Translational regenerative medicine research: essential to discovery and outcome

Abstract

Regenerative MedicineVol. 2, No. 3 EditorialFree AccessTranslational regenerative medicine research: essential to discovery and outcomeChris Mason & Peter DunnillChris Mason† Author for correspondenceAdvanced Centre for Biochemical Engineering, University College London, London WC1E 7JE, UK. Search for more papers by this authorEmail the corresponding author at chris.mason@ucl.ac.uk & Peter DunnillAdvanced Centre for Biochemical Engineering, University College London, London WC1E 7JE, UK. Search for more papers by this authorEmail the corresponding author at chris.mason@ucl.ac.ukPublished Online:21 May 2007https://doi.org/10.2217/17460751.2.3.227AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Today’s pharmaceutical business had its origins in the late nineteenth century with the dramatic expansion of a new industry based on chemical synthesis. By the time that modern biology began to be established as a basis for medical intervention after the Second World War, this chemistry had been immensely refined and scaled-up. Not surprisingly, it became the basis for the chemical pharmaceutical era that dominated the scene for the following 40 years. Because of this history, the chemical pharmaceutical industry and the academic scientists associated with it tended to focus almost completely on discovery and gave little attention to scale-up. The half century of applied chemistry and chemical engineering usually meant the eventual mass production went smoothly. This process apathy was, however, shattered with the discovery of more complex but potentially potent biopharmaceutical drugs. Unlike small-molecule drugs, there was no history of large-scale processing – the science of genetic engineering was too new so quite often scale-up did not work.Biopharmaceuticals are drugs such as recombinant proteins and monoclonal antibodies that are produced by means other than direct extraction from a natural (i.e., nonengineered) biological source [1]. The starting materials are typically engineered microbial or mammalian cell lines. Being produced in living organisms, the challenges to mass production include extracting and purifying single human-engineered proteins from the thousands of host proteins and other cellular contaminants. This was problematic in the early years but the results are now spectacular. For example, recombinant erythropoietin, which is prescribed for the treatment of anemia caused by chronic renal failure or cancer chemotherapy, generates billions of dollars every year. Revenues from such products have propelled Amgen (Thousand Oaks, CA, USA) from a start-up biotechnology company in 1980 to a top ten position in the league table of the world’s leading drug companies. Indeed, biopharmaceuticals are now the fast-growing part of the industry.Regenerative medicine materials will be an even greater challenge for mass production because live human cell therapies are several orders of magnitude more complex than proteins. Quite simply, the process will define the product because it cannot be characterized by the kind of analyses that can completely specify small molecules and even some smaller proteins [2]. To the basic stem cell scientist, this difficulty might not appear to matter much. Given a passionate interest in the exciting biology, the translation process can seem distant and alien. However, there are important connections, both in terms of scientific and funding issues, in addition to the overall goal of delivering safe and effective therapies to patients.Governments and individual states, such as California, increasingly want to see a return on the very large sums of money they commit to research [3,4]. The long-cherished freedom of the research funding agencies to choose their fields of activity is much more constrained as issues, such as climate change, national security and exhaustion of energy sources, loom and so demand research. Strong funding of fundamental research, whether for discovery or translation, will only be assured if there are successful commercial outcomes or a major impact on the quality of life. If regenerative medicine can both satisfy patient expectation and reduce the spiraling healthcare costs in an era of greater old-age dependency, it will be a major contender for more government funds.As well as this political connection, there are also scientific reasons why successful translational research will be good for academic scientists. It is another reflection of the complexity of stem cells and their progeny that achieving consistent results is more difficult than with molecules, even large ones. At present, the achievement of reproducibility in discovery research labs is often a challenge. The efforts of the International Society for Stem Cell Research (ISSCR) Stem Cell Standards Committee in facilitating international guidelines and standards is a reflection of this global realization. However, there is an aspect of consistency that is closely associated with more translational research. This is concerned with the impact of the physical and bioprocess engineering environment upon such cells. It is increasingly clear that factors such as dissolved oxygen tension and mechanical forces are critical, in addition to more established ones, such as pH and temperature. To understand and control these effects and, for example, the impact of delays between operations on outcome, demands an attention to consistent operation. This is given much more emphasis when the object is translation to multiple preparations of highly regulated living materials for patients than is usual into laboratory discovery studies. In research laboratories, both intra- and inter-operator consistency tends to be harder to achieve in procedures that are largely manual. In this situation, the demands of translational activity will have value to discovery scientists in defining how consistency can be achieved and, increasingly, how semi or full automation of certain operations can yield a better outcome, even at the discovery stage.The first tentative steps in such translational research are now visible [2]. However, they must cope with the fast-moving situation in the underlying science. There are major doubts over exactly what adult mesenchymal cells are and the extent of their proliferation potential. With human embryonic cells, there are uncertainties over the uniformity of the cell lines derived from blastocytes. Such issues bear heavily on translational research. This does not imply, as some basic scientists would suggest, that translational research should be put on hold for a decade – the healthcare needs are too immediate and ambitious entrepreneurs have never waited for every last detail of the science to be available. Rather, what is needed is the closest possible dialog across the discovery–translation research boundary and a willingness by both groups to borrow ideas from other fields [5].In all countries at present, it is small biotech and start-up companies that are pressing on towards commercialization of regenerative medicine. Being sensitive to their investors’ expectations of high returns in short periods of time, their absolute priority must be to demonstrate clinical efficacy by whatever methods are immediately to hand. The best of these companies are well aware of the needs that will follow for full-scale production with high