Most people admit that the one thing they can’t do without for long is oxygen (if you think otherwise, try holding your breath). My laboratory has worked for 30 years to understand how the body reacts when it senses changes in the amount of oxygen.
“No one is left behind”: the program of the 2023 Salute Festival 25 September 2023
The red blood cells
I’ll tell it at the Salute Festival: we started by studying how the body controls the production of red blood cells, which intercept oxygen in the lungs and deliver it to each cell among the many trillions. Your bone marrow produces over two million red blood cells per second, so if your employer or spouse accuses you of not being productive, you can now prove them wrong and set the record straight.
When severe bleeding occurs, the number of oxygen-carrying red blood cells decreases and the amount of oxygen available to the body decreases. Some specialized kidney cells detect the decline and intervene, producing a hormone called erythropoietin (Epo), which tells the bone marrow to work harder and produce more red blood cells. By doing so, the number of red blood cells returns to normal, the oxygen supply returns to normal, the Epo levels return to normal. But what causes those kidney cells to produce more Epo in reaction to the lower amount of oxygen?
Factor 1 protein levels
We found that oxygen-deprived cells had higher levels of a protein we called hypoxia-inducible factor 1, known as Hif-1. I’ll translate for you starting from the bottom: a factor is a substance we don’t know much about; induced means produced in reaction to a stimulus; hypoxia means low oxygen levels. Therefore, Hif-1 is a substance that is produced as a result of low oxygen levels.
To understand more about this factor, we stripped Hif-1 of thousands of other proteins and determined that it is made up of two proteins, which we called Hif-1alpha and Hif-1beta (because scientists love the Greek alphabet as much as they love abbreviations). We found that Hif-1beta was uninteresting. On the contrary, Hif-1alpha was very interesting: it was difficult to find in cells with high oxygen levels but, as these dropped, the levels of Hif-1alpha in the cells increased.
One, ten, a thousand cyborgs inside your cells. The medicine of the future is already here by Gabriele Beccaria 23 July 2023
Abundant oxygen and Phd protein
At this point, three laboratories have made a beautiful discovery. When oxygen is in abundance, another protein called Phd introduces an oxygen atom into Hif-1alpha, thus signaling the body to destroy Hif-1alpha, so that excessive accumulation of the protein does not occur in the cells that have normal oxygen levels. As oxygen levels decrease, however, the rate at which oxygen atoms are introduced into Hif-1alpha also decreases.
The more oxygen levels drop, the more Hif-1alpha escapes destruction, finds its partner Hif-1beta and together they create a wonderful Epo. Not only that: it was discovered that Hif-1 is a sort of orchestra conductor who directs a symphony of thousands of genes in each cell. Could Nature have been more clever than this?
Chronic kidney disease
Perhaps the elegance of this system does not impress you. You might ask yourself: what’s the point of using all these abbreviations and letters? Well, among the most common diseases in the USA and Italy are chronic kidney diseases. In this type of pathology, the ability of the kidneys to filter toxins from the blood gradually deteriorates and, eventually, dialysis is essential to remove the toxins. For their part, the kidneys also lose the ability to produce Epo and this leads to anemia. Before 1986, anemia could only be overcome with blood transfusions, but, in 1986, the discovery of the Epo gene made its production in the laboratory possible.
Physics Nobel Prize winner Serge Haroche: “Research needs freedom” by Gabriele Beccaria 06 October 2023
Epo, the great success of biotechnology
When administered, the Epo obtained in the laboratory replaced that no longer produced by the kidneys and stimulated the bone marrow to produce red blood cells again. As a result, EPO has been one of biotechnology’s greatest successes. Unfortunately, however, not everyone reacts to Epo, because the bone marrow also requires iron to produce red blood cells and, in some patients, the ability to transport iron to the bone marrow is also compromised.
The role of iron
Meanwhile, the researchers found that Hif-2 (you would be right to suspect there was a reason to assign the 1 to Hif-1) had an important role in the absorption of iron from the intestine and in delivering it to the bone marrow. Other researchers have developed substances that increased the production of Epo, suspending the ability of the Phd protein to insert an oxygen atom into Hif.
These substances also improved iron absorption and, unlike Epo which must be injected, they can be taken orally. In some countries one or more of these molecules have been approved.
Dividing cells and their effect on tumors
Meanwhile, the scientific community has realized that rapidly dividing cells can consume the available oxygen in tumors. Hif turns on genes that help cancer cells invade tissue. At a certain point, there was the impression that substances that blocked Hif, preventing it from acting, could be useful for treating the tumor. The first substance approved blocks the action of Hif-2 and is a breakthrough for patients who have hereditary kidney cancer. Once it spread outside the kidneys, there was no effective treatment for this cancer. Now there is.
Salute Festival 2023: all the protagonists 25 September 2023
Molecules that can destroy Hif-1 and Hif-2 in many types of tumors
In conclusion, the discovery of Hif has led to the development of molecules that prevent Hif itself from being destroyed to correct anemia and to the development of a substance that blocks Hif-2 as a tumor therapy. In my laboratory we are perfecting other molecules that can destroy both Hif-1 and Hif-2 in many types of tumors. These substances appear safe and effective, but need to be tested in clinical trials. The essence of biomedical research is this: a better understanding of the great Plan of Nature leads to better treatment of diseases, and this in turn leads to a better quality of life. This is why we do what we do.
Translation of Anna Bissanti