Stem Cell R&D: In Need of Global Harmonization
Deborah M. Shelton, Esq. - Reed Smith LLP
Human embryonic stem cells (hESCs) offer great promise for medicine, including drug development and therapeutic products. Although the global market for hESCs is poised to become a significant component of the pharmaceutical industry, the laws, policies and funding sources for this market sector vary dramatically from country to country, leaving research and development efforts severely fragmented. These vast differences highlight the need for increased global collaboration in order to speed the advance of these promising technologies.
There are three general categories of stem cells—totipotent, pluripotent, and multipotent—each producing cells that can either remain as stem cells or become cells with more specialized functions. Whereas totipotent cells have “total” potential, pluripotent cells, including hESCs, can give rise to nearly any type of cell in the body. All stem cell types can serve as repair systems for the body and—at least theoretically—to divide without limit so as to replenish other cells for as long as the host is still alive.
Currently, however, the actual uses of stem cells to treat human disease focuses on a type of multipotent stem cell—adult stem cells. Such uses include the decades-old practice of transferring blood-forming stem cells (hematopoietic stem cells present in bone marrow, placenta or umbilical cord blood) in bone marrow transplants. More advanced techniques of harvesting adult stem cells are also now used to treat leukemia, lymphoma and several inherited blood disorders, and the clinical potential of adult stem cells is being studied for the treatment of diabetes, advanced kidney cancer and other diseases.
Despite important technological advances in harvesting adult stem cells, their usefulness is constrained by the same limitations that apply to all multipotent cells: adult stem cells cannot develop into all cell and tissue types. Furthermore, adult stem cells are present in only minute quantities, making them difficult to isolate and purify. Adult stem cells may also lack the capacity of hESCs to multiply. Moreover, concerns have been raised that adult cells may contain more DNA abnormalities than hESCs, due to increased exposure to sunlight, toxins and errors that arise from the cells’ having made more DNA copies during the course of a lifetime. In light of these concerns, many scientists have turned their attention to hESCs.
Because they are pluripotent, hESCs have the capacity to generate nearly all of the tissues and cell types of the body and can thus serve as the source for neurons, cardiomyocytes (heart muscle cells), insulin-producing cells, liver cells, pancreatic cells, bone, cartilage, blood vessel and blood cells, skin and many others. Thus, hESCs could be used to repair damaged areas in organs such as the brain and spinal cord, heart, liver and pancreas or as replacement for cells that have been destroyed by diseases such as Alzheimer’s and Parkinson’s. Because of their ability to permit modifications, inactivation or replacement of almost any gene in an embryonic cell, hESCs are also being studied as potential vectors for introducing missing enzymes into diseased tissues—an approach that potentially could treat inflammatory, immune and metabolic diseases, as well as neurological disorders such as epilepsy, pain and depression.
There are two primary sources currently used to obtain hESCs.1 One source of hESCs is frozen embryos donated by in vitro fertilization clinics, which routinely create more human embryos than are needed for fertility treatments and are thus left with excess embryos to discard. These frozen embryos provide the source for hESC lines, which are grown by isolating hESCs from the inner cell mass of a human blastocyst. These embryos are the hESC source that researchers worldwide primarily rely upon today.
Although the use of donated embryos has generated its share of political controversy, including in the U.S., it is the second technique —somatic cell nuclear transfer (SCNT)—that is the subject of even greater global divide. Sometimes referred to as “therapeutic cloning,” the SCNT technique replaces the DNA of a donated oocyte with that of the donor cell.2 The oocyte develops in a petri dish until the embryonic stem cells are removed. Unlike hESCs derived from a donated IVF embryo, the resulting cell line using SCNT is genetically identical to the donor of the nucleus. Therefore, hESCs derived from SCNT can be directed to develop into cells or tissues that could be transplanted back into the donor, avoiding the tissue-rejection problems that frequently arise after transplants. In addition, SCNT technology may offer a way to study the development of disease by observing disease cell lines.
