Collaborative Chemistry

Last year my then colleague at CDD, Nadia Litterman and myself put together an article on databases and collaboration around the area of human stem cell research. This built on Nadia’s extensive experience of working with stem cells. My additions were mostly around software and collaboration. It was a fun paper to write as I learnt plenty! The Review has now published in Drug Discovery Today (I am on the editorial board) and you can get a free copy for the next month or so here.

This took a while to see the light of day as we bounced around at a few Nature and Cell journals. See reviews below!

I think the article may be useful also for funding bodies to propose more collaboration and data sharing. There may also be interest in this from rare disease research groups. Bottom line, more collaboration and sharing would help and with software available currently this could happen. But who will catalyze it? Based on the reviews we had from Nature Genetics..it was pretty much nit picking and turf protection as you can see.

Reviewer #1 (Remarks to the Author):

This Commentary is about a stem cell database and repository. The basic thesis that such a worldwide database/repository would be beneficial is clear and obvious. It has been stated previously in several venues – but it could be positive to have it stated again in a high impact journal. But I think that the commentary has a number of problems.

The commentary stresses the need for worldwide acceptance and inclusivity. I therefore found the relatively partisan and skewed presentation of the topic to be peculiar. For example, I do not think that it even mentions the world’s first clinical trial with iPSCs run by Riken in macular degeneration. Yet the authors manage to mention the trial being done by Advanced Cell Therapeutics (in which one of the authors has stock ownership) in macular degeneration.

A European Bank for induced pluripotent Stem Cells (EBiSC) was recently established and I do not think that it was even mentioned in the commentary. The EBISC self-description is:
The EBISC iPS cell bank will act as a central storage and distribution facility for human iPS cells, to be used by researchers across academia and industry in the study of disease and the development of new treatments for them. Conceptualized and coordinated by Pfizer Ltd in Cambridge, UK and managed by Roslin Cells Ltd in Edinburgh, the EBiSC bank aims to become the European “go to” resource for high quality research grade human iPS cells.
How can there be a world-wide bank that does not include this and/or Europe?

The table of “selected” companies doing stem cell research adds little or nothing and it immediately violates the concept of inclusivity. There are more than 60 stem cell companies. Highlighting just a few would alienate the others and be counterproductive.

There were other statements that were out of sync with the view of a worldwide effort. For example, they say: “While other countries like Japan are investing heavily in stem cell research, it will be important that the USA is not left behind”. This commentary is not about the USA – it is about the rest of the world also.

Perhaps the most disappointing thing about the article is that it did not give any suggested pathway for accomplishing the task. They say that doing it “would require significant sponsorship, world-wide support, active participation, and continual maintenance”. At the very least, they should put forth some suggested ways of proceeding to get to the goal. As written it doesn’t help the field progress or give any clues on how progress might be made.

The authors’ biases show in many ways. For example, they say: “In 2006, the research groups of Drs. James Thompson and Shinya Yamanaka discovered a method for generating induce pluripotent stem (iPS) cells. Yamanaka made the discovery (and got the Nobel for it). Thompson merely confirmed it (and did not get the Nobel). Listing Thompson at all is questionable, and listing him first is unacceptable.

Overall I agree completely with the basic point that is being made, but the presentation of the concept seems biased and not particularly helpful. This commentary is not up to the quality of the Nature Genetics.

Reviewer #2 (Remarks to the Author):

The commentary, “Databases and Collaboration Require Standards for Human Stem Cell Research”, by Drs Litterman and Ekins is a very reasonable call-to-action for the stem-cell research community. In this commentary, the authors point out the need for a centralized database to serve as a repository for the enormous amount of data being generated by this community of researchers. They specifically urge the development of “Minimum Information About Stem Cell Experiments” (MIASCE) that will require consensus in the field about the critical pertinent information required for stem cell lines and differentiated cells. The ultimate aim would be to project this information into a secure, cloud-based database for information sharing. The authors point to a similar centralized effort that has apparently been successful in TB research.

I think very few would doubt the need for this kind of information. Indeed, the authors point out numerous attempts (albeit decentralized) at achieving this, and consensus panels (eg at ISSCR) recognizing the need.

