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La Terapia Celular. Tutorial sobre las células madre recogido de "Nature Reports. Stem cells"
Stem cells have a great but still uncertain medical potential. They offer scientific insights into how animals grow and develop and how some diseases might be treated. Here we define them, describe how they are studied, and sketch their potential and the controversies that surround them.
What are stem cells?
How does a fertilized egg develop?
What are the major types of stem cells?
How do tissue-specific stem cells produce specialized cells? What is the stem cell niche?
What makes embryonic stem cells special?
How are embryonic stem cell lines made and grown?
Why do scientists need many lines of embryonic stem cells?
Can stem cells from one tissue be grown into many other types of cells?
Can embryonic stem cells be tailor-made for certain patients or diseases?
What’s the difference between cloning embryonic stem cells and cloning a new organism?
Are stem cells hard to grow?
How can stem cells advance medicine?
What ki1nds of stem cells are being tested in humans?
What are some risks of stem cell therapies?
What’s the relationship between stem cells and tumors?
Who says stem cell research is wrong? Who says it’s right?
Can embryonic stem cells be made without destroying embryos?
What policies govern stem cell research?
1. What are stem cells?
Stem cells build tissue when and where it's needed.
Without stem cells, wounds would never heal, your skin and blood could not continually renew themselves, fertilized eggs would not grow into babies, and babies would not grow into adults. Stem cells are quite unlike the specialized, or differentiated, cells in your body — such as the nerve cells, muscle cells and blood cells that enable you to function. In contrast, they are the body's silent reserves. At any given moment, many of the stem cells in your body won't be doing very much. They will only spring into action when you need either to produce more stem cells or make more of other, specialized types of cells. And they're not just found in people. All multicellular organisms, from plants to humans, need stem cells.
Usually, when a stem cell divides into two, one daughter cell goes on to make a more specialized type of cell, or even gives rise to several different cell types. The other daughter cell remains a stem cell, ready to produce more stem cells when they are needed. Only stem cells have this versatility, although some fully specialized cells, such as liver cells, can divide to give more cells exactly like themselves.
A fertilized egg is the ultimate stem cell, as it is the source of every type of cell in the body, from oxygen-carrying red blood cells to electricity-conducting nerve cells and throbbing heart muscle cells. But of course this doesn't happen all at once. As the fertilized egg divides to make an embryo, cells become specialized gradually.
Within three to six days after a human egg is fertilized, it has grown into a ball of a few hundred cells called a blastocyst. Within this ball lie a small number of cells that will go on to develop into the embryo. Scientists have learned to extract these stem cells from a thickening in the blastocyst called the inner cell mass and to grow them in the laboratory. These are known as embryonic stem cells or ES cells, and they have the potential to produce all the cell types in the human body. When a blastocyst implants in a woman's uterus, the cells of the inner cell mass will keep on dividing and differentiating into the earliest types of embryonic cells. Human ES cells in culture are not created from eggs that have been fertilized inside a woman's body. They come from the inner cell masses of 'spare' blastocysts that have been created in the laboratory as part of in vitro fertilization (IVF) programmes.
Less than three weeks after a human egg has been fertilized, these most flexible of stem cells have disappeared and embryonic cells become gradually more restricted in their potential. Instead of dividing to make one more specialized daughter cell and a back-up all-purpose stem cell, later embryonic cells are more likely to make two types of more differentiated cells when they divide. At this stage, the embryo's cells have 'committed' to become one of three general types of tissue that each has distinct types of stem cells. Many of these persist into adult life. As embryonic development continues, cells become even more specialized, forming recognizable tissues such as heart, muscle and blood.
In adults, dozens of stem-cell types have been described; more remain to be discovered. These stem cells are called tissue-specific as they will normally only replace one particular tissue. They are also sometimes called adult stem cells. The best understood are the stem cells that grow new blood cells, those that renew the skin, those that renew the gut lining, and those that can grow new skeletal muscles. Stem cells in the bone marrow make blood cells and have been used therapeutically for years. These are the cells that make it possible for a bone marrow transplant to renew a person's complete blood system.
Scientists across the world are trying to figure out exactly what these stem cells are capable of becoming in the lab and in the body; right now, however, tissue-specific stem cells appear to be specialists, quite good at making a few types of cells. Stem cells found in bone marrow naturally make new red blood cells and new white blood cells, for instance, but not new brain cells, at least, not robustly. Stem cells occurring in the brain make new neurons plus the cells that support them, but they don't seem to make muscle cells.
