Skulachyov’s Ions
Текст: Aydar Fahrutdinov | 2014-07-11 | Фото: Mitotech company archive, weim76, belizar /; Apisit Thongsan, Andrew Orlemann / | 14703

Mankind has probably never searched for anything with such zeal and diligence as it did for the philosopher’ stone – a mysterious substance able to turn mercury into gold and create an elixir of immortality. Doing this has never come off, but for modern science and engineering the dreams of the alchemists no longer seem fantastic. Thanks to the discovery of atomic structure and the creation of the nuclear reactor by American physicists, in 1947 scientists were finally able to make the first durable artificial gold by transmuting mercury – a nugget of it is still kept in the Museum of Science and Industry in Chicago. Today we are on the brink of solving the second problem: the aging mechanisms of the human body are close to being uncovered, and an active search is already under way for drugs that can stop them. One of the leading experts working on this problem is world-famous Russian scientist Vladimir Petrovich Skulachyov. 

Vladimir Petrovich Skulachyov is a scientist, professor, doctor of biological sciences, a member of the Russian Academy of Sciences, the New York Academy of Sciences, and the European Academy of Sciences, Honorary President of the Russian Society of Biochemists and Molecular Biologists, director of the Belozerovskiy Physical and Chemical Biology Research Institute at Moscow State University, and head of a research project developing a drug to slow the aging process.

The scientist works from the premise that aging and death are processes programmed on a genetic level. If that is the case, then it can be hacked, as computer programmers say. For now this is only a theory, but a fairly large number of facts supporting it have accumulated.

First of all, it is worth mentioning a very important discovering of the late 20th century – the detection of death genes in human cells (and in the cells of other organisms.) It was found out that the fatal program is launched in certain strictly determined situations with the help of strictly determined substances, ending in the death of the cell. Carrying out this program expends energy, and if the cell is denied this energy, it will live much longer. Proof was also found that the aging and death of at least a few complex organisms were also programmed. For example, if you remove two out of 22 genes from Arabidopsis (a plant whose life cycle from germination to death is only a few weeks), then it will live and grow several times longer than the period allotted by nature. The situation in the animal world turned out to be similar. A case in point is one species of octopus whose females stops eating and starve to death after producing offspring. If special glands are removed from the young mother, she will not lose the ability to feed herself and will live longer, continuing to reproduce. 

Programmed death is biologically justified. A good illustration of this is the salmon. Adult salmon live in the sea, where there is plenty of food. There also many predators, which is why salmon go to crystal-clear water at the headwaters of rivers to spawn. There are no predators there – there is nothing for the predators and young salmon alike to feed on. This is what nature came up with: after spawning the salmon die in droves, and their bodies are eaten by small crayfish, who reproduce like mad after such a feast. The crayfish are then eaten by the young fish. Scientists, by the way, have found a way of  preventing death in salmon – to do this they need only remove the gonads or the cortexes of their adrenal glands. 

There is a similar example from the plant world. Several species of bamboo grow so thick that no room remains for new plants. For this reason, soon after flowering bamboo plants die, giving the younger ones room. 

However, here – as with any rule – there are also exceptions. We know of long-lived organisms that have extremely slow aging programs, or do not have them at all. Animals and plants like these are immortal under certain conditions, since they do not die of old age, but from external factors – disease, starvation, predation. Pearl oysters, for example, live up to 200 years, during time which they keep growing and reproducing. They die from the uncoordinated growth of their shell and the muscular foot that holds them in an upright position. Eventually the shell becomes too heavy and falls to the bottom – the pearl oyster can no longer filter plankton, and starves to death.

Science knows of cases proving that aging is not an essential characteristic of life. Naked mole rats – small rodents that live in Africa – do not age, dying primarily in confrontations with predators and rival clans. In captivity, where there is no danger, their longevity record is 32 years (which is probably not the limit). To put this in perspective, a mouse – an animal of the same type – lives only about three years, by the end of which it grows grey, becomes visibly unhealthy, goes bald, and shows all the other signs of aging. The naked mole rat, in contrast, lives a minimum of ten times longer and even at the age of 30 is just as active and energetic. On the whole it is just as much alive as it was earlier: it does not develop wrinkles, does not lose its teeth, and continues to actively reproduce. 

And then there is the record-holder for longevity – the Rocky Mountain bristlecone pine, which lives five thousand years!

This and many other examples gathered by scientists are good corroboration of the theory that an aging program exists, and that it can be turned off. The program is not an inescapable feature of life.

