A perspective from clinician & researcher: An interview with Prof. A. Ghofrani, FPVRI

PVRI Member Authors: Michael Seimetz, Nikki Krol

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Dr. Michael Seimetz (MS):

 Hello Prof. Ghofrani, thank you very much for coming here and taking the time for this interview. Prof. Ghofrani, in profession you are a physician, a clinician. But in addition, you also work as a scientist. The question is why. It is very time-intensive, why do you that? Why do you think it’s important?

Prof. Ardeschir Ghofrani (AG):

 Well, you may know this already, but I had a previous history, starting as a scientist. Then in parallel to my medical studies, I worked in the laboratory quite extensively, both on acute models of lung injury and chronic models of pulmonary vascular disease. So this was my heritage basically, before I re-started doing my clinical work. When med school was finished and my doctoral thesis was finalised, I then became more and more interested in both patient care and clinical studies, clinical science. And I found it, at least for myself, quite fulfilling, and also basically the goal of my career would be more in the interface between basic science and clinical application, what we nowadays call translational medicine. Before this new title was invented, in our working group we were already living this translation from bench to bedside. So that was the start of the kind of work that I’ve been doing the last couple of years until now. I think that mainly the beauty of it and the reward you can personally get from it, when you are involved- it is of course a team effort, but still, when you are part of the train that delivers new treatment to patients- that is the ultimate goal you can have, in my view at least, when you follow the career of a physician scientist.

 

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MS: I think in the last ten to fifteen years the methodology and equipment have really improved. It has become more efficient and allows us to do more complicated things. But can you remember back when you first started working- what did the lab look like? What was the methodology? 

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AG: So, I started in a physiological lab. We worked in the group of Werner Seeger and Fritz Grimminger, in those times we were very much interested in the basic physiology of lung function, and particularly the interaction between the ventilatory and the circulatory system. From there on, of course, the experimental setting became more and more complex. So in these physiological and also pathophysiological models, the readouts became more and more sophisticated. So instead of only measuring organ weight and pressures, for instance, we became more and more able to measure subtle function of the organ by means of elaborate measuring technologies. Things moved forward, and we became interested in the metabolism of these organs, in the inflammatory responses, in the signalling cascade and cells that were involved. That was the reason why, for instance, the morphology and histology was implemented in the technologies of the laboratory. That was also at a time when the molecular biology aspects became more and more interesting and also available to our laboratory. You said very rightly that this was an incremental process for which none of us was a, let’s say, ‘generalised expert’ for all the fields that had to be addressed. But fortunately, with the growth of the group, we were able to hire and also to engage new members of the research group who came to us with a given level of expertise in particular technologies. That’s how the group gradually grew, and of course it was also necessary to be able to keep the scientific standard- sometimes even be ahead of the scientific standard and technologies- to be able to be innovative and original. So that was basically how it started- it was very basic settings with quite- at that time it was advanced technology, compared to nowadays we’d say quite basic technology, but then of course there was this gradual evolution of expertise in different areas, and that is I think also one of the secrets of this group, that it steadily grew. The new additions to the group were very carefully chosen and nicely complimented, I think, the existing expertise.

MS: If you look at recent publications, let’s say from the last years, you can see the New England Journal of Medicine papers, which contain very nice clinical studies, and most people know, for example, the Sildenafil studies, very exciting stories, the work that you and your colleagues did. What would you like to tell us about the story, the Himalaya story?