2. How does a fertilized egg develop?
An adult human contains trillions of cells of more than 200 types. All these cells (plus the many, many more cells that are shed throughout life) can be traced back to the fertilized egg, the one cell that can, ultimately, create every type of cell in the body.
The most versatile stem cells occur earliest in life. As a fertilized human egg divides, it first becomes a solid ball of cells, the morula. Next, about five days after fertilization, it becomes a hollow ball, the blastocyst. The cells of the outer layer of the blastocyst eventually form part of the placenta. Inside the ball is a small clump of cells, the inner cell mass, that will form all the tissues in the body. When isolated from blastocysts created by in vitro fertilization (IVF) and grown in culture, these are the cells known as embryonic stem cells (ES cells).
The floating blastocyst takes another day or so to attach to the wall of the uterus and begin to draw nutrients from it. The basic structure of the placenta forms in about three weeks.
Well before then the embryonic cells are already "too old" to make ES cells. They have already become committed to more restricted fates. The initial flat sheet of embryonic cells folds and twists and grows to form a recognizable embryo, with a rudimentary head and a central cavity surrounded by three "layers" of cells. The cavity lengthens to form the gut. Cells in the innermost layer, the endoderm, make the lining of the gut and associated organs like the pancreas and liver. Cells in the middle layer, the mesoderm, form pretty much everything else on our inside: muscle, bone, heart, and kidneys, and all the connective tissues in between. Those cells in the outermost layer, the ectoderm, become skin and brain.
By about eight weeks after fertilization, all the major structures and tissues of a human body, including the heart and even the eyelids, are in place, although they've still got a lot of developing to do. The result, less than 4 centimetres (1.5 inches) long, is now called a fetus.
As pregnancy continues, stem cells become more and more specialized. Fetuses and adults have many types of stem cells, but each type generally makes fewer different kinds of cells than stem cells from earlier stages in development. The so-called bronchoalveolar stem cells found in the lungs in adults, for example, make only cells found in particular parts of the lung.
Stem cells are broadly classified as either adult or embryonic. Technically, even stem cells that come from fetal tissue or umbilical cord blood are classified as adult stem cells, and so most researchers prefer the term tissue stem cells for all stem cells other than those from embryos.
Embryonic stem cells (ES cells) are obtained by extracting cells from very early embryos — at the blastocyst (hollow ball) stage — and growing them in laboratory dishes. Human ES cells are generated mainly from blastocysts that are the result of in vitro fertilization for assisted reproduction, but are not needed for implantation into the mother. In some countries, such as Britain and the United States, the parents can donate these 'spare' blastocysts for medical research.
Adult stem cells are also called tissue-specific stem cells because each type of adult stem cell produces only a limited set of specialized cells characteristic of a particular tissue — epidermis, blood, and so on. In adults, tissue-specific stem cells are located throughout the body. The so-called hematopoietic stem cells in bone marrow and umbilical cord blood, which make all the different types of blood cells, are the easiest to isolate, and have been used in therapy for decades — as bone marrow transplants for diseases such as leukemia, where the normal development of blood cells has gone awry.
Other types of tissue-specific stem cells are usually found deep within tissues and are harder to get at and harder to study, especially in humans. Familiar examples are the epidermal stem cells which continually renew the outer layer of the skin as it gets worn away, and the epithelial stem cells in the gut, that are similarly continually replacing the gut lining. More recent discoveries are of bronchoalveolar stem cells from the lungs of adult humans, which are thought to renew the lining of parts of the lungs, for example. And adult stem cells have been found in the inner ear in mice that could be involved in renewing cells involved in balance sensing. But even when cells are discovered that appear to behave like stem cells when grown in the laboratory, it's hard to know whether they act like stem cells in the body, because their natural behavior is hard to observe.
Stem cells know when and how to act through 'conversations' with other cells. An ecosystem of surrounding cells — a stem-cell niche — both keeps stem cells in their self-renewing state and guides their differentiation into specialized cells.
