1. What are human embryonic stem cells?
Stem cells are cells that have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit to replenish other cells for as long as the person or animal is still alive. When a stem cell divides, each "daughter" cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.
A more detailed primer on stem cells can be found at /info/basics.
2. What classes of stem cells are there?
There are three classes of stem cells: totipotent, multipotent, and pluripotent.
* A fertilized egg is considered totipotent, meaning that its potential is total; it gives rise to all the different types of cells in the body.
* Stem cells that can give rise to a small number of different cell types are generally called multipotent.
* Pluripotent stem cells can give rise to any type of cell in the body except those needed to develop a fetus.
3. Where do stem cells come from?
Pluripotent stem cells are isolated from human embryos that are a few days old. Cells from these embryos can be used to create pluripotent stem cell "lines" —cell cultures that can be grown indefinitely in the laboratory. Pluripotent stem cell lines have also been developed from fetal tissue obtained from fetal tissue (older than 8 weeks of development).
4.Why do scientists want to use stem cell lines?
Once a stem cell line is established from a cell in the body, it is essentially immortal, no matter how it was derived. That is, the researcher using the line will not have to go through the rigorous procedure necessary to isolate stem cells again. Once established, a cell line can be grown in the laboratory indefinitely and cells may be frozen for storage or distribution to other researchers.
Stem cell lines grown in the lab provide scientists with the opportunity to "engineer" them for use in transplantation or treatment of diseases. For example, before scientists can use any type of tissue, organ, or cell for transplantation, they must overcome attempts by a patient's immune system to reject the transplant. In the future, scientists may be able to modify human stem cell lines in the laboratory by using gene therapy or other techniques to overcome this immune rejection. Scientists might also be able to replace damaged genes or add new genes to stem cells in order to give them characteristics that can ultimately treat diseases.
Healthcare Questions
1. Why are doctors and scientists so excited about human embryonic stem cells?
Stem cells have potential in many different areas of health and medical research. To start with, studying stem cells will help us to understand how they transform into the dazzling array of specialized cells that make us what we are. Some of the most serious medical conditions, such as cancer and birth defects, are due to problems that occur somewhere in this process. A better understanding of normal cell development will allow us to understand and perhaps correct the errors that cause these medical conditions.
Another potential application of stem cells is making cells and tissues for medical therapies. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing a transplant far exceeds the number of organs available for transplantation. Pluripotent stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis and rheumatoid arthritis.
2.Have human embryonic stem cells been used successfully to treat any human diseases yet?
Scientists have only been able to do experiments with human embryonic stem cells (hESC) since 1998, when a group led by Dr. James Thomson at the University of Wisconsin developed a technique to isolate and grow the cells. Moreover, federal funds to support hESC research have only been available since August 9, 2001, when President Bush announced his decision on federal funding for hESC research. Because many academic researchers rely on federal funds to support their laboratories, they are just beginning to learn how to grow and use the cells. Thus, although hESC are thought to offer potential cures and therapies for many devastating diseases, research using them is still in its early stages.
Adult stem cells such as blood-forming stem cells in bone marrow (called hematopoietic stem cells, or HSCs) are currently the only type of stem cell commonly used to treat human diseases. Doctors have been transferring HSCs in bone marrow transplants for over 40 years. More advanced techniques of collecting, or "harvesting", HSCs are now used in order to treat leukemia, lymphoma and several inherited blood disorders.
The clinical potential of adult stem cells has also been demonstrated in the treatment of other human diseases that include diabetes and advanced kidney cancer. However, these newer uses have involved studies with a very limited number of patients.
3.What will be the best type of stem cell to use for therapy?
Pluripotent stem cells, while having great therapeutic potential, face formidable technical challenges. First, scientists must learn how to control their development into all the different types of cells in the body. Second, the cells now available for research are likely to be rejected by a patient's immune system. Another serious consideration is that the idea of using stem cells from human embryos or human fetal tissue troubles many people on ethical grounds.
Until recently, there was little evidence that multipotent adult stem cells could change course and provide the flexibility that researchers need in order to address all the medical diseases and disorders they would like to. New findings in animals, however, suggest that even after a stem cell has begun to specialize, it may be more flexible than previously thought.
