According to molecular biologist and physician Marek Mráz, the absolute key to the treatment of oncological diseases is understanding their causes and the mechanisms that trigger the aggressive behaviour of cancer cells. Having amassed experience at the Mayo Clinic and in the labs of UCL San Diego, five years ago a grant from the European Hematology Association helped to bring him back to Masaryk University in Brno, where he is now working as head of a lab at CEITEC MU and at the University Hospital. In 2018, he received a prestigious ERC Starting Grant from the European Research Council to investigate the biology of leukaemia and lymphomas, and the possibilities of their targeted treatment.
Researchers in other fields sometimes complain their work lacks the flattering public image of medical research. Marek Mráz examines what happens at the cellular and molecular level in the bodies of people suffering from leukaemia or lymphoma. So, when asked what his research may turn up, he can quite simply answer: improvements in the treatment of an insidious haematooncological disease.
Does he see this as an advantage? “I’m not sure,” he says, pausing silently.
“Yes, we also explore issues that provide fairly direct leads to new drugs and drug combinations. At first sight, the context of my work seems easy to explain and understand, but it’s still primarily basic research – I’m not one who’s going to sort out someone’s illness in six months and make it go away. The issues I deal with are often more theoretical than practical, it may not even be immediately apparent how they relate to the treatment of cancer patients,” he adds after a moment.
Looked at this way, he says, it makes no difference whether you are doing basic research in botany, physics, or – as is his case – in oncology. And he points out that he dislikes the emphasis on applied research, especially when it happens at the expense of basic. “You never know where the next fundamental breakthrough for humankind might come from.”
You don’t get far without science
He holds degrees in medicine and molecular biology from Masaryk University (MU). “I chose this combination after I’d realized that if any real progress in cancer treatment is to be achieved, it must be preceded by understanding the disease at the molecular level.”
He thinks that for a long time, medicine has worked ‘only’ by trial and error. “Empirical findings indicate that some drugs help patients, and with some drugs we even know why, but – especially when cancer is concerned – the absolute key is to understand what causes the disease, what turns normal cells into cancer cells, and what triggers their aggressive behaviour. Really effective and targeted intervention isn’t possible until we’ve understood the basic principles.”
Science as a philosophy of life
Marek Mráz is clearly eager to start discussing the ins and outs of his research, but I am also interested in the events in his life that have brought him to science.
“Science is my guiding philosophy and my lifestyle. By the same token, it imposes limitations on my other activities and hobbies. I like literature and the arts, I even occasionally try my hand at painting, but science as an attitude towards life is what I really identify with,” he says.
“I’ve simply decided to spend my life examining things, phenomena, and trying to understand how they work. There’re few things that I enjoy more.”
The workings of living machines
Nonetheless, he does not want to dwell on his ‘résumé’ for too long. It was his parents who brought him to biology and a turning point was a book called Microbe Hunters by Paul de Kruif. “I read it as a gripping adventure novel,” he reminisces. He has never been deeply interested in technical stuff. “I didn’t care how machines worked, but what I found totally engrossing were the workings of ‘biological’ machines – beetles, animals, people.”
Growing up, he collected – minerals, pinned beetles, pressed plants – and was enrolled in a variety of after-school science clubs. “But I definitely wasn’t a pale kid hunched over the microscope. I had lots of friends and we’d take trips into the countryside, play football and video games, too,” he assures me.
Today, he still enjoys going on naturalist field trips. “I can’t identify any creepy-crawlies or plants any more, but I like to hear experts talking about them. At the lab, I work with cells, which is extremely abstract – so it’s nice to see a living, perfect creature.”
He also tries to compensate for the abstractness of his discipline – at least mentally – and make it more concrete and tangible by thinking about the situation of patients. He zooms in and out between a single lymphocyte and the totality of a human being. “What helps my work a lot is when I think about tumours within the context of the whole organism, in relation to the ‘ecology’ of the human body.”
