Preface to the Special Issue: The Skulachev Project

Maxim V. Skulachev

DOI: 10.1134/S0006297924020019

The greatest danger for most of us is not that our aim is too high and we miss it, but that it is too low and we reach it.
Michelangelo Buonarroti

Vladimir Petrovich Skulachev. I called him in different ways; at home, in the family, he was, of course, dad. “Dad, there is news about SkQ, let me come and tell you”, “Dad, are we going for a walk with the dog?”, “Dad, sorry, I can’t pop by tonight, I’m completely drained. Was there anything interesting at the seminar?” There was no problem with that. But how should I have referred to him behind his back, if it is not something personal, but about work? I always twitched when people asked me to pass something on to “dad”. Well… it sounds too presumptuous. Therefore, as soon as we started working together (which did not happen immediately – only since 2005), the formula of addressing has emerged: Vladimir Petrovich (in Russian a polite way to address someone is to use his/her first name and patronic name) or VP. So, this is an essay about VP’s last and, I believe, the most significant chapter of life – the Project.

In the Project, I was VP’s right hand, his trusted lieutenant, and probably one of the few who saw and sees the overall picture of our enterprise. We disagreed with him on many things and argued relentlessly about how the Project should be organized and what it should do. Being both terribly stubborn, we always tried to push our line. Even if we came to some kind of compromise, we still did not stop trying to covertly turn the work in the direction we each thought was right. But I want to officially declare that VP was always the main one, the true leader, the Project has always been his endeavor. VP came up with it, he proposed the organizational structure and strategy, he found the first (and substantial) funds for financing the work, he put everything he had into the project: his scientific name and reputation, 100% of his time and energy, connections at all levels, including the international network of his students, and his entire family. His wife and four sons worked 24/7 in the project, and sometimes his daughter was also helping us. In the last years, VP started casting glances at his grown-up grandchildren more and more often and (accidentally, of course) inquiring if they were being occupied in some nonsense and whether it was time to engage them in the family business. I assume the genes of his paternal grandfather, a peasant and master carpenter, and head of a huge family as well, were awakening in him.

For VP, people were always very important. He never considered his employees, subordinates, or partners as “functions”. There is a fashionable trend in project management and management in general, which considers a person simply as a set of functions important for the business. It is believed that in routine businesses, people are easily replaceable: if someone leaves, we just look for the corresponding functionality in the market, and their carriers themselves are not so important. Such an approach was categorically unacceptable for VP. Hearing something like this, he would explode and almost shout that when we start “making chairs”, then we can talk in such terms, but for now, we are doing some real science, and here, “personnel is everything”. By the way, I am sure that if we were really making chairs, people would still be more important to him than any indicators.

VP used to say you cannot work with more than 12 team members (sometimes he looked at you cunningly and added that a couple of thousand years ago, one prominent group leader took a 13th disciple, and it somehow did not end very well…). At the same time, of course, the Belozersky Institute is much larger, it consists of hundreds of people. But we know how VP managed it all these years. He always had 1-2 favorite laboratories, which were engaged under his leadership in something very interesting to him. All the others worked on their grants and projects following the rule of “live and let others live”. The chief never interfered in the scientific work of other departments and research groups. Of course, the duty of the director includes ensuring the general functioning of the institute, making sure that common services work, defending and promoting the institute in the outside world, and solving all sorts of internal conflicts. VP was doing it successfully. But in terms of our main activity, scientific work, all groups were free to do what they think is necessary.

I do not know how it was arranged in the ancient USSR times. I started my scientific career in the beginning of the 90s; back then the Belozersky Institute never had money, a budget for research. There was no way to apply for any internal funding for your project. One could not come to the institute’s authorities and say: “Look, I have a great idea on research about the mechanism of mRNA quality control in plants! Give me a budget for a graduate student, a technician, and consumables for RNAseq. This is going to be an outstanding project!” I often complained to VP that this situation was outrageous and he should do something about it. What a shame for one of the most powerful biological institutes in the country! VP looked at me condescendingly and said that he fully shared my indignation at the injustice of the arrangement of this world in general and the financing of science in particular. However, he noted, our Institute, nonetheless, does not yet charge the researchers for entering their own labs. Indeed, in Russia, in 90s some scientific institutions had to impose such internal tax on their scientists to pay for utilities. I am still outraged by the situation, but maybe there is also some blessing in it. If the chief of the institute does not deal with the distribution of money, then he does not have to manage a team of hundreds of people. He just ensures the institute works as a whole. As a result, the director can have time for his science which can be done by a team of no more than 12 people. VP did it great.

