What is the goal of the Institute for Cancer/Stem Cell Biology and Medicine?

The institute will study the basic biology of stem cells and translate discoveries from this research into treatments for diseases such as cancer, Parkinson’s disease, Lou Gehrig’s disease, diabetes, cardiovascular disease, autoimmune diseases, allergies and neurodegenerative disorders. Work at the institute could help the scientific community understand fundamental processes in biology such as how adult stem cells self-renew and differentiate to regenerate tissues and organs, what genetic processes are disrupted in cancer cells, and how cells with disease-causing genetic mutations develop into those diseases.

Stem cells can also be coaxed to form many different cell types of the body, providing researchers with a way to better understand the function of these cells when healthy and diseased. A primary goal of the institute is to use this knowledge to help treat cancer and to understand the processes involved in cancer development. Stem cells might also be able to replenish healthy cells that are lost because of aggressive cancer treatment.

Who is the director of the institute?

Irving Weissman, MD, the Karel and Avice Beekhuis professor of cancer biology, will direct the institute. In 1988, Weissman became the first to isolate an adult stem cell by developing a method to identify adult blood-forming stem cells found in the bone marrow of mice. He later isolated blood-forming stem cells from human bone marrow and helped identify adult brain-forming stem cells. Weissman’s research has focused on using purified blood-forming stem cells to treat cancers.

What are adult stem cells?

Adult stem cells are cells capable of dividing and replacing damaged tissue. They exist in tissues such as the bone marrow, brain, muscle and liver. Unlike their neighbors, which are already differentiated into specialized cell types, adult stem cells remain immature. When tissue becomes damaged, the adult stem cells divide (a process called self-renewal) to produce new cells. Some of the resulting cells divide, but unlike stem cells they mature to take over for the damaged cells. Within any organ or tissue, generally only the stem cells have the ability to self-renew and appear to be the only cells that regenerate tissues when they become damaged. In the bone marrow, blood-forming stem cells make up only about 1 in 20,000 cells.

What can be learned by studying adult stem cells?

Studying adult stem cells can teach researchers about processes that lead to cancer and other diseases. Most mature cells of the body no longer divide. In many cancerous tissues, genes that block the cell from dividing and direct cells to mature are turned down or off, and genes that stimulate division are turned on. In many cancers studied thus far, a small population of cells, called cancer stem cells, self-renew to replenish the growing cancer. These cancer stem cells can use the same genes that adult stem cells use in the process of self-renewal. By studying adult stem cells to learn more about the genes involved in self-renewal, it might be possible to identify new molecular targets for drug and immune therapies that destroy the self-renewing cancer stem cells.

One important area of research involves learning whether all cancers have cancer stem cells. For each type of cancer, it is also important to learn which genes are used in self-renewing adult stem cells compared with cancer stem cells in that same tissue. Both of these cells are capable of self-renewing, but only the cancer cells go on to grow indefinitely and spread to other organs through the blood stream. If researchers can learn which genes are mutated or used differently in the cancer cells they can develop drugs to block that behavior.

In addition to studying cancer biology, adult stem cells can be used to learn more about the adult tissues from which those stem cells are derived. Researchers have already identified adult stem cells in the brains of mice and humans, and can now use those stem cells to understand how cells of the developing brain differentiate into the many different cell types found in the adult brain. By studying the cells in the lab, researchers may be able to understand what processes go awry in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Researchers at the institute hope to identify adult stem cells from other tissues such as lungs or liver to understand how those tissues develop and what goes wrong when those tissues become diseased.

How can adult stem cells be used to treat disease?

Adult stem cells can be used to replenish damaged tissue. One example of this is in bone marrow transplants, where blood-forming stem cells regenerate the blood of transplant recipients who receive otherwise lethal doses of chemotherapy to destroy all the cancer cells in the body. Stanford was the first institution in the United States to use purified blood-forming stem cells rather than whole bone marrow transplants to regenerate the bone marrow in chemotherapy patients. By using purified stem cells rather than whole bone marrow taken from the patient before chemotherapy, doctors avoid re-injecting patients with their own cancer cells.

Researchers at Stanford are also pioneering the use of blood-forming stem cells to treat type 1 (juvenile) diabetes. In this form of diabetes, cells of the immune system attack pancreas cells that produce insulin. Working in mice, the researchers replaced the cells of the immune system that are prone to autoimmune reactions with healthy adult blood-forming stem cells from a related donor. These cells matured in the bone marrow into immune cells, but lacked the autoimmune reaction. This type of research in laboratory animals could eventually lead to new diabetes treatments in humans and might be extended to other autoimmune diseases such as multiple sclerosis, lupus, and rheumatoid arthritis.

