by Harald H.H.W Schmidt
Professor Harald Schmidt, head of the Department of Pharmacology and Personalised Medicine, Faculty for Health, Medicine and Life Sciences at the University of Maastricht spent some time talking to Damian Doherty about his new book ‘The End of Medicine as we Know it–and Why Your Health Has a Future’. He explains in the first half of the book that we are in the midst of a reactive sickcare crisis which needs to adopt a predictive, preventative and proactive systems approach. The basic fundamentals of course underpin precision medicine. He gives us hope for the future in the second half of the book by explaining how we can fix a broken system and create a more efficient and democratized healthcare landscape for future generations.
Q: How long has this book been incubating?
A: The book has evolved over many years. Initially, I expanded my scientific talks and became more and more courageous in questioning our status of medicine and biomedical research, our disease definitions, drug efficacy, and the use of animal experiments. The positive, sometimes enthusiastic feedback encouraged me to be on the right track and go further. Eventually, I changed my research approach, received funding and now I lead several clinical trials. Being optimistic that these trials will work and prove the necessity to radically change medicine, I wondered how these changes could be implemented. I then spoke to many active colleagues and friends who are active in healthcare though. They introduced me to more cracks in the system and eventually engaged with several patient organisations. Then during the CORONA lockdowns, I had the time to sit down and write it all up from front to end in one flow, 2–3 days per chapter. I did not have to research many things. It was all out there, even published in medical journals. I just had to put one mosaic stone next to another and it all made sense. Now it’s all there in one book together with all the evidence. That was a great feeling because I no longer needed to memorize all the little facts and things, I had come across. I even sometimes go back to my book and look up certain references or numbers.
Q: Any lessons learned you could share with anyone contemplating publishing their first book?
A: There may be different motivations for different people when they write a book. The most obvious one is to sell as many books as possible. I assume that’s also the primary interest of a publisher. However, if I’m honest, for me it would also be totally sufficient if some key people and politics and academia, who make decisions, read the book, make the right conclusions and implement the necessary changes. However, I think it needs more pressure, i.e., bottom-up from patients. Thus, the book addresses mainly lay people, patients or hopefully not-yet-patients, to empower them to demand changes and question aspects of their healthcare system. Insofar as I would like as many people as possible read the book.
Q: Can you explain what the book sets out to say and why it’s important?
A: I want this book to be perceived as primarily positive, i.e., about all the opportunities of a much more precise preventative medicine ecosystem that lies ahead of us. However, many people and even insiders of the current healthcare system and state of medicine think things are pretty good. Thus, my book required to begin with a negative, eye-opening part 1, which shows all the things that we do not know and the many false incentives in research and clinical practice. With this sense of a crisis, I hope patients and healthcare providers are more open for the radical change that I demand and outline and that they understand the necessity when entering part 2 of the book and then part 3, which specifies innovations they can use or already apply today, not in a far away future.
Q: Your central analogy with BP resonated given I have hypertension. It made me think about my own underlying cause. Do you see cardiovascular PGx as an obvious starting point for precision medicine?
A: I think it’s a very good example, but we need to operate with clear and indisputable facts, i.e., the important term “numbers needed to treat” and what it means: taking your medication and lowering your blood pressure hardly protects you and still requires intense lifestyle changes. Also, cardiovascular diseases are close to my former background in cardiovascular research. However, I now belong to an “organ-agnostic” systems medicine movement, which wants to overcome organ-based disease definitions. So, my group does not use terms such as cardiovascular or neurological diseases anymore but moves to mechanism-based definitions. To stay with the example of hypertension, we believe we have found one causal mechanism of hypertension affecting primarily the microvasculature which can lead to hypertension but also to heart failure with preserved ejection fraction, cognitive impairment with Alzheimer’s-like symptoms and an increased risk for stroke and myocardial infarction. Quite a mix, you might say. And how should we name this disease? After the molecular mechanism. This is not even new. Most rare diseases are already named after a gene or protein and have symptoms in several organs. When I talk to industry, however, who will bring our new treatments to the market, they are of course still faced with an organ-based medical structure and organ-based “key opinion leaders.” Thus, they will probably need to market the drug not for one mechanism but the three symptoms or organ-based indications, i.e., in neurology and cardiology.
