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.