Special Harvard Commentary: Stem Cells 101
  
   The controversy over stem cell research has become a front page story. It was highlighted by the death of former president Ronald Reagan from Alzheimer's disease, and the belief of his widow, Nancy Reagan, that stem cell research might one day offer a cure for Alzheimer's disease. It was also highlighted by the death of actor Christopher Reeve, a vocal campaigner for stem cell research who believed that it might one day offer a cure for people, like him, paralyzed by spinal cord injuries.
 
   What is the controversy about? Here are answers to some common questions about stem cell research.
 
   Why Are People Excited About the Potential of Stem Cells? Most diseases are caused by the death of healthy cells in a particular organ. For example, diabetes is caused by the death of insulin-producing cells in the pancreas (an organ that lies beneath the stomach); Parkinson's disease is caused by the death of brain cells that produce a chemical called dopamine; and heart attacks cause the death of heart muscle cells. Almost all the organs in our bodies cannot, on their own, replace the cells that die (the liver is an exception). Nor have medicines been discovered that prompt our bodies to replace dead cells.
  
   Stem cells have the capability to replace cells that have died, in different organs. In mice, stem cells have in fact replaced dead cells, and cured the mice of particular diseases (including heart muscle damage). That is the main reason that there is such excitement about using stem cells for what is called "cell therapy." Background to Understanding Stem Cells Before explaining what a stem cell is, we need to describe what cells and organs are. Cells -- Every animal and human being is composed of cells. Each human being consists of trillions of cells. Organs -- Cells are grouped together into organs -- for example, the eye, the brain, the heart, the pancreas. Within each organ are groups of different types of cells. These different types of cells support each other and even "talk" to each other using chemical signals.
 
   The three miracles of development The first miracle of development is that all of those trillions of cells came originally from just one cell: the fertilized egg. The second miracle is that all of these cells are so different from one another, each specialized for a particular purpose. Certain cells in the back of our eyes detect light, allowing us to see. Certain cells lining our stomach make acid that helps to digest food. Certain cells in the pancreas make insulin, which drives a source of energy (sugar) inside our cells. These different types of cells, which live in different organs, are called specialized cells.
 
   The third miracle is that all of the specialized cells are formed in the right place (the light-sensing cells in the eye, the acid-producing cells in the stomach), and in the right number: not too many and not too few. First inside the mother's womb, and then outside, some miraculous process in each of us has directed one cell to both multiply and to change into very different cells, in a highly controlled way.
 
   How genes control our development What controls the process of growth and development? Inside every human cell is a set of about 30,000 genes -- the same 30,000 genes in each cell. Genes work only when they are turned on. What makes one specialized cell different from another type of specialized cell is that different genes are turned on and off in each type of cell. For example, different genes are turned on and off in the light-sensing cells of the eye than in the acid-producing cells of the stomach.
 
   But what controls the turning on and off of different genes? Chemical signals in the immediate environment -- chemicals produced by the cells next door -- activate or inactivate certain genes. Recently, scientists have begun to identify which genes are turned on or off in a particular type of cell, and what the chemical signals are that influence these genes.
 
   One final concept is important. Once a cell has become specialized, it cannot make copies of itself, and it generally cannot turn into any other type of cell. With a few exceptions, once a cell has become specialized, it will exist unchanged until it dies. What Are Stem Cells?
 
   In addition to the trillions of specialized cells, we also carry within us a small number of cells called stem cells. Stem cells can reproduce themselves, and they can go on to produce specialized cells -- if they are coaxed to do so by certain chemical signals.
  There are several types of stem cells: Embryonic stem cells are found in an early stage of the embryo. These cells -- discovered in mice 20 years ago, and in humans about six years ago -- can reproduce themselves, producing more embryonic stem cells, or they can turn into many and perhaps all specialized cell types.     

   Umbilical cord stem cells are present in the umbilical cord blood, which is removed at the time of birth. They are currently used in treatment of human blood cancers and related conditions, as explained below. Adult (or somatic) stem cells are found in certain organs, such as the bone marrow, brain, muscles and skin. These cells also can reproduce themselves, and they can turn into different specialized cells of the organ where they are found.
 
   For example, brain stem cells can form into neurons -- the cells responsible for the main activities of the brain, such as thinking, emotion, vision, hearing, and directing body movement. Blood stem cells, for example, can produce oxygen-carrying red blood cells, all the different types of white blood cells, and the cells that form blood clotting cell fragments called platelets.
 
