Challenges in translational research.

We have seen, with some paternal pride, the first issue of EMBO Molecular Medicine (EMM). I am pleased to see the quality of the articles and the many lively sections of the journal; even more so because despite the excitement for this new initiative, I was slightly apprehensive about what seems to be a never-ending proliferation of scientific journals. In the case of EMM, however, I feel that there is a need to fill the gap that appears to exist between basic research, its application and clinical experimentation, a gap that also impacts on the scientific life and research activity of many of us.

To fill this gap we are moving into a largely unexplored territory, where the excitement of providing new therapies for otherwise incurable diseases must often cope with a number of problems and risks.

»we are moving into a largely unexplored territory.«

The field of stem cell research is currently facing such a challenge. The International Society for Stem Cell Research recently published the Guidelines for Clinical Translation of Stem Cell Research (http://www.isscr.org) in order to advise scientists, clinicians and patients on the necessary steps to be undertaken to start clinical experiments on stem cells with minimal risks and maximal chance of success (Hyun et al, 2008). As a member of the Task force that wrote these guidelines, I experienced the difficulty in writing this document, where almost each word had to be weighed very carefully. On one hand, it was mandatory to propose rigorous controls to make new procedures as safe as possible; on the other hand, it was important to realize that pushing the controls and the rules too far would lead to an arrest of medical progress.

Six years ago, an unpredictable, severe adverse event in a trial of gene therapy for children affected by a congenital immune deficiency led to severe restrictions on the clinical use of genetically corrected hematopoietic stem cells, and to heated debates on the safety of retroviral gene transfer vectors (Gaspar & Thrasher, 2005; Williams & Baum, 2003). Since then, five out of twenty children treated in two different clinical trials developed T-cell leukemia that in one case was fatal (Hacein-Bey-Abina et al, 2008; Howe et al, 2008). Is it possible that more pre-clinical work would have prevented this? Probably not, because the problem had never appeared in any of the animals treated with the same procedure during pre-clinical investigation. Could a deeper analysis of the effects of retroviral integration in the human genome have provided useful information? Possibly, but it should be considered that the sophisticated technology currently used to look at viral insertions into the human genome did not exist at the time, and that the wealth of information now available on the subject would not exist had those adverse events never occurred. Most importantly, it should be kept in mind that the large majority of the patients treated with gene therapy for two forms of lethal congenital immunodeficiency are now alive and healthy – thanks to this ‘risky’ therapy (Aiuti et al, 2009; Hacein-Bey-Abina et al, 2008; Howe et al, 2008).

While the above problem occurred in a trial conducted by internationally recognized groups with an outstanding record in gene therapy, and fully complying with rigorous safety controls, things may become more fuzzy and complicated when we move to the use of pluripotent or multipotent stem cells. Stem cells are not distinguishable from progenitors by any physical feature, and still only poorly in terms of the antigens they express, therefore the only reliable criterion of identification is their biological activity, that in vivo can only be assessed retrospectively. Anyone can work with stem cells and claim to obtain a biological and/or therapeutic effect, with little chance of being controlled in advance. The explosive proliferation of private clinics all over the world that promise therapies for incurable diseases and are the target of ‘stem cell tourism’ is in part due to the above considerations. Warning against these treatments by academics will have little impact on those who are desperate and see a disease progress daily, taking more and more of their own life or that of their loved ones.

Amariglio et al (2009) recently reported that donor cell-derived tumours grew in the CNS of a young teleangectasic patient, transplanted with human fetal neural stem cells in a centre in Russia. The consequences of this situation for the patient and for those who may be treated in the future are not clear and have obviously made the research community apprehensive. The limited information available on the nature of the transplanted cells (Poltavtseva et al, 2003) makes it difficult to predict whether this event is a consequence of inadequate cell characterization or whether it may re-occur in the future, even in the most rigorous and controlled trials. As an obvious and general rule, the cell population to be transplanted should be characterized in deep detail. If fetal or embryonic in nature, strategies should be implemented to either prevent uncontrolled proliferation of transplanted cells, or kill them if such proliferation happens. Also possible contamination by infectious agents should be rigorously assessed.

Other issues such as survival, proper differentiation and functional integration in the transplanted tissue are crucial for the success of the transplant but are less relevant to safety. At present, much of this information is not available for the cells transplanted in the patient, and thus it is very difficult to draw conclusions. Nevertheless, several people will soon state that stem cell therapies are dangerous and should be halted until further evidence is accumulated. But how, if trials in patients are stopped? These voices may not remember that many of the first patients receiving bone marrow transplantation (BMT) did not survive (Thomas, 1999); they may not consider that with current regulations, none of the hundreds of thousands of patients who received BMT would be alive today. So precaution must be rigorous and trials controlled as much as possible, but new therapies must continue to be tested.

Although it is the stem cell research community that is now confronted by this thorny dilemma, similar challenges are likely to arise wherever advances in basic research open up new possibilities for treatment of diseases. In such cases, the risks involved need to be responsibly balanced with the safety of and the benefits to the patient. To report on these challenges and actively discuss them is essential to successfully overcome them, and I hope that EMM will be your journal of choice to report the results of this novel translational research and that it will become the forum for the scientific community to comment and discuss on the topic.