Today I’d probably choose solid tumours
But we are getting ahead of ourselves again. After finishing secondary school, the young naturalist went on to study medicine, and – as already mentioned – he also took up molecular biology. “When I was about to graduate from medical school, the options for cancer treatment consisted mainly of chemotherapy, radiotherapy and, of course, surgery. I felt this wasn’t enough, that more sophisticated treatment approaches were necessary – but to get us there, the research had to be done first,” he recalls.
He chose haematology, the most progressive branch at the time. “Haematology had the best understanding of the molecular basis of tumours and it was also the area with first targeted medications; the other fields were lagging behind.”
Over the last fifteen years, however, the study of solid tumours has been catching up with haematooncology. “A huge shift in the understanding of tumour biology and in the possibilities of targeted treatment has occurred there. If I were choosing today, I’d go for solid tumour oncology,” he smiles. But he feels no regrets. Just consider the remarkable people who have crossed his way...
“Professor Jiří Mayer – nowadays head physician at the Internal Haematology and Oncology Clinic of the University Hospital in Brno and the MU Faculty of Medicine – recognized my interest in research; he helped me a lot and we’ve collaborated ever since. I also recall immensely inspiring debates with Associate Professor Martin Trbušek. Professor Šárka Pospíšilová, who supervised my thesis, played an important role, too,” he lists the names.
He is convinced that it is critical to have intrinsic motivation and a drive to do research, and also to meet inspiring and supportive people. This was precisely his case. And good luck has stuck with him.
Becoming a scientist in California
Having finished his studies in Brno, he left for America. He started out as a postdoc at the famous Mayo Clinic, but the decisive encounter occurred later, when he was working at the renowned Cancer Center at the University of California San Diego.
“I embarked on my scientific career in Brno, but it was in California that I became a scientist,” says Mráz. He got a job at the lab of Professor Thomas Kipps, a legend in his field.
“That’s where I came of age as a scientist, it was an incredibly intensive collaboration.”
What does he mean by ‘coming of age as a scientist’? And what does it actually mean to become a scientist? And a good one at that?
“There are a lot of aspects to it. Some of it comes naturally, some of it is sheer hard work. The important thing is probably having the right dose of scepticism. Not about people, but scepticism about data, about received knowledge; the ability not to ‘yield’ to older, established concepts, to discern their shortcomings and obscurities. Where are the weak spots of extant knowledge? Where won’t it hold up?”
Yet at the same time you must be tenacious, hard-working and you have to analyse your own findings with a critical eye to see whether there is anything new about them. “The essential thing is not to compromise in your experiments, so that you can unambiguously interpret the result against your hypothesis. When it comes to experiments, I’m a stickler for ensuring proper controls.”
He learned this under Tom Kipps, who was a very exacting boss. It was in a debate with Kipps that Mráz first posed a challenge to received knowledge.
“Together, we described the first case in which non-coding RNAs, so-called microRNAs, regulate the BCR signalling pathway, a pathway which is – in terms of B-lymphocyte research – one of the most examined because it regulates the production of antibodies,” says Marek Mráz. B-lymphocytes will be discussed in greater detail later in this article.
“We demonstrated that there’s a new level of regulation related to non-coding microRNAs. But Professor Kipps was the first person to originally express doubts about it. So, first of all, the two of us had to fight it out – in the best sense of the word – which is, after all, what happens between virtually every good scientist and their postdoc,” he recounts.
“I had an idea and I had to convince him that it was worth the trouble, that I – and largely also he – should spend three years of our lives working on this project,” he explains.
The tug-of-war went on for quite a while: Kipps considered that it would be better to start on a different project instead. “And it was a good project, too. Eventually someone else picked it up and it paid off, but I managed to persuade Tom that we would take on microRNAs.”
Gradually, their research revealed two microRNAs that directly regulate the activity of BCR signalling in both normal and cancerous B-lymphocytes. They were aware they would have a hard time convincing the community that the system actually needed this level of regulation – why should it, when existing knowledge explained its workings well enough?
