Below are answers to several questions that were submitted during Mini-Medical School on Nov. 28, 2006. They were answered by David Crouse, Ph.D., associate vice chancellor for academic affairs and professor, genetics, cell biology and anatomy.

Questions have been grouped when possible and a single answer has been developed to cover the related topics.

If the Bush-approved embryonic stem cell lines are considered too old to be useful in some research, what is the determining factor that makes them still viable in other research? Given that, is there any concern of the accuracy of current research using Bush-approved ESC lines?

Embryonic stem cell lines are notoriously difficult to work with.  The experience gained with the approved but older lines is still useful with respect to understanding the special needs in handling this type of cell.  Some basic biological and molecular characteristics of these cells also can be studied and there is no reason to doubt their “accuracy” in providing useful information for future research.  The main problem with the Bush-approved cell lines is that they were derived in the presence of mouse cells to help nurture the rather finicky embryonic stem cells and are therefore contaminated with non-human materials (newer unapproved ESC cell lines do not have this limitation).  The risks associated with potential presence of one or more mouse viruses makes them completely unsuitable for any transplantation applications.  In addition, the small number of available cell lines are aging, accumulating genetic mutations and gradually reducing in number as they cease to function.  They simply will not last much longer but have been useful tools to understand the unique and potentially important therapeutic applications they may bring.

In pediatric oncology, I’ve been told that patients can get a “cell transplant.”  What exactly is this? Is it comparable to stem cells?

Without knowing more specifics it is hard to be certain about what is meant in this situation.  Many childhood cancers, particularly those related to the bone marrow, blood and immune system can be treated using a stem cell transplant.  In the case of children, this stem cell transplant may come from bone marrow or blood (including cord blood) and it is often collected from a closely related donor (sibling, parent, etc.).  After many years of research, such transplants have now become very successful in many diseases.  Many major medical centers, including UNMC, have active pediatric stem cell transplantation programs.

How could stem cells be used in the field of rheumatology?
 

Rheumatology is a specialized field but it still covers a broad range of diseases, many of them autoimmune in nature.  Among those diseases are a few, like severe cases of rheumatoid arthritis or lupus, which have been treated using bone marrow or blood stem cell transplantation.  The objective of such transplants is to use high dose drug therapy to rid the body of the cells that are attacking their own good tissues and replace them with new cells (derived from the stem cells) that should not have that characteristic. 

Can stem cells be mutated into a more beneficial form of a particular type of cell, e.g. a white blood cell?

Stem cells do not “mutate” in to other cell types but can divide many times and gradually go through a process that we call differentiation whereby their “offspring” become the functional cells that are needed for the replacement of the missing or otherwise defective cells.  As an example, bone marrow stem cells give rise to many types of white blood cells as well as red blood cells and platelets.  Stem cells in the skin give rise to all the cells associated with the skin including hair follicles, sweat glands and other secretory cells.

Is there stem cell research being done that could maybe reverse the effects of radiation from cancer treatments?

Most of the basic knowledge about adult bone marrow stem cells came just after WWII when scientists were trying to understand why radiation killed and how we could treat for radiation injury.  We learned that a major effect of significant whole body radiation exposure can be destruction of the bone marrow stem cells and all of their cellular offspring.  Without those cells you will die.  In the clinical situation, that knowledge is now used in some cancer therapy where doses of radiation or drugs are given that would kill a person without additional treatment but “rescue” is provided by transplantation of normal unexposed bone marrow or blood stem cells that replace the lost cells.  Most clinical applications of stem cell transplantation today use stem cells to reverse the bad effects of radiation or chemotherapy drugs which were used to eliminate the cancer.

Aside from bone marrow transplants for hematopoietic (blood and bone marrow) diseases, what are the data to support cures, literal cures, of human diseases by use of adult stem cells from whatever source?

