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slide show december 2002 |
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The Swiss national research program NFP37 'somatic gene therapy':
success, disappointment, or something inbetween?
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slide show december 2002 |
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click here to download the slide series (1 Megabyte!)
slide 1: CV S Rusconi and title of the report.
My CV illustrates the fact that my competences are not at the medical level but rather at the molecular biology level. I have been interested since almost twenty years in the possibilities of gene transfer into living organisms, initially with transgenics, later with somatic transfer through viral vectors. I have interpreted my nomination as the scientific director of the NFP37 as due in part to my long-standing interest in gene transfer questions (including an early collaboration with the team of R Seger) and in part to my location at the university of fribourg, which is at the border of the two cultures, thus a 'neutral' place which should give a 'neutral' director. There were advantages and disadvantages from that choice, for instance the fact of not being a medical doctor could have complicated the interaction with the clinicians involved in the NFP37. Nevertheless, this did not happen, at least in my interpretation. The duty as director did coincide with my initial years as full professor and the workload rendered these years quite busy, and I must confess that the aspect that most suffered from this adventure was my own research.
slide 2. Gene therapy's principle is simple Yes, but the devil is in the details
Many things in common life sound simple in principle, like getting a train ticket, parking a car or counting votes in a ballot. However, some erratic details make sometimes these activities extremely complicated, confusing or time consuming. This is a bit what happened with gene therapy. At least when thinking of monogenic diseases (caused by a hereditary single loss of function of a gene). In that case if one manages to bring back the functional gene in the relevant tissue, then the disease should be compensated. So if we have the cloned gene and we have patients with the disease, it is sufficient to combine these two. Yes, but the detail is precisely 'how to do that efficiently, safely and with a persisting effect'. We shall come back to those questions in the next slides. Further details can be seen in another commented slide show at genetherapy2003ecpm.html
slide 3. Somatic Gene Therapy's Principles (somatic gene transfer)
The principle in somatic gene therapy is to re-insert either permanently or transiently functional genes into somatic cells in order to cure or treat a disease condition. This can be a genuine hereditary disease, but can also be an acquired condition, such as a trauma, an infarct or an infection. Thus gene transfer can be used for the treatment of acute conditions, chronic conditions or even as a preventive strategy (vaccination). Examples of currently studied popular disease models are illustrated in slide 34 at genetherapy2003ecpm.html
Slide 4: Somatic Gene Therapy's four fundamental questions
In one gram of soft tissue there are about thousand millions of cells and if willing to transform them genetically, our artificial gene should be designed and formulated no only to enter into the cells but into their cell nucleus and possibly to stably integrate into the genome. This is obviously not such an easy task and depending on the type of disease that we intend to treat, we have to manage to comply to the following needs: efficiency of gene transfer (which percent of cells can we attain); specificity of gene transfer (which sub-type of cells or tissues can we target and how can we avoid the trans-gene being inappropriately expressed); persistence (do we need, and if so how can we guarantee the transferred gene to continue to act and the engineered cells to survive long enough to exert the therapeutic effect?); toxicity (how can we guarantee all of the above with a minimum of short term and long term toxicity?). Some specifications of toxicity and other risks are recapitulated in slides 39 and 40 at genetherapy2003ecpm.html. All these properties must be included in the type of gene transfer vehicle (the so called 'vector') and in the method of delivery.
Slide 5: TWO classes of gene transfer vehicles: non-viral & viral
There are essentially two classes of gene therapy vectors: nonviral vectors and viral vectors. Nonviral vectors include various formulations in which a DNA segment (usually a plasmid) is packaged into delivery particles such as liposomes or cationic polymers, or is delivered ad pure DNA either by direct injection or by helps of pressure, ultrasound, electroporation biolistic particle acceleration etcetera. In either case the delivery is usually rather inefficient if counted in number of transfected cells per number of used DNA molecules. The major barrier does not seem to be the penetration of the cell membrane since this can be tricked out by exploiting natural endocytosis or internalisation pathways. The biggest trouble seems to be to decorate the DNA such that it is protected from degradation while in the cytoplasm and such that it finds rapidly the way to the nucleus. Within the NFP37 program there has been one research team successfully addressing this nuclear translocation enhancement of nonviral DNA formulations (Nat Biotechnol. 2001 (12):1155-1161). Viruses are small protein particles that protect and accompany a DNA or an RNA genome. Their peculiarity is that they have evolved all the properties that we would like to have from a gene vector: they protect the DNA while outside the cells; they can recognise specific cells (specificity); they can very efficiently internalise (efficiency) and protect the cargo from lysosomal degradation and can find the way to the nucleus. Finally some viruses contain activities and sequences that permit their efficient integration into the genome (example retroviruses). This is the reason why engineered viruses have been the preferred vehicle for many gene transfer protocols of these last thirteen years.
