On more patents, the potential of genistein and whether it will finally get a chance as a breakthrough drug for the treatment of neurodegenerative diseases, and about the strength of the team in science. Join us for an interview with prof. dr hab. Grzegorz Węgrzyn.
Julia Bereszczyńska: - Professor, it has been two years since you obtained a patent for your invention entitled ‘Genistein for use in the treatment of Alzheimer's disease’. At the time, you said in the context of collaborations with pharmaceutical companies: ‘Time will tell whether genistein will get its chance as a medicine’. Did it get it?
Prof. dr hab. Grzegorz Węgrzyn: - It is not easy to talk to pharmaceutical companies because they take a very business-like approach. And genistein is so much more difficult business-wise as it is a naturally occurring compound, which means it cannot be patented. If we created a new chemical compound, then we could do that. With a natural compound, you can only patent its use - and that is what we have done. Pharmaceutical companies are very cautious about this because the clinical trials necessary to register any drug cost a lot. If a company has a patent on a molecule, the clinical trials come out positive, and the drug can be registered, then no one else can sell or manufacture it. If, on the other hand, we have a patent on the use of a substance in the treatment of, for example, Alzheimer's disease, then the company says: we are now going to spend a lot of money on clinical trials and, of course, no one will be able to sell this compound as a cure for Alzheimer's disease, because it is protected by the patent, but any other company will be able to produce this compound, because it is known, and sell it under the banal name of, for example, a supplement for better skin. The other company did not spend millions on clinical trials; therefore, their drug will be cheaper - you know, the company that would have spent the money has to recoup it somehow. People would obviously buy the drug that is cheaper. So these discussions are very difficult, but we are not giving up. We are now in close contact with prof. Karaszewski from the Medical University of Gdańsk and we have an idea to apply for a grant to the Medical Research Agency for a clinical trial of the use of genistein in Alzheimer's disease.
- Speaking of the grant - two years ago, after you obtained the patent, the plan was to apply for a grant for research with patients. You said that if you get the grant, the first medical experiment involving a small group of patients could start in about two years. Has human research already begun?
- There was a grant application to the European Research Agency. Unfortunately, we did not receive funding at the time. The competition was huge and the main objection was that we should first show the effects of genistein on other animal models. We had a study done on a rat model, and the Agency suggested that we first show it on some mouse models to see if the effect was equally satisfactory. As it happens, we have already carried out these studies to a large extent. They are not yet published, but I can say that the effects are positive. These are preliminary studies and we still need to work on the mechanisms, so I will now be submitting a grant to the NSC precisely to observe the mechanisms. So this will be more basic research. Preliminary observations on mouse models, however, provide the basis for applying to the Medical Research Agency for a grant for a clinical trial on patients.
- If you could estimate, when could such trials on patients begin?
- If we get the grant, it will be a three-year one. However, this will only be the first phase of the study. If confirmed, it would be attractive in a way that further studies could then hopefully be carried out with some pharmaceutical company. It is estimated that it takes eight to fifteen years from the first studies to the drug being brought to market. It is important to remember that Alzheimer's disease is a very difficult one. After recent consultations on the clinical side with prof. Karaszewski, we know the problem is that if there are already more severe symptoms of the disease, it involves the loss of about 80% of the brain cells. And this can no longer be reconstructed because nerve cells hardly regenerate. Therefore, if there are already severe symptoms, the only thing we can do with a drug that we assume would work perfectly is to prevent the disease from getting worse. So the most important thing in this disease is to start treatment at the beginning, at the onset of the first symptoms.
- Was there much interest in your invention from pharmaceutical companies, even those two years ago?
- There was, of course, interest, but after the information that genistein is a natural product and cannot be patented, this interest from the business side immediately diminished. I cannot reveal the details yet, but we have submitted another patent application using genistein. And I can say that this is a very promising one. We are now waiting for a decision, which can sometimes take a year and sometimes even six years.
- In your work on using genistein to treat diseases such as Alzheimer's or Huntington's disease, are you collaborating with any research centres?
