Prof. Grzegorz Węgrzyn
Professor Grzegorz Węgrzyn, Chairman of the Council for Scientific Excellence, Head of the Department of Molecular Biology at the Faculty of Biology of the UG, talks to dr Beata Czechowska-Derkacz about alternative therapies, drugs for rare genetic diseases, pharmaceutical companies, and the Nobel Prize for Polish scientists.
You are working on molecular biology, genetic diseases, DNA biochips and bacteria. Have I left anything out?
There are two types of scientists: some focus on a single molecule and study it all their lives from different angles, while others go broader and try to understand the general mechanisms of action and their relationships. We tend to represent the latter option and study quite broadly, which is not to say shallowly. We also go into molecular details. At the University of Gdansk in the Department of Molecular Biology, there are several research groups, geneticists. I head one of them - we deal with very different research subjects: from bacteria to viruses and bacteriophages, to genetic and neurodegenerative diseases.
You said 'We deal with' - how many scientific teams do you lead and what issues do these teams study?
It is virtually impossible to do independent research in biology, especially experimental and molecular biology. Progress is so rapid that one person cannot plan everything, carry out experiments and analyses and describe the results. Often several scientists are working simultaneously on several aspects of the same issue. This is teamwork. There are currently three teams working in the UG Department of Molecular Biology. I head one of them. We study the mechanisms of genetic and neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease or storage diseases. Another team, which studies autoimmune diseases, skin diseases, is headed by Professor Stefan Tukaj. The third group, in whose work I am also involved and which I co-lead with Professor Bożena Nejman-Faleńczyk, studies bacteriophages, i.e. viruses that attack bacterial cells, and pathogenic bacteria. We are looking for therapeutic possibilities for the diseases under study, but in order to think about therapies for these types of diseases, we first need to understand their mechanisms of action, understand what is happening at the cellular level, find out how pathogenic cells function and what the effects are.
At this point, I would like to emphasise the enormous commitment of the members of these teams. In the group dealing with genetic and neurodegenerative diseases, the role of dr Karolina Pierzynowska and dr Lidia Gaffke, leaders, without whom it is difficult to imagine the effective research of this team, cannot be overestimated. Dr Magdalena Podlacha is our leading expert on animal models of disease, doctoral students Zuzanna Cyske, Estera Rintz, Karolina Wiśniewska and Magdalena Żabińska are incredibly committed to their projects and spend long hours in the lab performing laborious experiments and gaining a lot of scientific experience, which also determines the strength of the entire group. Some are currently completing their PhDs and are already employed at other research units or biotech/medical companies, such as Joanna Brokowska and Michał Grabski. This is also an added value. Professor Tukaj's team includes Krzysztof Sitko, a doctoral student, and dr Ewa Piotrowska has recently joined the group. The core of the group led by prof. Bożena Nejman-Faleńczyk consists of her 'right hand', dr Sylwia Bloch, and doctoral students Natalia Lewandowska, Aleksandra Łukasiak and Wojciech Wesołowski. This is an interview with me, but without the above-mentioned people, we would have nothing to talk about. Now, the head of a group alone means little scientifically without the team he or she works with, but a team needs a head to achieve significant research results. If one were to compare it to sports: a coach alone in team sports can do nothing without excellent players, but a team needs a good coach to be successful.
You said that large research teams are needed to work on particular aspects. Do they have to be international teams?
If you have a big enough team, you can rely mainly on their work, but you cannot do it without exchanging information. You can work closely or more freely with different centres, not only international but also Polish. A lot depends on the capabilities of the research team: the competence of the scientists, specialised equipment, and access to laboratories. Cooperation between several centres is definitely very developing and with large projects gives the most effective results. We have collaborated with foreign and Polish centres on many occasions, which has resulted in promising results and, importantly, further research and projects.
You led the team of scientists that developed the first effective treatment for Sanfilippo disease. Can this chapter be considered closed?