However, finding the aging genes in humans and turning them off is practically impossible today. Scientists would have to experiment and modify gametes, after which genetically-modified children would be brought into the world. If something goes wrong, it will already be too late. There’s no geneticist who would take that risk. But that in no way means that developing an anti-aging medicine is impossible. Genes in and of themselves cannot do anything. They are merely a code that а cell reads so that it can synthesize the “molecules of life” – proteins. For that reason, it is enough merely to determine which protein contributes to the synthesizing of the substances that bring on aging, and block that protein, or render those substances harmless. The second option seems to be the most acceptable to scientists, especially since the leading candidate for the title of killer substance – reactive oxygen species (ROS) – is already known. Scientists consider it very likely that ROS building up in an organism slowly poisons it, bringing on aging. Neutralizing ROS is possible with the use of well-known antioxidants. But here lies the main problem – most antioxidants cannot get inside mitochondria, the main deliverer of ROS within cells.  In order for antioxidants to work at full capacity, they have to be delivered to exactly the right address – the internal membrane of the mitochondria, where they must then be placed within a few nanometers of the proteins that carry out respiration and form ROS.

Vladimir Skulachyov was one of the scientists who found a solution to the problem of delivering drugs to mitochondria. The solution was penetrative charged particles – “electric locomotive molecules”, which American biochemist David Green aptly named “Skulachyov’s ions.” To put something inside a mitochondrion, one need only attach it to one of these ions.

This discovery allowed scientists to begin developing next-generation antioxidants, and the first to take advantage of this was Michael Murphy, who joined the coenzyme Q to a cation. It turned out the antioxidant properties of such a substance were much higher than in the original coenzyme. Later Skulachyov used a much more powerful plant-derived antioxidant, plastoquinone, in a similar structure, in the end getting the antioxidant SkQ1, intended for the mitochondria.

That is the form the idea took and how scientists synthesized the substance that would contend with free radicals and, presumably, slowdown the physical process of aging.

With the support of the fund Volnoye Delo, founded by Oleg Deripaska, trials of the drug on animals were begun in 2004, and the company Mitotech was created to handle the project. In 2009 the project Skulachyov’s Ions received the support of the fund Rostok, which financed the project until 2010, when an agreement with the corporation ROSNANO went into effect, and Mitotech received its first tranche of 95 million rubles from the corporation.  The project, coordinated by ROSNANO, has a budget of 1.4 billion rubles, of which the corporation invests 700 million rubles, and the rest is provided by private co-investors.

The immediate results of the project will not be anti-aging tablets, but drugs to fight specific age-related diseases. The first in this line will be eye drops for a number of ophthalmological diseases.  These eye drops have already gone through the first stage of clinical trials, which allowed the project to register them in Russia as a medicinal product in 2012. Clinical trials are now ongoing, with the goal of widening the list of aging-associated diseases against which these drops can be used. In the near future American clinical trials of the “drops with Skulachyov’s ions” should also start.

We will not get into the technical details of the project and the results of the research carried out – you can read all about these things on Mitotech’s website.  No less interesting for us is the unique management system that was built around the project. It was this system that we discussed with Mitotech’s general director Maksim Vladimirovich Skulachyov and general director of Verysell Icontri and Mitotech advisor Vadim Valeryevich Perekhvatov.

Vladimir and Maksim Skulachyovs; Vadim Perekhvatov.

– Tell us how you came up with the idea for the project, and how its organizational structure developed.

Maksim Skulachyov (MS): It all began when Vladimir Petrovich said at a scientific seminar that they had produced a substance that could cure aging and a lot of other diseases. After discussing it for a while, we decided to try to develop a medicine and launch an investment project for it. Now there’s a factory next to us that produces this substance, and it’s already being sold in pharmacies.

The members of this biotechnology project are an all-star hodgepodge, and a very complex hodgepodge at that. Investors, innovators, the government, people from education and professional sectors… The project has 300 employees, who are also heterogeneous.

As an initial resource we had the Belozersky Institute and a few laboratories with biochemists and biologists. When we began in 2005, and today even, the salaries of our scientists weren’t that high.  For that reason there was and still is the opportunity to attract very well-qualified workers part-time, though, as a rule, this led to most of them working on our project practically 100 percent. The general message was this: “We understand that your scientific interest lies in studying the energy storage mechanisms of cells, but forget about that for once. Use your knowledge to help us make medicine.” It’s the dream of any biologist to have his work eventually reach people. 

