Saturday, August 22, 2020

Unity Biotechnology failure: aging isn't a disease

In recent years, some rich people and companies started to invest into a "desirable" technology that we know from some science-fiction films: "Let us stop aging". Doubled or infinite lives are great, they said. Google founded Calico in 2013, Oracle's Larry Elison made an investment. Jeff Bezos and Peter Thiel invested into a competing San-Francisco-based Unity Biotechnlogy Inc.

Only minutes ago, I read the mission of Unity Biotechnology:
[to] extend human healthspan, the period in one’s life unburdened by the disease of aging
I exploded in laughter. This looks like the ultimate snake oil with a science-fiction flavor. OK, many people want to stop aging. But is it possible? And is it right to call aging "a disease"? My answer to the second question (and probably the first one) is a resounding No.

Note that not everyone wants to stop aging. In 2019, a well-known Czech singer Ms Hana Zagorová (*1946) who first impressed as a singer in a 1963 competition (and as a kid, I was routinely saying that she was my favorite female singer, unusually next to Ivan Mládek who won the male Lumo category LOL: they had almost no interactions with one another), recorded this song:

She's not afraid of aging, she doesn't look to the past but she doesn't look to the future, either. She enjoys the present, she doesn't count the grey hair, it's OK for her to start forgetting things because she would love to forget many things right away, and so on. A wise song. ;-)

OK, with all my respect, I feel some "Peter Thiel's ingenious fingerprint" in the promise to eradicate the disease of aging. And I would guess that he also got some background about the aging processes (he studied biology in the college) and decided that the "disease of aging" is all about the senescent cells. Those are cells that stop dividing. Just to clarify the mission: you're healthy when you're young and it's because you grow because your cells keep on dividing all the time. Then the process stops and you become old i.e. ill. Even if you feel healthy, don't believe it: According to Unity Biotechnology Inc, you're sick just because you are old!

In practice, the task to "stop aging" was reduced to something more modest – stop the painful inflammation of joints that is often associated with the old people! It seems rather comically disappointing to reduce "the stop sign for aging" to "improvement of those damn annoying knees" but let's accept that this is a legitimate switch that you get instead of the bait. With this more narrow definition of aging (which is squeezed to the knees), Unity developed UBX0101, a drug that probably removes those cells (at least it was the dream, by blocking proteins p53 and MDM2) that no longer reproduce. You will be left with the healthy, young cells that keep on dividing, and therefore you or your knees will be eternally young.

A week ago, Phase II of the test ended with a spectacular failure. They interupted the test in Week 12 (out of planned 24 weeks) because it became clear that the placebo group cannot be distinguished from the groups with the new drug. The stock price dropped from $12.43 last Friday to $2.96 now (after-hours). Some half a billion dollars was eliminated from the capitalization which is close to the 2019 Palantir's loss. Yes, I searched for Thiel's name to be updated.

Now, drugs that are doing "roughly something like that" could work or at least achieve some improvement of the seniors' knees' condition. I don't have a universal proof of a no-go-theorem, of course. But what I see is that the whole development – and perhaps the whole operation of Unity Biotechnology (and, I guess, many similar "science-fiction" companies), is driven by a protocol that I would consider naive, childish, and fundamentally unscientific. It seems that the path from the ludicrous "mission statement" (about the disease of aging) to the rough working of the drug is way too direct. It seems to me that someone invented that aging should be spat upon and "disrupted", the first proposed mechanism (senescent cells) of aging was blamed within a minute, and then the details were left to the biologists at the bottom. They were just ordered to fill in the details. Prepare a molecule that stops some proteins that are responsible for senescent cells, they were told.

OK, I just think that this is not how a company believing in science works. The probability that an algorithm of that type leads to the desired drug is nonzero but it is tiny (because the scientific method that actually and systematically increases the probability that similar work succeeds hasn't been exploited). It is similar to the success of alchemy. In fact, I think it's fair to say that it is an example of alchemy because alchemy also places a wishful thinking at the top as the priority and the most important assumptions are prejudices, guesses, and wishes, not conclusions extracted from impartial research. After all, the elixir of youth was one of the most famous goals of alchemy – so even the goals haven't changed. Some people want something, invent some additional details why the desired thing "should" be possible or what "should" be helpful in the development of the elixir, and then everyone is pressured to believe in the orthodoxy and work on the details only (because the main guru is the guy who simply invented the mission statement, the actual scientists are considered to be on par with janitors). Sorry but the main point is that genuine scientists, even those who work in an utterly applied science within the commercial sector, must have the freedom to shape their opinions about questions, including the most important questions (e.g. whether aging is a disease and whether it is a consequence of the spreading senescent cells), according to the evidence combined with their conscience, not according to the job contract or orders from their boss (or other shareholders, let alone the media).

Rudolph II, the CEO from "Baker's Emperor, Emperor's Baker" is auditing the employees. The first one is producing gold by disrupting the lead atoms. (Prague was Silicon Valley in 1600. Kepler and Brahe worked there, too.) Another guy is learning to fly from his childhood. Elixir of youth is discussed from 0:41. It's still not completed, his excellency. But instead, he managed to find a wonderful new detergent. (Scota uses the polishing product for some entertainment at a different moment, especially when Kepler the astrologist comes at 2:15.) After the detergent's failure and a death threat, he promises the elixir again. He was just grating the mandrake root. Well, horseradish, a replacement of it, they found out. Well, Scota had sausages with horseradish. Can't he find a proper mandrake? Yes but he needs an English 9th cousin dog with a pedigree after the sunset. The foreigner has this exact dog in his inventory. Meanwhile, the foreigner brought them know-how from the New World, a cigarette. The emperor coughed and predicted that it would never succeed in our lands.