There are currently several limitations to using adult stem cells. Although many different kinds of multipotent stem cells have been identified, adult stem cells that could give rise to all cell and tissue types have not yet been found. Adult stem cells are often present in only minute quantities and can therefore be difficult to isolate and purify. There is also evidence that they may not have the same capacity to multiply as embryonic stem cells do. Finally, adult stem cells may contain more DNA abnormalities—caused by sunlight, toxins, and errors in making more DNA copies during the course of a lifetime. These potential weaknesses might limit the usefulness of adult stem cells.
4.I have Parkinson’s Disease. Is there a clinical trial that I can participate in that uses stem cells as therapy?
The public may search a database of NIH-sponsored clinical trials at www.clinicaltrials.gov. Enter the search terms of interest (in this case, Parkinson's Disease and stem cells) to search for applicable clinical trials.
5.Where can I donate umbilical cord stem cells?
NIH cannot accept donated umbilical cord stem cells from the general public. The National Marrow Donor Program maintains a Web page on donating cord blood at http://www.marrow.org/NMDP/cord_blood_bank_list.html, and the International Cord Blood Society has one at http://www.cordblood.org/public/insights.
Research and Policy Questions
1. Which research is best to pursue?
The development of stem cell lines that can produce many tissues of the human body is an important scientific breakthrough. This research has the potential to revolutionize the practice of medicine and improve the quality and length of life. Given the enormous promise of stem cells therapies for so many devastating diseases, NIH believes that it is important to simultaneously pursue all lines of research and search for the very best sources of these cells.
2. Why not use adult stem cells instead of using human embryonic stem cells in research?
Human embryonic stem cells are thought to have much greater developmental potential than adult stem cells. This means that embryonic stem cells may be pluripotent—that is, able to give rise to cells found in all tissues of the embryo except for germ cells rather than being merely multipotent—restricted to specific subpopulations of cell types, as adult stem cells are thought to be.
3. What are the NIH Guidelines on the utilization of stem cells derived from human fetal tissue (embryonic germ cells)?
The Federal Register Announcement National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells (230k PDF; get Adobe Reader), published August 25, 2000, was "superceded as it pertains to embryonic stem cell research" on November 14, 2001). However, Section II. B, titled "Utilization of Human Pluripotent Stem Cells Derived from Human Fetal Tissue," still governs human embryonic germ cell research. In addition, Section III, titled "Areas of Research Involving Human Pluripotent Stem Cells That Are Ineligible for NIH Funding," governs both human embryonic stem cell and human embryonic germ cell research.
4. May individual states pass laws to permit human embryonic stem cell research?
Individual states have the authority to pass laws to permit human embryonic stem cell research using state funds. Unless Congress passes a law that bans it, states may pay for research using human embryonic stem cell lines that are not eligible for federal funding.
5. Where can I find information about patents obtained for stem cells?
The U.S. Patent and Trademark Office offers a full-text search of issued patents and published applications. Try searching for "stem cell" or "stem cells."
Cell Line Availability and the Registry
1. I am a scientist funded by the NIH. How many cell lines are available to me, and how do I get them?
In the third quarter of 2004, there are 22 human embryonic stem cell lines that federally supported researchers can purchase. The cell lines can be purchased by contacting the cell line providers directly. Information on the lines and how to contact providers can be found on the NIH Stem Cell Registry.
In addition, this site provides researchers with a unique NIH identifier code to apply for federal funds to do research using human embryonic stem cells.
2. I'm interested in purchasing more than one cell line from the NIH Stem Cell Registry. What is known about the status of the cell lines and their availability?
Many of the cell lines have been characterized as embryonic stem cells by detecting expression of surface antigen markers specific to embryonic stem cells, determining if the cells are pluripotent, and demonstrating that the cells are undifferentiated. A number of scientific publications have described the characterization of human embryonic stem cells. Although the characterization approaches may differ across laboratories, an example of the strategies used can be found in Thomson et al. (1998), Science, 282,1145–1147.
Providers of the federally eligible cells are working to make them available to researchers. This includes developing quality control measures to grow and reproduce the cell lines in sufficient numbers, having the administrative structure to receive and process requests, and establishing material transfer agreements with research purchasers. The providers of federally eligible cell lines have the most up-to-date information on availability. A list of these sources and contact information is available on the NIH Stem Cell Registry.