If you look at the history of our biochemistry publications in scientific journals, you’ll see that in 2006-2007 there was a certain lapse, followed by a surge. That was directly connected with the project –for the first few years we couldn’t publish any articles because we were still getting patents. 

Of course, we needed some sort of management for all these scientific groups. At first we were very reluctant to bring in “efficient managers” from outside, because human relations in our project is pretty unusual. You need to understand the scientific essence of what is going on, which is why a laboratory head can “con” any manager, even if he has an academic grounding in chemistry or biology. That’s why part of our management crystallized out of our scientists, and we just gave them extra responsibilities. Now the following situation has become common: a former grad student formally manages his professor – within the context of the project, of course.

Finally, we needed technical specialists – technologists, chemical technicians, quality control specialists. We were able to find them in related institutes and at the pharmaceutical plant.

Recently we also added a small team of two people – they’re marketing specialists who help us set up the sale of our medicines in pharmacies.

Vadim Perekhvatov (VP): When the project was getting started, we weren’t especially tempted by development institutes. We didn’t want to going through ridiculous bureaucratic procedures to first prove the project’s validity and then be selected. We didn’t want to wait months for a decision. In 2005 we had an easier way – we directly approached people who were able to finance our project, and convinced them to give us money. The entire procedure was quick and transparent. They either said “yes” or said “no.”

In our case the task was worthwhile and the investor recognized that our capabilities were considerable, so our project was launched without any real problems. The problems started later. Everyone pretty much understood us, supported us, sympathized with us, but solving even the simplest problems was incredibly difficult. Since we didn’t want to give up on the project, we were forced to create a strategy to overcome this resistance. 

In situation like this one there are always two choices. The first is to get rid of the resistance, i.e. create a perfect environment in which all of the people are good, all of them have good intentions, and they all understand each other. The second is to accept that the environment was and will always be unfriendly, and that you have to strategize and build around this fact. The entire time we’ve gone the second route.

Of course, to make a project on this level happen, a lot of things have to come together. You need a wonderful idea, and we had one – Professor Skulachyov’s great discovery. The people who made the discovery wanted it to see the light of day. There was a team of scientists from leading scientific schools. There were wonderful international contacts, thanks to the authority of the project’s head and thanks to the fact that many of his students now work all over the world, in all kinds of places. There were all the necessary conditions, but that was enough, because we understood that the resistance we felt was actually resistance from the people we were working with – investors, managers, scientists, business partners, officials, all of whose interests in some ways coincided with ours, and in other ways didn’t. People act based on their own interests. You have to understand that, accept it, and run the project so that you minimize the negative effects of people working together and maximize the positive ones. We understood that we could only do this through proper management. This determined our first task in setting up the project. We placed emphasis on building a management system, which isn’t typical of innovative companies, because they’re usually preoccupied with technical issues. 

 – What specific things did you make use of?

VP: There’s one fairly standard approach. It says that you need to set up a business by writing up and setting up business processes – then you can accomplish tasks with maximum efficiency by working out the proper operations. But in the creative part of an innovative business that’s impossible – processes are secondary. When solving problems requiring creativity specialists don’t follow processes that have been set up for them. If there is an idea and competent specialists, then they will do everything right, no matter what processes you set up for them. With a talented scientist an efficient process starts in his head: his thought processes themselves are efficient, and that helps him move toward his goal. There are geniuses who do everything instantaneously. Processes don’t exist for them – there’s only a beginning and an end; they see the result right away. You can’t set up a system for them; you have to agree on results. That’s why as our primary management technique we picked the idea of “agreement” – the contract – over the idea of “process.”

MS: We choose the stakeholder approach – that is, the idea of managing interests – as the basis of our management system. There was an incredibly large number of interests that grew up around the project, and if we didn’t balance them somehow, everything would have come crashing down, and it would have ended up being a sheer waste of money. The money, of course, wouldn’t have gone into our pockets (we’re talking about scientists here); it would have gone into the project.  No matter how you look at it, scientists in any case look at the project as a way of financing their work. And this is a very powerful group of stakeholders, even though it isn’t the scariest. The investors are the scariest group – they’re capricious and nervous people who put a lot of money into something that will give an unknown result. As a rule, the main conflicts that face Russian and Western investors alike are conflicts with investors, because development of innovations can’t be planned ahead with perfect precision – at the end of the day it’s not a technical process. Often there are questions about changes in the direction of research, project parameters, and for any investor these are nerve-wracking and complicated situations. We’re constantly having to sort them out, which isn’t the easiest thing in the world when one of your investors is Oleg Deripaska and ROSNANO is under the management of Anatoliy Chubais.

