo.

At PPL Therapeutics, the Scottish company that cloned Dolly the sheep, scientists are removing the genetic material from eggs, then shaking the eggs to create mini-eggs, just as a water drop can be splattered into smaller droplets. The scientists then try to fuse these mini-eggs with adult cells, like skin cells. The mini-eggs are so small that an embryo cannot be formed, said Dr. Alan Colman, the company's research director.

PPL, which is working with cow and pig eggs, has derived small colonies of cells this way, but the cells stop growing after a month or two in culture. While some of the cells look like embryonic stem cells, the company cannot make enough to study them fully.

TRANSDIFFERENTIATION Making a skin cell de-differentiate back to its primordial state in order to turn that primordial cell into a brain or heart cell may be a roundabout approach. It may be possible to turn the skin cell directly into the brain or heart cell.

Dr. Philippe Collas of the University of Oslo in Norway and Dr. James Robl, president of Hematech, a biotechnology company in Westport, Conn., tried this using the nuclei of fibroblasts, which are cells that produce the body's connective tissue. They incubated the nuclei in a mixture of the nuclei and cytoplasm of T-cells, or immune system cells. The fibroblast nuclei took on many of the characteristics of T-cell nuclei, evidence that they had been reprogrammed.

"Certainly the long-term goal is to be able to transform one cell type directly into another cell type," Dr. Robl said. "This study provides preliminary evidence that it may be possible."
 

Copyright 2001 The New York Times Company