Slide 6: THREE classes of physiological gene delivery
Anatomically, gene formulations can be delivered in various manners. A very laborious but relatively safe method is the ex vivo gene transfer. Cells are explanted from the patient (example bone marrow cells), then briefly cultured in the laboratory. There they are exposed to the gene therapy vector. After transduction, the residual vector is rinsed away and the cells can be selected if an appropriate marking system has been included in the transfer vector. Reinfusion of the treated cells will recolonise the affected tissue, hopefully restoring the missing function. This protocol is the one that has given the best therapeutical values so far (see below). A second popular protocol for some treatments (such as tumors or localised disease such as in the eyes, joints, brain) is the local in vivo delivery of the vector. The advantage of this delivery is that there is usually little dissemination into the rest of the body and therefore there is no particular risk of contamination of germ line cells by the transfer vector. About the question of germ line cells see also slide 14 at genetherapy2003ecpm.html
A third highly desirable but still poorly applicable way of delivery is through compartments that permit a broad diffusion and readsorbtion of the vector (intravenous, intra-arterial, intravascular, intraperitoneal). These types of application are extremely simple but must be coupled with a number of arduous conditions: how to make sure the vector is not trapped unspecifically (e.g in the capillary system or by scavenger cells); how to make the vector stable against antibodies and against degradative enzymes (in the serum or in the lymphatic fluid), How to make the transfer particles preferentially accumulating in the proximity of target tissue (e.g how to interpret the vascular zip code)?, how to make the vector docking and entering specifically into the target cells (e.g going though several cell layers, and how to select the proper cells); finally how to prevent similarly delivered vectors to reach the germ line, thus contaminating it with events of random insertional mutagenesis?
This is the reason why we still need several years of research before being able to safely and efficiently deliver genes though systemic protocols
Slide 7: Gene therapy turns teenage in 2003, but: has it really grown up?
The fundamental questions and the model diseases did not change since the first trials registered in 1990. Our appreciation has instead probably changed. For instance the correction of the ADA deficiency by the earliest ex-vivo lymphocyte transduction protocols were for long time considered to be unsuccessful, but this was probably due to the concomitant administration of a therapeutic enzyme that did not permit the engineered cells to have the necessary selective advantage. This was reportedly demonstrated in 2002 by C Bordignon who, with essentially the same vector and delivery system employed in 1993 was able to cure two young patients, exactly because they could not be supplemented with the rescuing enzyme xref. I take this example to demonstrate that taken at face value it seem that we have learned very little, because we worked under the wrong impression that a protocol was not working, while it was working satisfactorily, and thus we have lost a decade in turning around the same corner. In fact it is exactly the opposite, because the impression of non-functionality prompted a spectacular number of attempts to create new vectors new systems and new strategies. Thank to that big effort we have today much better vectors and will have even better ones in few years.
Slide 8: Gene Therapy in the clinic: Trials World-wide
Gene therapy has been extensively tested in experimental clinical protocols. About 630 trials have been registered and 3500 patients treated. Somebody may be perhaps surprised by the fact that the majority of protocols has been devoted to cancer-treatments (see cumulative plot of trials versus time). The monogenic hereditary diseases, which at least theoretically should be the best models for gene therapy represent only less than 20% of the trials. Another consideration that is noteworthy is the large number of trials in clinical phase I and the extreme small number in phase III (less than 1 %). I remind that a protocol must go successfully to phase III before being ready for registration (which is yet not guaranteed).
Slide 9: Gene Therapy Milestones
In this slide I mention some of the successes scored by gene therapy protocols in the past years. In fact those are all erratic or anecdotal and not systematic successes, and the history was also marked by many failures. For further comments about past and recent failures go to slides 38 and 40 of genetherapy2003ecpm.html
Slide 10: The reality is that all current popular gene transfer vectors have intrinsic limitations
The small number of successes and the several failures can be explained by the simple fact that all the vectors that are in the gene therapist's weaponry have some intrinsic limitations. Some are efficient but cannot persist, some can persist but are not efficient or can package only a small insert, some are specific but are neither efficient nor specific. It is something like trying to assemble an engine that produces a lot of energy, yet with minimal fuel consumption, minimal noise, minimal greasing needs, very light weight, and that can last a very long time without repair. Even the extremely promising second generation vectors such as lentiviral based or adenoIII have some intrinsic limitations. They still have to be clinically tested and they probably will show a reasonable potential, however they will not be able to make gene transfer as efficient ad as safe as we all want. This is the reason why the current trends go in the direction of hybrid vectors that combine the advantages of two (example a vector that has the same high-infectivity as an adenovirus but can specifically integrate into the genome). Also several attempts are devoted to the idea to make totally artificial particles that include many features present in viruses. This is probably the third generation of vectors that will bring gene therapy out of the current loop circuit.
