Bioenergetics Pioneer Vladimir Skulachev: The Neoteny Puzzle

Russian biochemist Vladimir Skulachev---who first coined the term “bioenergetics” and then proceeded to pioneer the field---has essentially been thinking about the puzzle of neoteny for half a century. Neoteny is the retention of youthful features of an organism in adulthood. It’s a phenomenon Stephen Jay Gould once characterized as the most important factor in human evolution, although neoteny is thought to be inherent in a wide range of life from whales to salamanders to jellyfish---even in plants.

Skulachev is an experimentalist who is currently studying neoteny in naked mole-rats at his lab at Moscow State University (apparently the “queen” can live for 30+ years). He is also a professor of biochemistry at MSU and serves as director of MSU’s Belozersky Institute of Physico-Chemical Biology, as chief of MSU’s Bioenergetics Department, and as dean of MSU’s school of Bioengineering and Bioinformatics.

But just how does neoteny work? I decided to ring up Vladimir Skulachev for some perspective on his recent Physiological Reviews paper, “Neoteny, Prolongation of Youth: From Naked Mole Rats to “Naked Apes” (Humans).”

Vladimir Skulachev began his scientific career in biology at MSU in the early 1950s and a decade later organized MSU’s first Department of Bioenergetics. He was also one of the early experimental supporters of Peter Mitchell regarding chemiosmosis, a hypothesis that would embroil Mitchell in the decades-long oxphos wars.

In an interview Skulachev gave last year to the journal Biochemical and Biophysical Research Communications, Skulachev cited as one of his scientific group’s most important contributions to bioenergetics “the demonstration of mitochondria, chloroplast, and bacterial electricity as the primary form of convertible and transportable energy produced by respiratory and photosynthetic mechanisms.”

Vladimir Skulachev told me it is clear to him what the special mechanism is for the timing of development of an individual organism from zygote to adult. His deep understanding of bioenergetics also accounts for the confidence he has in his approach to inhibiting and reversing aging through a mitochondria-targeted antioxidant drug therapy known as “SkQ”.

SkQ is now on the market in Russia as “Visomitin,” eye drops for the treatment of dry eye syndrome, cataract and glaucoma, and is about to begin Phase III trials in the US, with pre-clinical testing for wider application of the drug in pill form to follow. Vladimir Skulachev says it has always been his dream to be able to normalize a pathological process and thus satisfy Ivan Pavlov’s criterion for what it means to be “a specialist in physiology.”

But while Skulachev’s work has inspired scientists like Nobelist Günter Blobel in recent years to describe him as “the world’s best biochemist, world’s best bioenergetics person,” saying further that “we don’t have antioxidants of the type that Skulachev has developed”---there is also skepticism about the effectiveness of antioxidants, notably from British biochemist Nick Lane. Meanwhile, Skulachev reports that out of a million units of Visomitin on the Russian market, there has not been a single complaint about side effects.

Among Vladimir Skulachev’s honors are the following: Lenin Komsomol Prize (Science and Technolgy,1967), AN Bakh Prize (Academy of Sciences, USSR, 1972), Order of Red Banner of Labor (1972), State Prize of the USSR (1975). Skulachev is a member of the Russian Academy of Sciences and of the Academy of Europe, and also serves as Academy of Europe Russian Club President. His PhD is in biology from Moscow State University.

He is the author of these two books: Membrane Bioenergetics and Principles of Bioenergetics, and of hundreds of scientific papers.

Our interview follows.

Suzan Mazur: Key scientists like Richard Lewontin and Eugene Koonin and countless others now agree that the term natural selection is metaphorical, a term Darwin never intended generations of scientists to take literally. Eugene Koonin recently told me:

“No one in the mainstream scientific community now takes selection literally.”

However, in your current paper on neoteny---a phenomenon Steve Gould once described as the most important factor in human evolution---you say natural selection does play a role. You note that humans are able to inhibit aging by thwarting natural selection and that we’ve done it and continue to do it by being technologically innovative, highly social animals.

My question is how does the view that “[n]o one in the mainstream scientific community now takes selection literally” impact your neoteny hypothesis?

Vladimir Skulachev: By the way, Evgeny Koonin was a co-worker of my institute in Moscow.

