Aaron Ciechanover (2013) - Drug Development in the 21st Century - Are We Going to Cure All Diseases?

Good morning, everybody. I am not going to tell you today about the ubiquitin system but rather on my next hobby which is personalised medicine and the major revolution that medicine has entered already. But we are not yet there in full wind. And that’s the revolution of personalised medicine. And you know what it means? I will tell you a little bit about the technicalities but mostly alert you to problems on the way, obstacles, technical obstacles but even more important bioethical obstacles. So the issue is obviously to remain young forever, people always want to remain young forever, and to find the cure to all diseases. Is it at all possible? And we are not going to prophesise here. All I can tell you is that in the 20th century human life, the lifespan was extended by almost 30 years and more. At the turn of the century, of the previous century people lived on the average 50 years. They died mostly of infectious diseases. Many died in wars, also infectious diseases. We didn’t have antibiotics. And within 100 years with medicine, science, technology, understanding, diet and so on and so forth, sewage, sterility, cleanliness we managed to extend life span by 30 years. And if you think about the old Greeks and the Egyptians and the Romans which lived between 5,000 and 3,000 years ago, they lived about 30 years on the average. So it took about 4,000 years to add just 20 years, from 30 to 50. And then in one century alone we managed with science and technology and understanding of our surroundings to add an additional 30 years, But with it came a price. And the price is sitting under a big umbrella of degenerative diseases. We are typically doing well during the first 40/50 years of life. And then we are starting to decline a little bit. And I think that it’s correct to call all these degenerative diseases. Even malignancies are in a way degenerative diseases. It is degeneration of the quality control mechanisms. Certainly vascular diseases of the heart, vascular diseases of the kidney, of the brain and neurodegenerative diseases and so on and so forth. And even infectious diseases that we are able to cope easily when we are young. Because of degeneration of the immune system and the compromise of the immune system we are not able to cope with them. And people, old people if you go to hospitals die easily of complications, of flu in the winter, of pneumonia and so on and so forth. So with this achievement of extending our life span we are also paying a price. And new diseases came up. So cancer... people died of cancer. Actually if you read Science a few weeks ago, even the Neanderthal men did have cancer. But these are rare cases. And young people also have cancer. But this is rare, about 2% of the malignancies are in young people. We start to get malignancies in the 5th and 6th and 7th decade of age and certainly neurodegeneration. So you see that we are paying a price for it. And the question whether we are going to defeat all diseases is unknown to us. And I’m not sure how interesting it is because once we defeat certain diseases, probably new ones will await for us around the corner. And we are in the lab now and we need to solve current problems. So this was the dream. This came out of Judah Folkman from Harvard Medical School in the early ‘80s when he discovered that... we knew about it but he really floated the idea that tumours need blood supply. And the whole field of angiogenesis came to life. And he thought why to deal with a tumour, let’s deal with the blood supply. Let’s cut the blood supply. He invested a lot of work. But we are still depleting to cancer. Cancer cells are very sophisticated. They have all kinds of tricks to live under hypoxical conditions, to develop other blood vessels and so on and so forth. So it’s not that simple. So you see again people did launch major attacks on major diseases. But apparently nature tricks us. Many diseases are obviously preventable. You may have arguments about it, you know, for example obesity. If you walk a... typically in American streets, less so in Europe, you will see big balls rolling around. And obesity is not only affecting the vasculature and the heart and the brain, in recent years basically only in the last decade a tight linkage was described between obesity and cancer. There is a significantly higher incidence of malignancies in obese people. And the linkage is in inflammation. We now know what the old German pathologists told us already without knowing the mechanism, Virchow, that there is a tight linkage, mechanistic linkage between chronic inflammation and cancer. And in many organs which are subject to chronic inflammation there is a later development of cancer. And this is also the reason why there is a strong recommendation, I am going to talk about it, of anti-inflammatory drugs like aspirin, acetylsalicylic acid, to take it in a preventive way. And again just the recent annual review of medicine had a striking study showing that chronic intake of aspirin which is an anti-inflammatory drug reduces the incidence of colorectal cancer which is probably the second most prevalent or common cancer in the western world by 40%. 40%! The experiment was stopped in the middle because the results were so significant that there was no need to continue on with the experiment. So back to obesity. It turns out that obesity is accompanied by chronic subtle sub clinical inflammation. When you look for inflammatory mediators, interleukins in the tissue, you will find them, also in the circulation. And this is probably the reason why obese people are developing malignancies. There are some other mechanisms that have been described recently. But this is a preventable disease. I mean we can control it. In a way we may argue that this is also a physical disease, maybe even genetically or family oriented. Because, you know, our society out hunger for unlimited amount of food may be still anchored in organic reasons. But nevertheless we can control it. The same for smoking or any addiction that burns our lungs and vasculature and so on. So many diseases we can control even without drugs. We don’t have to go to the laboratory and to invest billions of dollars in development of new drugs. These are mostly behavioural diseases. Obviously the psychologist or