To have some idea about the various currently available vectors you are welcome to consult slides 24-30 of genetherapy2003ecpm.html
Slide 11: Ups and Downs of Gene Therapy: a true roller coaster ride!
The immediate consequence of such difficulties has been the relatively slow clinical progress of gene therapy. People used to say: 'gene therapy has cured a lot of mice but no human being'. Even if this statement is incorrect because some patients have genuinely benefited of gene therapy, it remains that the score has been meager. On top of that there have been several pitfalls that brought the mood back to extremely low level, just when the whole field was convinced that we had reached a safe cruise speed. There was a setback in 1995 when the first adverse effect reported by R. Crystal prompted the NIH to issue a moratorium and to force the scientist back to their labs before testing gene transfer on patients. Another major setback happened in 1999, just when extremely good news from the preclinical application of lentiviruses and generation III adenoviruses made many people dream. the death of Jesse Gelsinger (caused more by clinical malpractice than by the intrinsic toxicity of the adenovector that was used) prompted the NIH and the FDA to start a major investigation and to halt several trials. Just months later the extremely good news from the trials of A Fischer with the persisting cure of X.SCID xref and later on the encouraging data of Kay and colleagues on the treatment of haemophilia xref were bringing the mood back to high levels (although the media snobbed those good news). This was spoiled in 2001 by the debate suscitated by the alleged germline contamination by AAV and also by the alleged tumor incidence increase found in some animals treated with AAV transfer in the liver. Again, the spirits were brought up by the encouraging experiments by C Bordignon in 2002 (correction of ADA) and by the semi-secret announcements of the next-to-come clinical trials with lentiviruses. The adverse event reported by A Fischer in October 2002 (see adverse.html) followed by a second case reported in January, brought us back to the mood of the post-Gelsinger days. Frustration and disappointment. But gene therapy will recover, because it is its destiny.
Slide 12: NFP37 early times: visions anno 1993/1995
The gene therapy NF program was proposed in the early nineties by a triumvirate of scientific eminences: Marco Baggiolini, Bernard Mach and Charles Weissmann. They conveyed in their initial project all the enthusiasm and the naive perspectives of those years. With this i do not pretend those people were naïf. The generally accepted perspectives seemed indeed very solid and gene therapy appeared just as one of those examples cited in slide 2. Just matter of implementing it and ameliorating here and there and we get it. That is why in the original vision the idea was to establish two centers for clinical gene therapy with some attached research. This idea progressed into a more nuanced view in later sessions of the founding committee. Although still in January 1995 the establishment of a core facility for GMP production seemed to have a high priority, as if the concrete part of gene therapy would have been just in front of the door.
Slide 13: NFP37 gets realistic: paradigm change in 1995/96
Finally it was chosen extremely wisely to call for research proposals. 57 letters of intent came in and 30 were invited for a full grant proposal submission to be refereed. Finally 18 were granted for the first operational phase (1996-1999).
Slide 14: NFP37 operational phase 1, 1996-1999
The NFP37 entered its operational phase in late 1996 and had its first annual meeting in October 1997. A second annual meeting followed in October 1998. the quality of the presented research was considered to be very appreciable by the external speakers that were invited for plenary lectures. In august 1998 a call for proposals or renewals for the second operational phase was launched. 26 submissions were sent to 60 international experts. After two experts meetings finally 17 thereof were retained for granting. The operational phase II started in November 1999, Just after the third annual meeting which was exceptionally over two days and coincided with the setback of the Gelsinger case.
Slide 15: NFP37 operational Phase 2, 1999-2001
The second operational phase went rather smoothly with some delays and reports complements. There was a fourth extremely well attended i day annual meeting and a final three days meeting to celebrate the conclusion of the program. At that meeting there was also a round table on the situation of experimental biology research in Switzerland, with the participation of Franco Cavalli, Renato Galeazzi and Heidi Diggelmann.
It was quite laborious to convince the grantees to send their final reports and also to fill in some evaluation forms, and this work left some unfilled gaps. Also it was quite unrewarding to note the loss of enthusiasm by some members of the expert's board (fortunately not all) who had to be reminded dozens of times to send in their final evaluations.