AG: *laughs* Yeah, I think that was nice piece of translational success, as you said. The intermediate step was basically a volunteer study in otherwise healthy people, who simulated a disease situation, which basically happens to all of us if we expose ourselves to prolonged periods of environmental hypoxia. What you basically do is take an otherwise healthy person, put him or her into an environment in which you become sick. In this case, you develop pulmonary hypertension and consecutive right heart loading. In fact, that’s a very attractive way to build in an intermediate step if you have already uncovered a new signalling mechanisms, a new molecular target- maybe a new medication- could be useful to a certain disease, but the proof is currently limited to in vivo animal models, or even ex vivo but in the respective organ chronic animal models. And then you really want to go to the patient. Sometimes you are hesitant, because you are not quite sure whether undesirable effects could occur, which you haven’t seen in the animals but you’d really like not to expose your patients to before you really know if the concept works. And to prove the concept, in the sildenafil story that you mentioned, we decided to build-in an intermediate step in otherwise healthy volunteers who undergo a transient period of a disease which fortunately resolves in all of them once they come back down to sea level, but which very closely resembles the situation of the patients. Before that, there was a three or four years very sophisticated basic research program that strengthened the hypothesis and also the identification of the involvement of phosphodiesterase 5 in the evolution and the promotion of pulmonary vascular disease. In fact, our lab was amongst the first to show that PDE 5 is much stronger regulated and important for maintenance of normal pulmonary vascular function than it is in the erectile organ of the man for which the drug was originally invented and clinically approved. So we were able to show that this enzymatic system plays a much more important role in the lung circulation than it does, as I said, on demand in the erectile male organ.

 But to be able to show the concept that this inhibitor of the phosphodiesterase 5, which in that case was sildenafil, displays beneficial effects in the lung circulation required and disturbed lung circulation. You cannot find out in a normal pulmonary circulation whether PDE 5 inhibitors have a desirable effect, because the effects can only be displayed once there is a disturbance in the pulmonary circulation, namely if the pressure is elevated, if the resistance is higher, and also if the cardiac function is impaired. So we took Sildenafil, and we could have given it to healthy volunteers whom we put into a pressure chamber. But for the disease to evolve you need many days up to several weeks so you can’t do this just by exposing volunteers to short-term hypoxia. And I think at that time at least no institutional review board or ethics committee would have granted approval for a clinical study protocol in which you caged in 20 healthy people in a pressure chamber for 8 weeks- that’s not ethical. But it is ethical to accompany people who expose themselves voluntarily to a hypoxic state for a long period of time- and these are mountaineers. So we accompanied a highly trained group of professional mountaineers, who aimed to summit the Mount Everest in 2003. And in agreement with them, and according to best clinical trial protocols and clinical practise guidelines, we conducted a randomised, double-blinded, placebo-controlled trial in those healthy volunteers that exposed themselves to become pulmonary hypertensive. And we were able to show, and that was one of the major concept that it works, were able to show that the PDE 5 inhibitor, under conditions of hypoxia-induced pulmonary hypertension, reduces pulmonary hypertension. In turn, cardiac function improves, and not only at rest, but also during exercise. So it was the first proof that you could pharmacologically improve exercise capacity under hypoxic conditions. And of course, if you translate this to the patient situation, you can easily imagine that a patient who has either an underlying lung disease, but goes along with – in this case- internal hypoxia which has an effect on the pulmonary circulation, that you could overcome this mechanism. Of course, also for other patients with chronic pulmonary vascular disease, this could be a good option. Once we saw that it worked, we had good experiences with a few patients who received the PDE 5 inhibitor sildenafil, in a kind of compassionate treatment use. We and others published data in the early 2000s in a larger series of patients, of course uncontrolled data so far, and controlled that it was an efficacious treatment from which a lot of patients could benefit. Ultimately, of course, the randomised phase III placebo controlled study aiming to gain approval was conducted and was highly significantly positive. This led to the approval of sildenafil which, since then, is amongst the most frequently prescribed, if not the most frequently prescribed drug for pulmonary hypertension.  

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MS: The sildenafil story is really a fantastic story- it started from the basic science and finally went to patients, and the sildenafil was also approved for treatment of pulmonary hypertension. But if you look at recent publications, you and your group were not just a one-hit wonder. You also contributed to other potential treatments and even treatments, let’s say for example the recent soluble guanylate cyclase stimulator riociguat, which is now also near approval to treatment for pulmonary hypertension. What do you think is the difference between your group, the Giessen group, and others? Because it is very rare that you can find treatments, especially for pulmonary hypertension.