There are very few diseases or conditions that use adult stem cells for other than the many hematopoietic diseases and/or correcting the side-effects of chemotherapy or radiation therapy. Some congenital metabolic or immunodeficiency diseases have been treated using adult stem cells to correct the defect by providing daughter cells that replace the missing cells or make the enzyme or other product that is missing or defective in the recipient.  There has been some success in using adult stem cells of the skin to “make new skin” in culture. This new skin can be transplanted it to cover serious burn injury or similar defects.  The more severe or chronic diseases (diabetes, Parkinson’s, ALS, spinal cord injury, cardiac damage, most cancers, etc.) are not routinely treated by adult stem cell transplantation but some of those diseases are, or soon will be, the subjects of controlled clinical trials.  Although adult stem cell therapy for hematopoietic diseases is now very routine, it is completely false to state that this latter listing of  diseases are routinely and effectively treated by adult stem cell therapy.

Is there an application for stem cells in people with lung problems due to Alpha-1 antitryopsen deficiency?

We are not aware of any stem cell treatments for the disease this question appears to name.

If a blood cell is malignant, is it still possible to perform a DNA analysis or profile from affected bloods or is it necessary to use non-malignant tissue?

DNA analysis of malignant tissue compared to normal tissue has revealed many important clues about disease classification and relative response to therapy.  We will see much more from such molecular analysis in the future and it is expected to continue to be a major driver in the refinement of therapies which are increasingly also molecular with respect to design.

What is the comparison of relative dollars spent internationally with foreign government dollars compared to the U.S. federal research dollars in ESC studies?  What is the trend line in these studies?

Why is it so important that American scientists are leading in ESC research? Are we so power hungry that we need to be doing this research?

What are the advances in stem cell research in the U.S. compared to other countries, such as those with the most unrestrictive policy guidelines?

What are the implications for the U.S. falling behind in stem cell research?

Will Americans have to leave the U.S. for embryonic stem cell treatments that are developed and patented by scientists in other countries?

Is the rest of the world looking for the United States to get on board with embryonic stem cell research and to provide leadership and oversight? Is it too late for the U.S.?

How much money do you estimate will be made by developing, patenting and selling these stem cell lines that you would like to cultivate?

We are not aware of any public data available on the expenditures of foreign governments on ESC research.  In FY05 (the most recent data available), the National Institutes of Health spent $24.3 million on human ESC research.  That represents 0.08% of the NIH budget of $23.1 billion.  NIH funding has been relatively unchanged for about three years. A detailed summary of the federal regulatory landscape as well as state and international support for ESC research is available. (See the Congressional Research Service Jan 11, 2006 White Paper on Stem Cell Research for more details. Available at: http://digital.library.unt.edu/govdocs/crs//data/2006/upl-meta-crs-8295/RL31015_2006Jan11.pdf ).

One of the advantages of federal support of future ESC research would be to better control the use of ESC research and to possibly reduce the amount of inaccessible intellectual property held by corporate concerns.  Presently, U.S. control of ESC research in the private sector is non-existent while that control over federally funded research is highly limiting.

This country has been a leader in nearly all areas of medical research, which has allowed it to be a major contributor to the health of our citizens and the rest of world.  Indeed, human ESC were first described by American scientists. (NOTE: Some of the proposed federal and state laws would require leaving this country (or this state) to do the research or for treatment with ESC or related cells when they are developed.) Research results have also had direct or indirect effect in many economic areas (actual products, less sickness, better productivity, etc.).  The world has looked to the U.S. to be a leader but it is clear that other countries are more than willing to “fill our shoes” if we are not going to pursue a potentially ripe research area.  Those countries making rapid progress in embryonic stem cell studies include England, India, Japan, China, Singapore, Korea, Australia and several Scandinavian countries. Although it is not too late to change, we are falling behind other countries in ESC research.

Is it more advantageous for or is extended life expected to be much longer if an adult would have an embryonic stem cell transplant versus an adult stem cell transplant harvested by the patient themselves? What are the limitations on the outcomes of both? Just how beneficial is a stem cell transplant to the human body? What does it do?

The above represent a complex set of good questions that are difficult to answer in a short format.  First, there are potentially MANY different kinds of stem cell transplants that may be done for MANY different clinical reasons – almost always, they would be to replace a missing or non-functional cell population in the recipient (e.g., you could be missing the brain cells that produce dopamine, causing Parkinson’s).  In most cases “extended life” would be an expected outcome but, just as important, the patient may desire to alleviate significant debilitating symptoms of their disease rather than “extend life.”  An example of this could be a spinal cord injury that keeps a person in a wheelchair for the rest of their life – which may be long.  They would certainly prefer to be mobile even if it did not extend their lifespan.  Researchers believe that embryonic stem cells may have a longer functional differentiated life in their future compared to adult derived stem cells but the more important difference is their flexibility in producing many different cell types rather than a few different cell types.  On the other hand, ESC derived cells would still represent a tissue mismatch where as adult derived stem cells would not – that may require immunosuppression to manage the possibility of rejection of ESC derived cells in the transplant scenario.