Slide 16: NFP37 research categories
'Many were called, few were selected'. The rate of granting of full-size proposals was about 2 out of 3, indicating rather strict selection criteria. Sometimes I wonder how many applications would be filed these days (January 2003), with the current grim news and discouragement of the field. I estimate probably less than ten valid basic research projects plus a couple of clinical trials.
The subdivision of disease-orientation trends within the NFP37 was parallel to the international trends, with cancer-oriented strategies being mostly investigated. The level of research mostly represented was the fundamental one (with emphasis on vector-development), added to some preclinical approach in experimental animals and finally a small sample of genuine clinical trials. One of the trials (Baumgartner, limb ischemia treatment) was a multicentric trial at Phase I-II, the other trials were in Phase I. With two exceptions (Aebischer, therapy of ALS and Seger, Therapy of CGD) they were all multicentric trials.
Slide 17: NFP37 Major outputs 1: publications
It was difficult for the direction to summarize how many publications were generated as direct sponsoring by the NFP37. On one hand the researchers did not mention specifically the NFP37 program but only generically the Nationalfonds, on the other hand they did not send us all the necessary informations. Thus I made a survey at the end of the program and I specifically asked how many peer-reviewed publications, how many invited reviews and book chapters etc were published by each research team. Although not all the forms were returned (only 33 from 44 sent) I came to a sum of 119 genuine publications, 13% thereof in high impact journals, 32% in moderate impact, 22% as reviews or book chapters and 33% as PhD theses. It is possible that there will be further publications deriving from the research sponsored by the program but it will be extremely difficult to count them in absence of a serious and professional follow-up. There were also some other notable types of outputs: some meetings and workshops, two founded companies and five filed patents.
Slide 18: NFP37 Major outputs 2: annual meetings
The organisation of the annual meetings was the activity that took a fair amount of my time resources. First of all i had to travel myself to a certain number of meetings to directly know the people and get effectively acquainted with the who's-who in the field. Otherwise, just sending an invitation from the office would have meant an inevitable refusal. My request for assistance to the experts (launched only the first year, and asking them for suggestions about names of people to be invited) was met with a very meager response. therefore I had to proceed personally. Although it was time and energy consuming, this activity also gave me the possibility to directly touch this field and to get a certain profile. All in all the five meetings can be considered a reasonable success, from the attendance (over thousand attendants) as well as from the science quantity and quality (over 200 abstracts and over 40 high quality plenary lectures). It was particularly encouraging to notice that there were almost 50 abstracts from non-NFP37 teams and that many of the attendees were not directly attached to NFP37 teams. This suggests that the meeting was well perceived by the target scientific community. A negative point was perhaps the modest enthusiasm of the NFP37 experts for the meeting. With the exception of Dr Braga and Dr. Karlsson (and Dr Danos who was one of the invited speakers of the last edition), there was no other expert who attended. It was positive to note that the president of the experts board Bernard Mach and the NF Referent Marco Baggiolini attended quite a few times. The scientific secretary Françoise Kaestli was a constant and encouraging presence. A survey on the meetings is in preparation as an annex of the final report, including video clips of the last two editions (2000 and 2001).
Slide 19: NFP37 Major outputs 3: public impact
Gene therapy is a topic that suscitates a vivid interest in the public opinion. Myself I was progressively involved in a tornado of conferences at various levels: general public, business oriented public, science-oriented public and several interviews or contributions in different media (newspapers, magazines and TV or radio). All this costed also a fair amount of energy, but again contributed to open up my profile to new areas that I could never have touched otherwise. SWe started our WEB site 1997, initially only dedicated to internal business, then also directed to public lay people, with pages of media reactions and reports (starting with the Gelsinger case in 1999). Recently this WEB site has been hosting also some special pages on the human reproductive cloning claims (which have not much to do directly with gene therapy but this was posted exactly on the purpose to mark the difference), and on the serious adverse events that plagued the trial of Alain Fischer in Paris (October 2002 and January 2003, with likeable further queues). The visits on this WEB site have constantly increasing and are currently around 500 per weeks, with peaks over 100 in coincidence of mediatic events (e.g cloning or adverse events). It is certainly remarkable that a WEB site that is not offering gadgets, games, nudes, or not even particularly attractive graphics, can suscitate so much attention. By looking at the statistics many clicks come because of searches, but many other come from 'faithful' visitors who have this site in their bookmarks. A fund from the European community (EUREGENETHY2) will permit the conduction of this site at least until 2006.