the psychiatrist will argue again that behavioural diseases are physical, organic diseases. So we are in the same dance, in the same circle but nevertheless there is an element here of control that we can exercise unlike other diseases that we may not be able to exercise. So let’s go to drug development and to the revolution of personalised medicine. And let’s just go very briefly to the historical roots of it. And the first revolution is the era of incidental discoveries. People didn’t search for drugs. They just bumped into them. And lo and behold and surprisingly or not these drugs became blockbusters, probably the most important blockbusters of the pharma industry. Take for example Aspirin that is taken by hundreds of millions of people worldwide. You are mostly young here but when I am lecturing to a little bit older audience and I ask them: And many of those that don’t raise their hands are shying out. So, Aspirin is an old Egyptian drug, 4,000 years old, from the willow barks on the banks of the Nile River. When you chew the leaves, they are very bitter but the Egyptians already in their writings indicated that chewing these leaves alleviates pain. It was left in the literature for many years. Charles Gerhardt, the French chemist, came and took the bitterness out of it by isolating the active ingredient, here is the beginning of modern chemistry, by acetylating it. The current Aspirin is an awfully simple compound. It’s an acetylsalicylic acid. Every kid can produce it in the basement. And he acetylated it, took the bitterness but nevertheless was able to maintain the analgesic, the pain combating properties of it. And then it went to Buchner, a German chemist, and so on. And then it was forgotten again until at the turn of the 20th century Felix Hoffmann that worked at Bayer, a very famous German pharma... His father contracted rheumatoid arthritis which is a disease of the joints. It’s basically a severe disease. It’s not a fatal disease but not every severe disease must be fatal. It paralyses the people. The joints are inflamed, painful. The patients are basically paralysed. They cannot button up. They cannot dry themselves using a towel. They cannot write, they cannot eat, they cannot use a fork and a knife, certainly not chop sticks. And Felix Hoffmann remembered this drug. And he said to himself: “I want to alleviate the suffering of my father, just the pain.” He went to the basement and synthesised it and gave to his father a drug, a powder that he synthesised himself. And lo and behold the drug didn’t only take the pain away but also alleviated the inflammatory signs. Now we know, it’s the subject of another Nobel Prize in medicine or physiology, how Aspirin and inflammatory mediators are synthesised and working. It’s fantastic work. And then he went to the management of Bayer and convinced them to make the drug. And a new drug came to the world. And meanwhile Aspirin is still under the water. We are consuming it in larger and larger and increasing amounts year by year because we describe more and more phenomena. It’s probably the most successful drug that was ever made by the pharma. So, people discovered about 30 years ago that it prevents aggregation of platelets which are producing blood coagulation. So basically all patients in the world that have undergone myocardial infarction, heart attack, where there is a block in the flow of blood to the heart itself in order to prevent the second one they take Aspirin or another anticoagulant. Many people believe that it can prevent heart attack in the first place and they are taking preventively. Meanwhile I talk to you about inflammation and a new use of aspirin came to the world to prevent cancer, not only heart attack. And we are still at the beginning of an unbelievable wonderful story, all by coincidence. Egyptian bitterness, father sick, basement, no research. Probably the cheapest drug that was ever made. Another coincidental discovery is of the first antibiotic, penicillin. Sir Alexander Fleming, a microbiologist, worked on bacteria. Here there are bacteria, the smear growing on the petri dish. He left the petri dish... The story is right. The original dish is in the British Museum. And he left the dish open on the table. And there were 2 mistakes. He left it open and he left it at room temperature rather than covering it and putting it in the 4 degrees. Coming a few days later he found that the spore of a fungus that was in the air fell on the nutritious media, developed into a whole colony. But there is a halo here that he noted that didn’t allow the bacteria to grow all the way to the very border of the fungal colony. And he surmised that the fungus secretes an anti-bios material. Anti against, bios life. Antibiotics. He was not a chemist. He called to his help Sir Ernst Chain and Howard Florey and penicillin came to the world. And then people said: “Wow, fungi secrete antibiotics. Maybe there are other fungi that secrete antibiotics.” And Selman Waksman discovered streptomycin, another Nobel Prize. And Alexander Fleming got himself the Nobel Prize and the world changed. The world... You cannot imagine the world of medicine now without antibiotics. And you are going to hear with Ada about the obstacles that are still there when she will come. So you see serendipity, no research. The second generation is the generation of high throughput screens. The power of chemistry, millions of compounds available. People are having libraries of hundreds of thousands of compounds. And then they say let’s screen them. Tissue culture was evolved. Animal models were evolved, collaboration between chemists and biologists. There are a million compounds. Let’s screen them. One of them will fit the key that we forgot to take when we left home. We don’t know the mechanism. But we surmise that out of numerous compounds one will fit. And indeed numerous drugs came to the world between the ‘60s and the 2000s just out of screening. And the mechanism is discovered retroactively. I’ll show you only one, a multibillion dollar selling drug which is Statins, inhibitors of cholesterol biosynthesis. They inhibit the first enzyme in the biosynthetic pathway which is HMG-CoA reductase. I will not go into details. And they reduce cholesterol and by that reduce the morbidity and then the mortality of people from heart attack. We are back into heart attack. You can see