The short answer is that we don't fully know what kicks most stem cells into action. Many adult stem cells seem to divide quite infrequently, just ticking over to keep their numbers constant. Even in tissues that are being constantly renewed, like the skin, most of the cell proliferation that produces the new specialized cells takes place among the immediate progeny of the stem cell. Not surprisingly, injury is one stimulus that can start stem cells producing specialized tissue cells for replacement.
It usually takes several cell divisions for the progeny of a stem cell to become fully differentiated cells. Along this line will be cells that can still give rise to several different cell types but have lost the ability to maintain a supply of unspecialized stem cells. Such cells are called progenitor cells. Whether to classify a cell as a stem cell or a progenitor has spurred many a squabble among scientists, largely because it's hard to determine experimentally exactly what these cells can do.
In some cases, the frequency with which stem cells throw off specialized cells seems to be guided by an internal 'clock', which might perhaps be tracking the number of times the stem cell has divided. But stem cells also take cues from their environment, such as the temperature, and whether they are attached to something or floating free. Most important, stem cells communicate with the other cells that surround them — the stem-cell niche. The cells send signals back and forth, and in some way we don't yet fully understand, the stem cells go where they need to go and become what they need to become, whether in the developing embryo or the adult. Whether researchers can provoke or mimic these signals sufficiently precisely to use stem cells for repairing the damage to tissues that occurs in neurodegenerative, cardiovascular and other diseases still remains to be seen.
Stem cell niches control whether, when, how, and in what directions stem cells divide. Scientists working to understand and reproduce niches in Petri dishes draw much of their language and theories from ecology.
Stem cell niches exist across plants and animals and are source of tissue repair and regeneration.
Embryonic stem cells can, in theory, produce any type of tissue in large quantities. Researchers use these cells to study development and disease and, hopefully, to find treatments.
Within 6 months, the two or three dozen cells taken from a single embryo can generate millions of embryonic stem cells. That gives scientists enough cells to complete and repeat experiments and allows them to ask questions about disease that would be impossible with other kinds of cells.
Embryonic stem cells are easy to isolate and purify, at least in comparison with most tissue-specific cells, which exist in vanishingly small numbers deep within tissues. Although human embryonic stem cells can multiply in the lab for years without differentiating into more specialized cells, these cells are believed capable of forming every kind of cell in the human body, given the right conditions. (Mouse embryonic stem cells have been demonstrated to form every kind of cell in a mouse.)
Human embryonic stem cells are made from 4- to 6-day-old embryos that have been created in laboratories, usually fertility clinics. The inner cells from the ball-shaped embryos are isolated and placed in a dish along with the nutrients they need to grow.
Embryonic stem cells are currently made from very early preimplantation embryos originally created for in vitro fertilization, although researchers are working on other techniques. These embryos, or blastocysts, are hollow balls of cells with a small thickening at one side. With the right combination of skill and luck, scientists can separate these cells, place them in laboratory dishes and grow them. This process destroys the embryo.
The inner cells are placed in sterile dishes with the nutrients they need to grow. In a matter of months, the 30 or so cells collected from each blastocyst can divide to make millions and millions of embryonic stem cells. All the embryonic stem cells generated from a single embryo are called an ESC line.
Making a cell line is easier said than done. Most attempts to grow human embryonic stem cells fail. When the cells do grow, scientists must make sure that the cells have the correct number of chromosomes and pass a series of other tests for characterising them. For example, the cells must be able to form all three major types of tissue.
Scientists want to have a variety of stem cell lines so that they can pick the best ones for their experiments. Some lines are better suited for becoming pancreatic cells, others for neurons (no one is sure why). Moreover, older cell lines are harder to grow, and many contain mutations and chromosomal abnormalities.
Some of the most exciting embryonic stem cell lines are those that could closely model human disease. A mechanic hoping to understand a jet engine would be unhappy given a helicopter to study, but scientists studying human diseases routinely resort to studying artificial, animal equivalents of disease. Experiments with appropriate human cells could reveal information that experiments with mice could not.
In 2003, scientists in the UK created stem cell lines using embryos from fertility clinics that would otherwise have been discarded because they carried mutations for genetic diseases. These lines, along with cell lines created elsewhere in Europe, carry mutations for Huntington's, cystic fibrosis and other genetic diseases. Scientists hope to grow these stem cells into tissues afflicted by the disease, the better to assess and perfect treatments. (As of April 2007, none of these lines are eligible for U.S. government funding.)
