La familia focal ayuujk y los datos de campo

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to person during blood transfusions, the discovery of the ABO blood groups, the recognition of the importance of ABO matching to prevent deadly transfusion reactions, and the discovery of simple ways to keep blood from clotting (Figure 8.1). Today, human blood is routinely used to replace blood lost in accidents, surgery, or childbirth, or to supplement lack of certain blood components.

Figure 8.1 When a person receives blood, it is essential that the ABO blood groups are compatible. ABO Blood Group testing for blood transfusions is illustrated here. Antibodies in the serum (the clear part of blood) form clumps of red blood cells when they come in contact with red blood cells of an incom-patible blood group. For example, the sera of O and B transfusion recipients would cause clumping of red cells from donors whose blood is type A or AB.

Blood is also regularly tested, not just for blood group compati-bility, but also for infections carried in the blood such as human immunodeficiency virus (HIV) and hepatitis B and C viruses.

Early in the AIDS epidemic, before the AIDS virus was identified and a test developed to detect whether a person has been exposed to the virus, patients did contract HIV through blood transfusions.

Today, every unit of donated blood is tested for the presence of HIV, as well as for hepatitis B and C viruses.

But why transfuse blood? If your body is not able to deliver enough blood to vital organs, you can become unconscious and die.

Whole blood is rarely used for transfusions today. Immediate replacement of the fluid volume for substantial blood loss is criti-cal, but a sterile salt solution can be used for this purpose. Blood is composed of both a fluid part and cells. The fluid part of blood, the plasma, contains many different proteins, including disease-fighting antibodies and proteins that help the blood to clot (Figure 8.2). The red cells are the most numerous, but various kinds of white cells are important for fighting infections. The red cells carry oxygen from the lungs to the tissues and take waste carbon dioxide from the tissues to lungs. A substantial loss of red blood cells in an accident or during surgery may require a transfusion of red blood cells suspended in a small volume of salt solution. The proteins in the fluid portion of the blood, which can take the form of fresh frozen plasma or concentrate, may be used to help the blood of hemophilia patients to clot. Platelets—the small bits of cells critical for blood clot formation—are removed from donated blood, stored in a pre-serving salt solution, and transfused into patients who have trouble producing their own platelets because they have blood cancer or are undergoing cancer treatment. Additionally, infection-fighting white blood cells may be obtained from a donor and transfused into a patient who is unable to produce white blood cells. Recombinant drugs to stimulate the body’s ability to form red or white blood cells may also be used in patients.

Despite all the advances in storing or distributing blood, pro-viding life-saving red blood cell transfusions in disasters and on the battlefield remains a challenge because facilities are not readily available for cold storage of large quantities of red cells. Researchers have worked for decades to come up with a red blood cell substitute,

Figure 8.2 A developing blood clot is shown in this picture. A blood clot is made of platelets, membrane fragments of a bone marrow cell, and a network of insoluble proteins, particularly fibrin generated from a precursor protein, fibrinogen, through the work of a cascade of protein clotting factors. Several bleeding disorders result from inherited deficiencies in clotting proteins.

both before and after the introduction of biotechnology techniques that let scientists design protein at will. Scientists focused first on hemoglobin purified from human blood, and then on forms of hemoglobin engineered in the laboratory. Their goal was to come up with a protein that could be dehydrated for storage at room tem-perature and dissolved in a salt solution to provide the life-saving capacity to transport oxygen similar to that of intact red blood cells.

Researchers have even packaged the hemoglobin in a fat and protein sack to mimic the structure of a red blood cell. Despite all the elegant and laborious efforts, no red cell substitute has yet proven safe and effective. Now researchers are analyzing how hemoglobin is tethered inside red cells so that it is efficient at picking up and delivering the oxygen and carbon dioxide as needed.

STEM CELLS

Blood cells are not the only type of cell therapy on the horizon.

Scientists are now working on another type of cell therapy, called stem cell therapy, which would take immature cells and coax them into becoming specialized cells in the laboratory to repair damaged or poorly functioning organs. Stem cells are potentially the raw material that could make medical repairs that are currently impos-sible with drugs. To use these cells, scientists must understand how stem cells have the ability to divide repeatedly without specializing, yet under the right conditions, turn into all kinds of cells: liver cells, heart muscle cells, bone-producing cells, and so forth.

The human body’s entire system of a billion or more cells devel-ops from a single cell—the egg fertilized by the sperm. As this cell divides to form all the different tissues and structures of the growing fetus, the daughter cells become specialized in the kinds of proteins they produce. Think of the entire set of genes as inherited instructions to form more than 100,000 proteins when and where they are needed. Going from the single-cell embryo to the enor-mous collection of specialized cells that make up our body is an

orchestrated process of calling up particular sets of those instruc-tions and manufacturing the proteins as instructed so that the resulting specialized cells can perform particular functions. In very simple terms, the control of the process is what makes a liver cell perform liver functions instead of growing hair. This specialization does not occur in a single step. Instead, it happens as a series of discrete steps that the cells take as they commit to becoming a particular kind of cell. This process of commitment to specializa-tion is called differentiation. The embryo cell, and the cells produced during the first few rounds of cell division, retain the ability to become any type of cell in the body. As the cells of the embryo go through more rounds of cell division, the cells become more specialized and the kind of tissue or organ they can build appears to become more limited (Figure 8.3).

