Road to the Szechenyi Prize

Tuesday, 16 August, 2022

What does real success mean for academic László Acsády, whose scientific career is full of brilliant achievements and prestigious awards? The answer may surprise anyone who has not met him personally.

Success can be described and measured in many ways, although nowadays it is mostly measured in money. Despite the fact that success and wealth, acknowledged by the outside world, do not usually lead to satisfaction, and are far from what Vörösmarty says in one of his most famous poems: 'Thank you, life, for your blessings, / It was fun, it was a man's work'.

This could perhaps still be said today of a successful life, even if some might consider the wording a little outdated. And speaking of Vörösmarty.... No question, he was a famous poet, the author of the Szózat was known to everyone, he was respected as a selfless patron of young poets, including Petőfi, but he was never a popular poet. Nonetheless, when his widow and orphans found themselves in difficult circumstances after his death (1855), and Ferenc Deák appealed to the nation for money, they received donations not only from all over the country, but even from Kufstein. And this Kufstein is not close to the Hungarian-Austrian border, but to the Austrian-German border, to whose notorious dungeon Hungarians were sent with great preference after 1848.
Admittedly, this is a curious example of success, and I would not have brought it up if it were not for László Acsády, who reads not only bedtime stories to his 5 and 9-year-old children, but has also introduced them to The Bards of Wales written by János Arany.
He also had a lot to say about his greatest challenge and greatest success of recent times, which he will always look back on with a warm heart. The internationally leading researcher in the thalamus field was asked to give a lecture on the brain to the third grade class of the primary school where his son, Bálint, attends. It would certainly have been more difficult on his own, but he prepared and delivered the lecture together with his wife, Hajni Bokor, and together everything is easier. In the end, he says, every minute of preparation was worth it, because the most anticipated performance of his life was a complete success. According to the parents' feedback, the children pretended to be neurons for days afterwards. And an experience like that can go a long way. It could even lead to the highest state award for outstanding scientists, the Széchenyi Prize, which László Acsády won this year.
But every journey had to start somewhere. This is what he tells us now.

The beginning: the SOTE TDK
There is a specific professional background that leads to such a recognition, and there are the discoveries that you think helped him to win this prize.
One of the most important stages in my professional career is the scientific student community, which in my case started at SOTE Anatomy and then when Tamás Freund returned from Oxford in 1989, we moved here to KOKI. It is well known and very memorable that Professor Vizi took the unusual step, which was then very strange and strange to many, of inviting Tamás Freund, then 34 years old, but already a Nature author, to become head of the scientific department, which Tamás accepted. This is how four of us were transferred from the other side of Üllői street to KOKI: Attila Gulyás, Katalin Tóth, Erzsi Borók, assistant and myself, and when work started here, Zsófi Maglóczky joined us.

First successes at KOKI: description of interneuron selective VIP cells
The work here started and the scientific career began, the first step of which was the PhD in the mid-90s. I had the great fortune to be involved in the description of VIP (vasointestinal polypeptide) containing inhibitory cells, which have since become extremely popular. These are the exceptional interneurons that inhibit exclusively other interneurons, performing a function then unknown to anyone else by so-called disinhibition. Such neurons were previously unknown.
After the anatomical description, it took at least 20 years to prove that VIP cells were indeed capable of disinhibition, as it was only in the last decade that optogenetics was developed as a method to do so. And as it happens, the original discovery is no longer cited. This happened all the more because our submitted manuscript received several reviews and was thrown out of Nature. True, other papers on the subject have been cited quite widely, but it is no longer these original works that are referred to. But whatever the case, the discovery itself was a huge boost to my career and a huge motivation. After my PhD thesis, I came to Rutgers University, to the Buzsáki lab.

The second big discovery: the connectivity of hippocampal granule cells
In the Buzsáki lab, we have shown that hippocampal granule cells in the cortical network innervate excitatory and inhibitory cells in a unique way, with morphologically distinct terminals. Moreover, numerically speaking, they innervate more inhibitory cells than excitatory cells, resulting in a very strong feed-forward inhibition in the CA3 region. These insights have given impetus to a number of fields, including target cell-dependent synaptic transmission, memory formation or hippocampal epileptogenesis. It is still my most cited paper to date, and this work helped me a lot when I applied for the János Bolyai Research Fellowship, and it also helped me to receive, among others, the prestigious Cortical Explorer Prize and the Bolyai Plaque in the early 2000s.
The stay in the Buzsáki lab was outstanding in every way. In the short 14 months I spent there, I was able to contribute to 5 excellent papers, all of which are still highly cited today. And it was not only a very very good start, but also the key moment when I returned home, a little naively and perhaps with a bit of youthful arrogance, I went to Tamás Freund and asked him if he would support me to stop working on hippocampus - memory and switch to work on a thalamus. Obviously I dared to do this because I had already done some preliminary experiments in the Buzsáki laboratory, because I was curious to see how information is transferred to the cerebral cortex. And the results showed me that the thalamus is a very exciting area.