Regardless of which source is used to procure hESC lines—excess embryos from IVF or embryos created by SCNT—the extraction of stem cells destroys the embryo. An attempt to craft appropriate ethical safeguards is what has, in large part, given rise to the fragmented laws, regulations and policies that currently govern hESC research. A brief overview of the laws, regulations, and policies in the U.S., and in select countries of the EU, and Asia is provided here.
The U.S. Picture
Although U.S. law does not prohibit private-sector funding of hESC research, since 1995 Congress has forbidden the use of federal funds for research involving human embryos and, thus, for the derivation of hESCs.3 It was not, however, initially clear whether federal funds could be used on hESC lines that had already been extracted. The 1998 announcement that U.S. researchers had independently cultured hESCs cells culled from human embryos prompted further analysis of this issue. The U.S. Department of Health and Human Services concluded that such research could be federally funded, provided that derivation of the cells was carried out with private funds. NIH issued draft guidelines in December 1999 and final guidelines a year later. The guidelines permitted federal monies to fund research on hESCs, provided those had been derived in the private sector, but restricted all research to cells derived from embryos left over from fertility treatments and with the consent of the donors.4 Upon issuance of the final guidelines, NIH began to solicit, and receive, grant applications for work on hES cells under the new guidelines. A committee was appointed to review the proposals.
All of this changed on August 9, 2001, when President George W. Bush issued an Executive Order restricting the use of federal funds to research performed using those hESC lines already in existence. Under that Order, federal funding can be used for research only on hESCs that satisfy all of the following criteria: (1) the removal of cells from the embryo must have been initiated before August 9, 2001; (2) the embryo from which the stem cell line was derived must no longer have had the possibility of developing further as a human being; (3) the embryo must have been created for reproductive purposes but no longer needed; (4) informed consent for donation of embryo must have been obtained from parents; and (5) no financial inducements can have been offered for donation.
Currently, only some 22 distribution-quality human embryonic stem cells lines are available for federally supported research,5 and concerns have been raised about problems that may limit their usefulness —concerns range from those over the availability of affordable cell lines6 to concerns about the lack of genetic diversity and the possible risks of implantation in humans.7 The latter concerns arise from the fact that most of the cells have been grown in culture with the help of mouse stem cells which could potentially introduce animal viruses dangerous to humans. In early September a new study suggested that the longer the cultivation period for hESCs—and the more cell divisions they undergo—the more mutations build up in genes. Although the results need additional confirmation, the concern is that the apparent propensity for hES cells to mutate over the time would limit the practical life spans of these cells and, thus, their therapeutic value.
The Bush Administration’s intransigence has led Congress to consider legislation that would expand opportunities for federally funded hESC research in the U.S. In May 2005, the House of Representatives passed legislation that would ease Bush restrictions and allow government-funded research on tens of thousands of cell lines taken from frozen embryos donated by couples who have completed fertility treatment and therefore the excess embryos are to be discarded.8 The legislation’s prospects in the Senate improved after Senator Bill Frist (R Tenn.), in a surprising about-face, announced that he would support the bill. Though the Senate is expected to vote on the legislation during this fiscal year, President Bush has pledged to veto it.
Although federal funding in the U.S. is currently limited, a number of states have either enacted or are considering legislation that would provide state funding for hESC research. Perhaps the most publicized of these is California, which recently promised $3 billion in funding for hESC research, including the derivation of hESCs, over the next 10 years. Lawsuits challenging the constitutionality of the California legislation are pending, but the California Institute for Regenerative Medicine (CIRM), the agency charged with overseeing the grants, recently announced the award of its first grant.9
Economic development is also driving other states to consider legislation that would create state funding opportunities for stem cell research. For example, Wisconsin, Illinois, New York, Delaware, Texas, Florida, Washington, and Missouri are all currently considering such legislation. New Jersey has approved $150 million in state funding to build a Stem Cell Institute, and will vote on a $230 million bond this fall that would finance stem cell research over the next seven years. Connecticut recently approved $100 million for stem cell research. In Maryland, a bill to fund hESC research, which would have directed $25 million from tobacco company restitution to research on hECS cells derived from discarded embryos, was narrowly defeated and is expected to soon be reintroduced.