Few things have stirred more debate than the prospect of human cloning—producing an exact genetic copy of a person from his or her cells. There is little or no support for cloning to produce a child, because of both safety and ethical concerns. However, the potential of embryonic stem cells and therapeutic human cloning to provide treatments for a number of devastating and untreatable conditions, such as Parkinson’s disease, has received substantial support and media attention. Animal experiments suggest that embryonic stem cells may be able to provide cells to treat Parkinson’s disease, multi-ple sclerosis, brain and spinal cord injury, diabetes, hearts damaged by heart attacks, and many other conditions. Scientists have suggested that somatic nuclear transfer (SNT) be used to generate embryonic stem cells to avoid the risk that the patient’s immune system will attack and destroy the transplanted cells.

In 2001, President George W. Bush developed a U.S. policy regarding work with human ES cells. He proclaimed a ban on the use of federal funds for work on human ES cell lines that were not generated before August 9, 2001. Federally funded researchers may work on human ES cell lines created before that date. Research on human ES cells is going on without these conditions in several other countries. Several states, including California, have passed laws providing funding for work on human ES cells within the state.

U.S. Policy on Stem Cell Research

Figure 8.3 Specialized cells and tissues in our body develop in stages. The embryo inner cell mass develops into three layers: the outer layer, or ectoderm, that will become skin, eyes, and nerves; the inner cell layer, the endoderm, that develops into the lungs, liver, and the lining of our digestive system; and the middle layer, the mesoderm, that develops into bones, muscle, and blood.

Blood-forming Stem Cells

Scientists have known for a long time that stem cells taken from the bone marrow, the soft tissue inside the hollow part of most bones, can develop into all the different types of blood cells. These blood-forming, or hematopoietic, stem cells are now the most widely used stem cells in medicine. Most types of blood cells survive for only a short time and the hematopoietic stem cells are constantly replacing both themselves and the dying blood cells. Blood-forming stem cells are normally present in very small numbers in the blood, but will increase if a person is treated with recombinant forms of protein growth factors (described in Chapter 5) that dock onto a protein on the surface of the cells and trigger the cells to divide and become mature blood cells. Another source of blood-forming stem cells is the blood in a newborn’s umbilical cord.

Hematopoietic stem cells are used to treat people whose own blood-forming cells fail because of a rare condition called aplastic ane-mia, or to help people who have been accidentally exposed to very high doses of irradiation. Hematopoietic stem cells are most often used as part of the treatment for certain forms of cancer. Sometimes cancer patients are given very high doses of irradiation and/or chemotherapy drugs that destroy the blood-forming stem cells in the bone marrow.

Transplants with the patient’s own blood stem cells that were removed before the treatment, or stem cells from a healthy donor, allow the patient to recover. The transplant process is very simple: The cells in a salt solution are slowly injected into a vein just like a blood trans-fusion. If the blood stem cells come from a donor, then the donor and the patient must share certain inherited proteins to make sure that the donor’s immune system cells will not attack the treated patient.

This condition, called graft versus host disease, can severely damage the intestines, liver, and other organs, and may be fatal.

Multitalented Stem Cells

Recently, scientists have also become very interested in other, more versatile, kinds of stem cells—stem cells that may be able to develop

into many different types of specialized cells. Two different types of cells are the focus of interest, embryonic stem (ES) cells and adult stem cells. The ES cells are found in the very early-stage embryo. Adult stem cells refer to cells found in one tissue that may be able to develop into specialized cells of another tissue or organ. Think of a cell found in liver that, under the right circumstances, might be persuaded to develop into a nerve cell. In the laboratory, ES cells can divide over and over again, under the right conditions, producing many more ES cells that, with the addition of certain chemicals, can change into one of many different kinds of specialized cells. Animal experiments have shown that a single embryonic stem cell can become any cell in the body. Because, as the source of the entire adult body, ES cells can become every kind of cell, they are called ^totipotent.

Adult stem cells are tucked away in specialized tissues and organs, such as bone marrow, skin, liver, fat, kidney, and even the brain. The accepted and established role of adult stem cells appears to be to help maintain the organ in which they are found and to allow that organ to repair itself if damaged. But is the potential of adult stem cells limited to just a few options? Some scientists believe that stem cells in some adult tissues may have the ability, under the right conditions, to become many different kinds of specialized cells and not just the cells of the tissue in which they are found.

That would mean that some adult stem cells, though not totipotent like embryonic stem cells, are pluripotent, meaning that they could change into a number of different types of specialized cells, given the right circumstances.

