25 Interviews for the FNP?s 25th Anniversary. The Foundation for Polish Science (FNP) celebrates its 25th anniversary this year. To mark the occasion, we have invited 25 beneficiaries of our programmes to tell us about how they ?practise? science. What fascinates them? What is so exciting, compelling and important in their particular field that they have decided to devote a major part of their lives to it? How does one achieve success?
The interviewees are researchers representing many very different fields, at different stages of their scientific careers, with diverse experience. But they have one thing in common: they practise science of the highest world standard, they have impressive achievements to their credit and different kinds of FNP support in their extensive CVs. We are launching the publication of our cycle; successive interviews will appear regularly on the FNP website.
Pleasant reading!
Make a Difference
Anna Wójcicka, PhD and Prof. Krystian Jażdżewski, who design and offer patients sensitive and accurate genetic tests based on the latest scientific developments, talk to Patrycja Dołowy.
PATRYCJA DOŁOWY: Let?s start with you, Prof. Jażdżewski. You spent 10 years in the United States, and discovered an important gene?
KRYSTIAN JAŻDŻEWSKI: The research concerned thyroid cancer. An unusually large number of cases of thyroid cancer are hereditary. If one person in a family falls ill, the risk of their closest relatives getting thyroid cancer increases eightfold. That?s the highest hereditariness of all known multifactorial cancers. Only single-gene cancers are more hereditary. We had the highest hereditariness but no one knew what genes were involved! A challenge emerged. At first, actually, it was more social in nature. A famous endocrinologist said to a famous geneticist: ?Look, here it is, and you don?t know what to do about it.? The endocrinologist was Prof. Ernest Mazzaferri, a great figure in endocrinology, and the geneticist was the equally famous Albert de la Chapelle, a Finnish professor working in the United States. Thus we had this gentlemen?s bet: ?So you think I won?t find anything?!? And we started looking. Nothing was found for over a decade. Every new postdoc on de la Chapelle?s team would arrive and start trying, thinking, ?They didn?t find anything, but we will.? I was lucky because when I started my work, they?d already searched everywhere possible. We knew where not to look. This was also the time when a new class of genes was discovered: microRNA. These are small genes regulating the functions of other genes. So we started searching among them. And it turned out that one of those genes, number 146A, had a variant that increased the risk of getting thyroid cancer. At the same time, it is interesting in many other aspects. It was the first mutation discovered in a gene of this class. That was the beginning, followed by five years of hard work to confirm what we really had and check how it worked.
Is the research on thyroid cancer being continued in Poland?
ANNA WÓJCICKA: Yes, in a multifaceted way. The research involves a large team of people, including clinicians from whom we obtained data on the treatment of thyroid cancer patients in Poland over the past 20 years. Every year about 2,500 people in Poland are diagnosed with thyroid cancer, most of them women. In most cases the course of the disease is mild, but in 10% of patients the illness progresses very aggressively, rapidly leading to metastasis and death. Such people need very intensive treatment from the very start. The problem was, no one knew how to identify them.
KRYSTIAN JAŻDŻEWSKI: We asked ourselves: if genes influence this disease so strongly, then maybe we could find a gene that would indicate whose illness would be milder or more aggressive, and thanks to this knowledge find the people who could receive less gruelling treatment and those who needed to be treated more aggressively due to a high risk of death.
ANNA WÓJCICKA: To clinical data we added genetic information. This enabled us to find a gene in which one small change?from one letter to another?changes the course of a patient?s illness. Clinicians would like to know how to treat a patient in the case of every illness. Meanwhile, most therapies are directed at the average patient. Such a person doesn?t exist. The change we discovered can be determined in the blood before surgery. Then the surgeon knows whether to conduct a radical operation, removing the whole thyroid, or whether removing one lobe, the one with the changes, will be enough. If we remove just one lobe the patient won?t have to take hormones afterwards. There is also little risk of complications from the operation. So far there is one such gene that we have described and introduced into diagnostics, but we found a great many more. There will be further projects and, I hope, further recommendations on how to treat patients, how to personalize medicine based on the latest genetic information. The gene that enables us to determine the course of thyroid cancer is a traditional protein-coding gene.
But you haven?t abandoned microRNA?
ANNA WÓJCICKA: It is the second direction of our research. We use microRNA to search for new diagnostic tools in the treatment of cancers: thyroid cancer, hepatocellular carcinoma. MicroRNA is very economical in diagnostics because, as the name itself suggests, it is very short. It does not degrade and is easy to determine. Every disintegrating cell expresses nucleic acids. A cancer cell does it more intensively. We are able to diagnose cancer based on microRNA, which is stable so we determine it in a patient?s blood after cell disintegration.