Q: What do you see as the biggest challenge in effecting change with the healthcare ecosystem?
A: Probably prevention. Patients with low socioeconomic status find it very hard to engage into prevention, which is why their life expectancy is 9 years lower. Men live 5 years less and both disadvantages add up to a 14-year reduction in life expectancy. Moreover, even if a person is motivated and able, prevention is currently too imprecise. We cannot seriously suggest seven or more lifestyle changes to everyone but need to identify which of them is the crucial one for the specific patient in front of us. That will be doable, convincing and thus motivating for every patient. Another challenge in the healthcare ecosystem is input-based remuneration, which hardly rewards or pays for preventive measures. Finally, doctors in their 40s with senior positions will not like to hear that they need to change, i.e., to generalize more and give away authority and decision-making. So, I guess this last mile will be the toughest one, but for patients this is the mile that will count.
Q: Has writing the book galvanized any new ideas and projects you’d like to implement in your own work?
A: On the one hand it has been of course a very pleasant experience to receive so much positive feedback from readers from different areas but also health economists and so forth. Probably the most unexpected feedback and new directions came from very engaged patients, for example those affected by Parkinson’s disease. This went so far that I have started now working with them on joint projects, i.e., subtyping, finding causal mechanisms, etc. It’s almost becoming a standard workflow for us. This patient engagement translates also into clinical trials where patients should at least co-define primary outcome measures to make sure they are relevant to them and not just to the investigator or the sponsoring companies and their regulatory approval interests.
Q: Technology often outpaces regulatory and policy advances. Do you fear we’re always chasing innovation whilst overlooking pragmatic implementation?
A: I do worry about that and not all regulators think alike. Without naming specific countries, some are extremely risk-averse and make it extremely difficult, laborious, expensive, and time consuming for investigator-initiated trials. There are others however, like the European Medical Agency’s innovation board and other European institutions, who like to hear more of what we are doing, engage with us and I am pretty sure will support us. Our overarching goal is to achieve approval for our in-silico predictions process for disease mechanisms, patient subtyping, and precision therapy by showing several times that our predictions without fail lead to highly precise therapies. If that happens, we may rapidly see a flow of innovative precision therapies.
Q: Given neurodegenerative disorders are on the rise–how worried are you that our pharma industry continues to focus on certain indications over others?
A: Quite frankly, I think the era of Big Pharma is over. Their concept of billion-dollar drugs for millions of patients at the same time is increasingly failing. They have left many organ-based indication areas, e.g., neuro and cardiovascular, and are now turning almost exclusively to cancer and gene therapy. For many rare diseases gene therapy is the obvious and safe answer but, in a few years, we will have a sufficient set of out-of-patent methods available which we can then apply to almost any gene defect. However, gene therapy is not for multigenetic disease risk with low penetrance. Those complex diseases will remain to be treated with small molecules. Here we are repurposing registered drugs (repo-trial.eu and repo4.eu), which will also soon be out of patent. Thus, in the not too far future we will have all the drugs and therapies that we need at a low price. To produce and distribute these we will still need pharma, but this will no longer be Big Pharma but generic pharma companies and they will certainly no longer claim a substantial fraction of our overall health expenditures.
Q: You talk of modifiable risks–how do we ultimately change behavior? Can public health messaging and incentives work?
A: At the moment, we are spending only 1% of our so-called healthcare budget on prevention. Obviously, prevention has the largest potential to improve public health. Public health messaging and incentives may work. However, prevention needs to be personal and precise and this requires time and skill sets that are not trained in a medical course, and needs completely different professionals, like psychologists, personal trainers, nutritional advisors, community pharmacists, physiotherapists, social workers, and so forth. In the new and truly prevention-oriented healthcare system, not the current sick care system, prevention works so well that, ideally, a patient will never see a doctor.
Q: A forward-thinking healthcare system invests in preventative measures but the dire reality is that the existing status quo of sick care is pretty good for business?