Slide 20: Players 1: Experts Board
The board of experts was absolutely instrumental in conferring a scientific credibility to the granting procedure (coadjuvated of course by the many external referees)., and in the process of continuous monitoring of the scientific quality. All of them had the necessary competence and some were giving constant and useful feed-back when queried with some business or science-related questions. Nonetheless, some of them were less easily and promptly complying to their duty and this had sometimes slowed down or complicated the work of either the scientific secretary or myself. We came to the point of having to substitute some of them for lack of cooperation (I will make no name). As said initially the board of experts was initially presided by Charles Weissmann followed in 2000 by Bernard Mach. Both of those presidents demonstrated a very wise vision and an excellent political flair. Unfortunately, the change of presidency also implied a certain change of philosophy and both of the presidents were sometimes difficult to recruit if not for very urgent business. This was certainly due to their overbusy life style.
Slide 21: Players 2: Scientific Secretariate
By far, the most productive cooperation was coming from the scientific secretary Dr Françoise Kästli. This partner was absolutely instrumental in exerting the necessary authority in reminding grantees referees and even myself of the deadlines (either approaching or long past ones). I think that in absence of this strong input the work would have been stalling several times. Besides the routine work of forwarding the tons of documents and organise encounters and consultings, Dr. Kästli always had some useful advice in semi-critical or critical situations and i am profoundly grateful for her input. Without this help my work would not have been so concrete.
Slide 22: Players 3: Scientific Director
Here I am speaking about myself. As anticipated in slide 1, my competence field was specially at the level of gene expression and at the beginning I had zero competence at the clinical level and only a superficial knowledge of the real problems behind gene therapy. For instance I could not tell the difference between a Phase II and a Phase III trial. During these years i became familiar with many medical concepts and also with several business-related topics. So, all of that was 'learning by doing' but I must be thankful to the program to have exposed me to this opportunity. This sense of having learned a lot reminds me of an anecdote. In the spring 1997 I met Charles Weissmann at the Brupbacher symposium. At that time he was the president of the board of experts and it was natural to chat about the NFP37. At his question of how i was doing I answered that in that first year i had learned a lot. He replied cool as usual 'how much you learn only depends on how little you knew beforehand'. Well, five years later, I have the privilege to be considered an 'expert' in gene therapy who has the uncommon advantage of not being burdened by a conflict of interest since I am not involved in companies whose future depends on the well being of gene therapy. It is kind of a pity if this painstakingly acquired competence would be lost, and this can happen very quickly if I would not be able to attend at least one specialised meeting per year and to maintain some subscriptions to specialised journals. Fortunately, a small grant by the EU Network EUREGENETHY will probably allow this limbo situation to persist until 2006.
There were also some clouds over my directorship of the NFP37, the principal one was that my personal valence for conducting my own research was strongly diminished and this resulted in an awfully long scientifically rather 'productively sterile' (at least in terms of peer-reviewed publications) period. However, I think that I can come out reinforced from this experience.
Slide 23: Players 4: Service Presse et Communication
I am afraid that this slide does not tell exceedingly good news, since the support that i had from the P&C section was vanishingly small. Although the SP&C has some good infrastructure and a certain competence, the persons that were supposed to assist us at that time were not much pro-active and in fact even sceptical about the entire program. Therefore I unfortunately could not (or perhaps I was not able to) get much assistance from the SP&C. Talking to other program directors I heard similar impressions. Definitively, the relationship between the SP&C and the NFPs has room for improvement.
There were two categories of grantees: the basic scientists and the clinicians. Many of the former were characterised by a good and genuine enthusiasm, whereas the impression of some others was that they applied for granting just to have an additional source of financing and without the slightest intention of doing real gene therapy presently or in the future. In some cases it was even evident that the application was just camouflaged into something hat looked like related to gene therapy while the intention was obviously another. Those names will not be disclosed here but they will be clearly mentioned in the report destined for internal use. From the clinicians I did not have the impression of some just applying for an alibi-research but rather of genuine though sometimes naïf interest in this approach. Please understand that I am saying 'naïf' as much as we all were sort of 'naïf' at that time. One thing that disturbed mostly (which is not specific to this particular medically-oriented research) was the mutual looking-down of the two categories. There was in general a publicly undisclosed but informally very marked disrespect of each others' competence, and this is a very bad sign that will certainly impair the progress of many further biomedical projects. The success of molecular medicine relies on the close collaboration of fundamental scientists and clinicians and if there are such emotional (almost ethnical) barriers this success is relegated to the few exceptional spots where such collaborative effort really materialises..