Researchers at the institute hope to isolate adult stem cells from a variety of tissues in addition to the blood and brain stem cells identified so far. Doctors could then give high doses of radiation to destroy tumors in tissues such as brain, lungs or liver, and inject tissue-specific stem cells to replace radiation-damaged cells. Similarly, tissue-specific stem cells could replenish cells damaged by Parkinson’s disease, Alzheimer’s disease, multiple sclerosis or diabetes.

What are pluripotent (embryonic) stem cells? How are they different from adult stem cells?

Pluripotent stem cells have the ability to become any type of cell in the body; “pluri” means many, and “potent” means potential. These cells have the potential to become many different kinds of cells in the body.

Like adult stem cells, pluripotent stem cells are capable of self-renewal, but are unique because they can form specialized cells in any tissue type, whereas adult stem cells from a given tissue appear to only form cells found in that tissue.

Pluripotent stem cells can come from a very early stage of an animal’s development called the blastocyst stage. A blastocyst is a ball of cells that forms after the fertilized egg undergoes seven to nine divisions. It cannot give rise to a developing embryo or fetus unless it is implanted in the uterus. About 17 years ago, scientists learned how to take pluripotent stem cells from a mouse blastocyst and grow them in a lab. These cells could divide continuously in a test tube and go on to form cells from all tissue types. The cell lines that have been created by using this method in mice are also called embryonic stem cell lines.

What can be learned by studying pluripotent stem cells?

Studying mouse pluripotent stem cells carrying disease-causing mutations has already greatly enhanced scientific and medical knowledge of how genetic diseases develop. The hope is that a similar knowledge explosion will take place by studying human pluripotent stem cell lines carrying mutations found in such genetic disorders as cancer, Parkinson’s disease, Alzheimer’s disease, Lou Gehrig’s disease, adult and juvenile diabetes, autoimmune diseases, allergic disorders, and early onset heart and cardiovascular disease.

By studying stem cells that carry DNA with disease-causing mutations, researchers might learn more about how these mutations cause the cell to become diseased. They may also learn how the proteins made by the mutated genes fail to function properly, leading to an understanding of the molecular basis of the disease. This may enable researchers to generate drugs or therapies that make up for the genetic defect and treat the disease. Although this work has great promise, at this time only mouse pluripotent stem cell lines exist that carry disease-causing mutations.

How can pluripotent stem cells be used to treat disease?

At Stanford, pluripotent stem cells have already been used experimentally to treat mice with diabetes. Researchers found a set of growth factors that induced pluripotent stem cells to develop into insulin-producing cells normally found in the pancreas. When they implanted these cells into diabetic mice that have lost the ability to produce insulin, the implanted cells produced insulin in a biologically normal way and treated the diabetes. This work is still in the early stages of being tested in animals, but could one day lead to new ways of treating diabetes in people.

Pluripotent stem cells, like adult brain stem cells, might also replace nerves damaged in spinal cord injuries or cells lost in neurodegenerative diseases. For any of these treatments to work, researchers have to first learn how to grow the stem cells in a lab so they take on the characteristics of the cells they are meant to replace. At this time it isn’t clear whether pluripotent or adult stem cells will be best in this type of therapy.

Inducing stem cells to develop into mature cells in a lab dish might also reduce some of the side effects of using stem cells to treat disease. In early animal experiments using immature pluripotent stem cells to treat disease in animals, the cells often formed tumors called teratocarcinomas. This happened because the cells still had the ability to self-renew and did not all mature into non-dividing cells. In current laboratory experiments, researchers induce the cells to mature into the appropriate cell type before injecting these cells into animals. In the diabetes experiments, the mature, insulin-producing cells produced no tumors in the mice, whereas early experiments with less mature cells produced deadly tumors within a matter of weeks.

What are pluripotent cell lines and how are they created?

A pluripotent stem cell line comes from the pluripotent cells isolated from one blastocyst. These cells can divide in a lab dish and produce new cells – each of which is an exact replica of the original isolated cells – that the researchers can divide into multiple test tubes. A stable, dividing pool of identical cells is called a cell line. Researchers can share these cell lines so that labs around the world can conduct experiments on identical cells. If the cell line comes from a blastocyst with a genetic defect, then many researchers can contribute to understanding how that mutation leads to disease or discover drugs that prevent negative effects of the mutation.