But then VP came up with the Project. At the peak of “broad front” research in 2006-2008, more than 300 people participated in the Project simultaneously, so the Project from the very beginning turned out to be a significant management challenge. In 2006, as we were just beginning, we consulted with a highly respected and experienced specialist, a Vice President of a multi-billion-dollar American biotech corporation. He was initially impressed by the concept of SkQ and our preliminary results. However, his enthusiasm waned when he learned about our work’s organization and the number of people involved. He immediately expressed skepticism, asserting, “It will not work.” I was very surprised: “Why? Look, what an elegant technology we have, the first experimental results are astonishing, what can be wrong?” He replied: “That’s great, but you won’t be able to manage it”.

Of course, from the very beginning, we paid special attention to management problems, we were greatly assisted by a special information system, invented and created by my ingenious brother Konstantin Skulachev. But both I and VP are sure that a vital part of the success of our enterprise lies in the fact that we worked with good and intelligent people. And this made everything easier. Even when something did not work out, VP used to say “It’s better to lose with a wise than to find with a fool”.

I think VP would very much like to express his deepest gratitude to those people who contributed to our Project. I am sure that most of the current and past participants of the project will read this issue of Biochemistry (Moscow). If you have ever worked or are working now with SkQ in your laboratory – thank you very much!

Why was the Project so important for VP and all of us? On the surface, such endeavor represented the dream of many scientists: to merge their innovative fundamental research with practical application. I think 99% of us, as scientists, agree that regardless of how fascinating the complexities and nuances of biological mechanisms we explore are, or the significance of new functions we uncover (a function? “aim higher”, a whole signaling pathway!), there is still a lingering, uneasy question: will it ever find practical use? Even if your discovery is included in textbooks, will it be used in any other way besides just another query in PhD students’ exams? Oh, that might not be the case… Now imagine how VP saw before him the opportunity to use his* discovery, “mitochondrial electricity” – probably the greatest achievement of his career – to develop an actual therapeutic drug. This drug, based on “Skulachev ions” – lipophilic penetrating cations – was not intended for the treatment of minor issues like hangnails (though that alone would be an achievement for many). No, it aimed higher, perhaps even at addressing aging itself! He had enough wisdom to see this opportunity and the courage (oh, he had plenty of it) to rush forward and try to grab it. But that is not all. Looking backwards, I think that behind all this was another deep idea of VP, and when VP has a deep idea, it is, at the very least, worth listening to.

* VP never attributed this discovery to himself personally, he always acknowledged that he was a member of a team with Efim Liberman and all the co-authors of the epic article in Nature in 1969.

As I mentioned, in my conversations with VP, I often regretted that science today is not organized the way it was in the 1970s. The percentage of GDP allocated to science has decreased, and scientists no longer have the privilege to focus exclusively on their work, drawing research funds “from the drawer” – from the budget of their institute. Now, funding must be actively sought, competing for grants or looking for some industrial contracts. Life was different in the 70s! I then painted for him and myself a picture of the fictional institute of magic and wizardry, created by the genius of the Strugatsky brothers in their fantasy book “Monday Begins on Saturday”. In the end I always asked: “Tell me, oh, wise professor, when will we have such a system again?” He replied that it would likely never happen. In his opinion, humanity’s fascination with science was a strange “fluke”, a moment when people decided to allocate almost uncontrollable funds to scientists. “Everyone was so astounded by the power of science after the physicists created the Bomb” (a direct quote from VP), that for a while humanity decided to fill the scientists’ trough with as much money as they requested. Maybe they would invent something even more significant? For various reasons, this “gravy train” ended towards the end of the 20th century, and even earlier in our country, when the USSR went bankrupt.

How should science and R&D be financed in the 21st century? The grant system is decent, but its restrictions are well known, which is why VP disliked it, viewing it more as a means of survival for scientists rather than something that can propel progress forward. Something new is needed. I think that in the Project, VP saw a model for the future of science and decided to carry out another bold experiment. He often did that: spring bioenergetics schools, A. N. Belozersky Institute, biochemical “college” for students from non-biological faculties of Moscow State University, an attempt of revival of the Gelfand’s seminar, a tandem of institute and faculty inside the University, the first private biological research institute integrated into Moscow State University. These were all his experiments, but organizational, not biological. Some turned out to be highly successful, others did not. But all were extremely useful. Thinking of the origins and motivations behind the Project, I now realize it was yet another “acute experiment” conceived and implemented by VP.

From the very beginning, the Project was structured as a business enterprise: a company, investments, products, and markets. However, it is more than just a business venture. We may not have generated significant profits for our investors, but we have managed to sustain ourselves for 8 years following the investment period, balancing our earnings with our expenditures, including a sizeable research budget. Here, I would like to address a pertinent question: why has funding for science diminished so dramatically in comparison to the blessed 1970s? Ultimately, because society’s interest in science has waned, or in market terms, the price of its shares dropped. Although the analogy is rough, it contains a significant grain of truth. In the command-administrative system of USSR, resources were allocated according to the directives of the authorities. Whether it is good or bad, in the modern world, this distribution is done through the market, and VP understood this well at the beginning of the new century. If you need resources, go and get them from the market. There are downsides: you do everything at your own risk and nobody is obliged to fund your project, and upsides: freedom + the volume of resources is almost unlimited. But you need to offer something to the market. It could be a product exactly like an existing one, an improved product, or something completely new, a breakthrough product. VP’s favorite analogy was Christopher Columbus’s project to discover America, a typical investment project with investors being the Genoese merchants and the Spanish royal court. Columbus raised funds to discover something that did not yet exist – a shorter route to India. He did not find the route, but the result was even better!