Suzan Mazur: Really.

Vladimir Skulachev: Yes, he’s the most famous bioinformaticist in the world. He is sort of genius. If you say genome, then he will immediately say, yes this organism goes to that organism, etc. Real genius can come to such kind of conclusions. . .

Suzan Mazur: I’ve interviewed him a couple of times. He also has a profound delivery.

Vladimir Skulachev: But concerning natural selection, for humans and naked mole-rats (“NMRs”), the problem is the following. Natural selection is very slow and cruel. Unfortunately, normal organisms have no other ways to come to new inventions. Only by natural selection. And this is why the great majority of organisms invented mechanisms how to accelerate evolution. This is evolvability. How to increase evolvability of organism. Sometimes the result has been a discovery of some counterproductive programs from the point of view of the organism. But they’re very useful for point of view of the rate of evolution.

Suzan Mazur: So you don’t agree that no one takes the term natural selection literally anymore. You don’t agree with that?

Vladimir Skulachev: In these two cases of humans and NMRs, the role of natural selection is very limited for two different reasons. For humans because of technical progress, which is very much faster than natural selection and not so cruel. Natural selection still affects humans, but the degree of its importance is a lot smaller than for chimpanzee.

The same situation for NMRs. This is the main message of my article in Physiological Reviews---that only the NMR queen and her husband can reproduce. This means only they can be involved in evolution. Three hundred working class NMRs [in the colony] have no possibility to reproduce and are out of evolution. Even very important traits invented by this working class of NMRs cannot be transferred to the next generation. Only the queen and her husband can participate in evolution. The pressure of natural selection is also much less with NMRs than in the case of mice.

In the case of NMRs all the problems of enemies, of starvation, [taking care of newborns] and of digging the labyrinth are attended to by the working class NMRs---not by the queen and her husband. Natural selection is not needed anymore for the NMR queen and husband. . . .

Suzan Mazur: But you’re saying that in the case of humans our technological innovations and the fact that we’re highly social animals leads to neoteny.

Vladimir Skulachev: Both NMRs and humans are highly social---yes. But the difference is that NMRs have an aristocracy and humans are used to the democratic way. Results of technical progress are available for any humans throughout the world. . . .

Suzan Mazur: You’re saying human ingenuity accounts for neoteny? Our technical progress, sophisticated communication, medicine, spas, beauty creams, etc. are all enabling us to retard development, that is, aging.

Vladimir Skulachev: In the case of NMRs, the life span of the queen may be very long---up to 30 years or maybe even more, with the same husband. In the case of working class NMRs, the life span is only one year and a half because they are often killed by reptiles. However, this has nothing to do with natural selection--- their social organization doesn’t allow them to be involved in reproduction.

Suzan Mazur: You’ve said the following:

“The timing of the development of individuals from a zygote to an adult organism might be governed by a special mechanism occupying a very high position in the hierarchy of biological control systems.”

Did you also say the details of this mechanism are still unknown?

Vladimir Skulachev: No, the mechanism is known. It’s very simple. You need to be the NMR queen and have 300 working class NMRs to work for you. You should live in an underground labyrinth that is as long as two football fields where enemies cannot reach you directly because they are stopped by NMR soldiers. And where the same working class NMRs find you some plants to eat, etc., etc.

Suzan Mazur: Could the neoteny mechanism be mechanical? Or virus-related, perhaps?

Italian medical research scientist Corrado Spadafora advises that the same mechanism is at work in embryogenesis and tumorigenesis and it’s virus-related. Here’s his note to me:

“([E]ndogenous) retroviruses have contributed to shape our genome, are constitutive components of it and are currently playing crucial roles in fundamental processes such as embryogenesis, tumorigenesis and, in the long run, evolution.”

So could the mechanism contributing to the phenomenon of neoteny be virus-related or mechanical?

Vladimir Skulachev: You are right. In this case we have some unsolved questions concerning cancer. But for sure cancer is very, very rare---it exists but it is very, very rare among NMRs. It doesn’t matter if they’re working class or queens. Nobody knows why.

There are some hypotheses and indirect evidence of why this may be, but the problem is not solved. There is almost no cancer in NMRs, also no diabetes, heart attack, stroke, or infection. Bacterial and virus infections are very rare because the NMR immune system doesn’t decrease with age compared to other mammals.