For now, however, because of the limited federal and state opportunities, most hESC research requires private funding. Though the U.S. has attracted a large amount of venture capital compared with other countries, venture capital funding is nevertheless difficult to obtain at these early stages of hESC research. Meanwhile, countries with more supportive policies have reported “exciting advancements” in hESC research.
EU Developments
The positions of EU members on hESC research are diverse, and, consequently, so are the opportunities for government funding.10 Positions adopted in the EU range from permission to conduct hESC research using cells derived from either excess embryos or SCNT technology (with government funding in some countries) to U.S.-style restrictions either limiting hESC research, or, in some cases, banning it altogether. Still other EU countries do not yet have legislation in place.
The UK has one of the EU’s most liberal regulatory frameworks for embryo research, a framework equaled only by Sweden, which has long permitted hESC research with excess embryos and in April 2005 specifically approved production of embryonic stem cell lines using SCNT. In the UK, pursuant to recent amendments to the Human Fertilization and Embryology Act of 1990, hESC research may be done with cell lines derived from either surplus IVF embryos or obtained by SCNT. The Human Fertilisation and Embryology Authority (HFEA) licenses and monitors all human embryo research conducted in the UK and requires all prospective hESC researchers to undergo a rigorous approval process. Under HFEA guidelines, researchers must obtain approval from the local hospital ethical board before applying for a research license, upon which the HFEA inspects the quality of the science, the researchers’ justification for using human embryos, the scientists’ compliance with the law, and the scientists’ compliance with proper patient consent procedures. Stringent fines and up to 10 years of imprisonment can be imposed for those convicted of reproductive cloning.
In 2004, the UK established a national stem cell bank to serve as a repository for human stem cells of all types, supplying researchers worldwide with research- and clinical-grade cell lines from embryonic, fetal and adult sources. The bank plans to begin soon distributing cells, free of charge, to any researcher in the world. The Medical Research Council co-sponsors the Stem Cell Bank and will invest $30 million in stem cell research, which will be distributed in a number of grants awarded to universities throughout the UK. Meanwhile, the UK’s Department of Health is working with other countries to establish global standards for hESC, and the Dept. of Trade and Industry is working on collaborative R&D proposals.
France, on the other hand, has adopted stricter limits on hESC research, permitting use only of those cells derived from excess embryos no longer needed for IVF. Additionally, all hESC research must focus on major therapeutic advances not attainable through alternative means. Responsibility for overseeing this legislation falls to the Procreation, Embryology and Human Genetics Agency, which also provides guidance in the approval of hESC research protocols as well as monitors and assesses embryo research protocols.
Of those EU countries that allow some hESC research, Germany has perhaps the strictest constraints in the EU, permitting hESC research only on cell lines derived outside the country and imported into Germany, and even then, only for lines derived prior to 2002. Other significant administrative hurdles hamper hESC research in Germany and include extensive vetting, reporting and tracking requirements that can delay the authorizations necessary for importing compliant hESC cell lines. Finally, several EU countries, including Cyprus, Estonia and Maltado, do not currently have in place specific legislation governing hESC research.
What’s Happening in Asia?
Asian countries have been drawing increased attention as major players in stem cell research. Singapore has promulgated regulations, under the Regulation of Biomedical Research Act, permitting use of state funding for research on surplus IVF embryos and even SCNT on a case-by-case basis.11 Singapore reportedly spent $500 million on its “Biopolis Asia,” a 2 million-square foot biomedical campus that opened in 2003.
India shares UK-style policies on stem cell research and is investigating potential for collaboration. The biotech industry in India is projected to grow tenfold in the next five years, spurred, in significant part, by stem cell research and development. Nearly all stem cell funding in India is government-sponsored, though those funds total only approximately $5 million a year, with very little venture capital financing available. Limited financing from the private sector is attributable, in part, to uncertainty about time-to-market as well as the lack of clear regulatory guidelines for stem cell technologies. In addition, the lack of clear regulatory guidelines also hampers coordination between researchers, as do regulatory issues associated with insignificant infrastructure to perform the critical quality control and to develop good manufacturing protocols in cell therapy.