Slide 25: Evaluation by grantees, human resources
As mentioned before I have sent an evaluation form to be returned with several answers. One set of questions concerned the number of involved people. This could have been probably deduced from the financial reports but this would have been too laborious. According to the answers There has been over 4000 person-months of full-time involvement. The categories of personnel are mentioned in the graph. As expected almost 60% of this time was spent by PhD students and postdocs. The data concerning the engagement of the principal investigators are probably not much credible, since most of them did not dedicate exclusively to their NFP37 projects. There were also people who did not appear in the financial report as being on the payroll of the nfp37 but that were involved thank to the mobilisation of other resources. Still from the returned evaluation forms I learned that apparently over 3000 month-person must be added to the contributors of this effort. This brings the sum to an impressive amount of over 7000-month-person involved in the NFP37.
Since the operational phase lasted about 60 months (in reality almost 65 months due to various extensions) we deduce that at any given time over 110 persons worked full time for the projects. This implies also that the NFP37 mobilised more people than it could possibly finance, and this could be considered a success factor. However it must be pointed out that a great part of that balloon deflated very rapidly when the NFP37 funds terminated. many research teams went back to their original research, some simply vanished and only very few maintained de facto a part of the focus on gene therapy (see comments on slide 28). This cannot be blamed totally on the bad will of people but could be in part induced by the general low mood that has been entering the field in repetitive occasions (see also slide 11).
Slide 26: Evaluation by grantees, funding considerations
This slide tries to summarise the expenses categories that I have gathered from the returned funds. Obviously this could have been reconstructed again from the financial reports but it would have again required an intense scrutiny of all the various voices. About 80% of the expenses were in form of salaries and about 4% was dedicated to the organisation of the annual meetings and the 50% assistance secretariate that the NFP agreed to assign to the director for compensation of his dedication to this role. The majority of grantees perceived the funding as just appropriate (44%) or even generous (11%). 45% of the grantees declared that they would have liked more funding than the received ones. It was interesting to note that the most successful teams (in terms of publications) belonged to the category of 'satisfied' while the many of less productive ones felled in the category of the 'unsatisfied'. Taken from the view of the referees this is satisfying because the could argue that the money was well distributed. Taken from the view of the less successful scientists the picture is of course diametrically different. It must be emphasised that the NFP37 also invested 500'000 Fr for sponsoring the production of clinical grade material (GMP material). Thus, from that point of view this investment was probably the best proof of the concrete assistance for the clinical investigations by this program.
Slide 27: Evaluation by grantees, Perception of input from the program
The majority of the responding principal investigators declared to be extremely satisfied by the quality of the annual meetings and considered them as useful to indispensable. Also they declared by majority to have been positively influenced by attending the meetings. This is of course very gratifying, although I am not so sure whether all the answers were genuine or just checked in that manner just to please the director such that he would be happy with it and would not bother them anymore with further queries. Contrary to why the readers may believe, the preceding one was a very serious statement.
Slide 28: Evaluation by grantees, Opinions on own future
To the crucial question 'At which level will your research prospectedly maintain a focus on gene therapy?' Over 50% of the returned forms had the choice 'significantly maintained'. There are reasons to believe that this was overstated for the same reasons expressed in the preceding slide. In fact only 4 teams declared that SGT will remain their major focus. and those are probably the only truly believable ones. Also fully believable and honest are those 8 team leader who declared that they would abandon SGT research. To the question of how they would imagine the best way of funding for somatic gene therapy, 17 out of 30 answers chose 'a specific slot of funding'. This means that many investigators are convinced that somatic gene therapy should be financed separately and with a specific quota. it is an interesting point of view but it would be difficult to implement. Perhaps it would be better to envisage a specific slot for biomedical research rather than for specific disciplines. However, it is not the role of the NFP37 director to make these proposals, but rather they should come from the basis and be negotiated with the 'top'.
Slide 29: Players 6: Institutions
This is a 'mostly bad-news' slide, and a serious cause of concern and comments from my side. Universities, which are the gotha of the fundamental research, were not as such involved in this program. they showed no attention, neither at the beginning, nor during the operational phase and even less after the end of the program. The universities did not pay particular attention to the successful NFP37 teams and did not grant them some additional support and expansion possibilities., negative examples are Bern, Basel and Geneva. Fribourg was totally inert and did not even slightly support an initiative of the program director of creating a Swiss gene-based therapy network in form of an NCCR. Bern even dismantled a very promising research unit and totally abandoned the concept of gene therapy as a potential research focus. These were my biggest deceptions. Zuerich Kinderspital was the only exception because it reinforced the CGD therapy team towards a long term research unit for molecular therapy of immunodeficiencies. This was probably the biggest success of the program, since the team Hossle-Seger started as a relatively low key group but came near to clinical implementation towards the end of the program. Momentarily this trial is suspended as many other because of the fuss around suspicions of adverse effects of insertional mutagenesis in the trial of Alain Fischer in Paris. Updates on this story are posted on out page: adverse.html.
