When not in the lab, he is working on his family farm.

“When I’m working on the farm, I get ideas that wouldn’t occur to me in my lab or my office. I behave differently out in the country, especially when I’m wearing my dungarees. I talk like a regular farm hand,” Michal Šimíček laughs. He divides his time between his lab, family, and a farm that was handed down to him by his ancestors. Along with his wife, they decided to keep the family tradition going.

“Plus I’ve recently started brewing beer,” he says proudly. “I’m incredibly into it.” So, his résumé, boasting fellowships at Cambridge and the Belgian city of Leuven, now also lists a certified brewmaster course.

“Brewing beer is a science, too. A big science! And my little brewery is another lab,” he says. His special Christmas brew is maturing as we speak.

It was in Belgium that he fell in love with beer. “They have a brewery in every Belgian village. But beer was and has been an important part of my career as scientist, too,” stresses the immunologist. “In Cambridge, we’d often talk science over beers. We liked going to the pub where Watson and Crick figured out the structure of DNA. The pub even has a beer called DNA on tap,” he remembers.

“Not all that great, the beer,” he adds – unlike the ideas that emerged there. “I’m not one to promote alcoholism, but beer mellows out your mind and helps some very inspiring ideas crop up in discussions with similarly keen people.”

In Cambridge, he was part of an international team, a group of people with different social, ethnic, and religious backgrounds. “Beer brings people together and brainstorming over a pint draws out novel ideas and gives you different perspectives.”

That is why even nowadays, as team head in Ostrava, he occasionally takes his students out for a cold one. “A while ago, I discussed a problem with one of my students over a beer, and now, six months later, we have a patent pending. I’m not allowed to say more about it, but it began over a beer.” One probably ought to add that the patent was not born from drunken boasts. That is not how it usually goes.

Series | There and Back Again: Universitas is bringing you stories of distinguished researchers who have gathered experience at universities and institutions around the globe – and then returned to the Czech Republic. How are research and education carried out abroad? What compelled them to come home? And what are they doing differently here with international experience under their belts?

Cogwheels, rods, and belts

Ever since childhood, he has been fascinated by the operation of natural processes. “Like why plants are green and how human physiology works at the molecular level. It was the molecular scale that I was attracted to,” he adds.

At grammar school, he was trying to decide between chemistry and biology. “Eventually, the two came together for me in molecular biology. There you’re not just observing a cell under the microscope – you’re dissecting it, looking at the cogwheels, rods, and belts that drive the whole system. And if something goes awry, you’re working out why and what that means.”

And so Šimíček became a molecular biologist – immunologist.

“Each person has their own unique and inimitable immune system that keeps changing over their lifetime as the body develops. The immune system adapts to both internal and external conditions, but it also reflects your lifestyle,” he points out.

“Every cell in your body carries the same DNA – except for immune cells. They can tweak their DNA so as to be able to perform specific tasks,” he explains with obvious enthusiasm over a cup of espresso in the café at the National Theatre’s New Stage.

He has been brought to Prague from Ostrava by a slew of commitments. He works at University Hospital Ostrava, where he has his own research team, although it collaborates closely with physicians from the Clinic of Oncology.

An arms race

Immunity is a perpetual arms race between intruders – i.e. pathogens – and our bodies. “Bacteria, viruses, and even some larger organisms that live inside our bodies – although parasites are rather rare here – are constantly trying to adapt, so that they can escape our immune systems.”

And so they put on disguises, shape-shift, arm up. “And the immune system has to adapt too, to be able to keep up the fight over the long term,” the researcher adds.

“For example by producing specific antibodies based on information, DNA code. Meaning that immune cells actively change their DNA, so that they can produce antibodies capable of fighting particular pathogens.”

“I enjoy figuring out how they do it, why they do it, and then using the knowledge in subsequent applications. Linking basic research with clinical practice.”

That was not always the case, however. In the past, Šimíček used to be the kind of scientist who was concerned with – and completely engrossed in – basic research.

“I wanted to get to the bottom of things, to find out and describe how they work. For a long time, this brought me satisfaction and fulfilment, but then I reached a point where I needed to move on. I needed a new challenge. The connection with clinical practice pushes me to make my work benefit actual patients, and that puts a somewhat different perspective on things,” he says.

“I still find research enjoyable and interesting, but the other issue is very important to me, too: How can doctors use my findings to help their patients? How to modulate T-cells, how to take certain components and piece them together to enhance the immune system? The aim is to tailor immune cells to a particular patient’s needs so that the system efficiently eliminates the tumour without simultaneously damaging the organism.”

Cell therapy

Custom-made cell therapy is a fascinating principle. A progressive trend in the treatment of cancer patients. Yet, for the time being, it is prohibitively expensive.

“It’s very likely that cell therapy will get a lot cheaper in the near future, becoming a much more widely used treatment method,” Šimíček believes, optimistically (and he is himself working towards this goal). He offers an analogy with the development of computers.

