A feeling of freshness in every cell

What the Nobel laureates in medicine discovered

Alexey Aleksenko, "Snob"

The Nobel Prize in Physiology and Medicine could, of course, be given for something else, but it was given for the discovery of the mechanism of adaptation of cells to oxygen concentration. It's not very honest, if you think about it: the Nobel prizes "for oxygen" – for understanding how we breathe it and what happens when it's not enough – have already been given to Otto Warburg (1931) and Korney Heymans (1938). And on the other hand, this is an exciting scientific story, and we, scientific journalists, are the only ones to give: it's not all the time to write about boring things.

The story should begin with a hormone with the poetic name erythropoietin. Physiologists have known about this hormone for more than a hundred years. Erythropoietin is synthesized by kidney cells with a lack of oxygen and includes increased production of red blood cells. 

Such a description of the process seemed exhaustive until the second half of the twentieth century, and then the science of physiology imperceptibly changed: no answer to the question "How?" was no longer quoted if it did not mention genes and DNA. And so in the 1980s, Greg Semenza thought about how to weave a mention of genes into this story. Erythropoietin is a protein, which means it has a gene. Obviously, when there is very little oxygen, this gene turns on something, - so, apparently, Sementsa reasoned and began to search in the vicinity of the gene for pieces of DNA that manifest their effect in the presence or absence of oxygen. 

Here his first surprise was waiting for him: as it turned out, this regulatory mechanism worked not only with the erythropoietin gene. And not only in kidney cells: a variety of cell types (human and mice) responded to hypoxia in the same way, and whole bouquets of very different genes were included in them. Meanwhile, in Britain, another Nobel laureate, Peter Ratcliffe, was working on this story in parallel, and saw exactly the same thing.

Semenza turned out to be a little more persistent and after a few years found the very thing that can turn on different genes in different cells in the absence of oxygen. He called this protein "hypoxia-induced factor" (HIF). How did this thing react to oxygen? At first glance, it was insanely simple: in the presence of oxygen, HIF was unstable, and as soon as there was nothing to breathe, the protein began to accumulate and included the required bouquets of genes.  

But with such words, a scientific journalist can explain himself to his gullible readers, and scientists wanted more: why was he suddenly unstable? Why does oxygen harm him so much?

This irrepressible thirst for knowledge was helped to quench by the third hero of our story, William Cailin, who was engaged in a seemingly completely extraneous problem. There is such a "Hippel-Lindau disease", it is also cerebroretinal angiomatosis, in which the patient forms tumors in different parts of the body, and very often on the retina of the eye. William Cailin was interested in tumors – he was an oncologist. The most interesting thing about GL syndrome was that it was hereditary, which means that Cailin had the opportunity to catch the gene that caused all these poor people to get cancer.

The gene was soon found: in families where GL syndrome occurred, a broken copy of one gene was indeed transmitted. And here the observant Keilin noticed that tumor cells with a broken GL gene (its scientific name is VHL) behaved as if they were suffering from severe hypoxia. Obviously, the place of the GL gene in this story had to be looked for, as molecular geneticists put it, "upstream" from HIF: after the HIF accumulated, everything seems to be clear, but the causal relationship between oxygen and HIF is murky, and there could well be a place for another step of reasoning.

Then a good scientific race began: it was, of course, greatly spurred on by the fact that cancer appeared in the plot, and just at that time colossal money was allocated for cancer research in the United States. And the researchers finished with dignity: in 2001, in one issue of Science, articles by the Keilin group and the Ratcliffe group were published in a row, where all the details were set out: what's going on in the cells from oxygen.

Something happens to the HIF protein: hydroxyl groups are attached to two of its amino acids. This configuration – two hydroxyprolyl sticking out of the protein molecule – looks rather atypical, and it is immediately recognized by GL. This very GL, as it turned out, is nothing more than a component of a cellular garbage collection machine that sends unnecessary proteins for disposal. This is exactly the fate that HIF is destined for: here he was, and now he is not.

And what happens if there is not enough oxygen – or if one of the cogs of this machine suddenly breaks down, as in patients with Hippel-Lindau syndrome? Then HIF is not going anywhere. Healthy and vigorous, he turns on one by one all the genes responsible for the correct reaction of the cell to hypoxia. If at the same time there was no hypoxia in sight, and the cell turned out to be tumor – everything becomes quite unpleasant. 

But there is also good news. This chemical machine with hanging hydroxyls on proline, then recognizing them and sending the whole thing to the trash can is an ideal target for all kinds of drugs in its simplicity. It remained only to invent these drugs, and the victory over cancer is guaranteed to us. 

This is about what scientists have been doing for the next 18 years. There were particularly bright moments: in 2016, Threshold Pharmaceuticals' drug failed clinical trials with a bang, and the company fired 2/3 of its employees – everyone involved in the development of this fruitless direction. Something similar happened with other heroes – Cerulean. Eighteen years and one Nobel Prize later after the discovery of the hope of using it in the treatment of cancer remain illusory.

But recently approved (in China) the first drug aimed at HIF and effective for kidney failure. Such drugs are produced by three large pharmaceutical companies at once. So history, having described a smooth circle over the problems of big oncology, returned to its origins – the synthesis of erythropoietin in the kidneys. However, this journey is much more meaningful than it may seem from our simplified retelling. This story is about how, over three decades, scientists have come from the situation of "nothing is clear" to "even too much is clear, because it is very difficult." And if the Nobel Committee decided to celebrate this scientific plot with a prize, then it will probably be possible to cure someone with its help. Nobel stories in general often benefit humanity – not to mention the fact that some of them are quite curious.

The author is the scientific editor of Forbes.

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