Overcoming the “blood-clinic barrier”: ISSCR 2013

Author: David Brindley, 06/13/13

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Irrespective of scientific discipline, everyone is aware of the blood-brain barrier. Since its proposal in 1900 by Max Lewandowsky, and later confirmation of its discovery in the 1960s – facilitated by the advancement of the scanning electron microscope – it has gripped physiologists and contributed to significant advancements in our understanding of pharmacokinetics. However, as stressed by Harvard’s George Daley, developments in fundamental stem cell science now present another barrier to haematologists: theblood-clinic barrier”.

The production of synthetic blood from human cells is slowly becoming a genuine prospect for the cell therapy community, with licenses to manufacture clinical grade synthetic human blood granted only days ago to Scottish company Roslin Cells. This complements on-going DARPA funding for U.S. based Arteriocyte to develop cell-based blood substitutes for servicemen. Nevertheless, there are a number of multi-stakeholder challenges separating this scientific promise from a widely accessible clinical practice – a number of which are scientific in nature.

  1. Development of Functional Blood Units: The derivation of HSCs from ESCs is well studied, promoting genes, including Cdx4 and HoxB4, into the vernacular. To date, however, HSCs generated in such a manner have not been representative of in vivo HSCs; in part, due to their tendency to exhibit a myeloid bias.
  2. Mechanism of Hematopoietic Ontogeny: Despite the familiar diagrams of the haematopoietic differentiation pathway, we are still unable to effectively and reproducibly control HSC proliferation and differentiation in vitro, in a manner that would yield sufficient cells to support a therapeutic and meet the expectations relating to critical quality attributes (CQAs) required by a regulator.
  3. Culture Systems: At an elementary level, blood is a fluid and as such is subject to three- dimensional hydro-dynamic forces. Conversely, the majority of laboratory scale efforts to produce cell-based blood products relies on two-dimensional static cultures. Subsequently, the bioprocess forces experienced by cells are poorly representative of in vivo conditions, contributing to differences in cellular polarity during formation and differences in subsequent cellular functionality.
  4. Our Choice of Cell: While we are aware of the characteristics of the cells we wish to reproduce in the haematopoietic lineage, we are less certain of the optimal characteristics of the optimal cell(s) to be used as the source material for such a process. For example, a major challenge to utilizing cells already committed someway down the haematopoietic lineage is limitations in their ability to self-renew.

Therefore, while stem cell sources offer great long-term promise as a route to scalable and effective synthetic blood products, and are currently experiencing a peak of interest, it is important to remember that a number of factors constituting theblood-clinic barrier” remain. It is our shared responsibility as members of the cell therapy industry to work collaborative and efficiently to resolve these challenges.

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David Brindley
David is an international thought-leader in the translation of life-science innovations into commercially viable products and services. His expertise spans the ‘Valley of Death,’ encompassing regulation, basic science, process engineering and finance. This distinctive skill set positions David at the forefront of socially responsible investments – in particular initiatives that make impactful contributions to global health. David currently holds a joint appointment between the University of Oxford and the Harvard Stem Cell Institute and is an active Fellow of the Royal Institution of Great Britain and the Royal Society for the Advancement of Arts and Manufacturing. In addition to being an Editorial Board member of a range of international academic and industrial journals, David is also a founder of Translation Ventures, a boutique consultancy that is actively engaged in maximizing the financial and societal value realized from cutting edge scientific innovations. Disclosure: David A Brindley has no other 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 any postings apart from those disclosed. D.A.B. is subject to the CFA Institute’s Codes, Standards, and Guidelines, and as such, the author must stress that his contributions to this site are provided for academic interest only and must not be construed in any way as an investment recommendation.
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