The Project was initially aimed at creating something unprecedented – a cure for aging. There is no such thing, so our goal was to create it de novo. That is a breakthrough development, a world-changing technology. Taking into account VP’s favorite quote from Michelangelo (see the epigraph of this article), it would be strange if VP aimed for something less. If you set such a goal, you need to gain new knowledge, make some discoveries, and that is the work of science, hence of scientists. However, unlike traditional fundamental science, this new knowledge is not the ultimate goal. The goal is to create technology, and generating knowledge is just a necessary step on the way to this goal. The idea seems simple, but it, as VP loved to do, turns the whole field of high technology “upside down”. What is the traditional picture of Hi-Tech that most business schools will draw for you? Somewhere in universities, egg-headed scientists play with science and “generate” new knowledge, which theoretically can be useful. Sometimes rare creatures appear, called technology entrepreneurs, who understand a bit about this knowledge, carefully “peck around” in this treasure trove and “Ta-dam” – suddenly see the possibility of a business implementation of some randomly discovered knowledge (these guys have a special “sense”, an entrepreneurial nose). Then the entrepreneur grabs the knowledge, “refines” it with standard industrial methods and turns it into new technology. Everyone is happy. Except that it works worse and worse nowadays, and it is clear why. Gaining new knowledge is becoming more complicated, each subsequent step is more and more expensive, and if knowledge is generated in such, let us admit it, a stochastic way, then our chances of finding in the “treasure trove” something from which technology can be created are rapidly falling. It is a different matter if knowledge is produced purposefully, keeping in mind the final aim of creating technology. And I am not talking about applied research but about fundamental studies. However, what sets them apart from the usual grant work is the goal: not just to discover something new (which is more than enough for a decent scientific paper and a grant report), but to fill a missing gap in the formation of a technological solution necessary for creating a future product. That is the very one that does not exist yet and which your project is aimed at.

At the beginning of such an innovative project, it is hard to clearly define which gaps need to be filled. Whatever plan you draw up, any sane person understands that it cannot be final and subject to constant updates. By the way, this is the reason why actual breakthrough projects are practically impossible in a command-administrative system where resources are tied to a fixed plan and any deviation requires top-level re-approval. In contrast, business financing often offers more freedom. Once a contract is signed, you are generally bound only by its terms. If you explained to your investor that the presented plan is just our vision at the moment and we will have to update it in the course of work, and the investor agreed to this condition and you shook hands – no problem, that’s your business with them. However, at every stage, the project must have a plan with a potential for success, offering the investor a chance for profit. This was VP’s foundational principle for our project. Initially, I was skeptical about convincing anyone to accept our terms, given the complexity of this business logic. How to explain it to an investor? VP was adamant: “A smart person will get it. Fools – we do not need them!” I cannot say it was very helpful to my team, whose task was to implement this fundraising strategy. But it turned out that everything was possible, and we managed (more than once) to find smart investors who agreed to these terms. However, we also came up with a way to make the project a bit more attractive for them: by creating and bringing to market “intermediate products”. Aiming to transform the world, to defeat aging and other harmful programs in the human organism, we inevitably discovered along the way something new and could allocate some resources to the commercialization of this knowledge. As a result, we developed “Visomitin” eye drops and are currently working on clinical trials of “Plastomitin”, which is a systemic formulation of SkQ1. Plastomitin is not though a “cure for aging” yet, but a medicine for specific autoimmune and/or metabolic diseases. However, while developing these promising, but intermediate products, it is crucial not to lose sight of the main objective, which VP had set for us. It will be difficult to achieve, and nothing is guaranteed, but nevertheless, we must not trade this goal for simpler immediate tasks.

So, it turned out that the Skulachev Project became a large-scale experiment conceived by VP and entrusted to all of us, his team, to conduct. The experiment is very complex and long, but when did such details stop the great professor? If the great task is set, then even the passing of its initiator does not relieve us of the responsibility to accomplish it. Therefore, it is our duty to fulfill the VP’s will by making a bold attempt to complete the Project. And anyway, it would be unforgivably stupid to abandon such an interesting experiment halfway, as Vladimir Skulachev would definitely say.

Acknowledgments. The author would like to express his sincere gratitude to Matvey Skulachev for his assistance with the English translation of this manuscript and for his service in general.

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