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Stem Cell Research: What's at Stake

Two years ago U-M announced the opening of the U-M Center for Stem Cell Biology at LSI. Center Director Sean Morrison discusses progress with his research, the Center, and the current state of stem cell research.

Let's start at the beginning—why is stem cell research important?

Stem cell research is an interesting and important place to be scientifically because there are many fundamental scientific questions to be addressed. And there are many questions that impact on the future of medicine.

What are the questions your research seeks to answer?

My lab focuses on the regulation of self renewal. One of the defining characteristics of stem cells is their ability to divide to make more stem cells, and this property is what underlies their ability to make massive numbers of cells of interest. How a stem cell divides throughout life to make more stem cells is a fundamental question in cell biology. You have blood forming stem cells in your bone marrow that make new blood cells throughout life, in part by dividing to make more stem cells and perpetuating themselves.

My lab tries to identify the genes that are required in this process, because if we can identify the genes and what they do to promote self renewing divisions, we can understand more mechanistically what exactly is happening. That is important because if we could better promote self renewal, we may be able to promote regeneration after injury, for example. We may be able to address certain kinds of birth defects that are caused by premature depletion of stem cells. Cancer is a disease of dysregulated self renewal. When cancer is caused by genetic defects, stem cells inappropriately activate or hijack the normal self-renewal mechanisms to form a tumor. Each time we identify a new gene we understand something new about normal development—as well as how those mechanisms can go wrong to cause cancer or other diseases.

These are hard questions and most of the things researchers try don't work, but when you give yourself an opportunity to cure somebody, you don't know up front whether it will work or not. If it works some of the time, then people will be alive who might not be alive otherwise.

What are the links you've discovered between stems cells and cancer?

We learned that cancer cells hijack the mechanisms that normally regulate stem cell self renewal to proliferate out of control. If you try to target these mechanisms, to develop drugs that interfere with these pathways in a cancer cell, these drugs often kill normal stem cells too. One of the tragedies about leukemia is that people often die from the therapy because it is toxic to normal blood-forming stem cells. In an ideal world you'd like to target only those things that kill the cancer cells without harming the normal stem cells. And so we identified an example of this, and also in fact identified a drug that's already FDA-approved for other purposes that is incredibly effective, at least in mice, at killing leukemic stem cells. We plan to go into clinical trials at the University of Michigan hospital with patients we know we cannot cure with current treatments and testing whether adding Rapamycin to their current therapy would cure them. That will be really amazingly cool!

Will you clarify the differences between the stem cells types?

Stem cells have different properties at different stages of life. Embryonic stem cells only exist at the earliest stages of embryonic development, when embryos are microscopically small and they have the ability to make every cell type in the body.

Fetal stem cells are tissue specific stem cells, which in fact are adult stem cells in fetal tissue. They include fetal blood forming stem cells, fetal skin stem cells, and so on.

Amniotic stem cells characterize a population of fetal cells that is not at all well worked out, but those cells are different from embryonic stem cells and at this stage there is no evidence that they have the ability to make every cell type in the body.

Umbilical cord blood cells are blood-forming stem cells and have been used to restore the blood-forming system in children after treatment for leukemia. They are useful but they don't have the capacity to make new brain cells or cell types in other tissues.

So is one stem cell better for research than another?

There are many different types of stem cells out there and the whole conversation about which stem cell is better, for example, if we should work on adult or embryonic cells, is a political artifact. There is no stem cell biologist out there who thinks in those terms. All of the stem cell biologists that I know believe that work should continue on all types of stem cells because we can't predict at this stage which ones are going to be the most useful for which diseases. We want to be able to pursue all the options to use all the weapons at our disposal.

I'd like to emphasize that people shouldn't buy into this political framing of adult versus embryonic. All the scientists and physicians believe that we should be pursuing both types of stem cell research because it's not a question of good and bad. All types of stem cells have different properties, unique advantages and disadvantages, and there are some things that we can do with adult stem cells that we can't do with embryonic and vice versa. All scientists that I know want to pursue research with both.

How did this research become framed as controversial?

Journalists often come up to me and say that embryonic stem cells is really a controversial area. In fact among people that really understand the work, there is very little controversy. Among the experts in the area, including physicians, ethicists and scientists, there is broad agreement that first, the work should be done, and second, they agree about the guidelines that should be pursued to do the work ethically.