Stop and Consider

What are the possible uses of ES cells in healthcare? What are some of the scientific barriers to the potential of ES cells? What approaches are being explored to overcome these barriers?

The ability of adult stem cells to become something other than what they were destined to be is controversial. One team of scien-tists has reported that a particularly promising adult stem cell, isolated from bone marrow and called a multipotent adult progenitor cell(MAPC), appears able to develop into many different kinds of specialized cells in the laboratory. Other scientists have not been able to reproduce these results. Additionally, scientists have reported that stem cells found in fat can become muscle cells, nerve cells, or even pancreas cells able to make insulin, under the right laboratory conditions.

Researchers in Germany treated a girl who had a massive skull injury from a fall with bone-repair cells grown from her own fat plus a graft of her own bone. The story is an example of both the heroic efforts made on behalf of a patient when standard treatment fails and also of the uncertainty of whether these uses of the stem cell make a difference. Immediately after the fall, the child had developed increasing pressure in her skull and the surgeons had to remove pieces of her skull bone. They stored the pieces in a freezer for three weeks and tried to use them with plates of titanium to provide a protective covering for her brain. But the repair became infected and the bone graft failed. Next, a team of surgeons and technicians worked in the operating room to build an ingenious and novel graft. They spread a paste made from a piece of the girl’s hip bone onto a mold made of sheets of dressing that would eventually be broken down. They put the paste-covered mold in place, and covered it with more protective dressing. None of this was new technology—but then they added stem cells. During the surgery, they had taken a little bit of fat from the girl’s hip and had isolated stem cells from it. When the molded graft was in place, the doctors injected the stem cells into holes in the protective sheet and then sprayed the whole thing with a sticky spray made from the girl’s own fibrin, a blood protein involved in blood clotting and wound healing. After six weeks, the patched area was strong that the

child no longer had to wear the helmet she had worn for the previous year since her fall. At three months, scans of her skull showed bone formation where the defect had been. This was quite an amazing procedure, but there is no way to be sure that the addition of stem cells made a difference in the result. New methods will have to be developed to track the stem cells to see if they became part of the final graft. Early efforts like these provide hope that it may be possible to incorporate the use of stem cells into complex medical procedures, but like bone marrow transplants in their early days, it will take many years and controlled clinical trials to have full confidence in the role of adult stem cells.

In a general way, the question about the versatility of adult stem cells comes down to whether the library of genetic instructions is irreversibly changed as cells specialize, and whether some parts then become unusable. This is a fundamental question that scientists have been studying for many years, and the answers are not yet certain. It is also a practical question, since if stem cells from one or more adult tissue are pluripotent, then such cells might be taken from an individual and used to repair and replace any, or at least many, of his or her tissues that are not working correctly.

POSSIBILITIES OF STEM CELL THERAPY

Excitement about ES-derived cells has been fueled by several reports of laboratory and animal studies. In Parkinson’s disease, symptoms result from a loss of cells that produce a critical signal molecule. Cells that produce the signal were created in the lab from mouse ES cells. When injected into the brain, they reduced symptoms in mice with a form of Parkinson’s disease. Strains of rats and mice have been developed or discovered that are unable to produce myelin, the fatty insulation that normally covers the nerve fibers of the brain and spinal cord. Injection of insulation-producing cells generated from mouse ES cells produced myelin on the nerve fibers of these animals.

These results raise the possibility that stem cells might provide treatment for spinal cord injury and multiple sclerosis. Several groups of researchers have been able to produce working heart muscle cells from mouse and human ES cells. One study with mouse ES-derived heart cells found that the cells did not substitute for damaged heart cells but did trigger repair of the damaged muscle when injected into a mouse with a damaged heart. Mouse ES-derived insulin-secreting pancreas cells have worked when injected into mice whose own insulin-producing cells had been destroyed, though the experimental diabetes was not entirely reversed. These are just a few of the possibilities currently being studied.

Challenges That Face Stem Cell Research

There are many scientific challenges to the use of either adult or embryonic stem cells, including establishing conditions that will allow scientists to produce large numbers of stem cells in the lab.

Scientists must learn what needs to be done to allow stem cells to increase in number without dying off or changing, and what con-ditions are required to cause the stem cells to turn into one of the different types of specialized cells. Finally, researchers need to learn how to get the specialized cells to go to the part of the body where they are needed and to function correctly. The safety of laboratory-derived specialized cells for treating human disease is also unknown. The long-term safety of these cells has not been tested in animals. Will it be possible to produce specialized cells free of other kinds of unwanted or unnecessary cells? Will the specialized

Scientists must learn what needs to be done to allow stem cells to increase in number without dying off or changing, and what con-ditions are required to cause the stem cells to turn into one of the different types of specialized cells. Finally, researchers need to learn how to get the specialized cells to go to the part of the body where they are needed and to function correctly. The safety of laboratory-derived specialized cells for treating human disease is also unknown. The long-term safety of these cells has not been tested in animals. Will it be possible to produce specialized cells free of other kinds of unwanted or unnecessary cells? Will the specialized