This is the reason why NMRs are dying very rarely in captivity. Usually they die just because a rival attacked them, or because of an accident while digging the labyrinth. Also, because they are hairless, any damage to their skin can result in a loss of a lot of blood, such a huge amount that they die.

Suzan Mazur: Regarding this idea that ontogeny recapitulates phylogeny in humans---is there a mechanical, a physiological aspect that accounts for this phenomenon of retardation of development?

Vladimir Skulachev: I agree that this is an open question. But it’s not critical to my logic. My logic regarding neoteny is extremely simple---there is only a small role for natural selection with respect to humans for the above-mentioned reasons.

With NMRs, there’s a kind of communism, but for two persons, the queen and her husband. With humans---technical progress thwarts aging.

Suzan Mazur: Regarding your view that neoteny tends to be in evidence in animals that are “highly social,” like humans and NMRs---don’t all animals have to be highly social in order to thrive in the spaces in which we are all instantiated? Don’t we all have family of sorts plus a medium supporting our existence? Why wouldn’t neoteny be characteristic of life across the entire spectrum of life?

Vladimir Skulachev: You see, the closest relative of the NMR is the silvery mole-rat (SMR). The SMR is living alone. It has no community at all. The male never knows his children. As for the female SMR, she knows the children, but she organizes everything by herself for the children. Then as the children grow, they go away, find their own house and start to organize their own family. So the SMR is not really a social animal. Absolutely not social. Even in captivity, the SMR only lives seven years in contrast to queen NMR’s 30 or so years. Seven years is the maximum lifespan for SMRs.

So I am quite sure that the long life span of the NMR is because it is a highly specialized, social organism.

There is another animal called the Damara land mole-rat that is a little bit more social than the SMR. Its colony is about 15 members, but that is not enough of a working class to guarantee neoteny for the aristocratic leader, in this case, a male---the king. So the king lives a much shorter life than the NMR queen because he only has a rather large family, not up to 300 workers.

Suzan Mazur: Philipp Khaitovich et al. think neoteny affects the grey matter of the human brain but not the white matter. I gather you agree, but you see the issue as one of bioenergetics, involving mitochondria. You say neoteny is inherent in development of human brain regions where high energy demands are required for cognitive and memory-related functions. Is that right?

Vladimir Skulachev: Yes. This is absolutely necessary for technical progress. By the way, I am now writing the next paper concerning the numerous common traits of humans and NMRs. It’s very strange but NMRs are much closer to humans with regard to several components of brain construction than to the mouse. This is a fact. I think it’s the brain construction that accounts for why they are both highly social and the pressure of natural selection rather small---enabling technical progress in the case of humans, and for NMRs---aristocratic social organization.

Suzan Mazur: But do you agree with Khaitovich that neoteny affects the grey matter but not the white matter of the human brain?

Vladimir Skulachev: Evidently, this is the case.

Suzan Mazur: You also say that reactive oxygen species, “ROS,” produced by mitochondrial respiratory activity is the toxic agent that leads to aging. ROS slowly poisons cells causing their death.

Vladimir Skulachev: Yes, exactly.

Suzan Mazur: You also say that the mitochondrial-targeted antioxidant SkQ1 you synthesized a few years ago at Moscow State University can reverse various age-related diseases. Would you say a bit more about this?

Vladimir Skulachev: We are working hard trying to connect aging and oxidative stress. In fact, it’s not my idea. It’s the idea of the great American gerontologist, Dr. Denham Harman, who suggested in 1956 that ROS are poison, which leads to aging. In 1972, Harman put forth a second suggestion that mitochondria are the source of ROS, and this is why I started to study gerontology. All my life prior to 1997 I was studying the consumption of oxygen by mitochondria converting O2 to the harmless H2O. This is at least 99% of all the consumed oxygen under normal conditions. But what about the 1%? This is formation of harmful ROS instead of H2O.

At first, I believed that this 1% was so small an amount that it was not critical. But when I calculated how much poison is produced by the 1%, I realized that it is quite enough to kill us.

The problem is not why it is produced but why all of us are killed, after all, by this amount. This is why I started to think about the biological function of this 1%. And my conclusion is that nature, evolution uses this 1% to produce poison to slowly induce aging.

