Introduction
Yorgos Nikas/Photo Researchers Inc.
Tipping point? The ISSCR has moved to describe central principles concerning the sharing of reagent and materials in research on human ES cells (an early embryo is shown here on the tip of a pin); scientific societies and funding bodies in other areas biomedical research should follow suit.
New ethical guidelines of the International Society for Stem Cell Research (ISSCR; Northbrook, IL)1, 2 for work on human embryonic stem (ES) cells direct researchers, companies and academic institutions to share research materials, data and intellectual property (IP) rights necessary for published research to be validated and for other scientists to conduct further research. The guidelines are not only important for human ES cell research, but also send a compelling message to the academic and corporate biomedical communities at large, which continue to wrestle with the effects of academic competition and commodity-driven corporate forces on the scientific endeavor. These are eroding the central principles of reagent, materials and information sharing in science—a deterioration that will not self-correct.
Sharing standards are pivotal to ensure that research produces genuine public benefit, has societal value, truthfully represents public benefit to subjects and ethical review boards and results in benefits being justly shared among economically and geographically diverse participants. They are also necessary to equalize data and materials access among scientists in countries that approach patenting and other IP matters differently, and to equalize public access to its benefits globally. Although the new ISSCR standards apply only to human ES cell research, the reasons that justify them apply across biomedical research disciplines.
ISSCR guidelines
The ISSCR guidelines lay down several principles concerning the sharing of reagents and materials in human ES cell research, which in the United States has been plagued by restrictive licensing policies of certain institutions with key IP (Box 1). But I would argue these principles apply much more broadly in many other fields of biomedical research. For example, a central tenet of the ISSCR guidelines is that international "scientific collaboration and mutual trust among researchers are vital to the success and advancement of science and should be encouraged"2. In addition, collaboration and trust demand "the open exchange of scientific ideas and materials to maximize exploration and to promote innovation, and to increase the probability of public benefit through affordable advances made possible by human stem cell research." Desirable scientific norms of sharing, important in themselves, are explicitly linked to public benefit: "research with human materials is valuable to all," and "the proper practice of science requires unhindered distribution of research materials to all qualified investigators... and the dissemination of its benefits to humanity at large on just and reasonable terms."
The guidelines also illustrate how such general statements evoke specific duties from the institutions and stakeholders in the research endeavor. They indicate that institutions must "develop procedures whereby research scientists are granted, without undue financial constraints or bureaucratic impediment, unhindered access to...research materials for scientifically sound and ethical purposes...." Academic institutions must, "in arranging for disposition of intellectual property to commercial entities, take all possible care to preserve nonexclusive access for the research community, and to promote public benefit as their primary objective." Researchers, corporate and academic, must "make materials readily accessible to the biomedical research community for non-commercial research," as a "pre-requisite for the privilege of engaging in human stem cell research", and "submit any stem cell lines they derive to national or international depositories that allow open distribution."
Harsh realities for research
In truth, we are ambivalent about research sharing. In the United States, "responsible conduct of research" includes sharing materials and data3, but refusing to share is not misconduct4. Federal standards promote sharing data, materials and tools5, 6, 7, 8, but they do not apply to corporate or academic research that is funded by other mechanisms. They also do not protect a researcher whose basic research infringes another's patent9. Journal standards may require data and materials to be available for replication, but governments do not embody this principle broadly and unequivocally—even though sharing and transparency are vital to public safety10.
Scientific community ideals11 imply sharing, although with no binding communitarian requirement to share materials, data or research rights. In reality, research sharing is an aspiration vulnerable to compromise when it interferes with private incentives, whether researchers' academic self-interest or potent market forces that dominate the creation of biotech policy12, 13.