KRYSTIAN JAŻDŻEWSKI: We have a patient with a liver tumour. The tumour could be benign or malignant. It could be primary (as in the case of hepatocellular carcinoma) or secondary (e.g. metastasized from the large intestine). The question is, should we worry or not, and if so, then how much and what treatment should we apply? We answer these questions by determining the level of microRNA expression in the patient?s blood. We can say: a dangerous change coming from the liver?one treatment, a dangerous metastatic change?another treatment etc. This means the clinician knows immediately how to proceed.
ANNA WÓJCICKA: Primary liver cancer develops in a cirrhosed liver. First the liver changes under the influence of alcohol, medicines or viral hepatitis. Before, it was extremely difficult to capture the moment when cancer appeared in a cirrhosed liver. Based on microRNA, it becomes perceptible.
What else do you study?
ANNA WÓJCICKA: Another topic we are working on is why some patients respond to treatment with active iodine, which is used in thyroid cancer, while others do not. The thyroid captures iodine, so if we add a radioactive element to iodine, it is selectively absorbed by thyroid tissue and simply destroys it (including any cancerous tissue). Unfortunately in some patients cancer develops mechanisms that block iodine uptake. As it turns out, this is due to a deficiency of specific proteins that transport it to the thyroid cells. It wasn?t quite clear what caused the deficiency. Our research shows that it is linked to an excess of microRNA that regulates iodine transporters. The thing about microRNA is that its changes are reversible. It?s hard to reverse a genetic mutation but possible to change the level of a given product. If we have an increased level of microRNA molecules in a tumour, we can selectively muffle them. This means there will be more of the iodine transporter in a cell and it will be able to respond to therapy with active iodine. This is the road we have taken. It?s the right road, because two publications on this topic were published in the world at the same time. Unfortunately this happens?we did not make it in time with our publication.
But you continue to work on this? It?s important to you to put research into practice, isn?t it?
KRYSTIAN JAŻDŻEWSKI: All our research is translational research. We think in very practical terms. We try to make sure that everything we discover makes its way to patients as soon as possible. When we published a paper on the marker of an aggressive course of thyroid cancer, we almost immediately proposed such a test to patients. It?s the same with everything we do. It?s a big problem of science all over the world that there is a lot we know in the laboratory that translates relatively poorly into clinical practice. Years pass before scientists? discoveries bring patients any direct benefit. We keep this in mind and try to plan our research so that the results can be used as quickly as possible.
Prof. Krystian Jażdżewski by Michał Jędrak
How do you manage this?
KRYSTIAN JAŻDŻEWSKI: We are a team of doctors, close to patients from the beginning. Our desire to conduct translational research is supported by the Foundation for Polish Science. For a few years now the emphasis has been on the implementation of scientific research. Implementation means making it available to people. We take this very seriously, and the Foundation is very supportive. We both received grants in the IMPULS programme to refine diagnostic methods in hereditary cancer?thyroid cancer and colon cancer. As a result of this work, a genetic test is available on the market that can quickly and widely help determine predispositions to hereditary cancer: thyroid cancer, colon cancer, breast cancer. This met with strong interest from the rector of the University of Warsaw, leading to the formation of the Warsaw Genomics company aimed at passing on to patients everything that we manage to discover or analyze.
ANNA WÓJCICKA: The university cannot perform diagnostic tests. This becomes possible through the diagnostic and medical company. Everything we do at the laboratory, we are able to give to people. We are constantly working on new solutions that will be added to the services we offer.
KRYSTIAN JAŻDŻEWSKI: In our research work we make intensive use of advanced tools of genetics, high-throughput methods. These are studies based on microarrays, and in recent years also next-generation sequencing. Thanks to this method we are able to read complete sequences of genes, many of them even simultaneously, and if necessary also a whole genome, or 25,000 genes. We used these methods for research purposes, and at one point we thought: Why shouldn?t we use them for diagnostics, when we have an expert team that specializes in this? American and European universities are trying to transfer their skills into diagnostic areas, so why shouldn?t we?