How is UNMC getting the embryonic stem cells that it is using?
 

The ESC used at UNMC come from the NIH-approved cell lines.  They came directly from the labs that isolated them and provide training in the handling of the cells: the University of Wisconsin-Madison and the University of California-San Francisco.

Why not pour all the stem cell resources into adult stem cells, which have been shown to work but we don’t know exactly how? This is opposed to using some of those resources for ESC research, which has been shown to be a poor idea, with no promise and lots of ethical and moral problems?

We support expansion of research with adult stem cells as well as those derived from cord blood, amniotic fluid and other sources but recognize that all stem cells are not the same and those sources have not been shown to work in many diseases.  Anecdotal reports are not the basis for offering therapies. It is scientifically irresponsible to exclude a path of research (excess IVF embryos destined to be destroyed rather casually as medical waste) when we know that the animal research with those sources has shown great potential for these cells.  The great majority of research scientists and clinicians as well as American politicians and other world leaders do not accept the contention that this is “…a poor idea.”  There is clearly a great deal of promise but it comes with a need for seriously considering the ethical issues and probably an acceptance that there will not be an agreement on all points.

If widespread clinical use of embryonic stem cell research is 10-20 years away, won’t we run out of “excess” embryos before then? To keep from running out, won’t we depend upon continued production/creation of more “excess” embryos?

Most embryonic stem cells used in research are derived from excess embryos produced in the process of in vitro fertilization (IVF).  A recent New England Journal of Medicine article (vol 356, pages 379-386, 2007) states that, “In 2003, more than 100,000 IVF cycles were reported from 399 clinics in the United States…” and each of these cycles results in excess embryos.  That is simply an outcome of the way current technology is used for collection of eggs, fertilization, implantation and storage.  Not all of the fertilized eggs will be implanted.  Some will be kept frozen for future reproductive attempts by the couple; some will be lost in the process of thawing and culturing; some may be used by other couples; some will be destroyed at the request of the donor; and some will be specifically donated for research.  Many are currently destroyed as medical waste if “abandoned” or not used by the donor.  In any case, there does not appear to be any slowing of the use of the IVF process and there will predictably be excess embryos that would otherwise be destroyed.

Could embryonic stem cells be used to cure adults, such as an adult with diabetes?

That is one of the diseases frequently mentioned because of the successes of embryonic stem cells in treatment of diabetes in animal models and other experimental situations.  Presently, aside from possible use of pancreas or islet transplantation, diabetes is not cured in humans by adult or embryonic stem cell therapy.

If embryonic stem cells could cure diseases such as diabetes, I feel that only the rich will be able to afford the treatment. Even now diabetic supplies are very expensive. How would the average person be able to afford treatment?

Even in the current environment, there are significant disparities in the delivery of routine, critical and long term care.  Such disparities in medicine are an important problem that needs to be addressed but it is not specific to any new therapy that may be developed from studying embryonic stem cells.  We encourage the open discussion and public participation in solutions to address the health disparities that have been increasingly apparent.

Where are you going to get all of the eggs from to do somatic cell nuclear transfer? Will women be exploited in doing this research?

What are disadvantages with embryonic stem cells, such as tumor formation, rejection and genetic stability?

In using SCNT for people with cancer, shouldn’t there be a concern with replicated cells becoming cancerous?

In cloning, don’t the products still carry the mitochondrial and centrosome elements of the oocyte? Would this still require immunosuppression?

These questions address some points that need attention.  Egg donation is not without risk and clearly must be dealt with appropriately in the case of SCNT.  Although valid informed consent is part of the process when donors are recruited, “payment” for eggs could be coercive if the monetary value is excessive.  For that reason, most ethicists do not recommend significant compensation for donors.  Clearly, there are some altruistic donors that would provide eggs at no cost.  This should sort out in ongoing discussions that have been very public and somewhat heated.  Recall that leftover IVF embryos scheduled for destruction do not require any egg donation beyond that which was needed for the fertility treatment.  (As a side note, some recent studies have shown that “eggs” (as well as sperm) can be differentiated from existing embryonic stem cells and thus may avoid the need for an “egg donor” altogether.)