As of mid-2007, most embryonic stem cell lines are not considered good enough for human trials, though at least one company, in Singapore, is working on lines for exactly this purpose, and other researchers in other countries hope to derive therapeutic-grade cells from older lines.
Over a dozen countries have derived stem cell lines. Depending on the application they are intended for, some lines are better than others.
Every embryonic stem cell line is genetically distinct. Like the embryos they were made from, the lines are either male or female. Embryonic stem cell lines have also been created and grown under a variety of conditions. For all these reasons, stem cell lines behave differently in the lab. Some grow faster than others. A few lines are readily coaxed into heart cells, whereas other lines readily differentiate into neural stem cells and still others are particularly easy to maintain in culture.
In the United States, only research on human embryonic stem cell lines created before 2001 can receive federal funding. Of these, a dozen or less are in wide use. Many of these older lines have accumulated genetic flaws and don't grow as well as newer lines. Most researchers worry that the lines could be contaminated by the animal cells that they have been grown with; many researchers feel the lines don't grow well as newer lines. Moreover, at this time, the lines created for infertile couples reflect little racial or genetic diversity.
Even non-embryonic stem cells might be able to produce many types of specialized cells, but researchers are still trying to work out the details.
Recent studies show that some cells taken from human adult tissues seem capable of growing into many types of specialized cells, even ones that they would not become naturally. This may allow researchers to grow a wide variety of specialized cells for transplant or study.
Below are examples of tissue stem cells that appear especially versatile. The work is exciting, but as with any scientific study, they must be replicated in more laboratories before scientists can fully trust the conclusions. Scientists working with these versatile cells regard embryonic stem cells as the gold standard for gauging cells' ability to transform into other cell types.
Amniotic fluid stem cells. Human placentas seem to contain a particularly powerful source of stem cells. These cells appear easy to grow in the lab, and they can transform into nerve cells, blood vessel cells, liver cells, cartilage, bone and cardiac muscle—almost as many types of tissues as embryonic stem cells. The work still must be confirmed by independent laboratories.
Multipotent adult progenitor cells. Scientists report that these cells within the bone marrow can form all three of the major categories of tissue. Some aspects of this work have been replicated in separate laboratories, and other aspects await confirmation.
Testes cells. Cells within the testes of mice seem capable of generating an array of different kinds of cells in laboratory dishes, including heart, brain and skin cells. One company claims to have similar results from human biopsy specimens.
In the near term, stem cells that are genetically identical to someone with, say, diabetes or a neurodegenerative disease can be used to study that disease. Eventually, genetically matched cells could mean that patients receiving cell therapies wouldn't need antirejection drugs.
Besides making embryonic stem cells from unwanted embryos, many scientists hope to make embryonic stem cells that are genetically identical to an existing human, a process called somatic cell nuclear transfer (SCNT) or therapeutic cloning. At some point, scientists might be able to use such genetically matched cells to help replace or supplement a patient's failing organ, like the cells of the pancreas that secrete insulin. Closer to hand, scientists could work to understand how genes and environment collude to cause disease. (For example, custom-made stem cells from a person known to have, say, a degenerative disease, could be tested under different conditions or with different drugs to find which keeps the cells most healthy.)
Suppose researchers wanted to make embryonic stem cells genetically identical to Monya Baker, editor of Nature Reports Stem Cells (or any other individual, male or female). They would first collect some cells from Monya, most easily from skin or blood, and a large supply of unfertilized human eggs (from Monya or anyone else). Researchers would replace the nucleus of one of the eggs with the nucleus from one of Monya's cells. Next, they'd prompt the egg to divide again and again for a few days until it became a blastocyst. Then, they'd make embryonic stem cells just as they are made from unused embryos in fertility clinics.
Right now, that attempt would almost certainly fail. In fact, in one of the biggest scientific scandals of this century, scientist Woo-suk Hwang faked data, claiming to have achieved this anticipated breakthrough when in fact he had not. As of April 2007, no one has been able to perform the technique described above, which is called SCNT, nuclear transfer or therapeutic cloning. It has worked, however, for sheep, mice, cows, monkeys and other mammals, and there is no overwhelming theoretical reason why it should not work for humans; it just seems to be particularly challenging technically.