   There is some evidence that adult stem cells may be able to turn into some types of specialized cells found in organs other than their own. For example, bone marrow cells may be able to turn into heart muscle cells. There is considerable controversy as to how capable adult stem cells are in this regard. However, there is no doubt that embryonic stem cells are capable of turning into many more types of specialized cells than are adult stem cells.
  Because embryonic stem cells appear to be much more capable of turning into virtually any type of specialized cell, they have theoretical advantages over adult stem cells in cell therapy. However, because embryonic stem cells come from human embryos, they are the subject of ethical controversy (see the discussion below on ethical issues). Stem cells are present in every embryo. Here is the process by which scientists cultivate embryonic stem cells: A fertilized egg grows into an early stage of embryo.
 
   The early stage embryo is called a blastocyst. It develops after about five to seven days. As it grows, the blastocyst forms a ball, and there are a group of cells on the inside of the ball. These are the embryonic stem cells. The stem cells can be removed, which destroys the blastocyst. Scientists then place the stem cells into a laboratory dish that is full of nutrients, to encourage them to grow. The nutrients and other chemical signals that are put in the dish either encourage the cells to keep reproducing themselves, or to begin to change into specialized cells.   

   With the right chemical signals, the embryonic stem cells can be encouraged to grow into: a. red blood cells; b. neurons (nerve cells); c. muscle cells; or other types of cells.
  
   Are Stem Cells Used in Treating Human Diseases?    For many years, doctors have used adult stem cells successfully in treating human disease, through bone marrow transplantation. Bone marrow transplantation is used most often in the treatment of cancers, particularly cancers that require chemotherapy.
   When chemotherapy is given to kill cancer cells, it also kills many bone marrow cells. Very high doses of chemotherapy kill more cancer cells but also kill more bone marrow cells. Without bone marrow stem cells, a person would be unable to make the blood cells that are essential for life.
  
   In autologous bone marrow transplantation, patients donate their own cells prior to receiving chemotherapy. The cells from the bone marrow are removed through a needle. The removed cells include adult stem cells, the kind that make all of the blood cells. Those adult stem cells are put in laboratory dishes that are filled with nutrients, where they multiply.
  
   Then high-dose chemotherapy is given -- a dose that will kill all the bone marrow cells in the body but that also, hopefully, will kill all the cancer cells. Then your own bone marrow cells that have been multiplying in the laboratory are placed back into your body. When the procedure works, the bone marrow stem cells begin making new blood cells -- and the cancer is cured.
   Although using bone marrow transplantation is a common example of using a particular type of adult stem cell -- bone marrow blood-forming stem cells -- to replace dead cells, it currently is the only such common example. If you need to replace cells in your brain, heart, liver, kidneys -- indeed, all organs other than the blood -- there is currently no stem cell therapy.
  
   In recent years, umbilical cord stem cells also have been used in place of bone marrow adult stem cells, for transplantation. They have some advantages compared with bone marrow cells: They are at least as likely to successfully grow into healthy adult blood cells, and are less likely to have certain major side effects.
   Umbilical cord stem cells can be easily extracted at the time of a baby's birth, and frozen away for years. Theoretically, should that baby need a transplantation for blood cancer or other condition later in life, the frozen umbilical cord cells would be ideal, because they could be transplanted without fear of rejection by the immune system. Some companies offer parents the service of collecting and freezing a baby's cord blood. While there may be cases where that makes sense -- such as a baby born to a family that seems to have a high rate of blood cancer -- most experts do not think there are currently many circumstances under which it would be appropriate to collect and freeze a baby's cord stem cells at the time of birth.   

   Making Your Own Stem Cells Through Nuclear Transfer Suppose you had a failing organ, and wanted to use embryonic stem cells for cell therapy. The embryonic stem cells would have to be your own, because embryonic stem cells from another human being would be recognized as foreign by your immune system and rejected.
   But how could you use your own embryonic stem cells, since you were an embryo a long time ago, and you can't turn back the clock? Scientists are working on a technique called nuclear transfer (also sometimes erroneously called "therapeutic cloning") that theoretically could do the trick.
   In normal development, a sperm fertilizes an egg. The sperm carries half of the father's genes and the egg carries half of the mother's genes in the nucleus of the egg. The fertilized cell (called a zygote) has the full number of genes. The zygote begins to divide, and after several days an early stage of the embryo -- the blastocyst -- is created. The blastocyst lodges in the lining of the mother's uterus, and begins to grow into a baby.
   In nuclear transfer, the steps are as follows: An unfertilized egg would be taken from a woman during a minor surgical procedure. The nucleus in the center of the egg that contains the woman's genes is extracted. The nucleus of one of your own cells, with all of your genes, is inserted into the egg. The egg doubles, and the cells keep doubling, until the ball-shaped blastocyst is formed. Embryonic stem cells would be removed from the blastocyst, and then grown in the laboratory. In a few months, there would be millions of embryonic stem cells. These cells would be your embryonic stem cells, with your genes in them. They could be given back to you, without fear of being rejected by your immune system. Nuclear transfer has worked in many animals. A South Korean team claimed to have made the techniques work in humans, but the scientific journal that published the claims and most of the scientists involved in the work have withdrawn that claim. Most experts think, however, that nuclear transfer will be shown to work with human cells.
   What Are The Ethical Issues in the Use of Stem Cells?
  