Researchers at the institute hope to learn the best way to create new pluripotent stem cell lines. They will first test several different methods in mice, then apply the most successful technique to human cells. At this time there are two likely approaches to generating the new cell lines:

1. Transplant an adult nucleus into an egg that has had its nucleus removed, stimulate the cell to divide as if the egg had been fertilized, and culture the blastocyst-stage pluripotent cells. This process, called nuclear transplantation, has been successful in mice but has not yet been shown to be successful using human cells.

2. Remove the nucleus from an existing but highly modified pluripotent stem cell line and replace it with a nucleus from an adult cell that carries genetic mutations implicated in human disease. This process has not yet been successful in any organism, but does show promise in mice.

In both approaches, the goal is to take a nucleus from an adult cell and reprogram it to behave like the nucleus of a pluripotent stem cell. The adult nucleus from a skin cell, for example, will use the genes that are needed by a normal skin cell. To become a nucleus in a pluripotent stem cell, that nucleus will need to stop using skin-specific genes and begin using those genes found in pluripotent cells. The first goal of the institute in this research area is to study and accomplish such nucleus reprogramming first in mice, then using human cells.

Why are new pluripotent cell lines needed?

About 70 existing human embryonic stem cell lines are said to exist worldwide. These cell lines came from blastocysts at fertility clinics and not from blastocysts created through nuclear transplantation. While these lines may be useful for some research, they do not carry disease-specific mutations that are of interest to many researchers. By creating human pluripotent stem cell lines that contain the genetic information that predisposes an individual to develop a specific disease, scientists can study the multi-step progression of that disease in many different tissue types. Scientists from around the world, as well as at Stanford, have identified this line of research as a critical part of developing therapies for diseases including cancer, neurodegenerative disorders, diabetes and others.

If human eggs are used to create new pluripotent stem cell lines, where will the eggs come from?

It is too early to know whether Stanford researchers will use human eggs to create new pluripotent stem cell lines. If researchers do choose this method, that work would be subject to review by an internal review board made up of doctors and bioethicists who would analyze the risks and benefits before deciding whether the researchers could move forward and where researchers could get human eggs. If the researchers do move forward with nuclear transplantation into human eggs, one possible source would be immature eggs in ovaries removed surgically during other medical procedures. For these eggs to be useful, researchers at the institute would need to learn how to mature the eggs to be suitable for nucleus reprogramming.

The institute will not use any human eggs, embryos or subjects without a thorough review process and without the donor’s fully informed consent. No biological materials – eggs or embryos – that Stanford currently has in its possession will be used in this research.

Why is creating pluripotent stem cell lines sometimes called therapeutic cloning?

Researchers at the institute refer to the creation of pluripotent stem cell lines as “nuclear transplantation to produce human pluripotent stem cell lines,” while others refer to the procedure as “therapeutic cloning,” “research cloning” or “cloning for biomedical research.”

The wording used by the institute’s researchers has been endorsed by two panels convened by the National Academies to debate cloning and stem cell research, one of which was chaired by Irving Weissman, MD, the director of the institute. The National Academies is composed of the National Academy of Sciences, the National Academy of Engineering, the Institute of Medicine of the National Academies and the National Research Council.

Both panels chose not to use the words “embryo” and “cloning” because of confusion in the public over their meaning. In scientific terms, all stages of development from fertilization up to organ development constitute the embryonic period. However, most people asked to draw an embryo instead draw a fetus with head, limbs, eyes and other identifiably human traits. Likewise, scientists use the word “cloning” every day to describe how they isolate genes; how cancer cells develop from a single cancer stem cell; or to characterize the progeny of a single blood-forming stem cell, or bacterium or virus. But to most people the word “cloning” conjures up images of mad scientists producing fully grown human clones.

For this reason, both National Academies panels chose to use language that accurately and dispassionately describes the nuclear transplantation technique. This language was also supported in a Science article written by the presidents of the National Academies of Science and of the Institute of Medicine.

1. National Research Council, Stem Cells and the Future of Regenerative Medicine (National Academy Press, Washington, DC, 2001). Bert Vogelstein, chair.
http://books.nap.edu/books/0309076307/html/1.html

2. National Research Council, Scientific and Medical Aspects of Human Reproductive Cloning (National Academy Press, Washington, DC, 2002). Irving Weissman, chair.
http://books.nap.edu/books/0309076374/html/1.html

3. Support for dispassionate language to describe nuclear transfer by the presidents of the National Academies of Science and of the Institute of Medicine along with Dr. Bert Vogelstein
Vogelstein, B., Alberts, B., Shine, K. (2002) Please Don’t call it cloning. Science 295(5558):1237
http://www.sciencemag.org/cgi/content/full/295/5558/1237

How is creating pluripotent stem cell lines different from reproductive cloning?