What is aging? Aging is the slow and concerted decline of many physiological functions resulting in death of an organism. ROS increase with age while our ROS antidotes (endogenous antioxidants) decrease with age. Aging is always accompanied by an increase of risk to be killed by this poison. At least, that is our working hypothesis.

ROS are produced mainly by mitochondria, now it is rather clear. It is why we invented this new compound SkQ, which physically targets mitochondria without the participation of any protein, just by eletrophoresis.

Suzan Mazur: You coined the name “bioenergetics” for the science of mitochondria. What is your thinking about the origin of mitochondria? I recently interviewed Deep Evolution scientist Charles Kurland who worked with James Watson back in the early 60s. Kurland challenged Lynn Margulis’s view of endosymbiosis, saying this:

“Her [Margulis’s] idea was that: Ah, the mitochondria, the chloroplast, certain kinds of flagella, were actually originally bacteria. Her idea was that if you look at mitochondria, the DNA that was there was the whole genome of that bacteria. It turns out that it’s nothing like that. And we should have been much more suspicious of the hypothesis as soon as it was discovered that a minor fraction of information for mitochondria is coded in the mitochondria. We should have been very suspicious of that.”

What are your thoughts about the origin of mitochondria?

Vladimir Skulachev: For me it is clear, I am not able to convince you because it is my feeling. Unfortunately, we cannot perform an experiment of such kind and I am an experimentalist---that’s my credo.

However, as a bioenergeticist, it is clear to me that mitochondria originate from bacteria, from respiring bacteria. Even more, I think the first function of these bacteria that traveled inside some eukaryotic cell was simply to remove oxygen, which was poisonous for the host. Not to form ATP but just to remove oxygen, to decrease the concentration of oxygen inside the cell. The second function was the formation of ATP. What is interesting is that mechanistically the formation of ATP by bacteria is identical to the formation of ATP by mitochondria. There’s a very strong indication that really mitochondria originate from bacteria.

You may ask why these genes encoding mitochondrial proteins are localized mainly in the nucleus and not in mitochondria. My answer is very simple. This is an attempt by the host to convert guests to slaves. At first these bacteria were guests and the agreement was between the host and guest as follows: The host supports the guest by substrate and the guest oxidizes substrate by oxygen. But later the situation changed and the host decided to use bacteria not as guest but as slaves. If there are slaves, it’s much easier for the host to control synthesis of the main mitochondrial proteins in the nucleus, not inside mitochondria.

Only about 15 proteins are encoded by mitochondria, a very simple explanation why not all mitochondrial proteins are encoded in the nucleus. If these 15 proteins were formed outside mitochondria, it would be extremely difficult to transport them into the mitochondria from the cytosol via an external mitochondrial membrane and internal mitochondrial membrane. The proteins in question are very hydrophobic. They like to form aggregates which are impossible to dissolve in water. Elements like these terrible proteins are sometime formed in Alzheimer’s, Huntington’s and other diseases--- those disorders are connected to deleterious proteins. So it is very, very inconvenient to synthesize them outside mitochondria and then transport them to mitochondria.

Suzan Mazur: Your drug Visomitin with the mitochondria-targeted antioxidant SkQ1 is said to be useful in treating dry eye, glaucoma, age-related cataract and other signs of aging and is already on the shelves in Russia.

Vladimir Skulachev: This is really the case. I am quite happy that almost one million units of Visomitin have been distributed to drugstores in Russia, and there has not been a single complaint with respect to any kind of side effect. In the case of a cataract, it’s better to start using the drug as early as possible. In our testing with rats, if an animal has a cataract for more than two years, then it is not treatable with SkQ. But at an earlier stage in cataract development, it demonstrated efficacy in those animals.

Suzan Mazur: Has Visomitin now finished Phase III trials in the US?

Vladimir Skulachev: We have carried out a successful Phase II clinical study in the United States. We are currently gearing up to start a Phase III study. The next study will be an important step to FDA approval. Such approval would allow us to distribute Visomitin not only in Russia but in the largest Western market as well.

Clinical trials of effectiveness of SkQ1 with regard to a wide range of other age-related indications will be the next stage of our work.