AG: Well, if there is a difference at all, and I don’t know that there is, I think that the whole community of so-called PH specialists worldwide is a very powerful community. In fact, as a worldwide network we work very closely together, at least at the final stages of clinical approval. So this network is key for the last step before a new treatment is a really deliverable to patients, after it has undergone very strict study protocols, placebo controls, with all the requirements according to the international guidelines. This is a collaborative effort, and really all the PH centres worldwide are united under this same philosophy that new treatments should be tested before they are given to patients, and for that purpose we have a clinical trials network. I think the exclusive situation in Giessen is that we have the fortunate situation that we have a very powerful basic research group, interested in many aspects of lung diseases, of which of course the core-interest is centred around the pulmonary vasculature. But also a lot of work is ongoing to increase our understanding of chronic lung diseases, parenchymal lung diseases, airway diseases- there is a lot of work ongoing with regards to animal models that provide us with clinically relevant information for human disease. There is a lot ongoing to try and decipher signalling pathways that are involved in different lung diseases. And all the evidence then comes together because many people inside this very large group interact very actively. We have regular sessions with our junior faculty, with the PhD students, with the post-docs who present the ongoing work- and that allows the group to generate collective ideas, basically. And from those you can even make a choice, depending on how ‘at reach’ a potential treatment is. The easiest way, of course, is if you identified for a disease a hitherto unknown signalling pathway, for example: you’ve clearly identified a molecular target. And then you go and screen the available therapies, and find out that there is already a medication, a molecule, available that is currently used for a completely different application. No one ever thought that it may play a role in your disease of interest. And that shortens the development time considerably, as was the case of sildenafil: the drug was already marketed for the treatment of erectile dysfunction. And then we and others found that it plays a potentially even more important role in the pulmonary circulation, but you didn’t have to invent the molecule from scratch, you did not have to investigate on all the pre-clinical science that is necessary, toxicology studies, first in man studies to prove the tolerability and safety and so forth; there was a marketed drug which was safe to be used in man. So that was a true shortcut, the same that of course occurred in the development of tyrosine kinase inhibitors, which were of course approved at that time for the treatment of oncological disorders. And then we could take the agents that were clinically available and forward it to patients, because we found out that the PDGF pathway signalling may play an important role. Slightly different from that was the story of riociguat, because riociguat is a molecule which has never been used before in patients. But we knew from research that was done in our group and in collaboration with colleagues from the company which produces riociguat, and also the inventor of the molecule, Johannes-Peter Stasch, we had very early interaction. And together we figured out that it may also play a role for pulmonary hypertension. That was the start of the clinical development, when we received this novel compound which was not clinically available, and that subjected it to all necessary steps until two independent randomised phase III controlled trials, which led ultimately and fortunately to the approval of this new compound. MS: You mentioned that as a clinician you work together with basic scientists, and pharmaceutical companies. And somehow, obviously, you are successful. Do you think it is necessary nowadays for clinicians to engage with the corporate network?

AG: Well, I think that we first of all have to acknowledge that academic research is still a very powerful tool, because you can investigate, you can design study protocols, you can follow concepts, more or less without any restrictions. The only restriction may be financial, but depending on the success of the group, and the rate of success of the grant applications, you’re basically not limited in what you’re doing as long as you have a reasonable concept, and you don’t waste money, but really invest it properly. That’s the first thing. The second thing is that academia has to acknowledge that we are not yet drug-makers. We cannot design and develop and produce drugs from scratch. And because of that we are very grateful for a very fruitful and early collaboration with the pharmaceutical industry, which has the capability to design drugs- even custom made. If you come up with a new concept, they can even screen their pipelines, and then find molecules that are designed in a way that they match the therapeutic needs, and become an eligible treatment for patients, for instance. So acknowledging the strengths but also the weaknesses inherent to academic research, I personally believe that it can be very fruitful to have early collaboration with pharmaceutical industry for the mutual interests and benefit of both sides. After a certain intellectual step has been undertaken from academia, from there on to develop in a collaborative fashion new treatments for patients- in my view this is quite an efficacious approach. Interestingly, there is a new trend which you may have followed, in which some pharmaceutical companies downscale their in-house research, and instead set-up collaborations with specific academic centres, which they know are 1. Much more specialised, 2. Much more streamlined in their particular field of interest. Additionally, the costs-effect for the entire healthcare system may be reduced by this approach, if not every single pharmaceutical industry, let’s say, has to provide the whole variety of exponential/experimental settings, programs, staff, but rather selectively cooperate with academic centres which are known to have a certain pre-clinical and clinical expertise. So that may shorten the duration of new drug development, may save resources overall, and may even help make drugs a little bit cheaper.