“We knew it was necessary to conduct our experiments very rigorously, so that opponents would have no other option but to concede. So that after reading our paper, an a priori sceptic would think: Oh, they’re probably right.” The paper was published in Blood (Mraz et al., Blood, 2014) and was followed by several more papers that broke new ground in researching the BCR pathway, and even led to the development of a new drug based on microRNA inhibition – now in the second phase of clinical trials.
Mráz continues to collaborate with Kipps, and they are also very close on a personal level. “This has been an amazing stroke of luck in my life and I still enjoy ‘fighting’ with Tom about CLL biology.” They are soon to publish another jointly written paper.
Yes to popularisation, but...
The principles and processes described by Marek Mráz are complex. He does try to simplify, but for people who are not well-versed in the natural sciences, immunological and carcinogenic processes are difficult to understand.
Of all the ERC grant recipients that I have interviewed for this project, he has the strongest tendency to delve deep into the explanation of his research, down to very fine details. Occasionally, I have to rein him in. Does he view simplifying as a problem? What value does he place on popularisation? Does he ever deliver lectures to lay audiences?
“I gave a few such lectures in Brno and Zlín as a part of the Science Café talks. It took the organisers a long time to bring me around, but it was a very good experience. I enjoy it, though I’m not sure how much I actually manage to get across,” he voices his misgivings.
In his opinion, popularisation has two levels. “It’s good when the public can gain some insight into the scientific way of thinking – and perhaps even make it their own – because the scientific method is nearly universal and it’s useful for sorting out all kinds of problems. It’s much better than other methods, such as religion or adherence to political leaders. That’s why it makes sense to give the public a chance to understand this method,” he concurs.
But: “Whether scientists should submit to public opinion or – to put it differently – whether their work should hinge on being understood by the public and politicians, well, that’s a whole different matter. I don’t think that’s how things should be,” he asserts.
He says that inherent to science is the fact that only a very small fraction of humankind may ever understand what exactly a scientist is doing. “It’s important that knowledge exists for itself; the existence of research shouldn’t be contingent on public approval, and the public shouldn’t be allowed to decide what is and what isn’t ‘worthwhile’ research.”
Not the happiest scenario, I agree – but I argue that the willingness to give laypeople an intelligible explanation of what scientists do is not the same as selling out. I believe that a scholar should be able to relate the basic outlines of their work to a general audience. To describe the principle, to give an interesting detail. Large sums of public money are channelled to science – the point is not winning public favour for oneself, but for science as such.
“That’s probably it. More important than relating the minutiae of my lab work is the effort to convey the general principle in the approach to problem solving,” he muses. “The scientific method, experiment, analysis, synthesis, and statistics are all widely applicable to other issues that people deal with in life and in society. Many people may find the scientific method somewhat counter-intuitive, but it is a very potent tool.”
When a cancer cell needs accomplices
But now let’s return to where Marek Mráz feels best. To his lab.
It is located at CEITEC MU, and partly also at the Internal Haematology and Oncology Clinic of the University Hospital in Brno and the MU Faculty of Medicine.
The thirty-seven-year-old researcher spends a lot of time there – he used to go there even at weekends, but since the birth of his daughter (fifteen months ago), he has been trying keep Saturdays and Sundays free. “Well, at least I keep telling my partner that I’m not thinking about work,” he laughs.
Blood tumours come in many forms. Marek Mráz and his team study a group of diseases technically known as ‘B-cell malignancies’, the most common being follicular lymphoma (FL) and chronic lymphatic leukaemia (CLL). It is the latter that is the main focus of his lab team.
“Other kinds of cancer are autonomous, they just grow in the body with little regard to the reactions of the organism that surrounds them. For the most part, the organism tries to restrict their growth – it definitely doesn’t encourage it. But a strange phenomenon occurs with CLL: these cancer cells depend on contact with the patient’s healthy cells,” he describes the nature of the disease.
