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The NIH and the regenerative medicine field “In 2011, the NIH allocated approximately US$1 billion to stem cell-related research, with approximately a third allocated to pluripotent stem cell work, which reflects its current proportion of activity in the field.”
KEYWORDS: adult stem cell n embryonic stem cell n ESC n induced pluripotent stem cell n mesenchymal stem cell n MSC n personalized therapy n regenerative medicine n regulatory standards n stem cell n translational
Stem cells come in many flavors. The scientific distinction to make between these cells is not whether they are embryonic, fetal, adult or cadaveric, but rather the properties of the particular stem cell that is harvested for use. For example, a bone marrow-derived hematopoietic stem cell is the best choice for marrowrelated disease, but adult neural stem cells are not. Similarly, an adult limbal stem cell is great for repairing a cornea, but a mesenchymal stem cell (MSC) from the same adult is not the best choice. Nor is a fetal MSC, or even a MSC derived from a pluripotent stem cell [1] . Rather, the utility of the cell depends on the tissue it came from and its functional properties. This has been borne out by numerous clinical studies with adult stem cells. Applying this again to MSCs, these look very promising for treating limb ischemia or graft-versus-host disease, as this appears to be their normal function in the adult. However, MSCs have not been useful in forming neurons in the brain or cardiac muscle in the heart, as this is not their normal function, and this has been borne out by studies carried out by responsible proponents of adult stem cell therapy. Embryonic and fetal cells in general are more immature than adult cells and take much longer to mature, even when transplanted. They are not generally preferred, unless there is no useful adult source or their numbers are limited. Thus, despite the fact that fetal neural stem cells take longer to mature, we consider them for therapy over adult cells when adult stem cells are not available in the numbers required for therapy. The NIH, therefore, has focused on funding the best science and – in terms of translation – the best cell for a particular disease
target, within the bounds of NIH policy on human embryonic stem cells (ESCs). As the field has evolved, the NIH has responded to the stem cell funding challenge in many different ways. Early on, the NIH led the effort to establish centers for manufacturing adult stem cells and establishing cord blood banks. As the pluripotent stem cell field matured, the NIH negotiated the first agreements to enable human ESCs to be widely distributed, and later set up a characterization unit to evaluate the quality and stability of the cells and a registry of human ESC lines approved for use in NIH‑funded research. More recently, as the regenerative medicine field has expanded, the NIH funding efforts have increased [2] . In 2011, the NIH allocated approximately US$1 billion to stem cell-related research, with approximately a third allocated to pluripotent stem cell work, which reflects its current proportion of activity in the field.
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Mahendra Rao NIH Center for Regenerative Medicine, 50 Center Drive, Room 1140, Bethesda, MD 20892-8024, USA
[email protected]
“The NIH … has never considered its support
for regenerative medicine to be a choice of funding one cell type over another, but rather a matter of focusing on funding the best science and … the best cell for a particular disease target.” The discovery of the induced pluripotent stem cell process in 2006 has electrified the field of regenerative medicine by showing that personalized or individualized cell therapy may be possible, either by generating ESC-like pluripotent cells, or by direct transformation of abundant adult cells into the cell type required for therapy without transitioning through a pluripotent stem cell-like state. The NIH realized that this breakthrough discovery could fundamentally
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change the discovery, screening and therapeutic models that dictated how research was done with human tissue, and developed a strategy to respond to this challenge. An important component of this strategy was the establishment of a new NIH Center for Regenerative Medicine (NIH CRM), a Common Fund-sponsored initiative intended to coordinate stem cell research activities and accelerate intramural efforts towards clinical treatment [3] . The mandate of the center is clear-cut: help transform the promise of stem cell therapy into reality in a responsible way; identify the key roadblocks in the process; and leverage existing investments that the NIH and other government agencies have made in the regenerative medicine field in order to ensure translation is coordinated and accelerated. One such roadblock that we have identified is the absence of uniformity in consent, cell line generation and availability of controls and standards [4,5] . A resulting initiative has been to draft a model consent form, with input from relevant experts and representatives from institutional review boards. In addition to developing a protocol book for cell line generation for wide dissemination, the center has also focused on developing agreements with commercial vendors to obtain and make available cell lines generated from patient material. Similarly, the center has worked with commercial vendors along with research laboratories to obtain controls and standards. Taking this further, the center is working with the US FDA Stem Cell Task Force to explore clinical-grade options for cell lines and controls.
