Recent challenges with stem cell banking

KEYWORDS:

• Stem cells
• biobanking
• harmonization
• ethics

1. Introduction

Stem cell (SC) research is rapidly evolving, holding great therapeutic potential for the treatment of many diseases, which were previously considered as incurable. In the last few years, the scientific community has held SC research in high regard with efforts in this area receiving an impressive two Nobel Prizes in the past decade: in 2007, Mario R. Capecchi, Martin J. Evans, and Oliver Smithies for their discoveries of ‘principles for introducing specific gene modifications in mice by the use of embryonic stem cells’ [1] and John B. Gurdon and Shinya Yamanaka, for the discovery that ‘mature cells can be reprogrammed to become pluripotent,’ in 2012 [2]. This rapid expansion has created a great demand for SC-related biomaterials, giving birth to repositories strictly orientated around the collection, storage, and distribution of SC, commonly referred to as Stem Cell Biobanks (SCBs). These SCBs have evolved in a relatively short time span, from simple extensions of already existing biobanks to internationally coordinated repositories with the purpose of simultaneously collecting SCs from different sources, storing and organizing samples and outsourcing them for research-related activities [3].

2. Purpose and scope of SC banking

The collection and storage of biological material in biobanks has been practiced over time, for various purposes. To better understand the necessity behind the development of SCB, we first need to understand the sheer magnitude of the ever-expanding area of SC research and therapy. In its short life, SC research has reported an absolute record number of discoveries. Improvement and reconstruction of damaged cells or tissues by SCs are the major findings reported in scientific literature. More impressively, organ development using SCs is a promising future medical perspective. Despite this progress, aside from treatments with hematopoietic SCs, all other SC-based therapies remain experimental. Other SC-based therapies are presently in clinical trials. Just by browsing the American database of clinical trials (clinicalTrials.gov) using the term ‘stem cell’ will generate over 4500 different results with more than a third being currently active. From these, the overwhelming majority are comprised of clinical trials using somatic stem cells (SSC), which are relatively easy to isolate from different tissues such as cord blood, placenta, bone marrow, or adipose tissue, can be easily expanded in vitro and have great therapeutic potential in multiple areas such as autoimmune diseases, neurodegenerative conditions, [4,5] and even cardiovascular events such as myocardial infarctions [6].

Risk wise, the greatest asset of SSC is their inability to give rise to teratomas. However, the risk of tumor development after SSC transplantation is still present, with studies linking bone marrow transplantation to an increased incidence of secondary solid tumors [7,8]. Human embryonic stem cells (hESC), which are derived from totipotent cells located in the inner mass of the blastocyst, have also been very popular due to their two fundamental traits: infinite self-renewal potential and the capacity to differentiate into every cell type in the human body. However, despite the immense possibilities generated by these qualities, hESC-based clinical trials were approved only a couple of years ago [9]. The clinical potential of hESC is theoretically unlimited but their later effect is unpredictable. The major drawbacks are the hESCs’ propensity to transform into teratomas [10,11], immune rejection by the host and the ethical conundrum that inherently comes with the manipulation of human embryos [12].

Thus, the reason for building public and private biobanks of different SC specimens is to ensure the availability of biological material for research and clinical use (Figure 1).

Figure 1. Design and application of biobanks of major stem cell types. Advantages and disadvantages.

3. SCBs in today’s world

Given both the great potential but also the number of drawbacks that define SC research, a more organized effort in the scientific community could be beneficial for a number of reasons. Quality wise, a SCB which adheres to international legislation regarding the purity and safety of its biorepository can offer SC lines of higher quality to interested researchers and clinicians. Having dedicated resources and personnel within the biobank, which are entirely invested in the maintenance and bureaucratic sides of SC research, are preferable to small working groups where such tasks can become an unsolicited burden, over time. A coordinated effort in a centralized banking system would lead to the development of standardized protocols regarding SC cryopreservation, characterization, derivation, and differentiation.

While SC research continues to grow, requirements in the field become more and more specific. A perfect example is the need for SCs which exhibit disease-inducing mutations. A large centralized SCB system should, theoretically, provide researchers with a more diverse array of SC cultures, in concordance with their specific needs.

Given the level of scrutiny around SC research, a centralized banking system would be more inclined to adhere to legal and ethical frameworks, only including cell lines with traceable lineage and only of certified quality. More so, larger SCBs with access to national and international legal counseling can work toward harmonizing their ethical protocols, making it easier to get approvals from regulatory bodies such as the Food and Drug Administration and making it easier to coordinate biobanks located in different countries simultaneously.