Research is still ongoing, and not only on Sanfilippo disease. It is one of the variants of mucopolysaccharidosis, a group of more than a dozen diseases that, on the one hand, are similar to each other and, on the other hand, each is different because the mutation in the genes is different. These are diseases that progress and have irreversible effects. Today, we already know that if a patient was treated before the first symptoms appeared, one could largely count on these symptoms either not appearing or being relatively mild. On the other hand, if they are already there and are quite advanced, all we can do is slow down the progression of the disease. Enzyme treatment works in a similar way. If the disease has already progressed far enough, even the normalisation of this primary factor, whose defect caused the disease, does not guarantee that patients will function normally. Secondary lesions remain. The project we recently finished showed that the primary lesions are the tip of the iceberg. We have shown the mechanisms of the disease: how the primary lesion causes a whole cascade of changes in the cells that lead to the destruction of individual cell organelles, or to further changes in cellular processes, resulting in further chains of events. For example, in Sanfilippo disease, there is a lack of an enzyme that breaks down glycosaminoglycans, a type of sugar. This seemed previously to be the primary and only cause: sugars accumulate and a cell "clogged" with them cannot function. Therefore, if we removed them, the cell's functioning should normalise. But it is not that simple. The sugars that accumulate in cells interact with proteins that are important for the cell to function, and if there are a lot of these sugars, they form aggregates with these proteins, which are insoluble, i.e. they shear off like chicken proteins in scrambled eggs. The proteins drop out of solution, they are insoluble, which means they cannot function. And if these are some important proteins, for example, those that regulate vital processes in the body (such as hormone receptors), then the entire cellular process is disrupted. In this case, therapy needs to be supported not only with something that removes these originally accumulated molecules but also with a substance that can remove the aggregates. This is what we are working on.
At what stage are the clinical trials of the drug?
Due to a lack of funding, the trials were done using academic methods at a centre in the UK, on a small group of patients. There were twenty of them and they included children who were about three years old and people who were about eighteen years old. Such a significant age difference in this disease is very important, because sick children live two decades without treatment. The three-year-olds had almost no symptoms at all, the eighteen-year-olds were in a terminal state. Suppose you take the average of the results of a three-year-old and an eighteen-year-old: in that case, it is extremely difficult to have an effect statistically significant enough to show an improvement in disease parameters. The eighteen-year-old's body is so degraded that you can only prolong their life a little bit, and in the three-year-old, you see very little change, because these children have almost no symptoms yet. As a result of these studies, biochemical improvement was obtained, while the aforementioned statistically significant changes and therefore clinical improvement could not be shown. We are still working on modifying this type of treatment and, as it is a widely available substance, patients are taking it, including those already at a relatively advanced stage of the disease. I have received information that one patient has already survived for twenty-nine years. These patients are not healthy, but the disease has stopped and their quality of life has improved. The disease is not progressing, but there is still the domino effect I mentioned earlier.
The next research that raises high hopes is related to neurodegenerative diseases. Are we close to finding a cure for Alzheimer's disease?
Many neurodegenerative diseases are caused by the intracellular formation of insoluble aggregates I have already mentioned. In Huntington's disease, this is caused by a mutation in the gene that breeds the huntingtin protein, but in Alzheimer's disease, there is an excess of beta-amyloid that builds up, and this is not the only toxic protein. There is also the p-tau protein, which is normally very important, but if it is biochemically altered, it precipitates out and forms aggregates. There are also several other compounds that in turn form large, insoluble aggregates that are very toxic to cells. So it is a sequence of very different causes, reinforcing each other. Pharmaceutical companies like to focus on one molecule, one mechanism of action, because it is easy to register a drug later. Years ago, there was a paper that showed that the leading cause of Alzheimer's disease is an excess of beta-amyloid. And this protein indeed accumulates in the disease, but it is not its only cause. In animal studies, when beta-amyloid-lowering drugs are tested, significant improvements are seen. But these animals are injected with beta-amyloid, so if you remove it, you remove the only cause of the disease. In humans, there is very little therapeutic effect because Alzheimer's disease is not monogenic, there are many causes, beta-amyloid being one of them. We need to do something to remove all the causes of the disease.