The thalamus: initial successes
So I submitted a young OTKA proposal on the thalamus, and Tamás thought it would be good for the lab's effectiveness if the activities were shared and the research profile expanded.
There is an English word, serendipity, which can be applied to both serendipity and the ability to discover something important unexpectedly. We were lucky, so to speak - it happens in science - when we unexpectedly discovered those giant inhibitory terminals, a feature of the thalamus, which are among the largest known inhibitory nerve endings in the nervous system to date. In contrast to all other known inhibitory terminals, they form many synapses, all converging on a single target cell and, as it turned out later, capable of maintaining strong inhibition continuously. My student at the time was Peter Barthó, and I remember when we were doing immunostaining and it turned out under the electron microscope that these giant terminals were inhibitory, I was happily running around the hallway with the micrographs in my hand, pointing it out to everyone: "Look, look, the giant terminal is an inhibitory one."
We didn't know at the time how it all worked, what it was for, but the result was enough to get me to apply for the Welcome Trust International Senior Research Fellowship. It was at this time, in 2003, that the first applications from the Visegrad Four countries were accepted for the first time. And Gábor Tamás and I, as two Hungarian neuroscientists, won the competition in the first year.
This grant was roughly comparable to the current ERC grants for a period of 5 years, which meant that it was possible to set up a laboratory, recruit staff and conduct research. Hajni Bokor was one of the first collaborators, and we have been working with her ever since, and we even got married. Then came Andi Slézia, who is now in Marseille, but whose collaboration with the Institute has not been interrupted, and our loyal and reliable assistant Kriszta Faddi, who can be trusted with all the sections.

The Welcome Trust International Senior Research Fellowship
At the time, the method we were doing was not common in the thalamus. We combined electrophysiological data from in vivo, anaesthetised animals with light and electron microscopy results, which were successfully published in a Neuron article two years later. In a broader context, this meant that we were slowly beginning to rewrite the picture of thalamic organisation that had been entrenched and treated as trivial for a hundred years. I think all the successes since then can be traced back to this.
The idea that a wide variety of things can happen in the thalamus because different areas of it can combine inputs in many different ways (which is not very common elsewhere in the brain) is still not trivial. In the hippocampus, although there are many different types of cells within a region, the unit of computation within the region does not change, whereas in the thalamus the composition changes step by step. Many people still need to be told this today, as if we were fighting windmill battles as Don Quixote!

The Gordon Conference
In finally reaching the current high point of my career, winning the ERC grant, I feel that a Gordon conference played a big role, where in a 20-minute presentation I managed to convince the audience of the importance and significance of this diversity so much that I was nominated as the chair of the next conference. And from then on, although there is obviously some precedent for this, it meant that the most important narrow community recognised what I had been doing.
And, to be fair, I also submitted the ERC to see what kind of reviews I would get, so that I could then write a better proposal. And then I received eight reviews with a total of half a critical sentence! I think it very likely that many of my reviewers were sitting at that Gordon conference! True, it must have been a well-written submission, as I even had three ERC winners read it over, and got good suggestions from each of them on what to change.
Well, that's how we got here. The recognition at home, the academia and then the Széchenyi Prize, basically a condensation of these international achievements.

What cannot be missed
But I must also mention a few things that are important to me.
In my research, when designing projects, I always keep in mind that the brain area worth researching is the one that is organised in a similar way in mice and humans. Only if the structures are similar can we assume that the conclusions will somehow be applicable to humans.
I often think about how many operations are performed purely empirically, because in many cases there is no evidence, for example, of where the brain nuclei are actually located in the thalamus.

It is also worth mentioning the "new love" that has emerged in recent years for the general organisation of the thalamus, the midline thalamic nuclei and stress.
We have found an otherwise tiny nucleus within the thalamus, which has a structure that is unprecedented not only in the thalamus but in the whole brain, and which spectacularly realizes what is called in English "hub" and in Hungarian "node", "centre", "hub point", which really receives inputs from millions of places and projects them to so many places that there is no other like it in the whole brain.

Finally, I would like to emphasise that research is for me a social activity. It is a formative experience for me to have all the students, researchers and collaborators with whom we design experiments together, evaluate them and get excited about the publication process.

The Széchenyi Prize
I was very happy to be nominated and to receive this award. It encourages me to make further discoveries, not for the sake of the awards, but for the joy of discovery. I am honoured to receive this prize bearing Széchenyi's name. For me, Széchenyi is the poignant tragedy of Hungarian greatness. He was already in the madhouse when the bridge was completed, he was never allowed to cross it, it was handed over to him by his greatest adversary (Field Marshal Haynau). However, his fate does not inspire in me a depressive type of bitterness, but a creative will to do something.

The mother tongue
My attachment to the Hungarian language is instinctive and deep. I am very fond of Hungarian literature. And although I also love English visionary poetry, it has a different effect on me. The mother tongue is not part of being a researcher, but part of being human.
But one thing must never be lost sight of.
You must always be able to say, to write down what you are researching with complete accuracy for the environment in which you live.


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