Tumor formation is probably the most common objection to using embryonic stem cells in any therapeutic application.  Indeed, nobody proposes to use the ESC directly but rather to use cells differentiated from the ESC as the therapeutic agent.  In animal models where differentiated cells have been used, tumor formation has been avoided.  Obviously, that approach has not been conducted in humans.  The concern about rejection, if it is a problem, could be managed in the same way the many allogeneic organ transplants are currently managed.  Genetic stability could be a problem if the cells were kept in culture for prolonged times or subjected to unnecessary agents. If done correctly this should be largely avoided.

As the question notes, some maternally derived mitochondrial DNA would be present in the product of nuclear transfer to an egg.  This DNA is not a significant contributor to the development of surface proteins that would call for immunosuppression if subsequently derived cells were used for some kind of stem cell therapy. That does not mean that the mitochondrial DNA is unimportant and scientists know that epigenetic effects (beyond normal inheritance mechanisms) can be very important in influencing and understanding normal development.

If stem-cell research were to be self-funded, what would the cost to the university be?

Most research programs bring money into Nebraska from the federal government, industry or charitable organizations.  Relatively little is funded by state funds and none of our embryonic stem cell research comes from state resources, if that is what you mean by “self-funded”. Research is a costly investment that seeks new knowledge and translation of that knowledge into practical applications. Typical NIH grants are for $1 million or more and that is for a single project of a single investigator.

Why doesn’t UNMC establish a bank for cord blood? Are we throwing away potential cures?

What is UNMC doing with umbilical cord and placenta stem cells?

UNMC has several researchers who are actively pursuing the applications of cord blood and placenta.  Because of the cost of establishing and running a cord blood bank, those researchers obtain the cord blood from consenting donors on an as-needed basis.  In addition, just this last year, the federal government provided funds to several major institutions across the country with the intent of establishing cord blood banks with available registered and “typed” donations that could be used anywhere.

How was Mini-Med School paid for?  Were tax dollars used?
 

The Stem Cell Mini-Med School program, like all others we conduct, was not paid for by state or federal tax dollars.

Is research equipment that has been privately funded used in federally funded research?

Research equipment at UNMC has been purchased using funds from a variety of sources, federal, state, corporate and charitable.

My wife has M.S. She and many others could not, in good conscience, use any therapies derived from human embryos. Why not make Nebraska a leader in adult and cord blood-derived stem cell research, from which all can benefit and which all can support, rather than diverting funds to embryonic stem cell research?

Not accepting therapies or pursuing them for personal reasons is your right.  Many do not think that you should be able to impose, through law, that personal belief on others.  Some scientists or patients may seek to develop and apply treatments or even cures locally.  Why would Nebraska seek to outlaw a research area and possible therapy when they may become available just across a state line?  By the way, UNMC is already a world leader in adult stem cell transplantation and some of the same scientists who are studying adult stem cells want to study embryonic stem cells. This is not an either-or issue.  Would you want this institution to only offer drugs for heart disease or would you prefer that we also use stents, bypasses and transplants when they are approved and appropriate?  It was not that many years ago that heart transplants and blood transfusions were considered “barbaric” by a vocal minority.  They were very wrong in their opposition.

What do you suggest about how the two groups, both pro-embryonic stem cell research and anti-embryonic stem cell research, be able to co-exist?

It would help greatly if intentionally inflammatory language was deleted from the exchanges.  Sincere and caring scientists and clinicians find the comparison to “Nazi doctors” and “baby killers” as well as other similar terms especially offensive.  I also am sure that sincere and caring opponents of the research do not like being portrayed as “unintelligent religious bigots” or “conservative lackeys”.  The distance between the two groups has been emphasized by exaggerated claims, intentional or not, from both sides. Even if more acceptable language and adherence to truth was present in the discussion, most of us doubt that there is any real compromise where we will all sit around a campfire and sing kum-ba-ya together.