A.  What is regenerative medicine, and what role does it play in the field of medical research?

 

            For centuries, medical research has sought to treat injuries and degenerative diseases that lead to organ failure and chronic health conditions.  Many of these conditions are genetic, and have been a leading cause of pain, suffering, and even death for generations of Americans.  From the time of the first blood transfusions in the eighteenth century, medical researchers have sought to replace diseased or damaged tissue through organ transplantation.  Although some initially opposed the concept of organ transplantation on religious grounds, on the basis that it altered the human body as God had made it, nonetheless millions of lives have been saved by heart, lung, kidney and other organ transplant surgeries.  The vast majority of Americans consider it commonplace and entirely moral to alleviate suffering by replacing diseased human tissue with healthy donor tissue.

 

            Organ transplantation has been hampered by long waiting lists for donor organs and difficulties in overcoming the human body’s natural tendency to reject foreign tissue.  As a result, researchers have developed mechanical and synthetic devices that can function as artificial organs and tissues.  These advances were also criticized by a vocal minority on religious grounds, on the basis that the transplantation of artificial organs into patients diminished the dignity of the human body.  However, once again the vast majority of Americans hailed breakthroughs like artificial hearts and insulin pumps for the countless lives that they saved and for the human suffering that they alleviated.

 

Unfortunately, artificial medical devices are not a complete substitute for the healthy organs that they are designed to replace.  In addition, despite advances in nanotechnology, researchers are still struggling to artificially replace human biological functions that occur at a cellular level.  Today the search continues for ways to completely cure damaged and diseased human organs and tissue through artificial replacements.

 

Meanwhile, beginning in the 1970s, significant progress was made in the field of recombinant DNA.  Researchers used strands of human DNA inserted into bacteria to manufacture drugs, proteins and artificial hormones that exactly mimic their parallels in the human body.  For example, for decades diabetics stayed alive by replacing the human insulin that their bodies no longer made with insulin harvested from slaughtered pigs.  Scientists now insert strands of human DNA into bacteria in order to manufacture artificial insulin that is genetically identical to human insulin.  The insulin must still be injected into the patient several times a day, so it is a poor second best to replacing the patient’s damaged pancreas.  However, the genetically manufactured insulin is superior to the pig insulin.  Cancer treating drugs, such as those that boost red blood cell production during chemotherapy, are also manufactured using recombinant DNA.  Not surprisingly, a vocal minority of Americans decried these advances on religious grounds, claiming that they would lead to human cloning laboratories.

 

            The field of regenerative medicine promises to become the endpoint of this long history of medical research.  “Regenerative medicine” applies tissue engineering, stem cell therapy, medical devices and other techniques in order to repair damaged or diseased tissues and organs.  Stem cell research allows us to understand the process of human biology at a cellular level, and is therefore one way that researchers hope to learn how to repair or replace human organs and tissues.  New cells can be created either through the transformation of one type of specialized cell into another or through the growth of specialized cells out of undifferentiated stem cell lines.  The creation of new human organs and tissues, if successful, would mean that seriously ill Americans could be treated with therapies that completely cure their conditions rather than merely treat their symptoms.  It is likely that, as with other medical advances over the centuries, there will still be a minority of Americans who react to these advances out of fear or by making claims that medical researchers are “playing God.”  However, just as was the case with blood transfusions, organ transplantation and recombinant DNA, the majority of Americans fully support these medical advances that have the potential to so greatly improve the quality of life for themselves and their loved ones. 

             

 

 

B.  What are “stem cells?”

 

            Stem cells are “unspecialized” cells that can generate healthy new cells, tissues, and organs.  They are the master cells of the human body that can transform themselves into more specialized cells, that in turn perform a specific bodily function such as making the heart beat or secreting a particular hormone.  In a human embryo, stem cells form four or five days after fertilization of the egg, and they are the precursor of all of the other cell types that will later be necessary for human development.  After birth, stem cells remain in some of our organs, continuing to create specialized cells to replace cells that are damaged or wear out.