Despite the numerous advantages that centralized SCB present, several key factors could prove to be detrimental. One major aspect is related to funding with considerable costs being expected to arise from the management of a SCB. Funding could be obtained from state regulated bodies, academia, the private sector, or from independent nonprofit foundations/organizations. However, each funding source comes with its own risks. Government funding is marred by the uncertainty of the political environment which can have a major impact on the success of a biobank. Unfortunately, the political or social landscape can have a detrimental impact on SCBs, with funding being cut over ethical concerns. Investors from the private sectors would be willing to invest money in a SCB, but given that these entities are profit-driven, the possibility of encountering conflicts of interest is very high. Academia and nonprofit foundations present the best options, but such organizations have substantially smaller financial resources in comparison to the first two entities.

Other important aspects of SCB are the ethical and legal governance. While international guidelines [13,14] provide ethical recommendations, due to the very delicate nature of the manipulation and storage of cells derived from human embryos, laws directly implicating SC can vary substantially on local and national levels. In order to facilitate the development of SCB, entities such as the International Society for Stem Cell Research, the National Academy of Sciences have already published guidelines or the International Stem Cell Banking Initiative (ISCBI) [15–17]. For example, the ISCBI represents an entity which aims to facilitate the adherence of multiple international biobanks under a common umbrella of minimum common principles, regarding all aspects pertaining to their operations such as ethical guidelines or recommendations regarding storage and distribution of SC.

It should be noted that such laws and regulations can also be subject to drastic changes on a national level making harmonization between biobanks especially difficult.

A final aspect which can influence the success of SCBs is the exact nature of the biological samples it accepts within its repository. If a SCB has very strict inclusion criteria, accepting SC belonging to a very specific niche, its content would be appealing to a small fraction of SC researchers. If a SCB accepts SC from a large array of donors, continuously expanding, it may ultimately succumb under its own weight as maintenance costs continue to grow while interest over a portion of its repository diminishes over time.

The advantages and disadvantages presented here are both plausible theoretical scenarios, such as the influence of the political landscape and real live situations, such as ethical issues that are most likely to be encountered by a SCB in its effort to expand and stay relevant.

4. Conclusion

In conclusion, we consider SCB central for the future progression of SC research, given that a rising interest from the scientific community for this subject would more than likely increase the demand for easily accessible and high quality biomaterials. However, even under this positive trend, precautions must be taken to ensure that SCB remains feasible both financially and ethically and continue to be in accordance with the expanding need for biospecimens.

5. Expert opinion

The rising therapeutic spectrum of SC has seen an exponential growth with major players such as large universities or pharmaceutical companies taking a keen interest in acquiring and developing repositories. These entities have different end points when it comes to SC research. While academic and governmental bodies have a more scientific-orientated drive, private entities are inherently driven by a profit-related goal. These two approaches are not mutually exclusive, as cutting-edge research requires substantial funding and having a lead over competition through innovation can be extremely profitable for large profit-driven entities such as pharmaceutical companies. This point is especially valid in the case of SC research, as different SC-related therapies stand to potentially cure diseases which were previously considered incurable, such as neurodegenerative diseases [4,5], myocardial infarctions [6], strokes [18], and diabetes [19]. These diseases also affect a large percentage of the world’s population, making any form of cure a gold mine for any entity that holds the patent rights to the treatment. While there is a large level of scrutiny regarding the handling and potential profit obtained from human SCs, especially hESCs, the rapid development observed in the field cannot be sustained without large commercial entities having an incentive to invest. We consider that not all SC biobanks should adhere to the same modus operandi in all aspects. While we advocate for shared principles when it comes to quality and safety guidelines and confidentiality and data protection policies, we consider that some aspects should be specifically catered to accommodate possible changes in the future. For example, if a SCB is sustained by a government or an international body with no prospect of becoming a shared public–private venture in the future and without any profit-driven policies for its repository, it should have a more broad consent model. In such cases, consent should, however, not be presumed because it could lead to legal backlash and low participation. In short, contributors should understand that the samples are beneficial to everyone and profitable to none in the long run. Smaller SCBs who, at some point in the future, might consider either outsourcing their samples in order to continue to grow or just keep up with growing maintenance costs or simply by joining a profit-driven venture, should present a different attitude toward donors. Consent forms should specifically state that samples could be subject to commercial purposes in the future, while giving donors more ample room to decide if, at one point, they want to withdraw from the project. Becoming a profit-driven or partially-profit driven entity can also be beneficial, with the owner having an incentive to redirect some of the profits toward keeping the infrastructure and protocols up to date, in order to maintain costs low and continue to provide quality biospecimens. This model has its limitations, with commercial entities always leaning toward maximizing profits while trying to reduce costs through practices which are not necessarily in the best interest of scientific progress. One way would be to limit the number of activities through which biobanks can obtain profit with strong restrictions toward activities which would be considered unethical or residing in a ‘gray zone.’ We consider that the SCB world needs to evolve into a more flexible entity, mainly because its accelerated growth will become a burden, collapsing upon itself if it does not maintain its relevance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Research Council and Advisory Council for Research, Development and Innovation (UEFISCDI), Romania, grant PN-II-ID-PCE-2011-3-1041