From bench to bedside on stem cell therapy for heart repair and vice versa: do we need a new consensus? John Martin British Heart Foundation Professor of Cardiovascular Science, University College London

Stem cell science What have we achieved? Much biological information. Little clinical knowledge: in the heart - something in other organs - very little.

Difficulties Translation Cells → animals → man There is almost an infinite number of combinations. We need good ideas to define the path. Creative ideas of quality arise in the collaboration of different disciplines in an environment of intellectual freedom. Or, man → animals → cells

Difficulties In the past science was ideas based, driven by excitement and personal commitment Now increase in industrial type projects driven by administrators, publications granting bodies promotion appointments salary

Difficulties Stem cell regeneration is a new science Discovery of a new organ (e.g. Harvey) → controversy within basic science within clinical science between basic and clinical science between politicians within the media between funding bodies

Contrast stem cell research with beta blocker research Beta blockers: Slow evolution over 90 years Specific understanding of defined molecular species and a receptor Strong industrial – academic collaboration Basic science and clinical science linked and reciprocal Stem cells Sudden discovery Little understanding Little industrial support Evidence of disjoint between basic and clinical science

Difficulties Will funding bodies continue to fund stem cell science if efficacy, in any organ, is not demonstrated soon? We make more promises encouraged by a press to which governments respond. When will the press turn?

Differences Basic science seeks truth, but cannot find it because of infinite complexity. Medicine seeks the truth for the individual, a finite objective, but cannot find it because of the heterogeneity of disease, the population base of clinical trials and the complexity of the individual. Law does not seek truth.

Differences Science brings melancholia. Medicine brings fulfilment in the thanks of the patient. Law makes money.

Good Medical Practice (2006) The duties of a doctor registered with the General Medical Council Patients must be able to trust doctors with their lives and health. To justify that trust you must show respect for human life and you must: Make the care of your patient your first concern Protect and promote the health of patients and the public Provide a good standard of practice and care –Keep your professional knowledge and skills up to date –Recognise and work within the limits of your competence –Work with colleagues in the ways that best serve patients' interests Treat patients as individuals and respect their dignity –Treat patients politely and considerately –Respect patients' right to confidentiality Work in partnership with patients –Listen to patients and respond to their concerns and preferences –Give patients the information they want or need in a way they can understand –Respect patients' right to reach decisions with you about their treatment and care –Support patients in caring for themselves to improve and maintain their health Be honest and open and act with integrity –Act without delay if you have good reason to believe that you or a colleague may be putting patients at risk –Never discriminate unfairly against patients or colleagues –Never abuse your patients' trust in you or the public's trust in the profession You are personally accountable for your professional practice and must always be prepared to justify your decisions and actions.

Problems What is healthy criticism and what is destructive rivalry? Questions: What “quantity” of mechanistic understanding is necessary before translation to man? tensions between basic and clinical science What is the best control in clinical trials? Should clinical control methodology be established in animal models?

Cardiovascular gene therapy Ylä-Herttuala, Martin Lancet 2000;355: Understanding of biological mechanisms necessary for translation Stem cells and repair of the heart Mathur, Martin Lancet 2004;364: Understanding of biological mechanisms not necessary for translation

The understanding of the mechanism of action of a therapeutic is always provisional, dependent on the state of science at the time. In translation safety is the overriding concern, but a risk has to be taken. Should we produce “therapeutics” or should we understand biology?

Need collaboration For mutual psychotherapy For understanding To create novel ideas To design the best route to translation (is it “the shortest route to the negative answer”?)

Need collaboration Ideas needed which are novel of quality of relevance Generated by mixing different disciplines in an environment of freedom

Use of autologous cells in large randomised control trials in patients with: – Acute myocardial infarction – Late presentation myocardial infarction – Heart failure (both ischaemic and dilated) Use of autologous cells in small clinical mechanistic studies Studies to test use of cytokines

British Cardiovascular Collaborative on Stem Cells and the Heart Meets every six months Approx. 50 basic and clinical scientists Real debate Little joint experiments

Conclusion Stem cell basic science augments some of the “depression” of science. Clinical science is difficult and the threshold risk is difficult to define. Competition may lessen the chances of funding. New ways of collaboration within and between basic and clinical science are needed.