Human reproductive cloning is an effort to create new humans with genetic material identical to that of the donor. The National Academies panel convened to study the issue of cloning and a special State of California panel both voted unanimously for a legally enforceable ban on implanting blastocysts created by nuclear transfer into the uterus of a woman, and therefore against allowing all reproductive cloning. In addition, all researchers involved in Stanford’s institute are vehemently opposed to human reproductive cloning.

In both reproductive cloning and in one method of creating new stem cell lines, the first step involves replacing the nucleus of an egg with a nucleus from an adult cell and stimulating the egg to divide seven to nine times to form a blastocyst. In generating a pluripotent stem cell line, the researchers remove pluripotent cells from the blastocyst. After this procedure neither the blastocyst nor the stem cell line can go on to become an adult animal. In reproductive cloning, such as that used to create Dolly the sheep and other cloned animals, the blastocyst is implanted into the uterus of an adult animal where it can develop.

Reproductive cloning has been used in several different animal species, but in all cases the technique has not been very efficient. In fact, on average more than 99 percent of the implanted blastocysts result in embryonic or fetal death. Offspring born from reproductive cloning also tend to have deformities and, according to some evidence, may age faster than other animals.

What is the controversy over stem cell research?

Research with pluripotent stem cell lines is controversial because, for religious and ethical reasons, some people feel that the blastocysts used to generate the cell lines are fully human and should not be the source of pluripotent cells. They hold this view whether those blastocysts come from fertility clinics or are created through nuclear transfer. If researchers at the institute are able to create new pluripotent stem cell lines by transferring a nucleus into an existing stem cell line, then they will not be destroying a blastocyst. These cell lines would not carry the same controversy as those created through nuclear transfer.

The issue about when personhood develops in an individual cannot at this time be settled scientifically, and so it will remain the subject of controversy and debate.

What are the federal and state laws regarding stem cell research?

No laws are in place regarding research using adult stem cells.

For embryonic stem cells, federal funds can be used only for research involving existing cell lines. However, there are no laws in place that relate to the use of private funding to create new stem cell lines. Both National Academies panels voted that nuclear transplantation to produce human pluripotent stem cell lines was sufficiently important that it should not be banned and should be the subject of a broad debate.

In the fall of 2002, California passed and Gov. Davis signed State Senate Bill 253, calling for research involving the derivation and use of human embryonic (pluripotent) stem cells, human embryonic germ cells and human adult stem cells from any source, including nuclear transplantation, with full consideration of the ethical and medical implication of this research, including a requirement for overview by an approved institutional review board. The legislation promotes the kind of research being conducted at the institute and has created a favorable climate for this type of work in California.

Other states have formed or are in the process of forming their own laws regarding nuclear transplantation to produce new stem cell lines.

1. Report of the California Advisory Committee on Human Cloning
http://www.scu.edu/ethics/publications/adbdreport.html

2. California Senate Bill 253
http://www.aab.org/california%20sb%20253%20stem%20cells%209%2022%2002.pdf

What are the federal and state laws regarding reproductive cloning?

There are no federal or California laws relating to reproductive cloning. Both National Academies panels and the California panel voted unanimously that human reproductive cloning should be banned.

How will work at the institute be funded?

All work relating to the creation of new embryonic stem cell lines will be privately funded or funded by the state of California. The institute began with $12 million in seed funding and hopes to continue recruiting new sources of private funding.

With so much controversy in this field, why is Stanford increasing its efforts in stem cell research?

The formation of the new institute is consistent with Stanford's history of embracing new technologies to aid in the discovery of treatments for catastrophic diseases. Researchers at the institute will be guided by a team of scientists working with legal experts and ethicists at the Center for Biomedical Ethics to continue putting respect for patients first and foremost in the mission of advancing knowledge and improving the lives and health of our world community.

In the end, physicians and scientists have the obligation to pursue the best medical therapies, making sure to do no harm, by translating today’s science into tomorrow's treatments. That devotion to discovery and to translation is the overriding goal of the Institute for Cancer/Stem Cell Biology and Medicine at Stanford.