Tag: and Reporting

Biomedical researchers have created and used animal models containing human cells for decades to gain valuable insights into human biology and disease development. For example, human tumor cells are routinely grown in mice to study cancer disease processes and to evaluate potential treatment strategies. To advance regenerative medicine, it is common practice to validate the potency of pluripotent human cells – which can become any tissue in the body – through introducing them into rodents.

With recent advances in stem cell and gene editing technologies, an increasing number of researchers are interested in growing human tissues and organs in animals by introducing pluripotent human cells into early animal embryos. Formation of these types of human-animal organism, referred to as “chimeras”, holds tremendous potential for disease modeling, drug testing, and perhaps eventual organ transplant. However, uncertainty about the effects of human cells on off-target organs and tissues in the chimeric animals, particularly in the nervous system, raises ethical and animal welfare concerns.

Currently, the 2009 NIH Guidelines for Human Stem Cell Research specifically prohibit introducing human pluripotent cells into nonhuman primate blastocysts and the breeding of animals into which human pluripotent cells may have contributed to the germ line (egg or sperm cells).  Given the direction of the science, however, NIH felt that it was an appropriate time to consider whether further policy provisions regarding other chimera models were needed before making funding decisions. Therefore, as I wrote about last fall, NIH instituted a funding moratorium in September 2015 (NOT-OD-15-158) for research proposing to introduce human pluripotent cells into animal embryos prior to gastrulation stage—the beginning of development of the three germ layers.

Since the moratorium was issued, NIH has reviewed the state of the science and also convened a workshop in November 2015 to bring together leading experts in the field of chimera research and animal welfare.  Today, NIH has published in the Federal Register and the NIH Guide to Grants and Contracts a proposal to make two changes to our policy in this area, for which we are seeking public comment (a table summarizing the proposed changes also appears at the end of the blog to assist stakeholders.) First, NIH is establishing an internal NIH steering committee to provide programmatic input to NIH Institute and Center Directors in making funding decisions for two areas of research in which:

1. human pluripotent cells are introduced into non-human vertebrate embryos, up through the end of gastrulation stage, with the exception of non-human primates, which would only be considered after the blastocyst stage, or
2. human cells are introduced into post-gastrulation non-human mammals (excluding rodents), where there could be either a substantial contribution or a substantial functional modification to the animal brain by the human cells.

NIH is seeking public comment on the proposed scope of the chimera research to be considered by the NIH steering committee. The committee will focus on the experimental design and likely nature of the chimeric animal model. The committee’s work will be independent of the peer review process. This committee will also monitor new developments in this field and provide analysis and advice to NIH leadership as needed.

NIH is also seeking comment on modifications to the NIH Guidelines for Human Stem Cell Research, where we propose to slightly expand the current prohibition on the introduction of human pluripotent cells into non-human primate embryos to include the preblastocyst stage, and to clarify that NIH will not fund research involving the breeding of animals where the introduction of any type of human cell may result in human egg or sperm development.

These actions are consistent with recently updated guidelines from the International Society for Stem Cell Research (ISSCR), which suggest that a specialized review of certain types of chimera research is appropriate. The ISSCR guidelines also contain useful suggestions of best practices for experimental design, which I encourage the research community to consider.

I am confident that these proposed changes will enable the NIH research community to move this promising area of science forward in a responsible manner. I encourage those interested in this field to to add their voice by utilizing the public comment form. While NIH awaits public comment, the moratorium on NIH funding for such research (NOT-OD-15-158) will remain in effect.

Frequently Asked Questions on Chimera Proposal

Draft Chimera Policy Framework

Key Embryonic Stages of Development

Fertilized Egg → Preblastocyst (Morula) → Blastocyst  → Gastrula

Next week, we mark the 40^th anniversary of the first publication of the NIH Guidelines governing experiments using recombinant DNA. On June 23^rd, 1976, former NIH Director Dr. Donald Frederickson announced that all NIH funded and conducted research involving recombinant DNA would be expected to follow the NIH Guidelines, noting both the great potential benefits that could arise from this new technology and the lack of certainty about the risks.

We have come a long way in 40 years, and the use of recombinant DNA is ubiquitous in research, medicine, and many other aspects of our daily lives. Recently, the NIH announced revisions to the NIH Guidelines that included amending the criteria and process for how human gene transfer protocols would be selected for review by the Recombinant DNA Advisory committee (RAC), limiting in depth review and public discussion only for exceptional cases.

Just such an exceptional case comes before the RAC during their meeting this week. During the June 21-22 meeting, the RAC will review a protocol involving the first-in-human use of gene editing via CRISPR/Cas9 technology.  This T cell immunotherapy protocol involves the use of CRISPR/Cas9 to edit two genes in T cells also modified to express T cell receptors targeting myeloma, melanoma, and sarcoma tumor cells.  Consideration of this study underlines the purpose of changing the RAC process: to better use the collective breadth of experience of the RAC members in reviewing gene transfer trials and novel technologies that pose unknown risks, exactly as described by Dr. Frederickson four decades ago.