The problem with this commentary is it doesn’t move far beyond urging the community that this kind of resource is needed and I think it’s already clear to the community that this is true. I think an effective commentary in Nature Genetics would provide more of a concrete path forward, and some tangible ideas on how to overcome the very substantial barriers to the enterprise proposed by the authors. The barriers are many and they are formidable, including:

1) Scientific – stem cell science is in its infancy; the community is still grappling with how to reprogram somatic cells and how to differentiate pluripotent cells into different somatic cell types. There are issues of epigenetic memory, ignorance over whether different reprogramming methods produce the same cells, and a plethora of non-standardized differentiation protocols. Differentiated cell cultures are heterogeneous and single cell profiling is just beginning to be undertaken in a few labs with access to the cutting-edge technologies required. It is becoming clear that most of the noise in cultures relates to heterogeneous genetic background and cell populations, rather than a “disease signature”. This is true in even isogenic cells differing at only a single genetic locus. Before we create a database, we need useful information to be stored there and I think some clear indication of what that information might currently be, given the nascent status of the field, would be a
welcome addition to the commentary.

2) Ethical – Any advocacy for the sharing of personalized biological data needs to address the ethical issues attendant upon this information. How will we deal with different IRB protocols and their variable conditions on information sharing, the potential risks of de-identification of material in “the cloud”, the types of consent required to use MHC-matched lines for regenerative purposes in other individuals, etc.?

3) Cultural – The authors allude to the need for collaboration. Unfortunately, there will be too many in the scientific community who will be hesitant to share their data to protect their intellectual property, publications etc. This is an intensely competitive field and this issue needs to be confronted overtly. Incentives for collaboration should be spelled out, and concrete precedents in other fields need to be stated. The authors point out a recent effort in TB – can they point out specific positive outcomes from this initiative, for disease research and patients, but also for individual researchers?

While I am absolutely in favor of the ideas projected in this commentary and recognize the timely nature of the message, I do not think this commentary in its current form – particularly if it is a stand-alone piece – goes far enough to push the stem-cell field forward.

Reviewer #3 (Remarks to the Author):

This commentary entitled “Databases and Collaboration Require Standards for Human Stem Cell Research” by Nadia Litterman and Sean Ekins emphasizes the need for a collaborative effort from industry and academia to build a comprehensive, mineable, and freely available database or repository to enable sharing of data with regards to stem cell research. The idea of the authors is to build a database with common nomenclature and minimal standards that will accelerate discovery and drug development. The authors illustrate an example of tuberculosis research where this database model has been tested.
The authors describe the current field of embryonic/iPS stem cell research and indicate the major potential of the field for human health, but they also illustrate in depth the challenges and roadblocks such as variability of differentiation, efficiency, and phenotypic outcomes. They mainly attribute this to a lack of standards, nomenclature, traceability, interpretation of data and poor repetition. They conclude that these challenges hinder industry to advance stem cell research into therapies.
The authors reviewed the literature and online sources for already existing databases that contain some of the information needed to move the field forward and how they can be useful for integration into a large database, but the authors indicate that most of the existing databases as data silos and not accessible for the community.
The authors indicate that this effort for the functional, lasting database needs sponsorship, world-wide support, active participation, and continuous maintenance to become successful resource for the stem cell community and to fulfill translational goals towards therapies.

It is a well written commentary pointing out a challenge of collaborative efforts to advance a scientific field to benefit patients more readily.
The authors give an excellent background where the field is and what the current bottlenecks are that need to be removed. All of this should be documented in a comprehensive database.
Suggested improvements: One aspect to complete the picture of stem cell research in academia and pharmaceutical industry are the “stem cell research enabling biotech companies”. These biotech companies have an extreme power to shape the field with their products/kits and setting their own standards. Today’s research does not rely on making one’s own buffers and buying individual chemicals for experiments, but ordering kits and premade formulations for experiments. The standards and optimization in this case are set by biotech companies. Not sure how this can be addressed and how to find an objective way to build this into a comprehensive database. Many of the commercially available kits work, but they contain proprietary formulations or supplements.
For completeness, the authors should include the California Institute of Regenerative Medicine and the New York Stem Cell Foundation (maybe others) as authorities to ensure standardization and to provide financial support.
The company Iperian was mentioned in the manuscript and their shift in focus from iPS cell model company towards an antibody program. For completeness, Cellular Dynamics International http://www.cellulardynamics.com/ is a successful model of a company that is providing iPS-derived differentiated cells to customers under standardized optimized conditions.

Conclusion: Overall, it is an important topic that will find interest in the stem cell research community. The authors point towards the right entities but do not propose a concerted plan how the collaboration and transparency between academia and industry needs to be approached which seems to be the bigger challenge than building an open-access data warehouse.

Clearly the final published version is modified from that submitted to Nature Genetics, we were actually encouraged to submit by the Editor.. and unfortunately the reviewers had other ideas. Thank you DDT peer reviewers for liking it.