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Home , Cell (biology), Regenerative Medicine, Stem cell

Cell Stem Forum

Whole- Analysis, Research, and the Future of Biobanks

Thane Kreiner1,* and Stefan Irion1 1The Center for , Technology, and Society, Santa Clara University, Santa Clara, CA 95053 USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2013.04.024

The convergence of the genomic revolution and biobanking with rapid progress in stem cell research holds vast potential for personalized and novel . In this Forum, we explore social and ethical considerations emerging from strategies to realize the promise of these remarkable technologies.

In 2005, one of the first genome-wide as- consequent knowledge could be lever- tion of individual genetic predispositions, sociation studies (GWAS) was published, aged to find new therapeutics and design and information about biological family in which over 116,000 SNPs in 146 indi- smarter clinical trials with and members who may not have provided viduals were screened to reveal a comple- exclusion criteria tailored to expected re- any type of informed consent (Cambon- ment factor H polymorphism associated sponses based on genetic variation (Bellin Thomsen, 2004; Knoppers et al., 2012). with age-related et al., 2012). Moreover, biobanks of cells Moreover, there is significant variation (Klein et al., 2005). Some 2 years later, with known and defined genetic profiles among informed consent for biobanks: successful of could facilitate development of cell-based specific to a particular study or broad; ob- fibroblasts to induced pluripotent stem therapeutics less prone to immune rejec- ligations, if any, to return results to do- cells (iPSCs) was reported (Takahashi tion. Researchers, funding agencies, and nors; and the right of donors to withdrawal et al., 2007). policy makers will need to converge on a from future studies (Knoppers et al., Whole-genome analysis technologies, common set of biological, ethical, and so- 2012). These issues persist and some including microarrays and next-genera- cial principles. are potentiated by the convergence of tion sequencing (NGS), are fueling the dis- large-scale genomic studies and next- covery of genetic variants associated with Biobanks as a Potential Source generation stem cell technologies. a wide variety of human conditions; both of Next-Generation Stem Cells However, stem cell experiments differ effect size and frequency are critical To fuel the next wave of regenerative conceptually from whole-genome anal- dimensions in associating genetic varia- medicine research and clinical application ysis: they are based on individual samples tion with diseases and other human con- development, integrated biobanks are rather than . Researchers ditions (Bush and Moore, 2012). Genetic essential. These integrated biobanks generally use readily available cellular ma- variants explain only a portion of pheno- would support GWAS and also serve as terial (e.g., rodent cells, cell lines, or types, with environmental exposures and source material for next-generation stem opportunistic clinical specimens) that epigenetic factors influencing cells technologies with known and spe- may not have been genetically character- expression and ultimately, human traits. cific genetic composition. ized. Well-concerted efforts to link stem While stem cell technologies, including Biobanks are repositories of samples cell generation and biobanks of represen- human embryonic stem cells (hESCs), for use in research studies. The biological tative human populations are in their iPSCs, transdifferentiation, dedifferentia- material itself is practically useless without infancy. One fundamental driver is that tion (Jopling et al., 2011), and adult stem some associated information. Age, sex, biobanked samples for stem cell genera- cells are rapidly accelerating our under- and continent(s) of origin are a few attri- tion have a high bar for preservation: living standing of and disease, none of butes nearly universal to human biobanks. cells. Existing biobanks, however, these have been applied to genetically Biobanks often include medical informa- often lack live, recoverable cellular mate- characterized samples from a broad pop- tion, particularly if they have been con- rial because the collections predate ulation base. structed to accelerate research in a next-generation stem cell technologies. The convergence of next-generation particular disease area. Some capture Each of these next-generation technol- stem cell and whole-genome analysis longitudinal information from individuals ogies presents challenges with respect to technologies presents an opportunity to to support studies, others are biobank creation. It is unknown whether create disease-relevant cell types with disease-specific, and still others comprise cells commonly used in reprog- known genetic variants that represent hu- residual tissues from medical procedures ramming such as dermal fibroblasts retain man populations and could accelerate or diagnoses (Knoppers et al., 2012). cell-of-origin epigenetic memory (Sullivan , advance drug dis- Large-scale biobanks that support et al., 2010) or whether epigenetic covery, and broaden our understanding of population-based studies such as markers will affect models of disease in disease biology. Such an approach would GWAS have raised numerous ethical, derived cell lineages for research or cell- discern the biological repercussions of legal, and social issues, among them the based . In contrast, dedifferenti- the , whether common or rare. The potential identification of donors, revela- ated cells may be epigenetically close to