ANNA WÓJCICKA: Until now, children who were born with a suspected genetic syndrome were not diagnosed for several years, sometimes more than a decade. Genetic analysis methods were available, but doctors had to specify in advance which gene, or actually which fragment of a gene, they thought was changed in the patient. The patient was tested, sent home if nothing was found, returned, was tested again and so on. Sick children are referred to us by clinical geneticists from hospitals all over Poland. In one test, whose results are available after about a month, we are able to check all the genes that could potentially be involved in a given disease and see whether there is any change in them or not. This is the most comprehensive analysis that can be performed at present.
Do you know all the genes involved in a genetic disease?
ANNA WÓJCICKA: There are diseases for which almost all the genes are described in databases. Of course we realize we don?t know everything. If we find no change in the suspected genes in a very sick child, we can always search deeper: perform an analysis of the whole genome, all the coding sequences in a given patient. Our analyses do not focus on single genes. In breast cancer, for example, we study all 24 genes and not just BRCA1 and BRCA2. In the United States, multiple-gene panel tests have been used for three or four years. We know that half the patients without mutations in the BRCA1 and BRCA2 genes have mutations in other, so-called medium-risk genes. Until now in Poland these patients were completely overlooked.
KRYSTIAN JAŻDŻEWSKI: Or you have a two-year-old with myopathy, and one of his 49 genes is damaged. The question is, which one? My reply: let?s study them all?
…and let?s do it within a month!
KRYSTIAN JAŻDŻEWSKI: In Poland we also differ from the Americans in that there are always shortages, so already at the research stage it is an important part of our efforts to do everything as cheaply as possible. As a result, we are able to conduct the tests we are talking about here at a fourth or fifth of the cost in other parts of Europe. That?s why they can function on the Polish market, which is poorer. We have learned to perform analyses more cheaply without losing any of their sensitivity and specificity. Now we are launching a project that?s very important to us, financed from FNP?s TEAM programme. Fortunately the project ended up among the beneficiaries. The aim is to develop a screening method that takes advantage of next-generation sequencing. We want to perform some ?magic? that will enable the price to slashed to a fraction yet again. All this is so that we can determine the increased risk of cancer incidence on the scale of the whole Polish population. We want to create the possibility of screening 37 million Poles and telling them whether they are at increased risk and what they should do not to fall ill.
That?s incredible. What are the costs of this test?
KRYSTIAN JAŻDŻEWSKI: I cannot say for certain yet. But if everything goes well, the cost of the test, which stands at EUR 3,500 today, should drop to about PLN 100. Then it really will be possible to screen the entire population. The health, social, personal and family benefits of this will be enormous.
Are such tests being carried out anywhere in the world?
ANNA WÓJCICKA: Not on such a scale, no.
KRYSTIAN JAŻDŻEWSKI: There is a chance of Poland being the first country where genetic screening tests are carried out on the whole population. No one has done this so far, because so far no one has been able to reduce the costs of testing so radically, and no country is rich enough to spend several thousand euros per person. I hope that in two years? time we?ll be able to speak of success. The project financed under the TEAM programme should end in confirmation that it is possible to perform screening tests at a very low cost without loss of sensitivity and specificity. The ultimate proof will be the screening of the population of one town. This will most likely be Rybnik with its population of almost 100,000. They have fantastic doctors there who believe in such projects.
So you are seeking to make screening widely available. You have also been successful racing against time, right?
ANNA WÓJCICKA: For example, we carry out prenatal testing directed at specific diseases, the kind that once diagnosed can start being treated right away. Even before the baby is born! A pregnant woman?s blood contains foetal DNA and we can detect it (at levels enabling reliable diagnostics) from roughly the 7th to 8th week of pregnancy by taking a 10 ml blood sample. It might seem that this is a time in a pregnancy when nothing can be done yet. One test tube of blood and we can isolate the foetal DNA and analyze it. First of all, we can determine the sex of the foetus. This is important if we know that the baby could have inherited a sex-related disease, or a disorder such as congenital adrenal hyperplasia. A mutation in one gene blocks the adrenal gland, preventing cholesterol from being converted into cortisol. A whole group of intermediate metabolites is formed, including testosterone, a male sex hormone. If the foetus is a girl, the mutation results in the child being born with both female and male sex organs. This causes her huge psychological and medical problems from the very beginning of her life. But, as it turns out, this can be prevented if the mother receives a medicine in the 8th week of pregnancy halting the production of excessive testosterone. Doctors cannot give the medicine to every woman whose child might have congenital adrenal hyperplasia, but if early prenatal diagnostics could be introduced, then all future mothers who have to start the treatment in order to give birth to a healthy baby could be found.