- As far as genistein is concerned, we do most of our work in our centre, however, we collaborate with clinicians. We have also received a collaboration proposal from Spain but we perform most of the molecular work at our centre in collaboration with clinical centres such as the Medical University of Gdańsk, the Children's Health Centre, or the Institute of Psychiatry and Neurology. We also have a new project. There is a disease called NBIA, which is an iron accumulation associated with neurodegeneration. This disease mainly affects children. At the moment, a medical experiment is being carried out in Lublin, where genistein is administered in a certain variant of this disease. From what the researchers conducting this experiment say, the effects are positive. I am very pleased about this, although it is not a great surprise, because the mechanism of action of genistein is such that it stimulates the process of so-called autophagy, that is, the mechanism of degradation of all unnecessary deposits, damaged organelles, etc. This process has, of course, been known for years. The problem is that artificial stimulators can be used but they act very strongly. Therefore, it is possible to create a situation in which the cell starts to degrade not only these unnecessary or damaged molecules but all the others as well. The consequence of this is cell death. The thing is that genetic and neurodegenerative diseases are diseases where treatment lasts for the rest of life, and we know that these compounds cannot be used long-term because of the very serious side effects mentioned. Genistein has the advantage that it stimulates autophagy effectively but mildly - and from what we have observed, it cannot be overused and lead to overstimulation. It is therefore completely safe.
- I suspect you are not the only team of scientists trying to develop a cure for neurodegenerative diseases. How do your achievements compare with other teams? Can you count on collaboration in this regard, or is it more of a race where the prize is human life?
- We have taken a slightly different path than most teams of researchers. Most labs that work on Alzheimer's disease have focused on nullifying beta-amyloid. This is, of course, a very important protein from the point of view of the pathogenesis of Alzheimer's disease - but it is important to remember that, in addition to beta-amyloid, there are many other proteins and substances in general that accumulate in the form of aggregates and that are very toxic to cells. There are already two drugs introduced for Alzheimer's disease that are effective in lowering beta-amyloid levels, only that the clinical improvement is very poor. Why is this the case? When we do research, we first do it on cells and then on animals; because there are no perfect models of Alzheimer's disease - it is a multifactorial disease - it has to be induced somehow. This can be done genetically, for example, by overproducing beta-amyloid. You can inject beta-amyloid into the brain and then the animal has symptoms that resemble those of Alzheimer's disease. If you can find something that destroys that beta-amyloid, whether it's antibodies or some enzyme, or whatever that doesn't lead to an abnormally coiled form, and that beta-amyloid was the only factor that caused the disease, well, then obviously in animals, it works. How does it work in humans? We can lower the beta-amyloid, it's just that in humans it's not the only problem - we get the beta-amyloid under control, but other proteins remain aggregated, and as a consequence, the patient is still sick. It's the same with a car - when we have four punctured wheels on a car, the car doesn't run. We replace one and are surprised that it continues not to drive. Beta-amyloid is important and if we don't destroy it, we don't move on, but because there are other factors involved, it is unfortunately not enough. That's why our team has focused on stimulating the process of autophagy, which is not a process specific to one protein but destroys everything that is precipitated. With this, we hope to get the issue of all aggregates under control.
- So it's fair to say that as scientists, you are pioneering this approach to treating Alzheimer's.
- The idea of using autophagy in this way has come up before, it's just that at the time they were trying to use these powerful stimulators. This is dangerous; that is, it works in the short term, whereas with long-term treatment patients develop adverse effects because the cells are overstimulated. Our clue was that substances such as genistein can stimulate autophagy in a safe way, that is, they do not exceed the limit above which the cell degrades itself.
- Research on proteins in the context of neurodegenerative diseases is also being conducted by prof. Krzysztof Liberek's team from the Intercollegiate Faculty of Biotechnology UG and MUG. For this work, he received an award from the Foundation for Polish Science at the end of last year. I don't know how familiar you are with the results of these studies, but is there any chance that your teams could join forces on the way to an effective Alzheimer's drug? Is this an approach to the subject from a completely different angle?
- Krzysztof Liberek studies so-called chaperone proteins. These proteins prevent the formation of aggregates, and once aggregates have formed, they direct them to be degraded. This is a different approach, a different process from autophagy; or you can say it is actually similar, just based on a different cellular process. What Krzysztof Liberek is doing is more basic research to understand the mechanism of how chaperones work. In neurodegenerative diseases, if they worked very efficiently, there would be no disease. When aggregates form, at some point there are too many of them for the chaperones or autophagy to cope with - the processes need to be stimulated. We stimulate the autophagy process, whereas, in Krzysztof Liberek's approach, we would need to stimulate the formation of chaperone proteins more efficiently than the cell does. That is, Krzysztof is involved more in finding out the mechanism of how they do it. Two different approaches, but we have a similar goal.