Researchers in the field of gene transfer are excited by the potential of utilizing CRISPR/Cas9 to repair or delete mutations that are involved in numerous human diseases in less time and at a lower cost than earlier gene editing systems.  While the application of new gene editing technologies in this field has great potential to improve human health, it is not without concerns.  In a previous statement, NIH Director, Dr. Francis Collins, reiterated NIH’s commitment to support innovations in biomedical research in a fashion that reflects well-established scientific and ethical principles.  Having a body such as the RAC available to publicly discuss the scientific, safety, and ethical implications of such cutting-edge experiments helps to ensure we are living up to that commitment.

As the application of biotechnology innovations moves closer to the clinical realm, we are confident that the changes we have made to the NIH Guidelines will enable the RAC to devote its full resources to where they are most needed. And as science continues to evolve, we will strive for parallel evolution in our policies to make oversight of research commensurate with the risks involved.

I encourage you to either attend the upcoming RAC meeting in person, or through the NIH Videocast to learn more about the exciting advances being made in the field of gene transfer.  Information about the RAC meeting, including an agenda and the meeting location can be found on the OSP website.

Posted by Dr. Carrie D. Wolinetz, June 16, 2016

Research with animals, including non-human primates, has enabled the development of treatments and cures for a host of devastating diseases and conditions in humans, and continues to revolutionize our understanding of health and disease.  Because non-human primates are anatomically, physiologically and behaviorally similar to humans, they are particularly valuable for answering some of the most complex questions germane to human health.  These research models have been instrumental to significant scientific and medical advances such as deep brain stimulation to treat Parkinson’s disease, experimental vaccines aimed at preventing the spread of Ebola virus, developing the polio vaccine, and new strategies that improve organ transplant survival today.  Non-human primate research retains a critical position in the biomedical research enterprise.

Equally important to their scientific value is upholding the highest possible standards of animal welfare, including ensuring that a proposed animal model is appropriate to the research and with an expectation of scientific rigor for every experiment. These precepts have been codified in research policy for many decades (https://awic.nal.usda.gov/government-and-professional-resources/federal-laws/animal-welfare-act) and are a central value of all biomedical research funded by the National Institutes of Health (NIH). NIH remains confident that the oversight framework for the use of non-human primates in research is robust and has provided sufficient protections to date. However, we believe that periodically reviewing agency policies and processes ensures that this framework evolves in a manner consistent with emerging scientific opportunities and public health needs.

Toward this end and in response to Congressional interest (refer to Page 72), the Office of Science Policy is taking the lead in planning a workshop on September 7^th, 2016 that will convene experts in science, policy, ethics, and animal welfare.  Workshop participants will discuss the oversight framework governing the use of non-human primates in NIH-funded biomedical and behavioral research endeavors.  At this workshop, participants will also explore the state of the science involving non-human primates as research models and discuss the ethical principles underlying existing animal welfare regulations and policies.  NIH is committed to ensuring that research with non-human primates can continue responsibly as we move forward in advancing our mission to seek fundamental knowledge and enhance health outcomes.

The workshop will be broadcast live and archived for future viewing on the NIH Videocast website.  Comments regarding the workshop may be submitted online in advance of and during the workshop for consideration. Please save the date, and stay tuned for more information, including a detailed agenda.

Posted by Dr. Carrie D. Wolinetz, May 24, 2016

You may recall from one of my previous blogs that there are policy challenges in balancing the sharing of valuable research data with the protection of the participants whose data is being shared. The NIH Office of Science Policy is taking a leading role in ensuring that genomic data is shared in a responsible way.

Under the NIH Genomic Data Sharing Policy, institutions must indicate the appropriate use of genomic data, including any limitations on the distribution and use of that data.  In order to assist institutions in recognizing potential data use limitations (DUL), NIH created several resources for investigators.  These include Points to Consider in Developing Effective Data Use Limitation Statements as well as a set of Standard Data Use Limitations.  However, even with these resources, there is still the possibility for multiple interpretations which may cause time delays and additional costs when trying to share genomic data.

This raises some interesting questions: could time delays and cost burdens be reduced if the conditions of potential data use and sharing were clearly communicated at the time the data is generated? What are the variations in the designation of data conditions, and what does that landscape look like, domestically and internationally? To begin to address these questions, OSP staff collaborated with members of the Global Alliance for Genomics and Health to a set of “Consent Codes” that could be used to assign genomic datasets to standardized data use groups in order to allow a consistent interpretation for the appropriate secondary use of vital genomic data.  As described in a recent article in PLOS Genetics, the consent codes should help in avoiding the introduction of unnecessary new restrictions on data use, while at the same time facilitating research with the greatest amount of data available.

The issue of genomic data sharing highlights the importance of international collaboration as well as the delicate balance between the broad sharing of valuable research and ensuring the protection of participants.  OSP will continue to develop resources on genomic data sharing while evaluating the existing policy landscape to ensure that researchers have appropriate access to data while simultaneously making sure that the data is not inadvertently or deliberately misused.

Posted by Dr. Carrie D. Wolinetz, May 2, 2016