3.Who owns the cells?
The stem cell lines remain the property of the individual stem cell providers, as listed on the NIH Stem Cell Registry. Researchers may negotiate a material transfer agreement (MTA) with the cell providers in order to specify their rights and responsibilities concerning resulting data, publications, and potential patents. Examples of MTAs negotiated between the Department of Health and Human Services/NIH and various stem cell line providers are listed by provider at /research/registry.
4.When does NIH anticipate that more stem cell lines will become available?
In the third quarter of 2004, there are 22 human embryonic stem cell lines that federally supported researchers may purchase. This number is up from only one or two lines in Spring 2002. The increased availability of the lines is a direct consequence of NIH's funding of infrastructure awards to support cell providers to develop their eligible lines into distribution-quality, well-characterized cell lines. Up-to-date information on available lines can be found on the NIH Stem Cell Registry.
5.What policies govern use of stem cell lines from WiCell Research Institute?
WiCell has published FAQs About WiCell's Policies on the Use of Its hESC Lines (136k PDF file; get Adobe Reader) to address this question.
Funding Questions
1.Does NIH fund embryonic stem cell research?
Research on human embryonic stem cell lines may receive NIH funding if the cell line meets the following criteria: removal of cells from the embryo must have been initiated before August 9, 2001, when the President outlined this policy; and the embryo from which the stem cell line was derived must no longer have had the possibility of developing further as a human being. The embryo must have been created for reproductive purposes but no longer be needed for them. Informed consent must have been obtained from the parent(s) for the donation of the embryo, and no financial inducements for donation are allowed.
In order to ensure that federal funds are used to support only stem cell research that is scientifically sound, legal, and ethical, NIH examines stem cell lines and maintains a Stem Cell Registry of lines that satisfy the criteria.
2.Are there any areas of research involving human pluripotent stem cells that are ineligible for NIH funding?
The Federal Register Announcement National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells (230k PDF; requires Adobe Reader), published August 25, 2000, was "superceded as it pertains to embryonic stem cell research" on November 14, 2001. However, Section II. B, titled "Utilization of Human Pluripotent Stem Cells Derived from Human Fetal Tissue," still governs human embryonic germ cell research. In addition, Section III, titled "Areas of Research Involving Human Pluripotent Stem Cells That Are Ineligible for NIH Funding," governs both human embryonic stem cell and human embryonic germ cell research.
3.Can a scientist supported by federal funds conduct research with stem cell lines that are not listed on the NIH Human Embryonic Stem Cell Registry?
No federal funds may be used, either directly or indirectly, to support research on human embryonic stem cell lines that do not meet the criteria established by President Bush on August 9, 2001. Cell lines not listed on the NIH Human Embryonic Stem Cell Registry do not meet these criteria. Thus, research on lines (or their derivatives) not listed on the NIH Human Embryonic Stem Cell Registry may not be supported by federal funds.
4.What if a scientist is conducting research with both federally fundable and non-federally fundable human embryonic stem cells?
Scientists who receive federal funds and study both federally fundable and non-federally fundable human embryonic stem cells must charge research costs for study of non-federal lines only to non-federal sources of funding. With respect to indirect costs, such as facilities and administrative (F&A) costs, scientists should adhere to the guidelines in applicable federal cost principles such as OMB Circular A-21 (Colleges and Universities). These documents describe how to keep budget and accounting records so as to prevent federal funds from improperly subsidizing non-federally supported research. These cost principles are also applicable to work on non-federally fundable activities using human embryonic stem cells not included in the Stem Cell Registry.
Technical guidance provided by the DHHS Division of Cost Allocation states that the cost principles and Cost Accounting Standards contained in OMB Circular A-21, particularly with regard to the treatment of activities sponsored by industry and foreign governments, are equally applicable to unallowable stem cell research. The regulations strictly forbid the shifting of costs from these activities to federally sponsored activities. Strict adherence to the principles contained in the circular requires the allocation of indirect costs, also known as facilities and administrative (F&A) costs, to both federally sponsored and other activities, which would include unallowable stem cell research. Federal policy is clear that no federal funding may be used, either directly or indirectly, to support human embryonic stem cell research outside the criteria established by the President on August 9, 2001. Therefore, the direct costs of such unallowable activity must be charged only to non-federal sources of funding. With respect to indirect costs, or F&A costs, institutions engaged in unallowable stem cell research must strictly adhere to guidance contained in OMB Circular A-21. Strict compliance with cost allocation methodologies described in the circular, including the Cost Accounting Standards, will prevent the shifting of unallowable stem cell research costs to federally sponsored programs. The F&A costs, which are allocable to stem cell research falling outside the criteria established on August 9, 2001, will not be charged to federally sponsored activities because the direct costs of such research must be directly charged to non-federal sources of funding. A properly documented F&A proposal utilized in the establishment of F&A rates should demonstrate that none of the costs of unallowable stem cell research or other unallowable activities have been shifted to federally sponsored activities.