“…the NIH negotiated the first agreements to enable embryonic stem cells (ESCs) to be widely distributed, and later set up a characterization unit to evaluate the quality and stability of the cells and a registry of ESC lines approved for federal funding.” Another major roadblock has been the lack of coordination among chief funding groups, which was more extreme in the USA given state efforts to help fund this exciting area. A key effort in this direction for the center has been to initiate collaborations with individual states. An early example of this is the recently announced agreement with the California Institute for Regenerative Medicine (CIRM). The NIH CRM brokered this agreement between the NIH and CIRM, which is intended to facilitate collaborations to leverage their respective 130
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resources in order to move stem cell research forward toward translation. Similarly, we have initiated discussions with international groups and regulatory agencies. An example of efforts with nonregulatory agencies is the recent preliminary agreement between our center and the Institute of Integrated Cell–Material Sciences (iCeMS) in Kyoto University (Japan). On a governmental level, our center, with the NIH’s Fogarty International Center, facilitated the Letter of Intent between the NIH and the Department of Biotechnology (DBT) in India, signed by the NIH Director on a visit to India in late 2011. Our intent is for the Memorandum of Understanding (MOU) already in place with CIRM to serve as a viable model for all of these various outreach efforts. But with no additional money allocated to this effort, no new joint funding grants and no new requests for applications are expected as a result of the MOU, one could quite legitimately question whether this new agreement changes anything. In actuality, we believe that the NIH–CIRM MOU will make a real difference. A critical factor is its focus on establishing a framework for accessing the respective resources of the NIH and CIRM for stem cell research. An oversight team is in place to focus on identifying leading areas with strong opportunities for joint efforts and the subsequent outreach to potential collaborators. The joint oversight will continue to facilitate the harmonization of efforts in targeted disease areas. In addition, both the NIH and CIRM have substantial infrastructure in place to fund and otherwise support stem cell research efforts, and the MOU allows for leveraging these resources to best promote collaborative efforts. As with anything, of course, the proof will be found in the execution. So far, signs point toward success, even beyond the strong interest already expressed in collaboration through the framework in the foundation of the CIRM MOU. Early announcements of synergistic services by our external advisory panel cohosting meetings with the FDA and promising discussions with groups about collaboration in support of induced pluripotent stem cell generation all strongly suggest that the larger community recognizes the need for proceeding in this direction and views our efforts in a positive light. The importance of this cannot be underestimated, given the complexity required to achieve the mission of stem cell therapy. With success clearly reliant on coordination of resources both within and outside the NIH, future science group
The NIH & the regenerative medicine field
as well as success on funding, regulatory and standard setting fronts, this community will be absolutely critical. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial
References 1
Rao MS. Funding translational work in cell-based therapy. Cell Stem Cell 9(1), 7–10 (2011).
2
Rao MS. Straight talk with... Mahendra Rao by Elie Dolgin. Nat. Med. 17(10), 1163 (2011).
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interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
3
Rao MS, Collins FS. Steering a new course for stem cell research: NIH’s intramural Center for regenerative medicine. Stem Cell Trans. Med. 1, 15–17 (2012).
4
Chiu AY, Rao MS. Cell-based therapy for neural disorders – anticipating challenges. Neurotherapeutics 8(4), 744–752 (2011).
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5
Rao M, Ahrlund-Richter L, Kaufman DS. Concise review: cord blood banking, transplantation and induced pluripotent stem cell: success and opportunities. Stem Cell 30(1), 55–60 (2012).
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