Therapeutic cloning creates a line of embryonic stem cells genetically identical to an individual. Reproductive cloning creates a new organism genetically identical to an individual.
Unfortunately, the word 'cloning' has multiple meanings. When a single embryo is split, forming identical twins or triplets, this can be called cloning. But so can copying a single gene.
Some people object to making human embryonic stem cells by nuclear transfer for two reasons. One is that it currently requires destroying an embryo. The other is that it creates an embryo that presumably could be implanted into a woman and grow into a baby. This technique, called reproductive cloning, has been successful for a dozen or so mammalian species, but attempts still fail more often than they succeed, perhaps because placentas fail to form properly. One team recently reported vastly improved cloning efficiency in dogs: the team was able to create 167 embryos through nuclear transfer. These were transplanted into surrogate mothers, and three live pups were born. In earlier work, it took 1,095 cloned embryos to produce two live-born pups, one of which died just after birth.
Reproductive cloning for humans has been banned in several countries (though not formally in the United States), and mainstream scientists consider it unethical, not least because it would almost certainly result in many miscarriages and severely debilitated offspring.
Difficulties in growing stem cells stymie research. Consistent conditions for growing stem cells will mean that more informative experiments can be performed in less time, and also that experiments done by scientists in different laboratories can be compared more easily.
Photo credit: S. Alden, Getty
Growing or "culturing" stem cells is difficult, largely because no one knows exactly what nutrients the cells need. All recipes for growing stem cells include a suite of proteins. These large, complex molecules are made by and purified from cultures of other cells. Other nutrients come from serum, a blood extract that is added to stem cells. Still more components are produced by other cells that grow in the same dish with the stem cells. These "feeder cells" are typically fibroblasts, the most common cells in connective tissue like cartilage and ligaments.
The first techniques reported for culturing human embryonic stem cells grew them over a layer of mouse fibroblasts bathed in calf serum. That was in 1998. Since then, researchers have figured out how to grow cells without serum and feeder layers, but they are still trying to work out exactly what nutrients embryonic stem cells need and how necessary nutrients vary under different conditions and with different cell types.
Researchers worry that contaminants from animals would mean that cells derived from embryonic stem cells could not be transplanted safely into humans. The cells could carry viruses or pathogens. Some researchers believe that human cells that have grown for years without animal products are free of harmful contaminants. Others favor human embryonic stem cells that have never been grown with animal components. However, these cells are not eligible for U.S. federal funding because they were created after August 2001, when President Bush declared that any embryonic stem cell lines created after that date would be ineligible for federal funding.
Human stem cell lines have been created and grown in a nutrient broth whose ingredients were highly defined and contained no animal products 2006,. However, both lines had chromosomal abnormalities, leaving researchers still unsure exactly what should be included in the recipe and why.
One reason why culturing human stem cells (both embryonic and adult) has been difficult is that research from other animals doesn't always apply to humans. For example, proteins that keep mouse embryonic stem cells from differentiating actually do the opposite to human embryonic stem cells, prompting them to differentiate into specialized cell types. However, human stem cells can be difficult to obtain and manipulate; experiments on human embryonic stem cells often require oversight by ethics boards and face funding restrictions, so new techniques tend to be developed first in mouse cells and then adapted to human ones.
Whether mouse or human, growing stem cells in culture is tricky. The proteins that stem cells need must be processed and stored carefully. Even then, the proteins vary from batch to batch. That makes testing different recipes difficult. And even getting all the right ingredients is not enough. Stem cells also need the right physical environment to grow. They must be attached to something, a complex web of support materials that scientists call the extracellular matrix. Human stem cells also seem to need close attachment to each other to survive and thrive.
Like avante garde architects designing new homes, tissue engineers are experimenting with scaffolding that prompt stem cells to proliferate and differentiate, or not, depending on the goal.
Stem cells could help medicine in three general ways: cell-based therapies, drug discovery and basic knowledge. Cell therapies would use stem cells, or cells grown from stem cells, to replace or rejuvenate damaged tissue. Scientists also want to use stem cells to understand disease and find drugs that might treat it.
Embryonic stem cells could be used to make more specialized tissues that have been lost to disease and injury. For tissues that are constantly replaced, like blood and skin, stem cells would probably be replaced directly. Researchers are also exploring ways to use stem cells to treat diabetes, Parkinson's disease, spinal cord injury, heart disease and vision and hearing loss, among others.