Stem cell research is also burgeoning in China, which now has a growing pool of capable researchers, many with U.S. training. Currently, there is no national regulation governing hESC research. The majority of China’s stem cell research funding comes through the government—agencies like the Ministry of Science and Technology and the Chinese Academy of Medical Science.
In Japan, the use of surplus embryos as a source of hESC has been permitted since 2001. Moreover, in December of 2003, a governmental science panel recommended that human embryos be used and created for research to combat serious hereditary diseases, provided a regulatory body is appointed to oversee the research.
In sum, hESC research holds the potential to make significant contributions to the treatment of human disease around the world, and, consequently, is projected to become a key segment of the pharmaceutical industry. But producing viable stem cell lines is clearly the first step. The current lack of global harmonization is impeding progress, and in the coming years, the patchwork of regulatory schemes and limitations on funding sources will likely become an even more formidable obstacle. Attention to developing a global approach to hESC technologies is critical to the full potential of hESCs being realized as quickly and efficiently as possible.
About the Author
Deborah M. Shelton is a food and drug attorney with Reed Smith LLP, a law firm based in Washington D.C. She specializes in FDA regulatory and litigation matters that affect the pharmaceutical industry. More info: (202) 414-9229; E-mail: dshelton@reedsmith.com
Footnotes
1. A third potential source of hESCs was also recently announced, but this research is in its very early stages. In August, a Harvard University study was reported as having converted skin cells into embryonic stem cells without using a new embryo or human egg.
2. Recently, hESC research and development in South Korea received a lot of media attention as a result of the announcement that a researcher there had, using SCNT, created the world’s first hESCs that genetically match sick or injured patients.
3. In the 1995 appropriations bill for the National Institutes of Health (NIH), Congress specifically proscribed use of federal funds for the creation of human embryos for research purposes, or for research in which human embryos are “destroyed, discarded, or knowingly subjected to risk of injury or death. . .” This provision has carried over each year to subsequent appropriations bills.
4. Many of the principles that were set forth in these guidelines are similar to those subsequently developed by the National Academies of Sciences. The latter are voluntary guidelines that are designed to encourage responsible practices in hESC research, regardless of the source of funding. See Committee on Guidelines for Human Embryonic Stem Cell Research (1995).
5. The stem cell lines that are available for federally funded research are listed on the NIH Stem Cell Registry at http://stemcells.nih.gov.
6. Stem cell lines purchased by researchers remain the property of the provider of the stem cell line. The researcher purchasing the stem cell lines may then negotiate a material transfer agreement with the cell providers in order to specify their rights and responsibilities concerning resulting data, publications, and potential patents.
7. Congress has asked NIH whether the mouse feeder component of eligible hESC lines would affect clinical research in this area. In its discussions with the NIH Stem Cell Task Force on this issue, FDA has stated that cell lines grown on human feeder layers are not necessarily safer for clinical trials than stem cells grown on mouse feeder layers, because either mouse or human feeder layers could harbor pathogens transmissible to the hESCs grown on them. In either case, then, FDA would need to evaluate safety issues, such as the characteristics of the stem cells, the method of derivation of the cells, the properties of any feeder layer used to propagate the cells, potential contaminants introduced through the media or sera used in culture, and the presence of infectious agents transmitted from feeder layer cells to cultured hESCs.
8. Stem Cell Research Enhancement Act of 2005 (H.R. 810).
9. The award will create the CIRM training program in Stem Cell Research, a 3-year program to train pre-doctoral, postdoctoral and clinical fellows at institutions in the State of California.
10. The EU nations that currently allow the procurement of stem cells from excess embryos are Belgium, Denmark, Finland, France, Greece, the Netherlands, Spain, Sweden, and the UK. Belgium, the Netherlands, Sweden, and the UK also permit the procurement of stem cells from SNT. In Austria, Ireland, Lithuania, Poland, and the Slovak Republic, hESC research is prohibited entirely. Germany and Italy prohibit the procurement of hESCs, but allow research using hESCs imported from other countries. Several other countries have no specific laws on the issue.
11. As in the UK, reproductive cloning is strictly prohibited in Singapore. It carries $100,000 fine and 10 years in jail.