CLL cancer cells are originally B-lymphocytes, the cells that normally function as a part of the immune system and whose purpose is to protect us. They are steadfast and relentless safeguards against infection. But with CLL something goes awry and a B-lymphocyte turns into a malignant cell. In order to divide and propagate – which unfortunately in this case means cancerous growth – such cell requires contact with other cells in the patient’s body (mainly with T-lymphocytes and stromal cells).
“You can see it clearly under the microscope,” the researcher comments. “If I take cancer cells from the peripheral blood of a person suffering from CLL and put them in a Petri dish, they behave quite innocuously. They really need the other cells. And that’s something we’ve been investigating.”
Is it a parasitic relationship? “Not really. They don’t get nutrients from the other cells, but they retain their dependence on contact with them. Such dependence is actually a feature of normal B-lymphocytes, too. Healthy B-lymphocytes require frequent stimulation from T-lymphocytes to be able to propagate and survive.”
Marek Mráz is interested in the way cells communicate, the way they ‘talk’ about what they need from one another. “We already know one or two signals that a cancerous B-lymphocyte needs to propagate and/or survive. What occurs alongside these cell-cell interactions is the activation of the so-called BCR signalling pathway, which normally regulates the production of antibodies by B-lymphocytes.”
Good and evil cells
So, if they managed to find out how exactly various cells interact and disrupted these interactions, would the tumour stop growing? “Yes, there could be therapeutic applications. And it seems that some of the already existing drugs have an indirect effect on the interactions. This is precisely what we’re interested in, broadly speaking,” adds Marek Mráz.
The interactions of ‘good and evil cells’ seldom take place in peripheral blood – i.e. the blood that flows in our veins and arteries – but in lymph nodes. Cancerous B-lymphocytes keep circulating between peripheral blood and lymph nodes, which swell in CLL patients, because this is where cancerous cells propagate.
Marek Mráz poses himself a great many questions. For example: what allows a CLL B-lymphocyte to migrate from the peripheral blood into a node, then out again, and then back in? Members of his team have managed to describe several molecules that regulate the process, and they have used these findings to design potential new drugs and drug combinations. These medications are now being tested in the lab, on blood from patients and on animal models.
And the already mentioned paper, co-written with Professor Kipps, also demonstrates that “microRNAs not only regulate the BCR signalling pathway, but they even regulate the interactions of T-lymphocytes with B-lymphocytes. We are demonstrating that microRNAs are important for the cancer cell in terms of synchronising the activation of BCR signalling and interactions with T-lymphocytes.”
A step change in knowledge
Let’s zoom out from the research of Mráz’s team and briefly focus on cancer research as such. There, recent years have witnessed an enormous leap in knowledge. “Now we have a much better idea of the gene mutations that cause certain kinds of cancer, and why a given tumour is resistant to treatment or behaves aggressively,” explains Marek Mráz.
“CLL research has perhaps sequenced one of the highest numbers of genomes from patient-donated samples, they go into thousands. Even the ‘non-coding parts’ of genomes have been sequenced. However – unlike with other haematooncological diseases – even though all the genes have been sequenced, no universal mutation or aberration responsible for causing CLL has been found. There’s still a lot to be discovered here.”
Once Upon a Time... Life
He steers the conversation back to healthy B-lymphocytes, which have the otherwise rare capacity for so-called clonal cell propagation: “It’s one of the typical features of cancer cells, but under physiological circumstances such propagation of B-lymphocytes is strictly controlled. This allows them to divide extremely fast when they march into battle against the germs in your body.”
Suddenly, I recall a scene from an old French children’s cartoon called Once Upon a Time… Life. A captain in a white spacesuit, patrolling in a sort of floating bubble, sees an ‘enemy’, issues a command and a handful of other floating bubbles around hers start multiplying. Two aircraft split into four, then eight… and almost in an instant they have turned into a large air-force. The aircraft open their ‘bellies’ and they start ‘raining’…
“Antibodies!” Marek Mráz promptly picks up on my memory. “Yes, that’s right. Over the span of a few days, an extreme proliferation of B-lymphocytes does take place in the body – something that practically never happens with other cell types. They have their own inner programming called clonal proliferation.”