As of April 2007, however, no therapies using cells derived from embryonic stem cells have been tested in humans. The efficacy of stem cell therapies depends on the introduced cells arriving where they are needed and either replacing or rejuvenating damaged cells. They should not contain undifferentiated embryonic stem cells, and either the cells, the patient or both should be treated so that the patient's immune system will not attack the transplants.
As an alternative to cell therapies, some researchers are looking for traditional drugs that would prompt adult stem cells to come out of hiding and replace damaged tissues. In one early study, rats with a strokelike injury had more control over their movement after being treated with a compound that stimulates stem cells in the brain.
Embryonic stem cells could be grown into more specialized cells for screening potential drugs. Cultures of cancer cells are already used for screening cancer drugs, and growing embryonic stem cells into heart, liver or nerve cells could be useful for testing drugs that affect those organs. Ideally, the human cells could be custom-made to represent the genetic diversity and traits typical of people who suffer from the disease being studied. Right now, potential drug molecules are tested first in mice and rats, but results of these animal tests do not always correlate with what happens in humans. Drugs that poison a human liver, for example, might do no harm to a rat's.
Many scientists think that testing pollutants and potential drugs on cells grown from human embryonic stem cells could be more accurate than current tests. This could mean that fewer animals would be killed for research and also make research faster and cheaper. However, if such experiments are to work, scientists will have to develop techniques to make sure that the cells and culture conditions remain constant; otherwise, differences between experiments could be due to factors other than the drug candidates being tested.
Bone marrow transplants containing blood stem cells are used routinely for blood diseases such as leukemia. Almost all stem cells currently in clinical trials are from the blood and bone marrow.
Many so-called stem cell therapies from bone marrow are actually mixtures of cells rather than pure stem cells. However, at least one company hopes to begin a clinical trial in spinal cord injury using neural cells grown from embryonic stem cells. Another company recently started a clinical trial using neural stem cells from fetal tissue.
Hematopoietic stem cells (HSCs) are found in bone marrow and create all types of blood cells: red blood cells, B and T lymphocytes, natural killer cells, neutrophils, platelets and more.
This type of stem cell was the first stem cell to be used medically. When a patient receives a bone marrow transplant during treatment for leukemia or other diseases, it is these cells that give rise to the new blood supply. Partly because samples containing these cells can be readily (albeit painfully) collected from individual patients, they are being explored for a variety of potential therapies. Therapies use a patient's own cells or cells from donors that, from a white blood cell's perspective, resemble the patient. Otherwise, the patient's immune system may attack the transplanted cells. Experimental therapies are trying to use purified populations of HSCs or looking for drugs that can cause a patient's own HSCs to proliferate without a transplant.
Mesenchymal cells (also called bone marrow stromal cells) are also found in bone marrow. They make many types of cells including bone cells, cartilage cells and fat cells. Like hematopoietic cells, mesenchymal cells are one of the few adult stem cells that can be obtained reliably. Mesenchymal stem cells are being explored in clinical trials for liver disease, heart disease, Crohn's disease and others. Like HSCs, these trials typically use a patient's own cells.
By adding hormones and other ingredients to the lab dishes, mesenchymal stem cells are grown in them. Scientists have been able to make a variety of more specialized tissue from these cells, including cells that appear to be nerve cells, skin cells and muscle cells. However, these cells are not understood as well as HSCs.
- Cord blood cells
Stem cells in a baby's umbilical cord can be collected right after birth. Cord blood mainly contains HSCs and can be used to treat leukemia and other blood disorders. HSCs from cord blood do not require painful bone marrow extraction. Because babies' immune systems are immature, the cells are less likely to be rejected by a recipient's immune system than those from an adult donor. However, recipients of mismatched cord blood can still reject the transplanted cells, and the amount of HSCs in cord blood is too small for widespread clinical applications. Treating an adult or large child would require cord blood from multiple births; alternatively, scientists must find a way to encourage the cord blood stem cells to expand in culture to form many more of themselves.
Nonetheless, several cord blood banking programs are in progress to match donated blood with unrelated recipients. In 2005, the U.S. National Academies issued a report on the topic. Although many doubt its utility, several private companies also store blood that came from a particular child for future use by that family.