So my view is that if and when the scientists in that company were pushed to accept the basic dogmas of the company, they just ceased to be the scientists. They became pseudointellectual prostitutes and the company probably didn't have any people left who were still scientists (especially in the moral sense that I described: but the morality really is needed for science to work).

Of course, I wouldn't be writing these comments "equally self-confidently" if I thought that the "required orthodoxy" is scientifically right. So indeed, I believe it is scientifically wrong. I think that the senescent cells aren't really "the cause" of the bad processes of aging. They're rather a consequence – they're signs of a totally sensible adaptation of the organism to other things that have occurred within the organism and that couldn't be avoided.

In particular, cellular senescence (the stop of division) is a very good thing because it suppresses tumors. As you grow older, it's more likely that your cells have mutations that lead to cancer. The risk of cancer could continue to grow exponentially if the total number of cells producer by the organism kept on growing exponentially! So it's a good idea for the organism to slow down or stop the division when the organism is already mature enough!

A more fundamental observation is that the eternal growth of a multicellular organism isn't the "ultimate purpose of life" or a decent goal. If something, the Darwin-type evolution creates the "desire" of the individual cells for their number to grow. But this is achieved by producing new generations of mammals and other organisms; not by the continued indefinite growth (or preservation) of the old one. The number of young organisms may be higher than the number of their ancestors (the populations may grow); and the young ones may do lots of things more easily than the old ones (although, as I have mentioned many times, the independent thinking isn't an example in these living generations).

For any organisms that are sufficiently similar to us (or mammals), it just makes sense that the life gets repeatedly refocused on the new generations, they repeatedly become more relevant than their ancestors at some point, and there's no point in keeping the old ones alive for a very long time because it would be getting increasingly technically difficult (and they would eat too many resources). Also, there is no reason why a human should grow (or his cells should divide) indefinitely. Even the shapes of the bones, face, and physique gets "older" in a sense that is mostly irreversible.

Macroscopic life processes are intrinsically irreversible due to the second law of thermodynamics. It isn't a law that you may circumvent by a clever drug developed by a team that is paid tens of millions dollars. Even if you collect billions from new shareholders, you can't invalidate the basic laws of physics. It is a damn universal law of Nature. One can prove it as a mathematical theorem and I have presented my "most logical universal proof of the second law" (using the CPT transformation and the averaging-or-summing probabilities over initial-and-final microstates) many times. The first proof due to Ludwig Boltzmann was the H-theorem.

So everything in the life sciences obviously had to adapt to the universal law of physics because physics trumps some stinky biology. You may whine, you may complain, you may deny this statement but there's nothing else that you can do against this fact or other facts. Most of the "spectacular" organisms have had finite lifetimes and the refocus on the new generations at least for half a billion years. We may return 1.6-1.7 billion years ago to the times when the Earth was dominated by algae and their lifetime could have been said to be "unlimited" in some way (maybe I should have picked some other organisms).

But the vertebrates (ending up with mammals, assuming that you still consider mammal supremacy PC enough) actually represented a huge progress from algae. The finite lifetime is a feature, not a bug! The life on Earth will be totally happy when this feature of the "dominant life forms", including their finite lifetime, remains a fact for the remaining 7 billion before the Sun goes red giant. There's nothing to be fixed here. The finite life expectancy isn't a disease; on the contrary, it is the result of an optimization process looking for the best solution (including how the later stages of vertebrates' lives may be designed) that was underway for hundreds of millions of years.

Here I am saying something general that has increasingly troubled me when I thought about the question what e.g. Peter Thiel actually believed in more detail (aside from his being a very curious billionaire). He is still a staunch "progressive" who just can't embrace and "like" the stability of certain facts and patterns about our lives, the civilization, or life in the Universe. So everything "should" change all the time, like in Trotsky's permanent revolution, and it doesn't bother him that the proposed "progress" is actually negative. Going from organisms with a finite lifetime to "individuals with unlimited life" is on par with going back to algae. It means to reverse billions of years of biological progress. In the same way, undermining capitalism means to reverse centuries of vital progress in the organization of the economy. Going back to the belief that humans should be blamed for weather events means to return to the Middle Ages. The claims that all those things and dozens of others represent some "amazing progress towards the distant future" is just totally dumb (and left-wing) ideology that can't evaluate the signs even for the most elementary things.

So just sit down and be satisfied with the damn world, progressives of all flavors (and with all possible jackets to mask your deep progressivism). Many basic properties of life around us are results of centuries... or billions of years of optimization and they represent an amazing progress relatively to what we had before. All good geographic plans will include a round Earth and everyone who is still stuck to a Flat Earth in 2020 is a total moron. Also, all good fundamental theories of physics must have been relativistic since 1905, quantum mechanical since 1925, and stringy from 1985 or so. There is still progress but the progress will take place within these refined categories that have new special properties. Their predecessors didn't have these special properties and the difference may sometimes be sold as a "bug of the new forms" but it is actually a "virtual of the new forms". To return to algae-like biology, to non-relativistic, non-quantum mechanical (i.e. "realist"), or non-stringy physics or to the Flat Earth means a self-evident negative progress and any claim to the contrary is just a propaganda that may only impress the morons.

So I think it's great if and when we get some drugs to improve the condition of the seniors' knees but I would bet against this drug's being based on the denial of the second law of thermodynamics – and on the forced obedience of corporate (no longer) scientists who have to believe that the second law of thermodynamics and the progress from algae to humans are illusions. My view is that the investors who lost money on the Unity Technology lost a bet against the need for the scientific method (and the need to take the fundamental laws of physics seriously) and I am happy about this loss of theirs.

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