But when things go wrong and cancer growth occurs, the clonal proliferation ‘program’ is triggered without there being an infection in the body. And the Brno-based biologist would like to understand how this occurs.
Limits of the self
“The role and behaviour of B-lymphocytes is immensely complex. They possess an enormous power, it’s they that decide what’s me and what isn’t. They, along with other immune system cells, define where the ‘outside’ begins.”
That is almost a philosophical question… “And a more interesting one than might seem at first sight,” Mráz resumes. “The human body hosts huge quantities of bacteria, in the airways and in the digestive tract. In terms of total figures, bacteria outnumber the cells our bodies are composed of. We’re like vessels, so to speak, carrying much of the ‘outside world’, too.”
And to prevent their power from veering into tyranny, B-lymphocytes are kept in check by the whole system, but even so, a stray cell may sometimes evade strict control.
Amazing and dangerous
“Moreover, B-lymphocytes can change their own DNA on purpose, generating mutations and cutting out the part of the DNA chain that codes genes for antibody production. No cells except B/T lymphocytes have this ability. It’s an amazing process.”
But just like virtually all such amazing processes, it also comes with greater risks, doesn’t it? “That’s right – which brings us back right where we started. With B-lymphocyte tumours it’s precisely during these DNA re-arrangements that aberrations occur. What makes these cells exceptional is the very thing that makes them dangerous.”
To make matters even more complex, things work still differently when CLL is concerned. “The causation mechanism is probably different in CLL, we still know very little about it and we can’t cure the disease yet, unless we transplant haematopoietic stem cells from the bone marrow.”
Contact with patients
I ask whether he is in direct contact with patients treated for leukaemia at the university hospital. “For the most part, contact happens only through intermediaries – the doctors that look after the patients and give us samples. We try and collaborate with the doctors on designing some of our projects. In the past, I’d occasionally go and see a patient whose samples I was using, but nowadays I don’t really have the time for that any more.
Is it not possible that such visits might actually be emotionally unwelcome, that he might feel upset for being unable to help these patients through his research? He pauses. “I’d say we’re probably getting to one of the reasons why I chose to study CLL and follicular lymphomas rather than something else. I was already sure fifteen years ago that I’d be doing haematological research, although the prognosis for adult patients suffering from acute leukaemias was very poor back then; it’s slightly better today, but these are still very serious and aggressive diseases. With chronic lymphatic leukaemia, on the other hand, and also with follicular lymphoma, median life expectancy is longer – ten years or more. Many people suffering from these diseases have a good chance that they won’t die of them, if the disease is kept under control.”
Still, regardless of treatment, 15 to 20 per cent of people with CLL/FL have a very poor prognosis.
So he chose to study a disease that is not quite so fatal and whose relatively long life expectancy gives fairly good odds that even long-term research might still benefit people suffering from CLL/FL right now?
“Yes, I sometimes think along these lines. If I were to research a disease that spells a very unfortunate outcome for patients, I’m afraid I might, in fact, find it stressful that there was nothing at all I could do about it,” he ponders.
Patent for a harbinger of bad news
Although Marek Mráz does basic medical research, his discoveries have already yielded some patents. For instance, his team has come up with a way of predicting the efficacy of particular CLL and FL chemotherapeutic regimens.
“By using a particular microRNA, we can discriminate between CLL or FL patients who wouldn’t respond to standard chemotherapy and those who should benefit from it. It’s not that the former would be harmed by the treatment, but there’re high odds the therapy wouldn’t succeed, so it’s a good idea to prescribe something else.”