- Neural stem cells
The brain maintains its own supply of stem cells. These cells seem to be able to migrate within the brain and spinal cord and even integrate with existing neurons. In mice, treatments like antidepressants and physiological conditions like exercise can stimulate these stem cells to produce new neurons. Songbirds form new neurons from their stem cells when they are learning new songs to attract mates, suggesting there may be a connection between neurogenesis and learning in humans. Neural stem cells derived from fetal tissues were tested in a clinical trial for Batten's disease in December 2006. In this fatal hereditary disease children's brain cells poison themselves, and the hope is that the transplanted cells will help clear the toxins. As with other transplant trials, subjects are taking drugs to keep the implanted cells from being rejected.
No one knows exactly what will happen when an experimental therapy is tried in humans.
In the twentieth century, many patients died as researchers struggled to perfect organ transplant techniques. Even today, while some transplants are routine (such as kidney), they are still not without risk. Researchers working on stem cell therapies (both embryonic and nonembryonic) worry that transplanting foreign cells could trigger an overzealous attack by the immune system (like a firefighter flooding a house for a piece of burnt toast). Another worry is that stem cells could start to grow in unexpected ways or places, establishing the wrong tissue in the wrong place.
The least regulated area of human research consists of treatments that infuse a person's own cells back into that person's body—bone marrow cells into the heart, for instance. Some scientists worry that these cells, introduced to a new environment, could do more harm than good, whereas others think even a small benefit is worth the risk and that waiting for additional studies in animals delay procedures that can benefit patients. Versions of this debate recur for all innovative therapies.
In most countries, therapies that would give patients cells from sources besides their own bodies must be tested in animals extensively before researchers receive permission to test the therapy in humans.
Like some stem cells, cancer cells can grow without pause. Some cancers use stem cells' tricks to do this, and so some cancer researchers study stem cells.
One test to determine whether a cell is an embryonic stem cell is to inject it into a mouse. Mouse tissue and embryonic stem cells will interact so that the embryonic stem cells form a bizarre, non-cancerous tumor, called a teratoma. Teratomas contain all the different tissue types embryonic stem cells can become. Though rare, these tumors occur spontaneously in the testes or ovaries. They can grow hair and even teeth.
Just as no hostess would serve milk with flour and call it cheese with crackers, embryonic stem cell therapies would not use embryonic stem cells directly. Instead, embryonic stem cells would be first grown into more specialized cells, say neurons (for diseases like Parkinson's or multiple sclerosis) or pancreatic cells (for diabetes). Of course, researchers will have to be certain they can select only the types of cells they want, and perhaps invent strategies to kill any transplanted cells that retain the embryonic characteristics after they are transplanted.
Many different types of cells live in a cancerous tumor, even if that tumor is no bigger than a pea. Cancer stem cells have been identified in leukemia, breast and brain cancers. Researchers aren't sure whether cancer stem cells come from stem cells gone bad or if mature cells somehow acquire stem cell–like characteristics. They also aren't sure whether the same mechanisms that allow stem cells to keep dividing are the same mechanisms that allow cancer cells to keep dividing. The answers probably vary by cancer type.
Recently many researchers have come to believe that cancer recurs when most of a tumor is destroyed, but a few cancer stem cells escape. Researchers are trying to work out how cancer stem cells resemble tissue-specific stem cells. One theory is that treatments that can kill cancer stem cells might leave normal cells unharmed but still eradicate cancer. A major worry is that treatments that kill cancer stem cells will also kill healthy tissue-specific stem cells, as now happens in some chemotherapy.
Some opponents of stem cell research argue that it offends human dignity or harms or destroys human life. Proponents argue that easing suffering and disease promotes human dignity and happiness, and that destroying a blastocyst is not the same as taking a human life.
Laboratory research on adult stem cells is generally uncontroversial. Research with human subjects becomes controversial because some experimental "therapies" could harm patients. Debate can be acrimonious between researchers who want to perform additional studies on animals to try to better understand risks to humans, and those who don't want to delay testing procedures that might help patients.
Most opponents to embryonic stem cell research think that it is wrong to destroy a 2- to 6-day-old embryo, even if it is not destined to start a pregnancy. Others argue that it is immoral not to do this research, if doing so could lead to treatments for disease. The groups disagree as to whether an early embryo deserves the same protection as a fetus or an adult human.