MS: Maybe, hopefully! I think based on your success in Giessen, different initiatives were founded, such as the Excellence Cluster Cardio-Pulmonary System, the German Lung Centre- these centres show somehow that the importance of research is nowadays recognised by the country. And in addition, based on your research, you were one of the founders of the PVRI. So we now have this annual meeting what do you think is the benefit for patients derived from the institute and the meetings?

AG: Well, in the very early days of the Pulmonary Vascular Research Institute, there was a very small group of people who thought that, despite the achievements in the field of pulmonary vascular diseases that had been achieved until then, that there was still a high unmet need to be addressed, particularly in the disease entities, that were not addressed sufficiently, at least in our view, a couple of years ago, namely, pulmonary hypertension associated with high altitude; pulmonary hypertension in associ ation with inflammatory disease or infectious diseases, such as schistosomiasis or HIV. But there was also a big educational gap regarding awareness of pulmonary vascular diseases, and the impact it may have on the general public’s health. The founders of the Institute, and the main driving forces at that time of course were Ghazwan Butrous, colleagues such as Stuart Rich, Martin Wilkins and Evangelos Michelakis- all the founding members- and from our group Werner Seeger, Fritz Grimminger and myself, we thought that there were many gaps to close. And that became the philosophy of this Institute. First of all, we wanted to be as inclusive as possible. So the Institute is very liberal in including members: basically anybody who is interested in the subject can apply and becomes a member; and becomes as valuable and important as any presumably ‘eminent’ person in the Institute. So it is a very collegial atmosphere. Secondly, one of the major achievements of the leadership group is that from the first day, the aim was to become global. To really try to encourage colleagues around the world to utilise their own expertise locally, to build up satellites of the PVRI, to become their own Pulmonary Vascular Research Institute. And this has now been achieved in many areas of the world, very successfully. They are very active branches and chapters of the PVRI, now spread all over the world- so it becomes a real world-wide network of people interested in pulmonary vascular diseases. And then of course comes the question of how we can cross-fertilise each other with the knowledge we have, how can we, let’s say, provide expertise regarding basic research with our group, but to collaborate with groups who have a geographic advantage and/or interest in a disease that is not so prevalent in our area. So this is already something the PVRI is executing on a daily level. There are many many fruitful collaborations, and therefore I think that the whole concept of the PVRI is already very successful. In addition, some initiatives have been undertaken inside PVRI to fulfil the goals that the Institute has set for itself- namely, educational purposes. PVRI is very active in using modern technology such as e-learning; web-based databases and registries, to increase the knowledge about PH also for people living in developing countries, who may not have all the resources to travel to international conferences, yet now get a handle on very important lectures and data, and even some histological specimen that are stored online that can be reviewed and learned from. So there is a lot ongoing in the field of clinical research, collaborative research on the basic research level, as well as on the level of education. And all that, with very  very small resources. I think this is one of the secrets of success- there is not a lot of money needed to potentially achieve great success with that kind of concept. And that, for sure, is something that particularly Ghazwan Butrous is the driving force for the success of this Institute in that way. 

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MS: I fully agree- I think Ghazwan did a great job, for example if you see the amount of members, which is steadily increasing every year. What role do you think the PVRI will play in ten years, even just in the future of pulmonary hypertension? AG: Well, for me it’s crystal clear that the PVRI is the main platform for people who are interested in the pulmonary circulation, starting from the very basic research up to clinical trial design and conductance, also with regards to educational purposes and exchange of information and thought and building up global networks and databases- I think that PVRI is really our main society for people who are interested in the pulmonary vascular disease area in general. I also believe that PVRI can offer more and more as a clinical trial platform, as we have collaboration and access to many many sites around the world, and have deep insight into the quality of work that our colleagues are doing, and it’s excellent in many many places around the world. But with this insight, we can recommend and even include clinical trial sites around the world for particular trials- that is another strength. But as you said, one of the biggest treasures we inherit is the interest of our colleagues in this Institute, and the steadily growing numbers of members, considering this institute started with 7 or 10 founding members and has now grown to a membership number in the upper 3-digits- and hopefully we’ll have a couple of thousands when we do this interview again in five years. 