reproducibility and acceptable cost. However, the companies cannot afford to embrace much basic translational research and, although a few robotics and instrument companies are helping by the adaptation of devices originally developed for the biopharmaceutical sector, they too are constrained by the lack of significant market pull at present [6].We should not underestimate the size of the step between manual operations, with the character of conventional medicine procedures, and those that can sustain a new industry. The notable absence of major pharmaceutical companies from the regenerative medicine field is a measure of the difficulty they see in creating the kind of business they are used to. In many instances, the challenge is made greater by the availability of existing approaches, such as bandaging of skin ulcers and insulin for diabetes. Neither is very satisfactory but they are proven and have achieved economies of scale. The gains from regenerative medicine are also often hidden in social care costs that can all too easily be missed in comparisons. Over time, efficacious stem cell-based therapies will appear for conditions, such as heart failure, stroke and Parkinson’s disease, that have no effective treatments, although these will tend to take longer and unfortunately governments get impatient. If they and other donors are to persist in funding basic research, they need some successes and these are most likely to come if the translational research base is there for the start-ups to use.The danger in tight public funding situations is that discovery and translational researchers see one another as competing for the same funds and set out to argue which is the more important. The early days of biotechnology proved that this was not the way to go. In funding terms, what both parties gain most from a coherent approach is the rapid establishment of a field clearly visible to government as exciting and showing promise of delivery. In biopharmaceuticals, it was the early successes with medicines such as recombinant insulin that countered other early disappointments, proved the value of therapeutic proteins and encouraged more basic research. Anyone with any familiarity with the history of, say, therapeutic antibodies knows that we will see early niche successes and some expensive disappointments. However, that will be equally true of the other top government and state research priorities, such as renewable energy.What regenerative medicine can distinctively promise from a united discovery and translational research community is a successful and sustainable commercial activity driven by advanced knowledge and capable of being integrated into existing sophisticated clinical services. It therefore offers an economic healthcare-based solution to tackle the burden of degenerative diseases in the growing proportion of the elderly, which is a top government priority. It also has the potential to produce world-class centers of clinical excellence in regenerative medicine that will generate substantial revenues from ‘healthcare tourism’. If the community can argue these virtues and demonstrate strength and cohesion across the field, it has the best possible chance of attracting the government support so necessary for underpinning such a demanding new field.The more advanced regenerative medicine becomes, the more it will involve a highly sophisticated clinical input. The clinician is already heavily engaged in a rather distinct aspect of translational research towards this goal. He or she tends to find the growing burden of regulation a wearisome extra load on an already exhausting professional combination of research and clinical practice. Here too, there is a large potential gain from linkage to those engaged in translational research towards industrial goals. For the latter, the achievements of a workable as well as rigorous regulatory framework is a target inseparable from bioprocess research. Everyone will gain from consistency here too [7] and indeed without it, as other industries such as diagnostics have found [5], it is not possible to achieve the best medical outcome.Molecular therapies have been the basis of extraordinary advances in quality of life and have also prevented millions of premature deaths. However, in many cases, they can only hold the patient in a state of tension with their disease, as is the case with insulin and diabetes. Regenerative medicine has the potential, for the first time, to achieve a state of full health without repeated treatment with all its associated side-effects. However, due to the increased complexity of the therapeutic material, the translational challenges also increase. Therefore, in order to build the future ‘Amgens’ of the regenerative medicine sector, it will be essential to achieve close cooperation and interactivity between basic scientists and bioprocessing engineers, and to do this early. In the case of penicillin, the first ‘big’ medicine from cells, it took 20 years for translational research to catch up with discovery. As a result, more people died in the interim from conditions that penicillin could have treated than were killed in the Second World War. We need to do better with the new paradigm of regenerative medicine. Plainly, great medical science is only ‘great’ if it produces real benefits for patients and is not ‘lost in translation’.Bibliography1 Walsh G: Biopharmaceuticals: Biochemistry and Biotechnology (2nd Edition). John Wiley & Sons Ltd (2005).Google Scholar2 Mason C, Hoare M: Regenerative medicine bioprocessing: building a conceptual framework based on early studies. Tissue Eng.13(2),301–311 (2007).Crossref, Medline, CAS, Google Scholar3 Proposition 71: The California Stem Cell Research and Cures Act of 2004.Google Scholar4 UK Stem Cell Initiative Report and Recommendations. Department of Health, UK. November (2005).Google Scholar5 Mason C, Hoare M: Regenerative medicine bioprocessing: the need to learn from the experience of other fields. Regen. Med.1,615–623 (2007).Link, Google Scholar6 Department of Trade and Industry Global: Watch Mission Report: Advanced Cell and Tissue Therapies – A Mission to the US. September (2006).Google Scholar7 PAS 83: Guidance on Codes of Practice, Standardised Methods and Regulations for Cell-based Therapeutics, from Basic Research to Clinical Application. DTI in collaboration with British Standards Institute, UK. November (2006).Google ScholarFiguresReferencesRelatedDetailsCited ByScalable microcarrier-based manufacturing of mesenchymal stem/stromal cellsJournal of Biotechnology, Vol. 236Concise Review: Hurdles in a Successful Example of Limbal Stem Cell-based Regenerative Medicine3 January 2014 | Stem Cells, Vol. 32, No. 1Reproducible culture and differentiation of mouse embryonic stem cells using an automated microwell platformBiochemical Engineering Journal, Vol. 77Quality control in cell and tissue engineeringDeveloping assays to address identity, potency, purity and safety: cell characterization in cell therapy process developmentJessica Carmen, Scott R Burger, Michael McCaman & Jon A Rowley15 December 2011 | Regenerative Medicine, Vol. 7, No. 1Human embryonic stem cells hemangioblast express HLA-antigens22 April 2009 | Journal of Translational Medicine, Vol. 7, No. 1 Vol. 2, No. 3 Follow us on social media for the latest updates Metrics History Published online 21 May 2007 Published in print May 2007 Information© Future Medicine LtdPDF download