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the cell they are destined to resemble. and link them to deidentified other aspects of living. Donors to inte- Here, only a limited number of steps are public data sets was demonstrated (Gym- grated biobanks should be assured that necessary to elicit proliferation without re- rek et al., 2013). As direct-to-consumer ge- their participation in no way jeopardizes verting all the way to pluripotency. Adult netic tests and personal genome initiatives future opportunities for themselves or bio- stem cells are local, -specific stem proliferate, vast amounts of genetic infor- logical family members. cells and may be more epigenetically mation are being generated, stored, and Informed consent principles for bio- similar to their differentiated counterparts searched. DNA from shed cells or banked samples are particularly complex within the organ but are extremely rare in can be collected without permission as whole-genome analysis and regenera- most tissues. Since dedifferentiated and or knowledge; massive law enforcement tive medicine technologies converge. An adult stem cells require the use of local databases, such as CODIS (see Web underlying principle of informed consent resident cells, a very limited number of Resources), already exist. Affordable, is that individuals choose how and biobanks exist. Creating new banks for easy-to-use DNA sequencing technology whether their tissues, cells, DNA, or asso- these methods would require the collec- will almost certainly become widely ciated data will be used. Some scholars tion of cells that are not readily accessible, accessible. limit the definition of true informed con- such as or pancreatic islet cells, Biobanked tissues and cells contain the sent to specific, well-defined research; presenting a significant obstacle for full genomes of the donors; thus, they others propose that broader consent is a some conditions. Furthermore, suitable include the same ELSI concerns as DNA tractable solution for longitudinal popula- long-term storage methods for some cell samples. Application of next-generation tion studies. The premise that research types do not currently exist. stem cell technologies to existing bio- studies be approved by institutional or Future biobanked samples for any stem banks will foster applications beyond the ethics review boards is universally held. cell approach should include accompa- original intent of the biobank. New cells, The future use of samples presents a nying clinical, biological, and sequence cell lines, or tissues with known genetic fundamental informed consent challenge information. Appropriate informed con- profiles are a likely outcome of the that is accentuated by the preservation sent will also be necessary and must be convergence between genome analysis of living tissue that can, in theory, considered in the broader context of the and stem cell technologies. Such prod- generate genetically identical tissues, or- accentuated ethical, legal, and social is- ucts may outlive the intended research gans, or that may outlive both sues emerging from the convergence of objectives by several decades, raising the donor and the researcher. Because whole-genome analysis and next-genera- new ELSI concerns. Nonautologous cells science is evolutionary and combinatorial, tion stem cell technologies. or tissues generated from iPSCs or dedif- the design of future studies cannot be ferentiated cells for anticipated at the time samples are Ethical, Social, and Policy Issues applications carry the donor’s genetic in- collected. Notification, opt-out, with- Even before the formal launch of the formation, subverting the notion of auton- drawal, return-of-results, and incidental Project (HGP) in 1990, omy or control over one’s own genetic finding provisions provide some potential the US National Institutes of Health formed information; in theory, the recipient could solutions (Cambon-Thomsen, 2004; a joint working group with the Department decipher the donor’s entire genetic Knoppers et al., 2012); however, they of to ‘‘identify and address’’ the code, revealing alleles that correlate with impose research transaction costs, which ethical, legal, social, and economic issues certain behaviors or early-onset, untreat- may appear virtually unlimited in the case (ELSI) that would arise with technology ad- able diseases. of incidental findings. Implementation of vancements for genome analysis (see Web Protection against genetic discrimina- some informed consent provisions after Resources). The first 5 year plan for the tion remains a vital ELSI concern. Howev- death may unintentionally compromise HGP included an ELSI budget allocation, er, it was not until 2008 that the Genetic the privacy of survivors. which continued throughout the 13 year Information Nondiscrimination Act finally Integrated informed consent will be an project. Among these issues are: privacy passed the US Congress; its protections essential feature of next-generation bio- and confidentiality, the potential for are limited to employment and health in- banks. Since the banks will contain live discrimination based on genetic informa- surance. In 1997, UNESCO adopted the cells with full genetic information, consent tion, and intellectual property. Universal Declaration on the Human must encompass future uses of the mate- The HGP and programs such as Small Genome and Human Rights (see Web Re- rial and the knowledge coming from it. En- Business Innovation Research (SBIR) and sources), Article 6 of which provided a gineered tissues could replace long-term Advanced Technology Program (ATP) more comprehensive statement against pharmaceutical treatment for chronic grants accelerated development of genetic discrimination, including preser- conditions such as and heart genome analysis technologies in the pri- vation of ‘‘human rights, fundamental disease; would donors of the progenitor vate sector. By the time the HGP was freedoms, and human dignity.’’ Con- cells be informed of results in recipients, declared complete in April 2003, a number verging advances in genetic analysis and compromising their privacy? Would of whole-genome analysis studies were regenerative medicine magnify the need recipients have a right to know the well underway. These advances in genome for broad genetic information nondiscrim- of tissues implanted in their analysis technology quality and declines in ination legislation in UN member nations. own bodies? Notification and opt-out pro- cost have made privacy protection for bio- Genetic information should not provide a visions could become particularly prob- bank samples untenable: recently, the abil- basis for discrimination in access to social lematic. Would initial cell donors or their ity to recover surnames from personal services, educational opportunities, or survivors have any rights to preclude use