And what are the scientists at the University of Gdansk doing?
We are looking into a process that is called autophagy. It is known and functions in the cell, but if there are too many pathogenic deposits, it is not effective; colloquially speaking: it cannot cope with cleaning the cells. We decided to stimulate it. Such studies have been conducted before, but it turned out that if the stimulation is too strong, the cell 'eats' not only the pathogenic aggregates but also itself. It is therefore necessary to find the golden mean, an effective stimulation action that is gentle enough not to cause cell death. However, these must be long-term measures, because Alzheimer's is a progressive disease and even if the effect lasts a week, the disease will return. We are currently studying all these processes, looking for stimulation pathways. We are working on different models, which allow us to also study other diseases involving cellular accumulation of disease-causing substances and processes or being related to defects in autophagy. We are dealing with Huntington's disease, as well as a condition referred to as NBIA for short, a group of diseases in which there is a process of iron accumulation in the brain. Thanks to the determination of the doctors in Lublin with whom we collaborate, an experimental therapy for children with one form of NBIA, called BPAN, has been available since January this year. We already have information about promising results. These children are not recovering spectacularly, but they are improving. One mum sent me a video in which a little girl of a few years old, who until now had hardly spoken, started to say her name and say: 'mama'. We don't know if a full recovery is possible, but just stopping the disease gives us hope that if we give the medication before the symptoms appear, we have a chance to manage the disease in the future. Suppose we include early diagnosis, which is genetically easy to do, and give the drug before symptoms appear. In that case, we have a chance of controlling the disease to a level where the patient can function normally. There is a well-known case of a boy who had a sister with a storage disease. He was therefore immediately examined and unfortunately, diagnosed with the same genetic defect. However, as early as possible, meaning when he was six months old, he was given dual treatment, including enzyme treatment, which works well on somatic tissues. He is now finishing primary school and is a completely normal boy.
Do such happy endings inspire you and motivate you to work?
On the one hand, there is undoubtedly great satisfaction and motivation for further research, because you can see that you can do something meaningful and good. On the other hand, in such situations, scientific and personal successes stay in the background. Most importantly, you can help the patient and his family. Finally, we see the result of many years of our arduous struggles in the laboratory or at the computer. What we are talking about now are the results of more than 20 years of research. On the other hand, the diseases we deal with are very difficult to treat, often seemingly without prospects, but as you can see, something can be done.
Pharmaceutical companies are reluctant to support research that affects a small number of patients.
It is unprofitable for pharmaceutical companies to fund trials that may result in treatments for small groups of patients. Clinical trials that lead to drug registration are just as expensive for rare diseases as for common diseases. Aspirin will be bought by a few billion people worldwide, while only a thousand people will buy a drug for mucopolysaccharidosis disease. Suppose it costs a billion dollars to bring a drug to market and the company estimates that a hundred million people will buy it in a year. In that case, it only needs to be ten dollars more expensive than the cost of production and the company will recoup its outlay. If a thousand people buy it, they would have to pay about a million dollars. People cannot afford such therapies. The only chance is reimbursement, in Poland by the National Health Fund and in other countries by various agencies or insurers. The first drug in gene therapy for muscle disease was registered in 2012. It was pretty effective, but the therapy cost over two million euros. The company registered this therapy for five years. During this time, only one patient was treated with this method, because only this one patient could afford it without reimbursement. The company did not renew the registration after five years and an effective drug for a dangerous disease such as muscular dystrophy disappeared from the market.
From the point of view of social responsibility, as well as ethics, shouldn't the financial commitment of pharmaceutical companies to rare disease research be more significant?
