As a student of creativity and innovation, I have always been fascinated by how the creative Nobel mind works. Ciechanover shared the 2004 Nobel Prize for chemistry with Hershko and Prof. Irwin Rose, a professor at University of California, Irvine, when he won the prize.
They won the prize for discovering how the body gets rid of damaged or unneeded proteins by using ubiquitin as a tag that marks them. Based on their discovery, major pharma companies have developed drugs – currently against blood malignancies. More drugs are in the pipeline, among them some which are against neurodegenerative disorders.
Here is what I learned, in conversation with Ciechanover.
Winning a Nobel almost always involves what Thomas Kuhn, in his book The Structure of Scientific Revolutions, called a paradigm shift – a radical change in how we see the world and how it works. Hershko and Ciechanover, with Rose, chose to tackle a research question few others found of any interest: How and why proteins die.
A key bodily function is the production of proteins. Vast research has been devoted to learning how this occurs. But in the past there was little interest in learning how proteins are broken down – and, we know now, there is no life without death, without getting rid of the junk.
“About 5% of our bodily proteins are replaced daily! Some are replaced even every few minutes. This process happens all our lives, even after we stop growing. And it ensures that we do not store unnecessary proteins, once they have completed their mission. It ensures that defective proteins are discarded and replaced by functional ones.”
Ciechanover, Hershko and Rose showed that a small protein called ubiquitin (because it is ubiquitous in all organisms except viruses and bacteria) plays a key role. It attaches itself to the damaged or unnecessary protein, marking it for death. The protein is then broken down by a cellular “blender” called proteasome – and like a sophisticated recycling plant, the pieces can then be used to construct novel functional proteins in the cell.
“Nature has evolved quality control systems to handle the damage [to proteins], that is caused, for example, by the high temperature (37°) we live in. Without such quality control systems, life could not have evolved. We would have remained cold-blooded, like frogs, with very limited biochemical abilities. There are numerous quality control systems in the body. The system we discovered is a critical one; one we call PQC (protein quality control) system, that removes damaged proteins.
“There are proteins that are turning over every two to three minutes, destroyed and renewed. Some are more stable, like hemoglobin, the protein of the blood, which lasts very 120 days.
“We exchange proteins at an amazing rate. Why? One reason is that some proteins complete their function and we don’t need them anymore. Their removal not only saves space needed for other proteins, but also avoids mistakes. We need proteins for cell division, for example. For cells to divide, there are proteins that drive it. Once the cell division is completed, we don’t need them anymore. If we would have stored these proteins for the next cycle of cell division rather than destroying them, we could have exposed ourselves to mistakes: if these proteins would have started to act again by mistake, cells would start to divide in an uncontrolled manner, and the result is cancer. So to avoid mistakes, the driving proteins are destroyed forever.
“The identification [of unneeded proteins] is carried out by more than a thousand enzymes that are kind of the policemen, and they walk around, find the protein that something happened to it, and attach ubiquitin to it. That’s the kiss of death. Once ubiquitin is attached to it, the protein is dead. Then comes the scissors, the executioner (proteasome) and grinds the protein to its basic building blocks.
In his Nobel Prize lecture, Ciechanover noted that aberrations in the process of degrading proteins inside cells “have been implicated in the pathogenesis [how diseases occur] of many diseases, malignancies and neurodegenerative isorders, which led subsequently to an increasing effort to develop mechanism-based drugs.”
Ciechanover notes that pharmaceutical products based on the ubiquitin process are now an enormous industry, generating many billions of dollars, and growing rapidly.
“I was interviewed by several mentors. Eventually I landed on somebody very young – Avram Hershko, who had just returned to Technion from a postdoctoral fellowship. Unlike other mentors who offered me a safe way, Avram warned me. He said, ‘you know, it’s risky. I have an assumption that there is a system that may destroy proteins, but it’s not clear that it exists at all. You are taking a risk.’ I said, ‘Wow! That is exactly what I need.’ I am an adventurist in character – a risk-taker. So I said, ‘I’ll try.’ In the meantime, I’ll also do medicine, I’ll do ‘on calls’, and keep in touch with medicine.”
“In my opinion it is like learning two interwoven languages – one of science and one of clinical practice, that are ideal whether you practice both professions or any one of them... In the seven years I invested in my M.D., and the five years in my Ph.D. – I did not feel I am counting time. It’s a matter of how you look at the process and what it means to you. I have had several excellent M.D.-Ph.D. students s in my laboratory, and the big advantage of this combined education is the ability to look broadly – to cover all the distance from the patient to the disease mechanism and rug development, and that what we try to do in the laboratory.
“In the Technion medical school we now have a formal M.D.-Ph.D. program. I did my M.D., then did my military service, and then did my Ph.D. independently. Today [the joint degree] takes about 10-12 years. People say, ‘Wow! That’s endless.’
“No, it’s not endless. Doing an M.D. and Ph.D. opens the road for you. If you are going to be a physician, you are a better physician, I believe. You are more humble, you understand nature and the complexities of disease. You understand mechanisms, what is a drug. If you become a scientist, you understand patients, you work along with physicians on relevant problems, understanding their language”
“The enjoyment – this is what makes one a successful professional, it does not matter what you do. Without loving what you do, being passionate about it and enjoying it, you can never be successful. In other words – when people ask me about my profession, I say I do not have one, I have a hobby, and the Technion pays me for that. This has to do with one’s philosophy on life – for me life has not just one single purpose, I am just moving from one enjoyable experience to another.
“People are asking me, ‘Oh, you won the Nobel Prize. What’s next?’ I say, ‘Next – what I’ve done for the last 40 years. I’m enjoying science every day. I’m now in my laboratory – you catch me now in my office at Technion, in the faculty of medicine.”