 

            A “stem cell line” is comprised of a group of stem cells that are isolated from either an early stage embryo called a blastocyst or from adult tissue.  These stem cells are then placed into a growth culture in a petri dish and induced to self-replicate, generating a colony of cells that continually replaces itself.  Researchers then begin the hard work of learning what factors cause the stem cells to transform into one type of cell versus another.  Although a relatively new area of scientific inquiry, the study of stem cells has already greatly increased our understanding of human cell biology.               

 

 

 

 

C.  What is involved in “stem cell research?”

 

            Researchers engaged in stem cell research seek to learn how to obtain human stem cells and how to induce them to become more specialized cells.  Goals of stem cell research include: a) a better understanding of both healthy and diseased cell development; b) the development of specialized human cell lines that can be used in clinical trials to test new drugs; and c) the eventual ability to grow replacement cells intended for human transplantation.

 

People mean many different things when they use the term “stem cell research.”  Failure to differentiate between these different types of stem cell research often leads to confusion and unnecessary controversy.  The different meanings ascribed to the phrase “stem cell research” involve how the stem cells are derived and how research involving the stem cells is funded.

 

Stem cell research includes:

 

a. Research using stem cell lines derived from adult cell tissue (so-called “adult stem cell research”).

 

b. Research using stem cell lines derived from human embryos (so-called “embryonic stem cell research”)

 

i. Embryonic stem cell lines created prior to August 2001 are eligible for federal funding under both Bush administration and Obama administration guidelines.

 

ii. Embryonic stem cell lines created after August 2001 are eligible for federal funding under Obama administration guidelines.

 

c. Research using stem cell lines derived from donated eggs obtained outside of the fertilization clinic process.  To the extent that this type of embryonic stem cell research is occurring, it is occurring outside of the United States or inside of the United States in privately funded companies.  Within the United States, state and federal funding requirements typically limit government funding to the use of excess embryos created during the IVF process. 

 

d. Research using stem cell lines derived from embryos “cloned” from adult donors (so-called “therapeutic cloning” or Somatic Cell Nuclear Transfer/SCNT).

 

e. Research using stem cell lines derived from adult skin cells that are “re-programmed” to become stem cells (induced Pluripotent Stem Cells or “iPS”)

 

In addition to the above categories of stem cells, researchers have begun to use the expanded knowledge of cell biology derived from stem cell research to experiment with ways to directly transform one type of specialized cell into another type of specialized cell, raising the prospect it may be unnecessary to create stem cells at all.  This process has been labeled “direct reprogramming.” 

           

 

 

 

 

D.  How are stem cell lines derived from adult stem cells?

 

            Adult stem cells are found resident in many but not all body organs.  An adult stem cell line is created by obtaining an adult stem cell from a donor and inducing it to self-replicate in a cultured petri dish.

 

 Researchers have long known that certain fully developed organs and tissues contain within them stem cells that the body uses to generate more specialized replacement cells.  These so-called “adult” stem cells have also been found in umbilical cord blood, menstrual blood, and wisdom teeth.  Adult stem cells have been used for over 40 years in such therapies as bone marrow transplantation.  Adult stem cells are said to be multipotent, meaning that they can transform into a limited number of specialized cell types, usually limited to the cell types that reside in the tissue where the stem cells are found.  In other words, adult stem cells derived from bone marrow may be able to produce different kinds of specialized blood cells, but it is unclear whether they can ever be used to produce nerve or muscle cells.   

 

There are currently several concerns about the wisdom of focusing solely on adult stem cells for future research.  Researchers have yet to find adult stem cells that can give rise to all of the various types of cells and tissues present in the human body.  In addition, adult stem cells are often present in only minute quantities in mature tissues in the body and can therefore be difficult to isolate and purify.  Unlike embryonic stem cells, which are relatively easy to grow in culture, adult stem cells do not appear to have the same capacity to multiply perfectly for long periods of time.  This is an important drawback, as large numbers of cells would be needed for stem cell replacement therapies.  Adult stem cell lines may contain more DNA abnormalities-caused by sunlight, toxins, and errors in making more DNA copies during the course of a cell’s lifetime.  Finally, any transplantation of cells derived using adult stem cell lines into non-donor patients would also require the use of immune-suppression drugs.  While researchers may eventually overcome some or all of these limitations, adult stem cells cannot currently be considered a complete substitute for embryonic stem cells.