We do not live in an ideal world, as one of my colleagues once said. In this case, economic mechanisms rule. It is difficult to expect a company to invest vast amounts of money and risk very large losses, because who would cover them?
Financial profits from aspirin?
I attend various Polish and international conferences where I come into contact with the pharmaceutical industry. There is a common opinion that if a company does not make half a billion dollars or euros a year on a drug, it will not take action. Companies that produce expensive drugs sometimes send their representatives to hospitals to donate a certain pool of the preparation. When such a person ends up in a children's ward, and few people are indifferent to the suffering of children, they donate far more medicine than they can. Increasingly, these representatives of pharmaceutical companies are not allowed on the wards. Such cooperation is risky for both parties: doctors and hospital management staff are suspected of benefiting financially, and the company may suffer losses. One can, of course, demand a little more from large, wealthy companies, but what about the responsibilities of the state? And the insurance companies? They, too, make very large financial profits in the area of health care. We should therefore discuss and seek solutions based on shared responsibility.
The Patent Office has granted four patents to a team of scientists from the Faculty of Biology of the UG and the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences for an invention using bacteriophages to prevent and combat infections in humans and animals. Is this an opportunity to fight antibiotic resistance?
By overusing antibiotics, we have bred many resistant strains of bacteria. But statistics show that most of this comes from the indiscriminate use of antibiotics in agriculture and veterinary medicine. Antibiotics are not only used as medicines but also as growth promoters. We eat products with antibiotics, we produce animal faeces with antibiotics, and bacteria are spreading everywhere. The World Health Organisation predicts that if we do not find a solution to this problem, in 2050 every surgical operation, even a trivial one, will be life-threatening for the patient because there will be nothing to treat sepsis with. It is possible to look for new antibiotics, but this is not easy today and means high costs and the risk of failure. One alternative is bacteriophages, i.e. specific viruses that infect bacteria without infecting human or animal cells, and thus destroy bacterial cells. It can therefore be said that the enemies of our enemies are our friends. Poland was, by the way, one of the leaders in phage therapy. At one centre in Wrocław, it was used with patients' consent in cases where no other treatment was available. In my opinion, this therapy has a future.
What is stopping it from becoming widespread?
Legislation. To bring any drug to market, it must be very strictly characterised chemically and physically. In the case of phage therapy, we are talking about isolating dozens of proteins and nucleic acid from thousands of bacteriophages. This could be done, but it would generate unimaginable costs and require a very, very long time. Without a change in legislation, therefore, there is no chance of phage therapy being registered, at least in the countries of the European Union, because it is impossible to accurately chemically characterise each of the thousands of bacteriophages separately. There is an ongoing debate about this in the European Union because current laws prevent authorising untested drugs, but in the case of phage therapy, this causes problems.
In order to carry out research that offers hope of solving major problems of civilisation and medicine, is it enough to be a scientist who works in a laboratory, or do you also need management skills?
They are certainly necessary when managing a large research team. You need to be able to write grant proposals, know the regulations, and raise money…
Be able to set up a competent, enthusiastic research team…
And know what to do next with our research and discoveries.
What is blocking scientists today? Money?
To a very large extent, although compared to previous years, we now have very good equipment and laboratories. Our principal asset is our human potential, excellent scientists, and Achilles' heel - organisation and administrative procedures. In the area of science in Poland, we apply the law in a way that slows down and sometimes blocks the work of scientists. An example is public procurement. We often buy more expensive because we have to carry out procedures that make no sense from the point of view of scientists and to top it all off, we cannot use the funds granted effectively. We are accountable for ensuring that everything fits in the tables and charts, rather than for the research results. There is a lack of trust in all of this. As a scientist, I am treated in advance as a potential thief, hence all this bureaucratic superstructure. And I'm not talking about the University of Gdańsk but about the top-down administrative procedures in Poland. Scientific research involves discovering hitherto unknown phenomena, processes, and mechanisms. Since unknown, I cannot plan what I will discover. I cannot predict what reagents I will need in a week, because it depends on the results I get today or tomorrow. This means that I can make a general plan, but I can't predict everything that will happen, which is what is required of me. And for tenders to make sense, planning expenses months in advance is necessary. This cannot be done in science. If it could be done, it would not be, by definition, scientific research.