- Very recently, at the end of February, we got news of another patent, this time a European one. Genistein is proving to be crucial in the treatment of another neurodegenerative disease - Huntington's disease. This is the third disease for which the use of genistein is very promising. Following this line of thought, could this substance also prove vital in the treatment of other neurodegenerative diseases?
- We would very much like that. The clue is that genistein stimulates the autophagy process. When we look at various neurodegenerative diseases, we find that more than half of them are caused by the accumulation of something - be it beta-amyloid or another protein - in the brain. In the case of Huntington's disease, we have a protein called huntingtin, which is very necessary, but as a result of a mutation - because you have to remember that Huntington's disease is a genetic one - it misfolds, precipitates and forms aggregates. And if we stimulate autophagy, it's all the same for the cellular process, whether it's beta-amyloid, pTau protein, or badly coiled huntingtin - it will destroy whatever the aggregate is. If something else is precipitated in another disease, autophagy will certainly help, too. So probably in all these diseases that are caused by the accumulation of some abnormal substance, genistein could potentially be effective.
- What are your immediate research plans?
- We are constantly trying to learn more and more about the mechanism of action of genistein. We recently published a paper largely showing the molecular mechanism of action of genistein, i.e. which specific autophagy activation pathways are stimulated, precisely on Huntington's disease model, which also allows us to extend our research to other diseases. It is fair to say that the immediate research plans are these two-pronged activities and a deeper understanding of the mechanism of how genistein stimulates autophagy in Alzheimer's and Huntington's diseases. Another goal is to look for where else genistein might have applications, and lastly, to work on other substances, such as resveratrol, which recent studies show also has autophagy-stimulating properties.
- In the scientific world, you are not only an authority, but also an inspiration for many researchers. What would you advise young scientists who are at the beginning of their scientific journey?
- First of all, I have to say that on my own, without my team, I wouldn't really have done anything. I could have no matter how brilliant ideas, but unfortunately in the field of biology or medicine, you can't do anything by yourself. You have to have a team of people working on it, doing experiments, analysing the results. It is a team effort. Of course, I lead this team, but what we are talking about today is the result of many years of hard work by the whole team. My advice to young researchers is to choose well the team you want to work with. Above all, though, to achieve anything in science, you need to have passion. Working from 8 am to 3 pm and doing the standard job is not going to achieve anything great in science - you just have to be dedicated to it. What the young researchers in our team achieve is only due to their passion and hard work, often after hours or at weekends. You also need to have a curiosity about the world to strive to discover new things. Parameterisation is quite a dangerous temptation these days. Many young people are looking at the number of publications they will have and how many points it will give them, rather than the substance. If we start approaching it this way, scientifically, we will soon become very shallow. The most important thing must remain the discovery of some mechanism, phenomenon, or process, and then publications will be derivative and will certainly be highly scored. This is a problem of the system, a global problem, not just ours. There was a desire to come up with a system to evaluate scientists, but unfortunately, the point system has greatly distorted this evaluation. If someone is working to have a certain number of points, then the cognitive goal recedes into the background. This is, paradoxically, a very dangerous situation: some papers can be published quickly in a journal, but they still mean nothing in science. This is a major problem because all point systems seem to be cleverly conceived but if this measure becomes a target, it ceases to be a measure and does not reflect the quality of research at all. This is the trap we have fallen into - the so-called 'scoring'. Its purpose is supposedly to make evaluation objective but unfortunately, it kills creativity in researchers. If there is any advice I can give to young researchers, it is to avoid falling into this trap. In the beginning, of course, these points give satisfaction, but already at the stage of obtaining degrees or titles, we see that most applications which are not supported are those whose authors have quite a lot of points for publications. And this is precisely the trap of the scoring - someone scores a lot of points, but it is meagre, and there are no important discoveries, the derivation of which should really be degrees and titles. Let's remember that we shouldn't be putting, for example, a doctorate, a habilitation, or a professorship as the goal of research. The aim should be to conduct research and solve scientific puzzles, to discover mechanisms, phenomena, or processes, and then degrees and titles will be a derivative of this.
- And this is a very valuable point. Thank you very much for the interview. I wish you continued success and more successful patent applications.