Why did the university officials care so little about the NFP37? I think that this is simply due to unawareness because of general structural problems with the NFPs as a whole. If the funds of the NFPs would be subjected to a similar procedure as the EU funds (with signature by the rectorate) and if they would be clearly linked to a sort of 'contract' in which the university formally commits to follow-up on successful teams, then the situation would be entirely different. Again, as simple molecular biologist I cannot change the world, but perhaps it would be useful if this option would be discussed seriously by the Forschungsrat. Otherwise the NFPs will remain just another slot of anonymous funding (essentially a business between the NF and the applying investigators) and will not be perceived as federally considered top-priority research. Is this the spirit that originated the NFPs?
Slide 30: The 'Swiss Gene Therapy Army', as of March 2002
According to the survey and to some personal enquiries i could assemble a picture of the 'legacy' (some people said 'the leftovers') of the NFP 37 adventure. 14 teams declared their maintenance of commitment to gene therapy research (perhaps overstated, as mentioned under slide 28, however two of the teams are clearly internationally top-recognised). The NFP37 granted five fellowships for specific postdoctoral training abroad and within the program about 40 doctoral students were trained in various aspects of human gene transfer. Even if we assume that only 1/3 thereof will maintain this research interest, I think it will be a great achievement for long term perspectives. Furthermore two companies were started and 7 patents were filed. We can even dare to calculate these trained persons in value. I know that all this can be easily criticised, however in my view 1 doctoral degree is worth about 1 million Sfr and one postdoctoral about 1.5 millions Sfr (these values are only the sum of crude costs from the high school up to the final training, and do not represent the potential latent value which is much bigger) . If we count all together, this makes a product of about 50 millions Sfr of gene therapy-oriented training. If we count the companies and the patents we easily come to a final product of over 60 millions Sfr. This is not bad if compared to the investment of less than 15 millions. Therefore, also the economical implications of the NFP37 should not be neglected. Outside the NFP37 gene therapy research also progressed very well (part of those teams were guests at our annual meetings). The large pharmaceutical companies have demonstrated only a transient and mild interest and seem currently more attracted by going through the next series of investor-oriented promises of genomics and cell therapy, than in solving the real problems of the yet potentially promising old good gene therapy.
Taken together there is still a reasonable framework in our country for continuing a solid and serious experimentation of therapeutical human gene transfer both at clinical and fundamental level. The major question will remain the criteria and modalities of financing (see comments on slide 26, 34, 34, 35 and 36)
Slide 31: What was achieved / not achieved
Little remains from the initial vision of creating two national centers for clinical and basic investigation. Four pre-existing/emerging teams with serious gene therapy commitments were reinforced (Aebischer, Baumgartner, Seger, Trono). Other teams were either discouraged and continued with other funds or just had a transient relationship with gene therapy. The major disappointment was indeed the rather meager cooperation between clinicians and fundamental scientists. But as we know, these interactions cannot be imposed and require a bottom-up motivation. The NFP37 provided some incentive to stimulate this cooperativity, but this was clearly manifested only in two cases. In all the other, the 'Roestigraben' between clinicians and scientists either was only cosmetically covered or remained blatantly visible. As said (comments on slide 29) if the Universities cannot be involved in this incentive, then a research program has only a very limited manoeuvring room. From the training point of view we can proudly declare 'mission accomplished' (comments on slide 30). The question remains: who will quantify which percentage of these trained people will indeed be re adsorbed into the Swiss research/clinical system as genuine gene therapists?
Slide 32: Own personal costs and benefits from the direction activity
The NFP37 was generous with the directorship and assigned a 50% secretary who immensely helped to conduct the daily business and also contributed to the conduction of the program itself. Also a postdoctoral salary was attributed, but this could not be covered continuously with a person who could really take care of the laboratory routine during my many absences. This is in partly due to the peripheral location of our Fribourg campus, which is not so attractive for young fellows who combine a certain level of talent and ambition. As a consequence there were a large number of unfinished or badly finished theses and diploma works which could not be published and my scientific credibility has strongly diminished during these last five years. This was compensated by a strong visibility in the field of gene therapy (even without major publications) and a solid personal training in the who's-who and what's-hot of this field. It is a pity that I will probably not be able to capitalise much on that knowledge, since there is no structure and little room for continuing research in this direction at the University of Fribourg, whose medical department (and probably the entire science faculty) is so obviously in the periscope of the restructuring aims of the federal strategists. Therefore, my personal know-how (which as said in slide 3 has the advantage of not being contaminated by strong conflicts of interest) could be rapidly diminishing, and this is certainly neither encouraging nor particularly motivating.