Do you also get random customers coming in, wanting to be tested?
KRYSTIAN JAŻDŻEWSKI: To us they are patients, not customers. We carry out most tests without making a profit. This is possible because we operate within a company of the University of Warsaw, and the rector has said clearly that he wants to pursue social and not commercial goals. So, you asked about our patients. We have inquiries from hospitals but also from families looking for diagnostic possibilities. We have patients who have family predispositions to cancer. We have prepared genetic tests for them. In one test we can analyze the full sequences of all the genes that are known to increase the likelihood of a disease. A patient comes to us and says: my grandmother had it, my mother had it, my aunt had it and I?m sure to get it, too. We can answer the question whether that person really does have a genetic predisposition and an increased risk of getting cancer, or if the risk is a population-wide one, i.e. no higher than for other people in the population.
Once a patient knows this, what can they do about it?
KRYSTIAN JAŻDŻEWSKI: Oh, a great deal! This is set down in the recommendations of medical societies. If a patient has a mutation that increases the risk of breast cancer, we propose MRI checkups from the age of 25, thanks to which we can capture any change at such an early stage that treatment is almost 100% sure to be effective and the costs are minimal. If a patient is born with a mutation increasing the risk of colon cancer, we perform colonoscopies from the age of 25, removing any polyps that could develop into cancer over time. If polyps are removed, there will be no cancer. But you have to know who should have a colonoscopy at such an early age. We monitor patients. We tell them very precisely what they should do to reduce the risk of falling ill or, if the risk cannot be reduced, to get checkups so the disease is caught at an early enough stage for treatment to be effective.
ANNA WÓJCICKA: Many people find their way to us, but unfortunately there are even more who don?t realize that such tests can be done at all. We want people to know that these methods exist in Poland and that very often they can save lives.
KRYSTIAN JAŻDŻEWSKI: When we are invited by TV or radio stations, we?re happy to talk about this, but we have no background in promotion. Luckily more and more people are working to spread the idea of widely available genetic tests and more and more people help us, giving their time and talking about it. There are many such people of good will on our path every day. Right now we?re conducting a huge pro bono campaign with the Dentons law firm. The campaign involves giving every employee at the firm the opportunity to get a genetic test determining their predisposition to cancer or other genetically based diseases, and simultaneously with the tests for the employee we perform two tests for free on children who need them from the Children?s Memorial Health Institute or other medical centres. This campaign has been hugely popular among the lawyers. They all have the opportunity for a medical consultation and tests. It looks as if we will continue such campaigns.
How do you make it all work?
KRYSTIAN JAŻDŻEWSKI: The team is key in our activity. This is also something we owe to the FNP programmes, which focus on building and supporting research teams. It is essential to create working conditions that will make young people want to, and be able to, stay in research. We are very proud of what we have built. These are fantastic people who joined us right after university or with PhDs. They are top European-class specialists in the latest genetic techniques. They conduct excellent, properly published research that brings benefits and involves interesting discoveries. Here in Warsaw! Not in New York, not in Paris. This is something that gives me the greatest joy: being able to come to work and see these fantastic people who enjoy what they do.
And you yourselves, why did you want to come back and build this wonderful entity in Poland?
ANNA WÓJCICKA: I have to admit that I found nothing in the United States or in London to keep me there from a scientific viewpoint. I sensed I could do important things right here, in Poland.
KRYSTIAN JAŻDŻEWSKI: My reply will be very American. It?s something Americans hear at every stage of their education: ?Make a difference.? Do something in your surroundings. When I heard it, I immediately decided to come back. It doesn?t have to be anything great, but something that causes the world to change. Working in the States, I realized very quickly that they will do very well there even without me. I felt that I could be needed much more in Poland. And fulfilling this was made possible by support from FNP, because if it weren?t for the FNP grant, I wouldn?t have funding for this work.
ANNA WÓJCICKA, PhD works at the Laboratory of Human Cancer Genetics at the University of Warsaw?s Centre of New Technologies and at the Genomic Medicine Department at the Medical University of Warsaw. She is the CEO of the Warsaw Genomics company and a winner in FNP?s IMPULS programme (2014).
PROF. KRYSTIAN JAŻDŻEWSKI heads the Laboratory of Human Cancer Genetics at the University of Warsaw?s Centre of New Technologies and the Genomic Medicine Department at the Medical University of Warsaw. He is a winner in FNP programmes FOCUS (2008), TEAM (2011) and IMPULS (2015).