 

 

E.  How are stem cell lines derived from embryos?

 

            Embryonic stem cell lines are derived from embryos that are typically obtained from eggs that have been fertilized in vitro (at an in vitro fertilization clinic) and then donated for research purposes with informed consent of the donors.  These donated embryos were not fertilized in a woman’s body, but rather the sperm and egg are united in the laboratory.  If not used for research purposes, most of these embryos would be destroyed.  A 2004 study found that 84% of fertility clinics routinely destroyed unused embryos.  The embryos from which human embryonic stem cell lines can be derived are typically four or five days old and consist of a hollow microscopic ball of cells called a blastocyst.

 

At the time of the union of egg and sperm, the unified cell is said to be totipotent, meaning the cell can develop into any of the three types of tissue (endoderm, mesoderm, or ectoderm) as well as the placental tissues needed for the embryo to implant. As the cell development progresses to two cells, then four, eight, and so forth, it reaches a stage where it is called a morula (“berry” in latin). At about day four, the solid ball of cells begins to transform from a compressed morula into a hollowed-out ball called a blastocyst.  The blastocyst is about the size of the period at the end of this sentence, and it contains a thin ridge of cells.   These are the embryonic stem cells.  A stem cell line is created by removing the stem cells from the blastocyst and inducing them to reproduce in a cultured petri dish.

 

These embryonic stem cells are said to be pluripotent. They can develop into any of the 210 or so different cell types of a human body.  As the blastocyst continues to develop, the cells become even more differentiated and specialized.  Until about day 14, the cell mass could be divided in two and it would result in two viable identical cell masses.  However, after day 14 the cells have become differentiated to the point that, if one were to attempt to divide them, the cell mass would arrest and stop developing.  Also by day 14, the cells have become so specialized that they are no longer pluripotent, but are merely multipotent.

 

            Because human embryonic stem cells are able to differentiate into any cell type in the body, researchers believe that they hold enormous promise as either direct treatments for a host of chronic diseases —including diabetes, cancers, heart disease, and numerous neurodegenerative conditions — or as laboratory targets against which drugs could be screened to develop new pharmaceutical treatments for those same diseases.  Their plasticity, and their durability as self-sustaining cell lines that self-replicate over long periods of time, comprise the primary advantages of embryonic stem cells.  For example, researchers have been able to use embryonic stem cells to create large quantities of red blood cells, raising the prospect that one day blood drives may be unnecessary.   

 

Self-perpetuating embryonic stem cell lines were first successfully isolated from humans and cultured by Dr. James Thomson at the University of Wisconsin in 1998.

 

 

 

 

F.  What is the technique for deriving iPS lines from skin cells that was announced in November 2007?

 

            In November 2007, Dr. James Thomson of the University of Wisconsin, along with a second team under the direction of Dr. Yamanaka in Japan, announced that they could create cells that behave like embryonic stem cells by adding a cocktail of four genetic factors to an adult human skin cell.  Their technique converts routine body cells, or somatic cells, into pluripotent stem cells (in scientific language, it “de-differentiates” them).  The reprogrammed somatic cells are called “induced pluripotent stem cells” or iPS cells.

The breakthrough involves using four factors — including cancer genes — that are inserted into human adult skin cells using retroviruses as a vehicle.  These factors “re-program” the skin cells with the result that they begin to behave like embryonic stem cells.  These iPS cells appear to have a plasticity similar to embryonic stem cells, although it is unknown whether they are an exact equivalent.   Another potential advantage of using stem cells created via the iPS technique is that there would be no immune system issues should those cells be transplanted back into the patient that donated the skin cells.  However, because this method involves the use of cancer genes and retroviruses to do the reprogramming — agents which can “switch on” cancer genes already present within the body — there is general agreement that such cells could not currently be used to treat patients.  Additional research is necessary in order to find new ways to introduce these factors into host cells.