You work in many scientific bodies, and you are the chairman of the Council for Scientific Excellence, so I will conclude with a question for the proverbial million dollars. Do we have a chance for a Nobel Prize in Poland?
Intellectually we are ready, we are in no way inferior to the world's scientists. But discoveries on the scale of the Nobel Prize require vast financial resources and freedom to conduct research. The annual budget for all the science in Poland is smaller than that at a single large university in the USA, such as Harvard or Stanford University. I don't like the expression, but we don't stand a chance in this race: it's as if we had an excellent driver, and we do have outstanding scientists, and we ordered him to race a Trabant against a formula one car because we can't afford either to buy the car or to pay solidly for the service. Let us assume that we manage to identify the mechanisms of Alzheimer's disease sufficiently to be able to offer a very effective therapy. We will carry out animal studies with spectacular results. But it is a long and costly road from such research to a cure. The prize will go to whoever has a specific drug; we cannot afford to put it into circulation. Another obstacle is administrative procedures, on which scientists in Poland spend more than fifty per cent of their time that they could devote to science and research. However, I still think it is optimistic that we have the potential for a Nobel Prize. Unfortunately, we are in danger of young, highly talented people either leaving science in large numbers or leaving our country, seeing no prospect of the kind of development we can afford. Through financial omissions (and this is funding that is not beyond the capacity of our state) and monstrous administrative and organisational blockages, we are losing the chance to implement changes that would push our science forward.
I am optimistic and wish you this Nobel Prize wholeheartedly.
Interview by Dr Beata Czechowska-Derkacz, Institute of Media, Journalism and Social Communication, UG, PR specialist for the promotion of scientific research
Grzegorz Władysław Węgrzyn
Professor of biological sciences, geneticist, from the beginning of his scientific path connected with the University of Gdańsk. In 1987, he graduated from the Faculty of Biology, Geography and Oceanology at the University of Gdańsk. He defended his doctoral thesis at the same faculty in 1991 and habilitated in 1995. In 1998 he was awarded the title of Professor of Biological Sciences and was at that time one of the youngest titular professors in Poland.
He has held and continues to hold many positions: among others, he was a member of the Council of the University of Gdańsk (2019-2020), Vice-Rector for Science (2008-2016), Dean of the Faculty of Biology, Geography and Oceanology of the UG (2002-2008), from 1993 to 1996 - Vice-Dean of the Inter-University Faculty of Biotechnology of the University of Gdańsk and the Medical University of Gdańsk (now the Medical University of Gdańsk). Since 2019, he has served as chairman of the Council for Scientific Excellence. He is a correspondent member of the Polish Academy of Sciences and the Polish Academy of Arts and Sciences.
He is involved in molecular biology, currently focusing on studying genetic diseases, neurodegenerative diseases, antibiotic resistance treatment, bacteriophages and phage therapy. He has led and still leads several scientific teams, including the team that developed the first effective treatment for Sanfilippo disease. He collaborates with scientists from all over Poland and many research centres worldwide. He has authored and co-authored several hundred scientific articles in molecular biology and genetics. Promoter of 57 PhDs.
Winner of many awards, including a scholarship from the Foundation for Polish Science for young scientists (now START), a professorial grant of the same foundation (later called the MISTRZ programme), the Jan Hevelius Science Award of the City of Gdańsk, awards: Minister of National Education and President of the Council of Ministers, awards from the American Society for Experimental Biology and Medicine, the international Vebleo award, the Polish Genetic Society award and - four times - the Polish Biochemical Society award.