Plans for old age
Who and how will look for a rejuvenation recipe with the money of Yuri Milner and Jeff Bezos
Polina Loseva, N+1
The first of them discovered a way to reverse cellular time – and received a Nobel Prize for it. The second one figured out how to accurately measure this time. The third and fourth showed that it is possible to prolong the life of transgenic mice by rejuvenating their cells. We tell you who Jeff Bezos and Yuri Milner bet on by creating a corporation to develop a cure for old age – and what task the star team they hired will actually solve.
The American magazine MIT Technology Review found out that Jeff Bezos and Yuri Milner (through a charitable foundation that he founded with his wife Julia) and possibly other major investors founded Altos Labs, which will study aging. The publication reports that the leading researchers of the newborn company are promised at least a million dollars a year and freedom of scientific search. At the same time, no clear goal – such as the creation of a specific drug or entering clinical trials – has yet been announced. The founders do not plan to make a profit from it in the near future.
This is not the first high-profile investment by American tycoons in the science of aging. The previous time this happened was in 2013, when Google launched Calico Labs. She also did not promise any immediate applied results – only an attentive and versatile study of the problem. These results, indeed, are still missing.
One of the sources of MIT Technology Review reports: the first product of Altos Labs should be "good science". But, unlike Calico Labs, this science will focus on a single potential life extension method. Researchers from the UK, Japan and the USA, classics of gerontology and Nobel laureates will solve a specific task: how to turn back the age of individual cells without harming the health of their host.
Up the hill
In the middle of the twentieth century , the English embryologist Conrad Waddington offered readers his monograph The Strategy of the Genes imagine a handful of marbles rolling down a high mountain.
With such a metaphor, Waddington described the events that occur with individual cells inside the developing embryo. Cells start from the top – a non-specialized state, which is unstable in itself, and roll to the plain, to a stable state of final differentiation. From time to time, a hill comes across the path of each ball, which forms a fork: knocking against it, the ball slides into the "right" or "left" hollow – and depending on this, the cell enters one or another path of differentiation.
The landscape of Waddington. Alexandra Chittka et al. / Current Biology, 2012
Waddington's model was just that a metaphor: he was trying to describe the principle by which cells choose their fate – and what closes their way back. The scientist did not set out to explain exactly how a particular fork looks at the cellular level – and it would not have been easy for him to do it: when he first started talking about his landscape (An Introduction to Modern Genetics, Routledge, 1950), there were still 14 years left before the Watson-Crick model of DNA appeared. It is now that we understand that the hollows and plateaus correspond to labels on DNA (epigenetic markers), which cause sections of its strands to twist or unwind, thereby prohibiting or allowing the work of the genes located there. Therefore, in order to roll the ball up the slope of the Waddington landscape, it is necessary to work with hundreds of chemical tags on genes: add somewhere, remove somewhere.
In 2006 , Japanese scientists Yamanaka and Takahashi: they turned skin cells into non–specialized ones - similar to those that make up the embryo in the first days of development. To do this, the Japanese needed only four proteins (they will later be called the "Yamanaki cocktail"): Oct4, c-Myc, Sox2 and Klf4. Under their influence, many sections of DNA unfolded, exposing genes to which skin cells had long lost access. It turned out that this is enough to make them stem cells – and then grow from them any types of cells of an adult organism.
So Yamanaka and Takahashi discovered a source of universal human spare parts, and some scientists thought that the problem of aging was almost solved – only time and money would be enough. For example, Aubrey de Grey, a proponent of the "engineering" approach to aging, proposed to solve the problem of organ wear in this way: to grow them in the laboratory from stem cells and replace them with those that could not be saved by other methods.
But even now, when Yamanaka has been a Nobel laureate for nine years, Japan is dotted with stem cell clinics, and scientists have learned how to grow eggs and neurons from reprogrammed cells, it's too early to count on artificial organs.
There are several reasons for this. Firstly, growing fabrics is still difficult and expensive. Secondly, not all parts of the human body scientists have so far been able to collect in vitro. If it is relatively easy to cope with hollow organs, such as the trachea or bladder, then no one has yet succeeded in reproducing the complex three-dimensional structure of the liver or kidney. Thirdly, reprogrammed cells turned out to be quite dangerous: like embryonic cells, they easily grow into tumors. Therefore, so far they are mainly used for relatively isolated organs such as eyes or implanted in capsules so that they cannot spread throughout the body.
Rolling a balloon to the top of the mountain was not enough. Now you need to learn how to control its descent.
Without old people
In Waddington's model, the journey of the balloon cells along the mountain slopes ended at the plateau of the differentiated state. Since the scientist was primarily interested in the development of the organism, he did not care about what happens to the cells afterwards. Now we know that their path does not end with differentiation: cells that have received a profession can slide even lower – into a state where they do not divide, do not perform their duties and live in a shortage of energy. This is called senescence, or cellular senescence.
There are different ways to push a cage into the gorge of old age. Sometimes this happens by itself – for example, if a cell accumulates enough mutations in its genes. Sometimes it is pushed by neighbors – other aged cells. Sometimes the cell ages dramatically due to stress, such as severe inflammation or poison poisoning. Anyway, the longer the tissue exists, the more cells in it begin to roll in this direction, catching neighbors along the way.
You can imagine that a person's life will become much better (and then, you see, longer) if you remove the senescent cells from his tissues. We even have a tool for this – senolytic drugs. At least, they relieve elderly mice from problems with the spine and some cognitive impairments.
Senescent cells (glow) in the body of mice before and after treatment with senolytics. Ming Xu et al. / Nature Medicine, 2018.