In the late 1980s, computers were the size of a large room and only a handful of people in the world were able to operate them. They were unbelievably costly to run. Could anyone imagine, at that time, that each of us would have a computer on our desk? Or in our bag? Even in a wristwatch?”

Fast forward a few decades, and what seemed unthinkable has become a reality.

“It’s much the same in cell therapy. Sticking to my computer analogy, we’re now at some point in the 90s. Now we’re past the single room-sized giant for each big city, but we’re still far from having a computer in every home. Nonetheless, with knowledge, development, testing, and practical applications all driving forward, cell therapy, too, will become simpler and, by extension, cheaper,” says the researcher confidently.

And progress could be fast, exponential. “In our labs, we’re testing prototype procedures that make the therapy ten, twenty times cheaper. Clinical trials are in the pipeline for the next year or two that might push the price even lower. So, in five years’ time, rather than ten million, it will only cost one or half a million.” And in ten or fifteen years? “It still won’t be routine by then, but it’ll have become an affordable method.”

On mice and men

Several trials of cell therapy for haemato-oncological conditions have been underway in the Czech Republic over the past two years, and it is at Ostrava’s University Hospital that another trial is being prepared.

“It doesn’t concern our own products yet, but rather cell therapies that we can apply in our trial within a European consortium,” Šimíček explains. “Our facility, however, is in the pre-clinical research phase, we’re testing our therapies on mice. And maybe next year… the administrative side of things is complicated,” he adds. Just getting a permission from the State Institute for Drug Control takes a year, sometimes even eighteen months.”

In any case, he hopes this year the hospital will launch a clinical trial whose initial phase will be primarily concerned with the safety of the therapy.

“Over the following year or two, the patient cohort will be broadened to test for effectiveness in comparison to other available treatments.” Once the new approach has been shown to be safe and more efficacious than existing methods, it can be put into practice.

“It will be a small victory, but we’ll keep honing the technology to make it more robust, economical, safe, effective, and better. To reduce its side-effects down to almost zero.”

Mouse models: “We care for our mice to the best of our abilities, in accordance with the strict rules for working with lab animals in research,” says Michal Šimíček. “Our mouse breeding facility is one of the best in the country, it’s up to 21st century standards.” They breed special strains of mice that are immunodeficient – they have no immune system. “The conditions have to be sterile, essentially, so that the animals are out of harm’s way. Our staff are well-trained, we’re dedicated to animal welfare. They have beautiful cages, AC, toys. And every experiment has to be approved by an ethics committee. But we couldn’t do without our mice.”

Stripping components off cells

So what is the principle underlying the cell therapy Šimíček’s team has been developing?

Currently, cell therapy involves removing T-lymphocytes from a patient’s cells, genetically improving their properties, multiplying them, and releasing them back into the patient’s bloodstream. Such boosted cells then have an easier job wiping the floor with their cancerous foes.

“That’s how it’s done nowadays. But I’ll tell you how it could be done tomorrow. How we are doing it,” Šimíček begins.

“When treatment is based directly off the patient, we’re already constrained by the fact that the immune system is severely compromised by chemotherapy, so that it’s only running at a limited capacity, if at all. That’s why a whole lot of patients drop out as a potential source of cells for cell therapy,” he explains.

And the rule today is one patient – one medicament. Consequently, the development process is extremely demanding in terms of manpower, money, and equipment. It may require as much as a month’s worth of work for a single patient.

“We, however, make universal T-lymphocytes that can come from virtually any healthy donor,” Šimíček arrives at the core of his method.

But the immune system rejects foreign T-cells, otherwise this could have been done ages ago, couldn’t it? That’s what has been the problem, I protest.

“That’s right, you couldn’t just donate your T-lymphocytes to someone else. Their body wouldn’t accept them. Just like it would reject blood from a person with a different blood type. Foreign cells could even attack and wreck the patient’s immune system,” he elaborates.

“We, however, can universalise the cells. Not a nice-sounding word, but I’m unable to come up with a better one,” the researcher resumes, explaining: “We extract a healthy donor’s T-lymphocytes and subject them to genetic modifications, getting rid of ‘components’ that cause the tissue incompatibility you mentioned. What we really do is strip them naked.”

The ‘universalised’, stripped cells then cannot attack the patient and destroy their immune system.

“Then we do what is already being done today: we provide these cells with receptors that recognise structures on cancer cells they can attach to and destroy them.”

In this manner, T-lymphocytes for as many as ten patients can be obtained from a single healthy donor.

“And what’s more, we can have them on hand whenever we need,” Šimíček continues enumerating the advantages. “With existing methods, we must harvest them from the patient, cultivate – that is, multiply – them, and then put them back. With our cells, we can stock up on them, eliminating weeks of waiting. I can take the cells off the shelf and hand them to the doctor who then goes on to apply them.”

Off to roam the world

Šimíček graduated in immunology from the Faculty of Science at Charles University Prague. In Leuven, he acquired his PhD in biomedicine. During his post-doc fellowship in Cambridge, he studied proteins, their structure, and drug design based on molecular structure.