Practical consequences of shackling access
In 1990, literature described sharing as an ethic "under pressure," citing reach-through rights extracted for use of materials and methods, and asserting that 15–20% of materials requests "are not completely honored"14. In 1997, 8.9% of 181 clinical and nonclinical research faculty reportedly refused to share research results with other university scientists in the previous three years15. Five years later a report documented how 46% of academic clinical and nonclinical research scientists, in genetics and other areas, had been refused access to data, materials and published information16.
A 2004 publication also found that university scientists discussing nonpatented work published it 1.21
0.16 years later, whereas the gap between conference and publication for those discussing patented work was only 0.0 0.19 years, implying that important scientific data are maintained in secret up to the time of publication, rather than discussed among peers at conferences17.
A 2005 study reported that 19% of academic researchers reported that their most recent request for research materials had been denied, with an average denial rate of 
18% (ref. 18). There were wide-ranging restrictions in materials transfer agreements (MTAs), including reach-through rights and publication restrictions (26%). Seventy percent of drug-related MTAs restricted publication of research results.
Last year, a national survey of clinical and basic science researchers reported that "data withholding is relatively common and takes multiple forms"12. Exposure to contrary training is ineffective. Between 38% and 42% of trainees were actively discouraged from data sharing. A companion article, surveying trainees, states: "[50.8%] reported that withholding had had a negative effect on the quality of their own research, [48.5%] on the rate of discovery in their own lab or group, [45%] on the quality of their relationships with other academic scientists, [33%] on the quality of the education they receive, and [28.5%] on the level of communication in their lab or group"19.
A 2006 National Academy of Science committee has also reported that "impediments to the exchange of biomedical research materials remain prevalent and may be increasing"20. Although noting a "general lack of awareness or concern among academic investigators about existing intellectual property," the report observes that patents would burden research if either patent-holders increased enforcement or risk-averse research institutions curtailed infringing research.
Is our science ethical if we do not share it?
Those practical consequences of sharing failure are harsh. But a further consequence is violation of fundamental principles underpinning science, including the basic demand that research have scientific and societal 'value'. In theory, research with animals must be scientifically sound, and its results disseminated, to contribute toward important scientific progress. Clinical research, even if it involves only human tissues and identifiable data, should produce just and real public benefit in the form of widespread gains in scientific knowledge and broadly available improvements in healthcare. Failures in research sharing cause us to question whether these demands are met. Can public benefit and value to society still be assumed, given deterioration in research sharing and aggressive patenting, licensing and materials strategies? Can justice be assured if commercial restrictions limit benefits to economic subsets of those who participated in the research? Evidently, materials are not shared, negative data are withheld, discoveries are delayed or secreted, patent rights are licensed only to prohibit practical bench-to-bedside translation, and rights are held by companies positioned to foreclose competition and limit consumer access. If these circumstances become increasingly common, or if they become accepted as practical norms, then assuming public bene-fit and 'value' will contradict well-evidenced behaviors.
If value and benefit cannot be assumed, then the integrity of institutional review board (IRB) review and truthfulness in seeking informed consent are also threatened. IRB approval depends on accurate weighing of risks and benefits, including "the importance of the knowledge that may reasonably be expected to result"21. If imaginary benefits replace realistic potential benefits and commercially closeted knowledge can substitute for publicly available research advances, then weighing public bene-fit is a sham. An IRB weighing benefit must be able to rely reasonably on institutional IP commitments, and a genuine scientific ethic that makes its assumptions about public benefit colorable rather than counterfactual22.
If public benefit is misrepresented, an informed consent form is untrue, altruism is abused and the limited distribution of benefits will be unjust from the perspective of research subjects. An instructive parallel arose in 2000, when parents of children with Canavan disease, altruistic donors of tissues and others sued an investigator and institution that had assertedly promised to develop a low-cost diagnostic test for Canavan disease. The gene was identified using their tissues, and a test developed and patented. According to the complaint, the institution and investigator secretly restricted research under the patent, collected royalties based on a fee far beyond the cost of the test and restricted the number of laboratories that could offer the test. As a result, many laboratories stopped offering the test. The Canavan Foundation could not offer free tests23.