5.Who is responsible for setting the policy to allow federal money to be used for human embryonic stem cell research?
As the head of the executive branch of the federal government, which includes the National Institutes of Health, the President of the United States has the final responsibility and authority to set federal government policy for funding human embryonic stem cell research. But Congress has appropriations authority and can possibly override the President's decision.
6.I am a university research administrator. One of our NIH-funded investigators would like to use a cell line that was created after August 9th, 2001, and it is not eligible for research using federal funds. What should I tell the investigator who wants to work with these cells in his laboratory?
Institutions need to provide clear instructions to investigators who conduct research that is "unallowable" under federal research funding policy. In laboratories where there is both federal and non-federal funding, investigators and their staffs must separate allowable and unallowable activities in such a way that permits the costs incurred in the research to be charged consistently to the appropriate funding source. In your example, for instance, the time and effort of laboratory personnel working on the stem cell line created after August 9, 2001, may not be charged to any federal grant. Acquisition of equipment, use of cell and tissue culture supplies in the project, and travel to a conference to discuss or present this work likewise may not be federally supported.
7. I am an investigator who receives NIH funding, and I am planning to derive new human embryonic stem cell lines. Can I conduct the derivations in my laboratory, or do I need to find a non-university-funded laboratory to do this work?
You may do the derivation in your university laboratory as long as: 1) you carefully and consistently charge all direct costs of doing the derivation to a non-federal funding source and 2) your university or research center has in place a method of allocating the costs of supporting your laboratory so that this activity's appropriate facilities and administrative (F&A) costs are charged to non-federal accounts. (See response to What if a scientist is conducting research with both federally fundable and non-federally fundable human embryonic stem cells?)
8. Can you explain what accounting principles are necessary to demonstrate that unallowable charges are not being absorbed by NIH-funded research, e.g., indirect costs?
Guidance is provided in the federal cost principles applicable to the type of organization. Specifically:
* OMB Circular A-21 (Colleges and Universities)
* OMB Circular A-122 (Non-Profit Organizations)
* Federal Acquisition Regulations (Commercial Organizations)
Accounting for unallowable costs is discussed in Circular A-21, Section C.12.e:
All unallowable costs covered by subsections a through d shall be subject to the same cost accounting principles governing cost allocability as unallowable costs. In circumstances where these unallowable costs normally would be part of a regular F&A cost allocation base or bases, they shall remain in such base or bases. Where a directly associated cost is part of a category of costs normally included in a F&A cost pool that shall be allocated over a base containing the unallowable cost with which it is associated, such a directly associated cost shall be retained in the F&A cost pool and be allocated through the regular allocation process.
In Circular A-122, see Section B.3 for unallowable costs and activities:
The cost of certain activities are not allowable as charges to Federal awards (see, for example, fundraising costs in paragraph 17 of Attachment B). However, even though these costs are unallowable for purposes of computing charges to Federal awards, they nonetheless must be treated as direct costs for purposes of determining indirect cost rates and be allocated their share of the organization's indirect costs if they represent activities which (1) include the salaries of personnel, (2) occupy space, and (3) benefit from the organization's indirect costs.
Each organization that receives federal funds on NIH grants and contracts must have in place adequate policies, procedures, and internal controls to provide reasonable assurance that federal funds are not used to support non-federally supported or unallowable costs. These policies are appropriate for work on stem cells lines not included in the NIH Human Embryonic Stem Cell Registry. Organizations will be well served by providing training to staff working with non-registered lines to reinforce these policies and procedures and the need to carefully document the assignment and allocation of costs between federally supported and non-federal projects.