“Then I came back to Ostrava, where I essentially combined all these approaches together and overlapped basic and pre-clinical research.”

Once upon a time he fled the small pond of Czech research – so that one day he could come back. “Things have always been this way, haven’t they? It’s like in the folktales: a backwoods youngster sets off to roam the world, earns their stripes, and then comes back home. That’s how it ought to be, that’s my philosophy.”

Strong family bonds tie him to the region around Ostrava. “When I got the offer to build my own lab, virtually from scratch but with decent resources to draw on, I didn’t hesitate for long.” He returned home, but with a vision that he would do European-level research there. Moreover, his wife was born in the same village as him.

He inherited a family farm and, along with his wife, they decided they would run it together, carrying on the tradition.

“We have fields, apiaries, an orchard, sheep, and we also want to get some cows,” ticks off the farmer-cum-researcher. “I enjoy it, I like the work it entails. I was unsure at first whether research and farming would be compatible, but it turns out they are, although it keeps me busy for more than twenty-four hours a day,” he shrugs.

“But I’ve married a woman who is even more of a workaholic than myself. So we kind of complement each other. My wife graduated from agriculture school, so she even has the right education. She’s a home-maker, mostly looking after our young children, but she’s also in charge of managing the farm.”

“When I leave my lab, I shut the door behind me and concentrate on the farm. Sure, I also think about lab stuff while doing physical labour. I don’t go to a gym, I have no time for sports,  I invest my energy into the farm instead. I’ve learned so many trades – from plumbing, through bricklaying, to tractor-driving.”

Eight years ago, the very first thing they started with was renovating the house. It was built in 1910, “and had never been touched since. It had no running water, electricity, or heating. Just a privy in the courtyard. We gave it a complete makeover. Our kitchen is now where the stalls used to be. It’s eaten up all our savings, but we’re moving forward. We’ve reclaimed our land from the local co-op farm. Our children are still very young, so we aren’t able to do nearly as much as we’d like. It’s coming on slowly, but surely.”

Outside the box

His aforementioned love for beer aside, what else has he brought back to Ostrava from abroad?

“Perhaps a slightly different mindset. A different perspective on science and research. I’d hate to generalise, these things differ from team to team, of course, but I found people abroad more daring, they’re not afraid to do more ‘outside-the-box’ thinking,” Šimíček opines.

He thinks researchers ‘out there’ are more open to greater and especially new challenges, instead of lingering over the same research problem for twenty years. “That’s one reason why it’s good to overlap basic research with practical applications: the idea is really not just to try and understand how things work, but to come up with new combinations, new approaches. That way you don’t get stuck in one spot,” he adds. “I’d say foreign fellowships have given me the ability to think more comprehensively.”

He also believes that going abroad toughens one up, makes for more seasoned researchers. “Going abroad for a few months is the bare minimum, but if you want to make some career headway, you should leave for a year or two, or even three years, to see any lasting difference. I encourage my students to go abroad, even if that’s not a compulsory requirement at my faculty.”

In hindsight, he reminisces about his foreign fellowships with a touch of melancholy: he had some hard times abroad, too. “Although I set off for the world intending to do research regardless of whether it was a Monday or a Sunday, I really did hardly anything else but work in Belgium,” he recalls.

“I was in Leuven, in the Flemish part of the country, and I even picked up some Dutch, but I didn’t make any friends there. The locals were rather reserved, they didn’t take to foreigners very much.

I think the social aspect played an important part in leaving me with these somewhat negative feelings. Ninety-nine percent of my time was taken up by work with no way to unwind. Cambridge was similar, work-wise, but there I had some work pals, it was more fun.”

A broad-based team

Today in Ostrava he runs his own team of approximately twenty people. “I’ve even managed to lure an Oxford colleague to come over. And others from different corners of Europe and the world. Most of our meetings are also attended by clinicians – doctors who don’t do lab work, but who are so versed in the science that they can hold their own in the discussions. It’s a broad-based and international team, we only communicate in English.”

He also speaks highly of his boss. “He’s an all-around great person, a very inspiring character. And an excellent manager, too. I’ve learned a lot just by observing what he does.”

Šimíček gives the impression of being a content, equable person. How is the expert on immunology doing in terms of his own immunity? Are the cobbler’s children the worst shod?

“They aren’t. I think my immunity is fine, I’m a healthy person and my immunity is in pretty good trim. Perhaps it’s also owing to the farm – farmwork and exposure to animals are immunity-boosters,” he reveals his formula.

“Juggling my job, the farm, and my family – we’ve got a four-year-old boy and a one-year-old girl – is taxing sometimes, but recently I’ve been able to maintain some work-life balance. And I offset my job-related stress with physical activity. Only I don’t get enough sleep,” he admits. “That’s not very good for me, I know, but then I’ve never been much of a sleeper anyway.”

Translated by Petr K. Ondráček

Photo: Dan Hamerník, Universitas

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