There are approximately 40 trillion cells in the human body and every one of them needs oxygen to survive. If the oxygen level drops, the cells must be able to sense the change and adapt to it. Sir Peter Ratcliffe discovered how this adaptation occurs. The discovery earned Ratcliffe and his associates the Nobel Prize in Physiology or Medicine in 2019. Ratcliffe visited the University of Turku 25 August and was the keynote speaker the 31st BioCity Symposium arranged together with BioCity Turku and InFLAMES.

Ratcliffe was invited as the keynote speaker to the Turku BioCity Symposium by Professor Panu Jaakkola, who is the Chief Physician of the FICAN West Cancer Center. He worked at Ratcliffe’s laboratory in 1999–2001 and was the first author in the Nobel-Prize-winning study.

– Panu was a key person in the research that led to the Nobel Prize. We are good friends and stay actively in touch, says Sir Peter.

Ratcliffe’s research identified the molecular machinery that regulates the activity of genes in response to varying levels of oxygen. When the oxygen level gets lower, a complex chain of events is triggered which results in the development of new red blood cells. The body generates red blood cells from the stem cells when stimulated by the erythropoietin (EPO) secreted by the kidneys.

The finding explained one of the basic phenomena in physiology and cell biology, but, at the same time, it opened new doors in drug development as hypoxia is a significant factor in many diseases. These include cardiovascular diseases, anaemia, diabetes complications, and many inflammatory diseases. In addition, hypoxia can promote cancer growth. 

– Cancer cells that grow uncontrollably need just as much oxygen as other cells. In a way, these cells capitalise on hypoxia in the tissue and start growing blood vessels. If we can control this event, we can stop the tumour from growing. In fact, medicines based on this idea have been available for some time, explains Ratcliffe.

The information on how cells adapt to hypoxia can also be utilised in treating severe anaemia. Anaemia is caused by a low number of red blood cells. If hypoxia is induced by to few red cells, the body begins to fix the problem by generating more red blood cells.

Inflamed tissue has a low level of oxygen

Ratcliffe was the keynote speaker at BioCity symposium. This year, the Symposium was organised together with the InFLAMES Flagship and its theme is immunology. The most central research area in immunology is the human immune system and one of the most fundamental observations in this field of medicine is that many long-term illnesses are in fact inflammatory diseases. Ratcliffe notes that hypoxia is a key factor in these diseases.

– Just like in cancerous tumours, the inflamed tissue has a low level of oxygen as the cells are very active and use a great deal of oxygen. We know that a low level of oxygen changes the way in which inflammatory cells and lymphocytes function. This is an emerging field of research, we still do not know exactly how this regulation works.

The currently-known regulation mechanism for oxygen level occurs in a situation where the body adjusts slowly to hypoxia. The process takes several days and it involves the the decoding of genes and tissue changes such as the development of new blood vessels. Ratcliffe says that this is only a part of a larger picture as parallel system have to exist.

– For example, the brain uses an enormous amount of oxygen and the brain cells can very quickly suffer from a lack of oxygen. Therefore, there has to be a system that reacts quickly to any changes in the oxygen level in the brain and maintains the oxygen balance, Ratcliffe explains. 

Find a question no one has yet asked

Sir Peter Ratcliffe is a nephrologist who specialised in kidney diseases. He established his own research group at the University of Oxford and was appointed as a professor in 1996. Among other positions, he is the Clinical Director of the Francis Crick Institute, London, Professor of Clinical Medicine at the Target Discovery Institute, University of Oxford and a Distinguished Scholar of the Ludwig Institute for Cancer Research. Winning the Nobel Prize in Physiology or Medicine has made Ratcliffe and his fellow Laureates William G. Kaelin and Gregg Semenza sought-after speakers and celebrities in the scientific world. Ratcliffe also has close connections to the University of Oulu and his view of the researchers and the level of research in Finland and other Nordic countries is very positive.

Ratcliffe is proud of the Nobel Prize, but still chalks it up to good luck. He believes that researchers cannot and should not strive to win a Nobel or any other prize in their careers. It is much more important to find a question to which you want an answer.

– My message to early-career scientists is this: find your own question. Resist the temptation to study a fashionable topic that everyone else is already interested in. If you go there, the field will be crowded or intractable or both.

When embarking on his study of hypoxia, Ratcliffe did not think of the possible benefits, fame, or praise from fellow researchers.    

– I was seeking a solution to a question, as I was sure there was an answer to be found. I had no idea how important that answer would be and whether others would be interested in it. It was actually odd to realise that our study was not necessarily regarded as very important at the beginning, but, once we completed the work, the results started to receive wider recognition as the years passed.

As a researcher, Ratcliffe seeks information and truth and thinks it is remarkable that information can lead to new therapies and drugs. However, the deepest satisfaction comes from something else.

– A drug that is currently a valid treatment will be obsolete in 50 years. But our discovery, the way in which cells react to oxygen, will still be true in hunreds and thousands of years – in fact for all time.