The acquisition of unfertilized human eggs is another area of controversy. The procedure to retrieve eggs from women requires a series of drugs and surgery. Women who donate eggs face a small but real risk of death and are certain to endure discomfort. In most countries, women can be paid to donate eggs to infertile couples, but many ethicists, lawyers and women's rights activists feel that women should not be compensated for donating eggs for research. Other ethicists, lawyers and women's rights activists feel that they should, at least to compensate for time lost from work and other costs to them.
To surmount the supply and ethical problems of acquiring human eggs, some researchers have proposed inserting human nuclei into animal eggs. Any embryonic stem cells derived would not be used for therapies directly but instead used to conduct research that could lead to therapies. Other researchers hope to make research-grade materials through cell fusion or genetically engineering other types of cells.
Regulatory agencies in the UK have launched a public discussion as to whether human-animal hybrids should be created. Researchers must agree not to let the embryos grow past 2 weeks, and the researchers must argue convincingly that their experiments address important questions that could not be answered any other way. However, some people object that mixing human nuclei with animal eggs offends human dignity or that scientists might not follow the regulations set for these experiments.
Scientists are working on ways to make embryonic stem cells without destroying embryos and to make cells that behave like embryonic stem cells. Even if these techniques work, many scientific and ethical issues remain unresolved.
Some people think that destroying an unimplanted blastocyst to make embryonic stem cells is wrong. Some equate it with killing a human being. To overcome these objections, some scientists are working out alternative techniques, like using just one cell from an embryo with 8–10 cells, or removing just a few cells rather than all of them from a blastocyst that is older than typically used. So far, these techniques tend to have lower success rates and have not been proven in humans. Perhaps more importantly, these techniques could unintentionally destroy or damage the embryo, leaving the ethical issues unresolved.
Still other alternatives include making embryonic stem cells that stop developing on their own (called "dead" or "arrested" embryos) or genetically engineering sperm, egg or donor nucleus so that embryos would be unable to move past a certain point in development. These solutions are also problematic: they would require gauging whether development has stopped, or they would require fertilizing an egg, just to destroy it. Advocates of these techniques also assume that a flawed embryo is morally inferior to one that has the potential to continue development. Additionally, whatever flaw stops the embryos from developing could mean that the embryonic stem cells are also flawed. That could make the cells less useful for study.
Another approach is to try to prompt nonembryonic stem cells to behave like embryonic cells, a feat that has been accomplished in mice and humans by fusing adult cells with embryonic stem cells. (These cells have chromosomes from both cells, although there might be ways to remove the extras.)
In reports released in 2007, rapidly dividing adult mouse cells behave shockingly like embryonic stem cells if they are genetically engineered to produce a set of just four proteins. These cells differentiate into many types of tissues and divide indefinitely. If mixed in with an early mouse embryo that then grows into a mouse pup, the engineered cells differentiate into multiple organ types. Whether or not these manipulated cells are as versatile as embryonic stem cells is not yet known, though results look promising.
Policies vary by country, by region and even by university. They govern whether research can be performed or funded on human embryos themselves and cells made from human embryos. Other policies also require researchers to show that certain stem cell therapies are likely to be safe before testing them in people.
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Some kinds of research are ineligible for government research funding; some kinds of research require approval by government or university officials, and some research is banned outright. The specifics vary by country, by region and even by institution. In some countries research materials and tools are covered by patents and so require researchers to obtain permission from patent holders before beginning experiments.
The World Stem Cell Map and an annually updated summary by researchers at Rice University track policies across the globe.
In the United States, scientists cannot use federal funding for research on human embryonic stem cells created after August 2001, when Bush articulated his policy. As of April 2007, attempts by the U.S. Congress to overturn this policy have failed. However, creating new human embryonic stem cell lines and conducting research on them is legal, so long as federal funding is not used.
Scientists in the UK and Australia must receive government permission to use early human embryos to create new stem cell lines. In the United States this research is covered under state laws. Generally, getting permission requires that embryos are acquired with appropriate informed consent, that the experiments promise to yield useful information and that the embryos will not be allowed to grow longer than 2 weeks. Two weeks marks the point when the embryo is no longer capable of "twinning" and so crosses the threshold of individuality.
Fuente: Nature reports. Stem cells.
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