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MS: Okay. Coming back to the quality of work that you mentioned; you’ve published in very high-ranking journals, but do you really think the impact factor reflects the quality of the work? For example, Aaron Chiechanover, he got a Nobel Prize for the discovery of ubiquitin-mediated protein degradation, and he published his data in a low-ranking journal. What do you think about that? AG: Well personally I believe that the impact factor is helpful. The journals that have a very high impact factor have this impact factor for good reason, because they proved that they publish science that is both of interest to a large readership, it’s frequently cited, and in most cases it is also durable. Because the quality criteria that were set for the papers that are finally published in those journals are very strict and very high. Having said that, sometimes fundamentally new ideas, that are against the mainstream, at a very early stage do not find their way into those high impact journals. Because of course, it is inherent to the system that current experts review the papers, and they value them, and sometimes they disagree with a completely different paradigm, or a completely different view on something that appears to be clear, and therefore the paper may be rejected due to the advice of the reviewers. And then it gets published in a lower-ranking journal, or a new journal that has not yet collected an impact factor due to technical reasons. Still, the research published there can be fundamental. So, not everything is dependent on the impact factor. Still, as a rough measure of quality and importance, the impact factor will remain important and certainly also a selection criteria. Having said that, I think with reference to the Pulmonary Circulation journal, I’m very sure, knowing about the quality of the research that is already published at a time when the journal, just because it’s so new and so young, does not yet have an impact factor, just because it needs time to accumulate a certain number of published articles and also a certain time over which statistics can be conducted to get an impact factor, I’m sure that we will have a good impact factor to begin with, and I’m sure the impact factor will further increase over time as the papers are already highly cited because of the quality of the work and the excellent job of the editorial board of Pulmonary Circulation. It is already, despite the fact that it does not have an impact factor, the most concerted and specific organ for people interested in the field of pulmonary vascular research. And that’s why I think that it’s a self-fulfilling prophecy to say it will become one of the most important organs that we will have for publication of topics related to the pulmonary circulation. 

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MS: Okay. One last question. You are very successful but you started as a young unknown scientist. What would you suggest to young unknown scientists and investigators today as important for their career? AG: That’s a very difficult question! I mean, part of success, however you measure it, is also related to chance and luck. My chance and luck was that I started in an already very active and successful group of scientists and researchers. I had excellent peers and role models in my PI’s, who were Fritz Grimminger and Werner Seeger at that time, but also I had excellent colleagues whom I started to work with in the very early days, who are still very good friends and still active collaborators, such as Norbert Weissmann and Ralph Schermuly. I think if you’re part of an interested and active group, that’s already a key to success. That way you can really develop things collaboratively, and compensate maybe for things that your partner is not as good in but on the other hand you benefit from the special abilities that your collaboration partner has. That’s one thing. The other thing is of course that we had a very supportive environment in Giessen. The university was always of help. The university hospital supported much of what we did. This also enabled us to conduct our studies with a lot of support from the environment. And ultimately of course, it needs passion, and you need a vision to really be able to overcome frustrations and drawbacks, which are inherent to research and everyone, young and old scientists alike, will repeatedly experience drawbacks and frustrations. But to overcome these, because you have a vision, a longterm vision, it keeps you on track and keeps your performance high, and you must never lose the trust that you can achieve your goals; you just have to be sustainable, you just have to not let yourself get frustrated and discouraged, even if you don’t have continuous success. At the end of the day, I think you should follow your vision, follow your goals, and partner with good friends. If you are lucky enough, find a good place, because the environment is of course also very very important.

MS: Thank you very much for this nice talk. 

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PVRI Chronicle Vol 1: Issue 2 cover image

December 2014

PVRI Chronicle Vol 1: Issue 2

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