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Aaron Ciechanover

Aaron Ciechanover

Distinguished University Professor, Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, Haifa; Nobel Laureate 2004 in Chemistry, Israel

Are we soon going to dispose of cheap (US$ <1,000) and fast (a few minutes) sequencing and processing of our genomes to have highly tailored treatments? The challenge in elaborating a new medical model overcoming the limits of standard care, is providing affordable practices that take in account the genetic variability of the patient, going beyond what has been done until now by traditional reactive approaches in individual care based on the study of family history, social circumstances, environment and behaviors. Aaron Ciechanover, after winning the 2004 Nobel Prize in Chemistry “for the discovery of ubiquitin-mediated protein degradation”, and the Research Award 2011 from the Alexander von Humboldt Foundation, is leading an interdisciplinary study at Technion (Israel Institute of Technology) in Haifa, that in the future might allow the identification and characterization of new disease-specific molecular markers and drug targets, necessary to the design of novel, mechanism-based, drugs to modulate the activities of these targets. Ciechanover will tell us how far we are from leaving the “one size fits all” medicine, to entering the “personalized” one, and what steps towards interdisciplinarity are required in our approach to scientific research and development and education.

Breaking the Wall of Diseases. Is Personalized Medicine Going to Cure All Human Maladies?

Transcription

Good morning. Just to continue on Sebastian’s introduction: for me, coming to Germany and speaking, especially in Berlin, always generates mixed feelings, that because of history. As Sebastian mentioned, today we are remembering 73 years of the Kristallnacht when hundreds of Jewish synagogues were set on fire. But nevertheless, our sight is to the future with science, technology, cooperation, peace, are our common themes, and there we are heading. For diseases, the human dream is obviously to get rid of all of them, to cure them all, to remain young forever, in other words, to break the walls of diseases, to eradicate and evaporate them from the world. But the question is whether this is achievable and what we as scientists and physicians can do about it. Can this dream be materialized? Is this dream realistic and should we aim at it?

The walls that separate us from this dream are made of different materials. Some of them are walls of knowledge. We need to break barriers of knowledge in order to understand the mechanisms that underlie diseases of the brain like Alzheimer, Parkinson, ALS, and other diseases like cancer, heart inflammatory and infectious disorders. To break the walls of knowledge, we have to fund generously science and research worldwide and educate passionate teachers and then brilliant and curious scientists and engineers. But there are also other walls that we have to break. They are not necessarily walls of knowledge. Some of those walls are walls of behaviour. Excessive eating which leads to morbid obesity and smoking are just two examples of walls of behaviour. Some of the walls are governmental walls: the industry that contaminates the environment or air pollution caused by cars can be controlled and regulated by governments. We need to clean the environment and keep it tidy. So, this is another type of a wall. Certain infectious diseases have also to do to a large extent with our environment. In less developed countries, in Africa, Southeast Asia, and some of the Caribbean countries, the walls are made of different materials. Those are financial walls, walls of accessibility and walls of corruption andtransparency. We also need to think of that. So, there are different walls to break, and I will focus mostly, since I am a scientist and a physician, still working in the laboratory, on the walls of knowledge.

In the walls of knowledge, development of novel drugs is a major challenge. If we look at the walls of drugs, there were three revolutions. The first revolution was the revolution of serendipity which occurred between the 1920s thru the 1950s. Discoveries were serendipitous, unintentional; drugs were not discovered as a result of an aimed research. Take, for example, aspirin, which is a very important drug, probably the drug that has been mostly used by weight. In its pharmaceutical form, it was discovered by chance by Felix Hoffman, who worked as a pharmacist at Bayer. His father had a disease, rheumatoid arthritis, and he decided to synthesise a known drug that has been there in different forms since old Egyptian times, gave it to his father, and generated a blockbuster.

Another major serendipitous discovery was penicillin, the first antibiotic discovered by Sir Alexander Fleming. He was a microbiologist and forgot an uncovered Petri dish on which bacteria grew on the table. A spore of a fungus that was in the air fell on the rich nutritious medium and grew. Fleming noted is that there was a halo around this Fungal colony where bacteria could not grow and surmised that the fungus secreted an anti-bacterial material, anti-bios (against life) and the rest of the story is history. The discovery of antibiotics revolutionised medicine in an unprecedented way, allowed treatment of infectious disease, and the development of surgery and gynaecology. Infectious diseases unfortunately have not defeated completely, but the discovery had enormous effect on our lives.