In 2003, the court ruled in favor of the plaintiffs24. Failure to reveal commercial intentions to donors is wrong, just as, years before—in the most overlooked part of the famous Moore decision—a court had protected a patient's right to be fully informed of his/her doctor's commercial intentions with his/her tissues25.
These cases illustrate a central theme: representations to donors and subjects concerning scientific progress, value and public benefit must not be falsified by commercial strategies or other radical constraints on research sharing, fair public access and public benefit.
What action is needed?
Self-correction is unlikely. Free riders can receive sharing benefits without sharing themselves. Furthermore, if benefits arise only if the entire community participates, then intervention is necessary to realign researchers' behavior and trust17. A new standard of universal research sharing is practically necessary.
It is also ethically necessary. It is a truism that sharing and transparency are scientific fundamentals. But we must think beyond that inward-turning ethic, recognizing the vital link between research sharing and public benefit. Ethical clinical research requires justice, beneficence and respect for persons26, 27. Risks and benefits—including public benefit that drives altruism—must be presented in a forthright manner. Research must also have genuine 'value'.
"Only if society will gain knowledge, which requires sharing results, whether positive or negative, can exposing human subjects to risk in clinical research be justified....[Benefits] to society through the generation of knowledge are assumed if the research is deemed to be of value and valid..." [emphasis added]28.
The evidence discussed above demonstrates that public benefit and value cannot be assumed, unless the global scientific community acts now to implement an unambiguous ethic of research sharing.
We should also remember this is not just an issue for researchers engaged in human testing and clinical trials: justifying research depends on promises of scientific progress, and access to discoveries, even at the basic science stage. In 2003, Cho et al.29 reported a survey of academic and commercial clinical laboratory directors in the United States performing DNA-based genetic tests: "[25%] reported that they had stopped performing a clinical genetic test because of a patent or license" and "[53%] reported deciding not to develop a new clinical genetic test because of a patent or license." Fifteen of the 22 patents relevant to the survey were held by academic institutions29. It is doubtful whether this is the public benefit—decreased testing—that altruistic donors and research subjects were promised to induce them to participate in basic genetic research.
In separate articles, Zoloth30 and Kuhn31 have argued for larger conceptions of justice and beneficence in ES cell research. The former has called for a social interpretation of justice that addresses access to healthcare across divides of wealth and poverty, and fair global distribution of benefits30; the latter suggests that equalizing benefits depends on a reevaluation of requirements for ES cell patents and licensing31. The lesson is broad: if fair distribution is essential to beneficence and justice, then so is the research sharing required to enable it. Furthermore, countries take radically different approaches to the patentability of human ES cells and their derivatives13, 32. An ethical rule geared toward fair global distribution must help equalize the differential research access produced by countries' different patenting approaches.
Conclusions
Research sharing should be recognized as ethically and practically indispensable. First, deterioration in research sharing is well documented. And the problem is not self-correcting. Second, obstacles inevitably follow from control by a few over patents and materials. Withholding patterns should not metastasize to new, platform-patented discoveries necessary for scientific progress. Third, the ethical underpinnings of research—particularly distributive justice, value and informed consent—require that promises of safety, efficacy and public benefit be real. Otherwise, those ethical values, as well as the integrity of IRB review and public research trustworthiness are all imperiled. Justice and beneficence converge to require that the research sharing that enables medical progress be required.
Finally, in a global scientific community, equalizing access by scientists across different patent systems is a community imperative, to avoid a lopsided system in which those who do not provide such patent protection are exploited by free riders within more IP-oriented systems. In this regard, the ISSCR guidelines are the first guidelines in a specific research area to address sharing materials and reagents both broadly and head on. Other biomedical disciplines, and other guidelines should follow suit, by defining strong, clear requirements that researchers have reasonable universal access to data, materials, rights and results, and that diagnostic and therapeutic innovations are widely available on just terms for the public benefit.