Management representing the investors is a third powerful group of stakeholders. They themselves don’t put any money into the project, but they are legal participants in the project and make important decisions. These are hired people who have their own assignments, and they are always trying to control the cash flow. Picture a situation where they tell you: “Do you want to buy up some reagents? Why don’t you buy them from the company I recommend? But in your report write that you picked it yourself.” If it later turns out that the reagents aren’t any good, the scientists will be held responsible. So this group of stakeholders can be very dangerous for the project.  It’s essential, however, to set up relations so that the project isn’t destroyed, because it’s these people who answer to their bosses for what is done with the money, and it’s these people who signal that the program should move on.

And then there’s also the government with its own demands, the university whose premises we use, the pharmacists, the final consumer and a lot of other people. You have to take a different approach in working with each group.

– What management tools do you use?

VP: The most important thing is that there are no verbal agreements. They have to be put into the form of a contract, and the contracts are all put into the information system. For us the information system is the most important management tool, and we put a lot of effort and resources into it.

We are always having to answer people who ask why such serious sums of the project’s money go into IT systems. Most people consider expenditures on IT to be inappropriate, practically money-laundering. But the system helps us with stakeholder relations, providing the investor with absolute transparency on every kopeck we spend, and providing the manager with complete monitoring of not only his subordinate’s activities, but also his own.

It was funny to see how one of our investor’s managers acted when they showed him the system. At first he loved it: “And can I use the system to forbid this or that expenditure? Can I use it to stop people from carrying out a task?” They answered: “You can. But if you do, the system will note who stopped them from carrying it out, and people will see what happens after you stop them. If it turns out that you were right, then everything’s okay. But if you’re not right, then we’ll know exactly who’s at fault, down to the last ruble.” Then he said that he didn’t need a system like that.

– If the stakeholders are at odds, how does that show up in the system?

VP: Here’s how conflict-solving works in the system: I want one thing, and you want something else. I have negotiations, the progress and end results of which are recorded in the system, along with the period in which they occurred, the resources expended, and who is responsible.  Further on conflict management consists of the system following the facts of the non-performance of obligations and presenting the information needed to sort out the conflict. The sorting out goes something like this: “Two months ago you broke down some tasks into such-and-such sub-tasks; you put your people here and here; I used my group to help you handle this sub-task; you and I agreed that everything could be done in three months’ time. I see your reports… and it turns out that you haven’t done anything.” So it’s simple: all the information that evaluates your work, your interest in the project, your demands on it – all of it goes into the system. If it doesn’t exist in the system, then it doesn’t exist anywhere. And in that case there’s nothing for us to even talk about. 

Scientists working in the laboratories of the Skulachyov project.

MS: By the way, people get used to this way of organizing work. The system, unlike most forms of agreement, is honest; it instills discipline without offending anyone, because it creates a fair form of reporting for each and every person. Human relations ease up very quickly – it’s only the system that’s guilty, and Vadim Valeryevich, the one who thought it up. In this context, though, he’s some sort of unreachable, intimidating guru somewhere up there. As a result, the contract is de facto made between the manager and the person carrying it out, but it looks as if together, as a team, they are fighting against an aggressive external environment and the system. 

– How is the structure of the project set up?

MS: The structure of the project is extremely important to us. On the one hand, we created the “investment” company Mitotech. The scientists don’t work for it, and its main job is managing the financial problem – how much money there is and what to spend it on, how to economize, etc. Now it also deals with the pharmaceutical functions. It’s this company that works with investors. The supreme governing body at Mitotech is the board of directors. This structure works extremely well for us, since it includes people who were here for the whole battle – entrepreneurs and investors.

Then the applied problems are the work of a separate affiliate – the Mitoinzheneriya Research Institute at Moscow State University. That’s the scientists’ domain.

– How do you plan to recoup investments? By selling pharmaceuticals?

MS: Selling new medicines in Russia isn’t profitable – you’ll never make back the cost of development. For that reason we want to make our money mainly by selling licenses to large international pharmaceutical companies – what’s called “Big Pharma,” another one of our stakeholders. At the same time we’ll keep the Russian market for ourselves – we’ll produce and sell our medicines in our own country, I beg your pardon, ourselves.