The second era reflects the development of chemistry. It spans the second half of the 20th century. Chemists synthesized millions of compounds for different purposes. They can generate basically any small molecule as long as it doesn’t violate the laws of thermodynamics. This era is the era of high throughput screening. Millions of compounds are screened for their effect on cells or biochemical reaction that represent the elementary reduced state of a disease. No questions are being asked at that stage about mechanism. One important group of drugs that came out of screening are statins. These are inhibitors of cholesterol biosynthesis, and they have had a huge impact on morbidity and mortality from heart attacks in the world, reducing it in a significant way. Cardiovascular diseases caused by atherosclerosis are probably the most common and economically burdening diseases in the developed world, and the success of the discovery of statins via screening, a method that led to the discovery of many other successful drugs is very important.

We are entering into the third revolution, that of personalised medicine. Medicine will be tailored personally to each and every one of us – not that we should get a packet with our name and drugs in the mailbox, but it is our DNA, and later the nature of other components in our body – proteins, lipids, sugars, and their dynamics, that will determine the drugs that will help curing us. It is important to understand the source of the need to enter this era and what enabled it, what were and are the technologies needed. The basic reason is that there is no one shoe that will fit all feet, and there is not one drug that can fit all diseases of that appear to be the same, but apparently are not.

Take for example breast cancer. Until recently, we grouped breast cancer as one disease. But it turned out that it is a large group of diseases that are very different from one another. Take a group of patients with breast cancer or prostate cancer that appear to be of the same stage of the disease and therefore these days will receive the same treatment. They are starting a journey of five years, undergoing a similar treatment of surgery, radiotherapy and/or chemotherapy; but at the end of the route, they are ending completely differently. Some of them, hopefully most of them, will be cured, but some will unfortunately die of a severe disease. The reason is that we were blind, at the beginning, to diagnose them correctly; not all patients with what appears to be the same disease have the same disease, there are sub-groups of breast cancer or prostate cancer - A, B, C, D, E, and possibly more.

We already have tools to stratify diseases. So for breast cancer we have mutated estrogen receptor positive patients that can be treated with Tamoxifen, or mutated HER2 receptor patients that can be treated with Herceptin. There will be many other mutations that drive breast cancer that will be discovered. Personalised medicine is aiming at those mutations that we have not discovered yet, and that profiling of our DNA and proteins will unravel. We have to identify new targets, so we should be able to classify these women into those that suffer from breast cancer, A, B, C, D, E and others, and to develop drugs that will fit each and every one of them.

The technology that enabled this progress was fast DNA sequencing and strong computational abilities, and the first important project – the sequencing of the human genome – was completed a bit more than 10 years ago. But this was one single human genome of one single person. In a few years from now we shall be able to sequence the genome of each and every one of us in less than a day and less than one thousand dollars. The first genome took several years and hundreds of millions of dollars. Profiling of DNA will become a routine laboratory test, like MRI or CT scan or a comprehensive blood test.

As for the road map, we are going to generate the cancer genome atlas to unravel most of the mutations that drive different cancers, and so we are going to do for many major diseases. It will all be based initially on our DNA, but then on its products, RNA and proteins, the small machines that drive all the activities of our body. The body is made of more than 20,000 different proteins, many of them are different from one person to another, some are changing along life, some are mutated – genetically or as a result of environmental events, and we are heading towards a comprehensive understanding of their diversity and its consequences in different people.

But let me warn you that there are no free lunches. There road is bumpy and I want to highlight some of the problems. We are entering an era where there will not be any more blockbuster drugs, as diseases are going to be sliced into smaller groups, and the drug companies are not going to like it, as the market is going to be sliced as well. So if there will be twenty breast cancers, there will be twenty or so combinations of drugs.

There are many other problems, but let me just talk about one which I think is very important – the bioethical implications of personalized medicine. By submitting our DNA for testing, we are submitting the most intimate information that we have. It is not only current information but also future information about our sensitivities to different diseases – physical as well as mental. There will be many bodies that would like to have access to this information - from insurance companies, to government and even ourselves. Think about the woman who has breast cancer, for example, and she has a gene that renders her sensitive to breast and ovarian cancer. What is she doing with it? Is she taking steps? What is she telling her young daughter that may also carry the gene? We have developed all these scientific technological tools, but now we have to introduce also other tools - sociological, religious, psychological, and communication tools to help us integrate the scientific and technological achievements into our different societies and to usher in successfully this wonderful era.

 

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