   Human reproductive cloning One issue on which virtually all scientists and the general public agree is that creating a human clone and then trying to let that embryo grow into a human baby is unethical. Such "reproductive cloning" has been performed successfully in animals, the most famous example being the sheep named Dolly. The moral argument against human embryonic stem cell research Ethicists agree that it is immoral to destroy a human life. The ethical controversy centers on the question of when life begins. This question is raised by research that involves human embryonic stem cells, but not research involving adult stem cells or embryonic stem cells from animals.
   Much research on embryonic stem cells has involved human embryos that are available because they are the products of abortion or created through in the vitro fertilization process but not used. The primary argument against such research is that an embryo that could have implanted in a woman's uterus and gone on to produce a baby is alive, has the moral status of a person and thus should not be destroyed, no matter how great the human benefit. Others think that it is moral to use embryos that came from abortions or in vitro fertilization, because those embryos otherwise would have been discarded.
   Human embryonic stem cells also theoretically could be created by nuclear transfer. If that technique is made to work in humans, it would raise ethical questions for some, because -- as with embryos derived from abortions -- it involves the destruction of a human blastocyst. Others disagree. They say that a human being can grow only from an embryo that has been placed into a woman's uterus: since that is not done with nuclear transfer, no potential human life has been destroyed. Some ethicists have argued that if the blastocysts created by nuclear transfer were unable to implant in a woman's uterus, and therefore unable to develop into a baby, then research involving such blastocysts would be ethical. A research team has indeed created such blastocysts by nuclear transfer, in mice. If nuclear transfer can be accomplished in humans, and if the blastocyst created cannot implant in a woman's uterus, then some ethicists who currently object to human nuclear transfer research say they would withdraw their objection.
   The moral argument for human embryonic stem cell research A different moral argument is made by people who support embryonic stem cell research using nuclear transfer. Many agree with opponents of such research in saying that human embryos never should be created experimentally and then implanted in a woman's uterus with the goal of creating a "cloned" human being. They argue, however, that it is immoral to prohibit the research using tissue from a legal abortion, in vitro fertilization or nuclear-transfer experiment, if slowing down research is likely to delay the day when embryonic stem cells can save human lives.
   The legal realities There are two legal realities in the United States that affect the argument over the morality of using embryonic stem cells. The first is that abortion has been deemed legal by the U.S. Supreme Court -- under certain conditions. The second legal reality is that in August 2001, President George W. Bush allowed federal funds to be spent only on a few lines of human stem cells already in existence. The result is an inadequate supply of stem cells. No use of embryonic stem cells to treat human disease is possible without a lot more research. Many scientists have argued that the human stem cell lines available before August 2001 are too few and too fraught with risks to be very useful for serious research.
  
   Could Scientific Research Change the Ethical Argument? There seems little likelihood that the ethical arguments will change as long as research or practice involves the use of embryonic stem cells. However, there are three possibilities that could make the ethical conflict irrelevant. If specialized cells from humans could be tricked into turning back into the embryonic stem cells from which they first came, then this too would eliminate the need to collect embryonic stem cells from embryos. Recently, sperm cells in the fruit fly were tricked into reverting back to the stem cells from which they had developed. If adult stem cells could be given the same ability as embryonic stem cells to turn into virtually any tissue, then there would be no need for embryonic stem cells. Recently, some adult stem cells called "multipotent adult progenitor cells" have been discovered that may have greater potential than most adult stem cells.
   However, it is too early to know if this potential will be realized. Finally, it is even possible that specialized cells may be coaxed into reproducing themselves. Recently, Harvard researchers found that, in mice, the insulin-producing cells of the pancreas can do so. If other specialized cells could be similarly coaxed, and if this could happen in humans as well as in mice, it could also negate the need for embryonic stem cells. Nevertheless, most scientists believe that the greatest potential for the future of human health comes from embryonic stem cells, and urge that the federal ban on embryonic stem cells be lifted. At the same time, those experts also point out that there is much more to learn before stem cell therapy can be broadly available for humans. They caution that, even under the best of conditions, it is likely to be decades before the great potential is realized.