 

 

 

 

G.  What is “direct reprogramming” of cells?

 

            Dr. Douglas Melton at the Harvard Stem Cell Institute recently announced the successful transformation of normal pancreas cells into more specialized insulin producing cells in experiments using mice.  He achieved these results by using a “cocktail” of proteins to transform one type of adult cell into another.  This process could potentially allow researchers to side-step the entire process of creating stem cell lines.  If this technique can be replicated using human cells, it would also seem to avoid potential problems with transplantation and immune system rejection.

 

            Potential problems with direct programming include the use of a virus as the vehicle for introducing the proteins into the cells.  A non-viral approach needs to be developed to avoid the risk of inducing cancer.  In addition, stem cell lines have the advantage of being self-sustaining and of generating large numbers of new cells.  It is unclear whether this new technique will be capable of producing specialized cells in a sufficient number to be effective.  

 

 

 

H.  In light of these new discoveries, why is it necessary to continue research using embryonic stem cell lines?

 

            While amazing progress has been made on multiple fronts, and all of the research discussed above is exciting, there is simply no way of knowing today which avenue of research will eventually prove to be the best for replacing damaged organs or for developing new drug treatments.  Medical research does not advance by picking a favored approach and limiting resources to that approach – unless there is a sound scientific basis for the decision.  Arguments to favor one form of stem cell research over another are ultimately premised upon religious or political agendas, not scientific data.  It is simply premature to declare that any form of stem cell research is the only form that should receive public support.  All types of stem cell research must continue, and all forms must be adequately funded.

 

            It is striking that both the iPS and direct reprogramming advances were made by researchers applying knowledge that they obtained through their work with embryonic stem cell lines.  All of these forms of research are related, and all contribute to a base of knowledge that is mutually beneficial.  At the same time, we should pause before we automatically assume that all types of stem cells are identical.  At this time we don’t know enough about iPS cells to know whether they are exactly the same in behavior and potential to the embryonic cells that scientists have studied for nearly a decade.

 

            Stem cell lines derived from donated embryos will continue to comprise an important part of the research agenda, even while researchers rush to explore other techniques for obtaining stem cells.  In order to determine whether stem cell lines derived from skin cells are an adequate substitute for embryonic lines derived from embryos, parallel experiments will need to be conducted comparing the longevity and malleability of these two types of stem cell lines.  Funding comparative research requires continued funding for research that uses embryonic lines.

 

Nor should we abandon experiments that are already well underway using existing stem cell lines derived from embryos.  Important knowledge is being gained every day that will be lost or delayed for decades if researchers start from scratch using new lines.  While promising, the iPS and direct reprogramming techniques should not cause us to abandon other efforts.  It would be unnecessary and counterproductive to abandon research that uses stem cell lines derived from embryos, just it would be unnecessary and counterproductive to abandon research already underway using stem cell lines derived from adult tissue or umbilical cords.

 

 

 

I.  What Do People Mean When They Say That They “Oppose the Creation of Embryos Specifically for Research”?

 

 

            This is a phrase that apparently means different things to different people.  Some people understand this phrase to signal opposition to any form of embryonic stem cell research.  This opposition is usually premised upon the religious belief that “personhood” begins upon the moment of the union of the sperm and the egg and that any destruction of the embryo prior to a stage capable of implantation in the womb is tantamount to murder.  It is not possible to reconcile this view with support for in vitro fertilization.  If embryos can be created in the laboratory as part of the process of helping infertile couples to conceive – embryos that are typically discarded after a couple decides to have no more children – then it is not immoral to create embryos as part of the process of curing disease.

 

 Other people appear to use the phrase to signal their acceptance of using embryos obtained from in vitro fertilization clinics but their opposition to the use of embryos obtained outside of the in vitro fertilization process.  A possible alternative source of embryos from IVF clinics is simply to use donated eggs and sperm to create the embryos in the laboratory.  To date, this type of embryonic stem cell research has been limited in the United States.  The United States imposes strict ethical guidelines on the payment of donors for tissue or organs.  Without financial compensation, egg donation may still occur but it is relatively uncommon.  It should be noted that without the transparency and oversight that accompanies federal funding through the National Institutes of Health, there is little hard information concerning the source of the embryos currently being utilized in privately funded research.  Foreign countries do not have the same strict policies against compensating donors as the United States.