In the hope that senolytics will be useful for people, Jeff Bezos five years ago made his previous investment in the science of aging – the Unity Biotechnology company. The company has launched several clinical trials of senolytics at once, on patients with knee diseases and visual impairment. But no noticeable results have been obtained so far. At the tissue level, the drugs work, but it does not become easier for patients. Why senolytics help people less than mice is still unclear. Maybe the researchers just didn't find the right combination and dose, and success is still ahead. Or maybe the strategy itself is wrong. Over time, all cells slowly roll from the top of undifferentiated youth into the canyon of senescence, and shooting those who have already fallen into it, senolytics do not ease the fate of those who stand on the edge of the abyss. The technology that Bezos is betting on this time should work differently – to move all the cells of the body up the slope of the epigenetic landscape and delay the onset of old age for each of them individually. And here four proteins from the Yamanaki cocktail can be useful.
To make sure that reprogramming can really move cells away from the edge of the abyss, you need to be able to measure quite accurately how close they are to it – that is, calculate the internal age of the cell. This became possible in 2013, when the American Steve Horvath designed the first "epigenetic clock": he compiled a list of epigenetic tags on DNA, by the presence or absence of which it is possible to determine how close a cell is to an embryonic stem cell or to a senescent one.
Thus, gerontologists have had two key tools for cell rejuvenation in their hands for almost ten years. It is known how to push the ball uphill. There is something to measure your progress with. But what is still unknown – and this task, of course, will have to be solved by Altos Labs employees – is how to stop the ball at the right point.
They will lead into the future
Conrad Waddington suggested that cells in the body can move along the epigenetic landscape only in one direction: from top to bottom. Now we have learned to move them away from the abyss, return them to the top and even transfer them from one hollow to another (this is called transdifferentiation). All this looks good in a test tube on individual cells, but for a living organism it can become a deadly experiment.
In 2013, a group of biologists led by Spaniard Manuel Serrano began reprogramming cells in vivo. They created a line of mice in which the genes corresponding to the four Yamanaki proteins were in the zone of action of a special regulatory site – and that, in turn, reacted to the presence of the antibiotic doxycycline. Thus, when doxycycline was added to the mice's drinking water, reprogramming began in their cells – wherever the drug could reach with the blood flow.
Serrano's group achieved its goal: cells similar to embryonic cells appeared in the body of mice. But there was no question of any prolongation of life – tumors began to grow throughout the body of animals, and especially often for some reason in the pancreas and kidneys. This, on the one hand, proved that the technique works, and on the other – that in this form it is not applicable to mice, much less to humans.
A mouse from the Serrano experiment and a slice of her tumor grown from stem cells. María Abad et al. / Nature, 2013
A few years later, another Spanish biologist, Juan Carlos Ispisua Belmonte, developed a more gentle version of the same method. His research group also raised transgenic mice, but fed them doxycycline intermittently – so that Yamanaka proteins would not work constantly. As a result, we managed to choose a mode in which the mice really lived longer. However, a special line of prematurely aging mice participated in this experiment.
In ordinary elderly rodents, using the same method, it was possible to force muscle tissue to regenerate. But for some reason, the researchers did not check whether they themselves began to live longer.
Mice from the Belmonte experiment: on the left, the one in which the cell reprogramming system worked, on the right, the control one. Alejandro Ocampo et al. / Cell, 2016.
But even this technology cannot be directly transferred to humans – for this they would have to be genetically modified. So, we need to find a way to deliver the Yamanaki cocktail to the cells from the outside. This method was invented quite recently: a group of scientists (which included Steve Horvath) injected adenoviral vectors carrying Yamanaki protein genes into the eye of mice. The design was also included in response to doxycycline, and this made it possible to improve the vision of elderly mice and teach old neurons to grow axons after injury. The epigenetic age of the treated neurons decreased, but they did not lose differentiation (that is, they remained neurons) – and not a single tumor appeared in rodents.
The list of Altos Labs employees, according to MIT Technology Review, includes everyone who made this technology possible: Yamanaka, Horvath, Serrano, and Belmonte. In addition, Jennifer Dudna, who recently received the Nobel Prize for the invention of CRISPR genome editing, was called to select projects that will receive funding from the company. This may mean that the creators of the company have their own plan on how to regulate the work of Yamanaka proteins in cells. With the help of a modified CRISPR/Cas system, it is possible not only to cut DNA, but also to turn on or off the work of genes – Belmonte also had a hand in this, by the way – and this in the future may be safer than feeding people with doxycycline.
Altos Labs is not the first company that specializes in cell reprogramming. The Calico Labs division is already playing in this field, as well as several smaller companies – for example, Turn Biotechnologies, AgeX and Genecure. However, none of them can boast of such a stellar composition. But many of them have outlined their goals – modest, but specific. So, Genecure is going to rejuvenate the knees, AgeX is aiming at the heart, and Turn Biotechnologies are interested in joints and muscles, and they are all slowly getting closer to clinical trials of their drugs.
The goal set by the founders of Altos Labs looks much more ambitious. How they propose to go to her, we can only guess. But it is already possible to imagine what tasks the fathers of cellular reprogramming will have to solve on this path: to reach deep–hidden tissues, make their cells younger - and learn to stop this process before it is too late.
And no matter how their solution looks, it is already clear that the procedure will be neither easy nor one-time. Cells cannot be rejuvenated all the time, you need to give them a break from time to time and the opportunity to grow back.
The mythical king of ancient Corinth tried to escape from the afterlife – and for this he was condemned by the gods to roll a stone uphill forever. Collective Sisyphus from Altos Labs will have to roll trillions of cell stones into the epigenetic mountain at the same time - precisely because it seems to be one of the most promising ways to postpone the approach of death. One of the investors of Altos Labs, 57-year-old Jeff Bezos, recently ventured to become the first passenger of a spaceship that his company built. Whether they plan to be the first to experience reprogramming together with 59-year-old Milner, we don't know yet.
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