This is most clearly illustrated by the fact that the head of the National Institutes of Health broke from the President and testified before Congress that embryonic stem cell research was critical to the future of medicine in the United States. He said that current federal restrictions put in place by the Bush administration where slowing the pace of that research and hampering the ability of the NIH to fund the most important science.

Then why is there opposition to this research?

There are political groups who frame the story in a different way. They try to create fear in the minds of the general public about science fiction scenarios like creating Frankensteins and other horrors and of course none of that is true. In-vitro fertilization is a mainstream fertility practice that most people in our society have no moral problem with. I think that stem cell research will be much the same in 20 years after it becomes possible to treat a disease with the products of embryonic stem cell research.

The public also hears about the adoption option, is that viable?

There are more then enough embryos thrown away each year to put all the embryos up for adoption that anyone would ever want and to make all the embryonic stem cell lines that anyone would ever want to make. The fact is that for every embryo that is actually put up for adoption, there are 100 more that are thrown away. The reality is that almost nobody out there wants to adopt other people's embryos, furthermore, most people who have leftover embryos from in-vitro fertilization are not comfortable with the idea of putting their embryos up for adoption.

A recent study showed that people with frozen embryos were more comfortable with the idea of donating their embryos for use in medical research then they were with the idea of putting their embryos up for adoption.

What is the biggest myth about stem cells?

The single biggest myth related to embryonic stem cells is the idea that opponents of this work try to create, which is that scientists want to divert embryos from reproductive purposes for use in medical research. That's not true. The existing federal and state restrictions are defended because "human embryos are special and need protection under the law," but in fact those restrictions don't protect a single embryo from destruction. The embryos that will be used for research and are currently being used in other states, are already being thrown away and can't be used for fertility purposes. The principle is not to choose between having a baby or making an embryonic stem cell line, the real choice is between throwing away embryos that can't be used for fertility treatment versus using them in medical research that might one day help patients.

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What's new with stem cells?

Recently, stem cell researchers have made revolutionary discoveries that have made headlines around the world.

While it was previously thought that differentiated cells were destined to remain confined to one pathway or somatic cell type, we now know that by inserting only a few select genes into a cell taken from a simple skin biopsy, the cell can effectively reprogram itself to regain pluripotency, meaning they can revert to become any cell in the body.

Three labs have been successful at reprogramming the cellular circuitry of differentiated skin cells of mice, including the Kyoto Univeristy lab of Shinya Yamanaka (who is moving to California), the Harvard Medical School lab of Konrad Hochedlinger and Rudolf Jaenisch's lab at the Whitehead Institute in Cambridge, MA as reported in Nature magazine.

Although attempts to replicate the experiment using human cells have not been successful, the findings from experiments involving the reprogramming of mouse fibroblast cells represent exciting possibilities in the microscopic realm of stem cell research.

Sean Morrison, director of the Center for Stem Cell Biology, views the results of these experiments as a promising forecast of the developments yet to unfold.

"What's exciting about stem cell research is you don't know what's going to come around the corner," he said.

This is especially applicable in the case of Woo Suk Hwang, a Korean stem cell researcher who claimed to have discovered the ability to derive embryonic stem cells through nuclear transfer (therapeutic cloning) but was later found to have falsified research and was ultimately discredited.

After a team of researchers in Boston reviewed Hwang's work, they found that while it was not what he originally claimed, the work did produce the first stem cells found to be produced from an unfertilized egg by parthenogenesis, a process by which an unfertilized egg can be tricked into starting to divide.

Findings like those from Yamanaka's lab, and even Hwang's roundabout experiment, have revolutionary implications for the ethics of stem cell research, and some have said that new procedures such as deriving stem cells from a skin cell or an unfertilized egg have the potential to do away with the need to harvest pluripotent stem cells from human embryos.

U-M's Morrison says it is important for stem cell researchers to be prudent about trying to predict which applications work best.

"We have to continue doing work on embryonic stem cells," he said. Morrison is optimistic about replicating the experiment using human skin cells, and thinks the lack of success at this point may indicate that a different combination of genes is responsible for resetting human skin cells to the pluripotent state.

Recently, Morrison has been working to identify genes required to maintain fetal hematopoietic, or blood-forming stem cells.

Along with LSI Research Fellow Injune Kim, Morrison discovered that stem cells in a developing fetus have unique properties, and can't be grouped into a category with either adult or embryonic stem cells. The team was the first to identify that Sox17 is a critical gene in the regulation of fetal mouse stem cells, but has little or no regulatory effect on adult stem cells. The findings of his lab's research were published in late July in Cell, a key scientific journal.