A: Exactly, everyone has settled in very well in the current system. That’s why some degree of top-down change will eventually be needed to enforce things. However, present concepts for prevention are insufficient. They may work statistically at a population level but not individually and need to become much more precise. It is totally demotivating to suggest eight or more healthy lifestyle changes to someone whilst maybe only one of them would be the important one. For example, if a patient has a risk for colon cancer. One key advice should be to eat very little red meat; if a patient has a risk for lung cancer or COPD, they should of course not smoke and not live in an area with highly polluted air; and so forth. So, I think once we can tailor preventative measures in the same way as we will be able for curative therapies people will be much more motivated to engage. Along with this, financial incentives need to move from treatment input to prevention.
Q: You are an advocate of systems medicine–to implement this we need a system reset would you not agree?
A: Systems medicine is focused on a complete re-definition of what we call a disease and how we structure biomedical research and clinical practice. It sounds however more revolutionary than it is once you look at rare diseases. Those are usually named after a gene or protein, which is a very precise disease definition, and they still may have symptoms in two, three, or four organs. In fact, many patients take 10 years or so before they get the correct diagnosis of a rare disease, a patient may easily be diagnosed with four different diseases until a clever doctor or algorithm finally finds out it’s only one disease caused by one gene. It’s easily imaginable how complex things can go if we enter more common diseases with several not very penetrant gene variants with a high lifestyle component. For these we currently use symptom-based disease definitions which are umbrella terms and most likely unify several molecular causes with different comorbidities. But we are making extremely fast progress to unravel these subtypes with the help of outstanding bioinformatics collaborators. Once we present to clinicians that our approach leads to an unprecedented precision in diagnosis and treatment, they will simply not be able to remain where they are. I would foresee that all organ-based disciplines need to reunite again in general medicine, which needs of course massive support by machine learning and decision making algorithms. The good thing is doctors will be relieved from time-consuming repetitive tasks and have much more time for patient engagement and empathetic conversations. Maybe we will then need a different type of medical doctor, not the rocket scientist anymore, but the data doctor-communicator.
Q: How would you go about reforming the peer review system and how could this advance research and ultimately translate to better outcomes in the clinic?
A: I think the whole problem with the publication frenzy, and the recent Alzheimer’s scandal is just the tip of the iceberg, are driven by the wrong incentives by those who give out research money and who promote scientists to professors and allocate resources to them. If those people in charge keep on relying almost exclusively on counting papers, impact factors, and grant money brought in, nothing will change. So, the change must come from the funding agencies, the deans and the vice chancellors of universities. At least for medicine it must count in order to move forward in your career by answering “What have you achieved specifically for patients? We’re not interested in all the pages that you have filled in different journals and books. Tell us what you have achieved for patients. Then we will make you a professor in medicine.” I have no idea how other disciplines should test for relevance and return-on-investment for science, but in medicine I think it should be clear that there can be only one criterion, namely helping patients.
Q: Finally–now that you have your life back, your wife remembers who you are, and you’re no longer writing into the small hours, do you have any other projects up your sleeve?
A: Actually, my wife is a pharmacist and was the first to read the book so she’s been with me on this journey! Vitally of course, we need to complete the clinical trials because this is the evidence that is needed to convince doctors and medical decision-makers. Other than that, I have the honor of co-leading a €50 million European platform project together with the REMEDI4ALL team with charities like Cures Within Reach, which will enable biomedical researchers, clinicians, and companies to successfully repurpose registered, off-patent drugs once a disease mechanism has been identified and preclude the need to search for years for a new drug and then take many more years to develop it. Instead what we should be doing is repurposing drugs for new indications and targets. Most small molecules bind to 30 other targets. So, there is a huge potential for drug repurposing, both for precision and cost-saving. I have a personal interest in contemporary art both in researching and creating it. Previously my work focused on social political topics (realitychanges.de) but Laszlo Barabasi, a famous network scientist and artist, recently recommended to me to also focus on health topics in my art, which will allow me to merge my research with my interest in art, and I think he was right. Research and art are wonderfully creative jobs, it’s a real gift to be able to work in any of them.