Slide 33: Limiting factors: structures, mentalities and functions
In this slide I recapitulate some of the factors that I think were and still are limiting, if willing to translate a program in clinical research into a successful adventure. As a first point I remind that the lack of a serious follow-up of the effects of an NFP threatens the very spirit of the NFPs (which as i understood are meant as 'seed money', yes, but what is the purpose of 'seeding' if nobody is going to watch whether anything grows from those 'seeds'?). Specially in experimental biology, the fruits of a research come decades after, and therefore it is difficult to say 'now' whether this program was a success, and inert effort or a failure. As mentioned before I think that the Universities should be made more aware and concerned about the short term and the long term feedback. The two above points are factors that are probably rate limiting for all the NFPs as they are conceived today. Finally, the chronic attitude problem between clinicians and basic scientists (which is neither new nor typically Swiss) is a factor that renders particularly arduous any effort that requires a strong collaborative effort of those two categories. This is a problem that cannot be cured with a small pill, and requires a long term treatment, not the least the intensification, streamlining and also the harmonisation of the MD-PhD programs. Thus, this work must be initiated at the junior training level and it may require several generations before we see the fruits of this effort.
Slide 34: Gene transfer research, are Swiss structures adequate?
A big dilemma today is to establish whether research structures need to be concentrated or whether they better remain diversified. Personally I am sceptical about the benefits of concentration, if the cultural-human problems and conflicts (see slide 33) are not solved before. Certainly Phase III clinical trials of many diseases cannot be easily conducted on a sole Swiss-based format, due to the reduced pool of qualifying patients. Many progresses have been made concerning the number of ethical committees, but their web is still rather complex if somebody intends to mount a multi-centric trial. In terms of registration and safety monitoring, there are reasons to believe that the reshaping of the older structures into the Swissmedic could substantially streamline and
In spite of those logistical difficulties, we have an absolutely excellent training system (and it will remain so unless it will be dismantled in the name of the globalisation pressure) and we have a serious and non-corrupt funding system (which is envied by many other countries). This latter has suffered in the last decade of an evident stagnation due to short-sightedness of some politicians, but recently there have been some really encouraging signals of attribution of the deserved increments.
Slide 35: Fundamental versus applied research: a dilemma for public funding agencies
There is another set of distinctions that granting agencies must clarify when evaluating applications from basic research or from clinical research. This is sometimes difficult to run 'under the same roof'. In fact I heard or read myself negative comments by the NFP37 referees about the supposed lack of originality of a clinical research proposal. This was prompted by the specific question asking for 'originality of the approach'. Effectively, it is extremely rare that clinical experimentations can be considered as genuinely 'original'. This is due to the simple fact that these approaches must be extensively tested in vitro and in pre-clinical setups before being applicable to the experimental patients. It is our own highly praised principle of safety that dictates this condition. Therefore, the concept of 'originality' which is extremely important in fundamental research, is only a marginal factor in clinical research.
There is also another distinction that must be made between fundamental research and applied (or sometimes euphemistically called 'goal-oriented' research). In applied research one tries to solve problems, whereas in fundamental research usually one addresses problems and generates new ones. Most importantly, the rhythm in applied research is usually marked by a priori set milestones, whereas in fundamental research, the milestones are set a posteriori. Also the two research categories have totally different requirements in terms of concentration of infrastructures (useful in applied research, not so necessary in fundamental research) and in the confidentiality levels for the refereeing system (financially important and contract-bound for applied research, only morally-bound in fundamental research).
Research that aims at therapy has both a clinical and an applied character, therefore it cannot be handled with the same structures/parameters as the fundamental research, Our Nationalfonds is undoubtedly extremely well structured for evaluating basic research, but (and here I am not expressing my opinion but what I heard from many clinicians) certainly will require further ameliorations in the sector of clinical research.
I have also a call of warning, because of a trend that seems to increasingly contaminate the Swiss research funding system: the tendency of encouraging of goal-oriented research to the disadvantage of fundamental research. Is this due to the neo-liberalism that pretends that everything should be conducted with a sort of profit-oriented spirit? I sincerely hope not.
Slide 36: NFP37 follow up, needs to continue gene therapy efforts, public understanding and political implications
To conclude, the NFP37 operational phase has revealed that there is a significant interest in this research/application field from both basic scientists and clinicians. The well visited Web site shall continue to operate thank to a fund from the EU (in the context of the EUREGENETHY2 network). Taking all together I remain encouraged to pursue some of the goals of the NFP37 and one idesa is to put together a Swiss core team of somatic gene therapy interessees, with the purpose of promoting the cause of this research at the scientific and at the political level.
Slide 37: END (opening discussion …)
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