Two more patents are pending. “These concern other biomarkers, but the main thing is that we’ve patented a potential new therapeutic drug (inhibitor) for B-cell malignancies. On the one hand, this substance prevents the cells from migrating, but it also directly kills them by inhibiting the BCR signalling pathway I mentioned earlier.”
His biomarkers, which allow the doctor to tell that a patient may be suffering from a more aggressive form of the disease – the kind that resists standard treatment – are actually harbingers of bad news.
“True, but if you get this bad news about the patient in time, the doctor can put them under closer observation, or enrol them in the clinical trial of a new drug or a potentially more ‘intense’ treatment aimed at reversing the unfavourable prognosis. It’s debatable, though, whether these biomarkers will remain relevant as therapeutic methods change,” he notes.
“The scope of therapies for both of the diseases we’re researching is large and the number of medications is rapidly increasing,” comments Mráz, alluding to the fact that there has been an enormous proliferation of new findings and applications related to cancer. For years, all that was available were chemotherapy and immunotherapy, and the emergence of new drug groups (BCR inhibitors, checkpoint inhibitors, BCL2 inhibitors) has unleashed a revolution.
“Chemotherapy, the context in which we researched our biomarker, is being gradually pushed aside by the new treatment strategies, so we’ll have to see whether the marker will stay useful within more up-to-date therapeutic settings.”
Is it not frustrating that while he is busily inventing something, the playbook changes? “No. This is a good thing, as long as it all leads to better and more effective treatment. Many new molecules have emerged in therapy in recent years. This allows for a customized treatment plan – finding particular drugs and drug combinations for a particular patient. It’s a difficult situation from the viewpoint of biomarker development, but it’s headed in the right direction.”
Let me get a glass of water first
With his American experience in mind, I ask him to compare conditions in research home and abroad… “Well… let me get a glass of water first,” he laughs and takes a breather. A moment to think things over.
“The implication is whether research is better here or in America, right?” he reframes my rather general question in more clear-cut terms. He takes a sip from his glass before answering.
“It goes without saying that in America the productivity of research is on a whole different level, even if you take the total populations of the two countries into account. Speaking about my own field, the problem is not the facilities and equipment – they’re excellent at CEITEC, and I’m sure things are much the same at BIOCEV and at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences. The problem isn’t the machines but the people, the lack of stability of funding for Czech science, and sometimes the absence of ambition and determination,” he believes.
In the US, the situation certainly differs institution to institution, but the ambitions of individual American researchers are related to the possible rewards. “Not just money as such, but the freedom of research it provides. For a researcher, financial stability makes everything else much easier. People who’ve made their mark in science then become team leaders, they get promoted, and along with the managerial position come new possibilities for career growth. What happens here, unfortunately, is that scientific success and financial stability are two separate things, and promotions are given to the less capable scientists.”
He thinks that the only way of improving the status quo is to entrust money and management posts in research institutions to those who do demonstrably good research. “Politics and science are inseparable the world over, but a high level of expertise should be a necessary prerequisite when it comes to deciding about the direction and funding of science.”
Meaning. In everything I do
Marek Mráz likes to see an equilibrium between different kinds of ambition. The inner ambition to discover something new and simultaneously a professional ambition to build a team, which gives one a chance to intensify the research, or to participate in decision-making about one’s home institution. He considers his team fairly ambitious. “I think – and hope – that we’re ambitious in the positive, constructive sense of the word, not in terms of self-interest and sharp elbows, but in our determination to discover something interesting.”
He tells his students and postdocs that whether the things they do are meaningful or silly, they will certainly be spending at least eight or ten hours a day in the lab – and, ultimately, all of their lives. “That’s why it makes sense to use your time well and do things deliberately, properly and ambitiously. To provide quality. When I look back in twenty years’ time, I want to see that I did something good, I don’t want to see wasted time.”
The author is an editor of Deník N.
Translated by Petr Ondráček
This project has received funding from European Union's Horizon 2020 research and innovation programme under grant agreement No 955326.