There is one thing: the large Western pharmaceutical companies do business only if they see a decent Western biotech company, with licenses and its research done in Western laboratories. They don’t trust Russians and start to run down prices. For that reason we have a company that does the Western biotech – it’s based in Luxembourg. So for “Big Pharma” it all looks like a small group of efficient managers who got the rights for a brilliant Russian product from their mother company in Russia, but then worked out all the problems in the West. That is to say, we don’t hide the fact that it’s Russian medicine, but we show them that the main part of our research – the preclinical and clinical trials – are done in America and Europe.

This is where our IT System comes in handy, by the way. We get money in Russia, and send a large part of it to the West to pay for our work. Operating procedures like this look criminal, so it’s essential to have absolute transparency of every expenditure there or transaction here. No words will have any effect – it’s important to provide quick access to information on the part of all interested parties.

– You have had a very interesting experience with your database. What did you rely on when creating it? What real-life basis did you have for it originally?

VP: I’ve been doing business with management systems since the ‘90s. I worked in the company IBS for a fairly long time, executing projects for, among others, Russian Railways, which was personally overseen by Yakunin. Then we had the job of creating a single commercial entity by uniting enormous masses of property, and after getting control over property, placing it under the command of a center of “generals” – very influential railroad managers. So, if in the energy sector Chubais strived to form separate companies and bring them out onto the market, then here the idea was to do the exact opposite – first get all of the assets together, and only then divide them. My team handled the collection and consolidation of data about railroad property. The situation in which those projects were carried out was not at all simple: we were always getting contradictory information, and work was carried out in a terribly contentious atmosphere. And we had to do something with this. Our management IT-models began to come together then. We created them from scratch.

– And so when did you get mixed up in a project connected with medicine?

VP: When Vladimir Petrovich understood that the fruits of his work could have a serious practical purpose, he began to get advice from people on what to do next – turn to the government, international development organizations, or someone else. As far as I know, there was still no talk of business. One of his sons was working for me then, and he suggested to his father that he meet me.

At that moment Russia there was an enormous amount of money floating around in Russia, and there were specific people – oligarchs – who controlled that money and made decisions about what to do with it. I got the crazy idea of simply tearing ahead and getting a decision like that by using Moscow State University’s enormous scientific authority. This idea worked out when Vladimir Petrovich met with Oleg Deripaska. 

At first I simply helped put together a business plan, but when there arose the question of cooperation with Deripaska, we needed to structure it somehow. His managers called the project “the dead rat” from the very beginning, thinking it a whim of their boss. Therefore all our agreements were unreliable – the next day an oligarch could simply stop giving money.  The question came up of how to make sure that an oligarch’s money went where it was supposed to, and wasn’t stolen, and how we were going to show that. We began by looking at how money is spent. The first version of the system did not suit Vladimir Petrovich at all, since it didn’t give him an idea of what people were doing. In the second stage we solved that issue. Time and again there popped up new and increasingly complicated tasks, which embodied themselves in the system. So the database evolved as an answer to the challenges of the project.

– Could you single out a few major mistakes that were made in the course of the project?

MS: In the beginning we got caught up in trivia and didn’t work out management problems well enough. We jumped in and started working on problems before we could put together a system to tell us how to do that. We weren’t interested in filling out papers – we wanted to give the rat a shot right away and see if it lived or not. Then later we realized that we needed to get a mouse, not a rat, and we should have fed it, not given it a shot, and that we didn’t need a rat, we needed 500 of them, and in Moscow, not Novosibirsk.

Another of our oversights had to do with patenting. It’s something crucial, because our entire project revolves around intellectual property. Now we’ve come up with a way of patenting the things we develop in one-third of the time and for one-half the price of how we used to, and not in Russia, by the way. As it turns out there’s a loophole that allows you to quickly apply for an American patent, all the while staying outside the US. In the US there is a very convenient way of filing for a patent in the form of a provisional application – it’s called that, “a provisional patent application.” You don’t officially register anything – you just write down your idea, and then you have an entire year to get it put through officially. In the process the date is recorded, so no one can jump ahead of you. But you yourself get the time to make аn attractive patent application on the basis of real data.

– Do you think your management model can be used elsewhere?

MS: Of course, although if we decided to launch a new start-up, there is a lot that I would do differently, knowing what I know now. Since then our country has changed a lot, too. The main principles of management we formulated correctly from the very beginning.

To be honest, we are already hatching several new projects. We know various molecules, where they can be used – we even know who can bring them into production and how. But to take on something completely and utterly new, first I have to get the main result of the project – a deal with “Big Pharma,” even if that’s only to prove to myself that we can do it.  

The apparatus where “Skulachyov’s ions” – the mitochondrial antioxidant SkQ1 – are synthesized.


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