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of derived tissues in certain individuals or eration may have more clinical utility. In toward standardization; such efforts are populations because of religious or other any case, the recent, rapid stem cell underway at several institutions and in personal beliefs? All future uses cannot research progress suggests that useful industry. To limit variability, stem cell be anticipated or imagined; therefore, applications will emerge and require lines must then be generated using ethics review committees proficient in meaningful intellectual property standard operating procedures (SOPs). both genetic analysis and stem cell protection. Moving from laboratory-scale stem cell research will be vital, raising the need for From an intellectual property perspec- generation to large cohort analysis raises integrated professional development. In tive, the convergence of whole-genome new challenges. First, how many clones addition to considering the ELSI implica- analysis and stem cell technologies raises need to be generated and characterized tions of genetic information and regenera- and accentuates challenging issues: who per donor? Investigators using iPSCs tive medicine, a ‘‘tiered’’ informed con- ‘‘owns’’ an individual’s genetic informa- often include three to five clones per indi- sent approach might enable donors to tion and the biology it encodes? What vidual, which would catapult a cohort opt out of future, undefined applications. rights, if any, should donors have to of 300 donors to over 1,000 samples. Although a meaningful review of gene profits generated from organs or tissues Second, how many donors represent and stem cell is beyond the con- derived from their cells? Who decides on a population (a challenge familiar to fines of this Forum article scope and limitations for use of DNA, cells, tissues, GWAS)? Third, should donors be followed space, ownership of biobank samples or organs? The courts thus far have held over time to collect material prior to, and commercial use provisions related that donors do not have ownership rights during, and after disease to capture to intellectual property rights merit some in biological materials derived from their potential epigenetic changes? While remark (for further reading see Mathews samples; however, the value of geneti- costs are declining, stem cell generation et al., 2013). Soon, the US Supreme Court cally proficient replacement hearts, , and differentiation remains laborious will hear the Association for Molecular and islet cells could impact the calculus of and expensive. A smart selection based v. Myriad case chal- commercialization over time, especially on allele effect size may help to reduce lenging the validity of the BRCA1 and as individuals are empowered to under- these numbers. Once integrated bio- BRCA2 gene patents in the US; whether stand their own genomes through con- banks are established, standard methods naturally occurring gene sequences are sumer genetics services. to differentiate and interrogate cells patentable varies by country. Similarly, The ethical and legal issues for regener- of interest also need to be developed. isolated stem cells are patentable in the ative medicine diminish substantially Funding must be adequate to solve US, but the European Court of Justice when new stem cell technologies are em- these technical, biological, and ethical ruled against patents on hESC lines (see ployed that enable use of the patient’s scenarios over time. Granting agencies Web Resources). own cells as starting material; the costs have already crafted RFAs designed claims may relate to composi- and time to cell and tissue therapies to surface and address some of these tion of matter, e.g., the DNA sequence become predominant factors in the infrastructure and standardization issues or stem cell itself, or to the method or pro- viability of these approaches. However, (see Web Resources). cess for using matter. Patentable subject it may not be advisable to treat some matter usually needs to meet three tests: medical conditions with autologous re- Future Directions novel, nonobvious to one skilled in the generated cells: they will bear the same We explore the convergence of two art, and useful. Composition of matter genetics, and possibly, the same epige- seemingly unrelated technologies that patents issued on naturally occurring netics. Thus, while autologous cells may now can act in concert to advance our un- gene sequences claim novelty because circumvent some ELSI concerns, bio- derstanding of human disease and accel- the sequence is isolated; once a single banking of allogeneic, genetically profiled erate development of potential therapies. gene had been isolated and sequenced, cells may be necessary to realize person- To realize this potential, we need to it seems obvious that one would wish to alized and affordable regenerative medi- reimagine biobanks as core infrastructure isolate and sequence all of them; hence, cine. The ELSI considerations are pro- to generate stem cells on a population the . The patent- found and warrant ongoing investment scale. Future ‘‘centers of excellence’’ for ability of technologies for genome anal- to fuel thoughtful analysis. biobanking should employ cell , ysis, however, is broadly accepted. Public investment is essential to realize bioinformaticians, clinicians, ethics advi- Patent filings for pluripotent stem cell the promise of this technology conver- sors, and policy makers. At these centers, generation and gence. Integrated biobanks that support standardized cell collection and cell pro- abound. Because these methods are rela- the convergence of GWAS and stem cell duction should be driven by SOPs; perti- tively novel, it remains to be seen whether research require infrastructure and stan- nent biomedical and data dominant technology claims will emerge dardization. No perfect technology to should be available in an open, search- such as Cohen-Boyer patent for recombi- generate stem cells at scale has yet able format with the option and require- nant DNA technology. Many of the earliest emerged. Viral reprogramming is best es- ment for resubmission of phenotypic and processes using viral vectors are unlikely tablished, but raises safety concerns. cellular data. to yield cells or tissues that are safe for Adherent fibroblasts are more suited for Both the biobank infrastructure and regenerative medicine applications; tran- automation, but are more thoughtful analysis of novel as well as sient gene suppression for dedifferentia- easily collected. Optimization of methods accentuated ethical, legal, and social is- tion or reprogramming followed by prolif- and comparative analysis is the first step sues emerging from the convergence of

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