Ongoing controversy about the way stem cells are obtained typically receives the most media attention, and Congress continues its battle over the ethics of using the discarded remnants of In-Vitro Fertilization procedures to progress embryonic stem cell research.

Although some debates are focused entirely on where researchers obtain stem cells, "it's only a small piece of the equation," according to Dr. Morrison.

For him, a large focus is figuring out how he can use stem cells, whether in transplantation or simply observing them outside the body to understand their mechanisms, or screening for new drugs.

For example, he has already begun thinking about how his discovery with fetal blood-forming stem cells can be applied to diseases like childhood Leukemia. As the mysteries of stem cells begin to unwind, many theoretical solutions have been predicted in the lab. "The actual work on how to treat a disease still needs to be done," Morrison says.

When it comes to Juvenile Diabetes, a disease that affects about one in every 400 to 600 children according to the National Diabetes Information Clearinghouse, stem cell researchers have been able to successfully generate fully differentiated normal insulin-secreting cells.

But many challenges remain before this information can be translated into a cure.

Researchers must now figure out how to transplant new functioning insulin-secreting cells into a patient and avoid the wrath of an immune system that has detected a foreign intruder.

Morrison said he hopes there will be areas such as this that will "lurch forward unexpectedly because of a few key discoveries," such as was the case in Yamanaka's most recent discovery.

"It's one of those areas that is moving much faster than people thought it would," he said.

For Morrison and his associates, a deep exploration into the cellular culprits of neurodegenerative diseases is one area that they plan to vigorously investigate, in hopes that they will experience such a leap in progress.

Morrison has been working in this area for years and collaborates with Sue O'Shea to figure out how to coax stem cells into becoming components of the nervous system, the region of the body that is devastated by diseases like Parkinson's, Huntington's, and Alzheimer's. These diseases affect millions of individuals around the world, but most are currently untreatable.

Recently, Morrison has been finalizing consent documents to obtain stem cells with genetic defects that cause neurodegenerative disease, but the process has been difficult because of Michigan's restrictive state laws restricting embryonic stem cell research.

In 2001, Bush's presidential veto left only a few viable lines of embryonic stem cells in the National Institutes of Health stem cell registry available for federal funding. These lines are extremely limited in genetic diversity and none have the right genetic background to model neurodegenerative diseases.

But because Morrison's lab is funded largely by a private foundation, he can apply to obtain embryonic stem cells that were created in other states like California that are not approved for federal funding. Although it may be a time-consuming process, he does not expect resistance to his requests. Nonetheless, the need to depend on scientists in California is one important reason why the state restrictions on embryonic stem cell research that are currently in place in Michigan put Michigan researchers at a great disadvantage relative to scientists in other states, and slow progress in this area within the state.

— Arikia Millikan, senior majoring in Psychology in at U-M and Michigan Daily reporter

Learn more about stem cells: www.lifesciences.umich.edu/research/featured/tutorial.html

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Stem Cell Researcher Joins LSI

Dr. Ivan Maillard joined the Life Sciences Institute as a Research Assistant Professor July 1. He is also an Assistant Professor Dept. of Internal Medicine, Division of Hematology/Oncology and the fourth faculty member of the U-M Center for Stem Cell Biology.

"Ivan was the top young stem cell biologist in the country on the job market last year. We had intense competition from other research universities that were also trying to recruit him," said Sean Morrison, Director of the U-M Center for Stem Cell Biology.

"He has done important work characterizing the mechanisms that regulate the maintenance of blood-forming stem cells in the bone marrow. Beyond this fundamental research, Ivan is also a physician, a hematologist/oncologist. We look forward to tapping his expertise as a physician-scientist to further our goals of translating stem cell discoveries to help patients."

Dr. Maillard earned his MD-PhD program at the Swiss Academy of Medical Sciences, University of Lausanne, Switzerland and worked on the interaction of Mouse Mammary Tumor Virus with the immune system of its host with Heidi Diggelmann, MD. He completed a post-doctoral fellowship with Warren S. Pear at the University of Pennsylvania, where he subsequently was a fellow and physician in Hematology-Oncology.

Dr. Maillard joined Morrison, Yukiko Yamashita and Cheng-Yu Lee in the Center.

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