 

            It is also possible that some people use the above phrase to signal that they support the use of embryos left over from the in vitro fertilization process, but that they oppose therapeutic cloning which uses eggs obtained from fertility clinics and creates an embryo through the introduction of donor DNA.  Some people equate the word “cloning” with the creation of a child being brought fully to term, despite the fact that stem cell research has nothing to do with the implantation of embryos into wombs or with the birth of children.

 

            Opponents of stem cell research should make clear the basis of their opposition.  It is not possible to have a reasoned debate on health care policy unless the issues surrounding stem cell research are clearly and fairly presented to the public.       

 

 

J.  Why Do Stem Cell Researchers Want to Create Stem Cells Using “Therapeutic Cloning?

 

In therapeutic cloning, also called Somatic Cell Nuclear Transfer (“SCNT”), an embryo is created by combining an unfertilized egg with the DNA of a patient.  The egg is given a charge of electric current to induce cell division and an embryonic stem cell line is then created through the normal process.  The result is to create a stem cell line that shares the patient’s DNA.

 

 The benefit of this process is twofold.  First, any specialized cells created through this process would share the patient’s DNA and could therefore be transplanted into the patient without fear of rejection by the immune system.  Second, researchers can create stem cell lines with known genetic predispositions.  This allows researchers to observe the formation of disease at the cellular level, increasing our knowledge of both possible preventive therapies and also possible drug treatments. 

 

Therapeutic cloning is perhaps the most controversial form of stem cell research in the United States, because some people fear that the embryos created via this process will not be used for research but rather will be implanted in a women’s uterus and brought to term (so-called “reproductive cloning”).  The creation of cloned children will not advance any of the goals of stem cell researchers, and is considered highly unethical by scientists.  Supporters of embryonic stem cell research favor of a ban on reproductive cloning, but oppose attempts to use broad definitions of the word “cloning” as a means of banning therapeutic cloning.

 

To date, only private dollars have been used to fund this kind of research in the United States, although some foreign countries do support this research with tax dollars.  Under current guidelines at the National Institutes of Health (NIH), no federal dollars are available to fund research using stem cell lines derived through therapeutic cloning.   

 

 

K.  What are the potential uses of stem cell research?

                       

Many diseases and injuries result from the destruction, damage, or depletion of essential groups of cells within our bodies. For example, diabetes can result from the destruction of insulin producing cells in the pancreas.  Heart disease can damage the muscle cells that pump blood through the body.

 

Stem cells are useful in treating these conditions in at least three ways.  Medical researchers believe that stem cells might someday be used to replace diseased cell populations within patients, effectively reversing the symptoms of a disease and perhaps even curing it.  In the shorter term, stem cells could be used to create colonies of cells bearing illness-promoting genes that can be observed in a petri dish so that scientists might uncover the root cause of medical conditions. Finally, stem cells could be used to screen potential medicines quickly and safely in the laboratory, without exposing human volunteers to experimental drugs.

 

  Stem cell research could lead to treatments and cures for many diseases and injuries including: cancer, heart disease, diabetes, Alzheimer’s, Parkinson’s, multiple sclerosis, ALS, spinal cord injuries, stroke, and more than 70 other diseases and conditions. These diseases and medical conditions inflict pain and suffering upon millions of Americans, their families, and their loved ones.  It has been estimated that the number of chronically ill Americans who can benefit from stem cell research “surpasses 128 million.” 

 

While stem cell research may be costly to fund, paying for the long-term care and treatment of chronic diseases is even more expensive.  Medical costs for treating the symptoms of chronic conditions are skyrocketing.  For example, diabetics often develop kidney failure and require expensive and frequent dialysis treatments.  Alzheimer’s and stroke patients may be unable to care for themselves, necessitating costly nursing home admissions.  Treating the symptoms, effects, and conditions of diseases raises the cost of health care.  Stem cell research holds the promise of uncovering the causes, cures, therapies, and preventative strategies of diseases, which will reduce health care costs over the long term.