here the reason for the heart attack, the accumulation of cholesterol in this atheromatous plaque in the coronary artery. And we are reducing the load of cholesterol in the coronary arteries. Statins came to the world by Akira Endo, a Japanese pharmacist that screened the library of natural products. He chose 10,000 natural products, put an assay, a radioactive, a very cumbersome assay of biosynthesis of cholesterol, and looked for one product that will inhibit the biosynthesis of cholesterol. It was in the early ‘70s, not too far away. And the first Statin came to the world. It underwent quickly clinical trials. Now we have much more advanced generations and much more effective ones. But just to give you an idea. The last year’s sales of Statin, the 2012 sales of Statin approached $40 billion. It’s probably the best seller of the pharma in terms of dollar making. We are in the third one, the current one. And I am citing Lee Hood, probably the father in a way of this revolution, personalised revolution which was going to be the 4 P’s revolution: Personalised, predictive... we are going to predict diseases. By predicting them we may be able to prevent some of them. And then it’s going to be participatory. I am going to tell you a little bit about participatory. It’s going to be a discussion between the physicians and the patient. Because the decisions that are being made here are heavy ones. And the old medicine, the old patronising medicine when the doctor was the god, the trustable person in the game, is not anymore. Patients are coming much more knowledgeable, fed by the internet, by friends. But also the decisions themselves touch the very heart and the very core of their soul and body. And they need to take part in the decision making process. And we’ll come back to it towards the end. And it’s all going to be based initially on the human genome. It’s again the advancement of chemistry. Wally Gilbert is here with us, one of the fathers of sequencing. It started with the ability to sequence the DNA. Then it moved to the ability to sequence the entire human genome, that was unravelled in April 2000. But this was a multibillion dollar, several years project of one genome. And now we can do a personal genome probably in the near future in a few hours for several hundred dollars. So it’s going to be a routine test. But it’s not only the genome because the information on the diseases is not only in the genome. The genome is the beginning. It’s in the transcriptome, in the proteome and in the posttranslational proteome. It’s much more complicated than that and the road map is rather complicated. But at least we know the elements of the road map. And the reason that we entered it, it’s not only the advancement in the chemistry and the ability to go into the genome but also the dissatisfaction for medicine which was kind of a pyjama type of a medicine of one size fits all because we look mostly into diseases. If a group of patients came to the doctor on the one day and we started to treat them, along the way we saw that they split. Some of them don’t react to the treatment. Some of them even react adversely to the treatment. And some of them react favourably and cured. And though at the beginning they looked to us like the same patient or very similar. A lump in the breast, no metastasis, everything looks ok. The lump is removed by surgery. Additional chemo and radio is added, everything looks fine. Nevertheless the patients take different routes. Why? Only now we realise why. Because patient A is not patient B. We looked at the disease and now we are going to flip the mirror to the disease within the context of the patient. And that’s the essence of the revolution. Let’s take breast cancer for example. You know breast cancer can be a lump in the breast as I said. But now we are starting to dissect it molecularly. Until now it was done by serendipity. So here are 2 women, woman A and woman B. You see that the biopsy of woman B is stained for something that the biopsy of woman A is not stained for and this is a mutated oestrogen receptor. And the mutated oestrogen receptor can be treated with Tamoxifen. But it will be useless to treat woman A with Tamoxifen because it won’t help her. She doesn’t have a mutated oestrogen receptor. And the same for the EGF receptor, the erb-B2 receptor. This woman can be treated with Herceptin that clusters the receptor, the mutated receptor on the cell surface, and direct them to degradation following ubiquitination in the lysosome. A woman that doesn’t have a mutated HER2 receptor it would be useless to treat her with Herceptin. So you see already that we are trying to stratify the breast cancer. There is no breast cancer. There is breast cancer with an address for gesterone receptor, oestrogen receptor, EGF receptor. And then there is the triple negative, the ones that doesn’t have any of those. And these turn out to be, because we cannot treat them, the most aggressive. But they have a reason for that. And we are on there, the community is on there to discover the reason. How? Now systematically rather than erratically. Systematically by going to the DNA, identify all the mutations, cluster the mutations into growth factor receptors mutations, signal transduction mutations, nuclear transport mutations and so on and identify the mutation that leads to the cancer. And then going back to the bench with a chemist in an interdisciplinary approach and synthesise now in a planned manner a drug that will fit into the mutated gene. So this is the road map. First identification. But in order to identify it we need to go not to one breast cancer. We need to go to several hundred or several thousand of them and sequence them so we’ll have a map of all the mutations that are leading to breast cancer. And then we shall be able to stratify. And there will be many more added. There will be no breast cancer anymore. There will be breast cancer A, B, C, D and E and F and so on and so forth. And each of them is going to have its own treatment. So we are going to a very different type of medicine. It’s a disease within the context of the patient. Now it’s not only about diseases, it’s also on the effect of drugs. Look at ADRs which are adverse drug reactions. Fatal adverse drug reactions appears to be between the 4th and 6th leading cause of death in the USA. When we give a drug to a patient we have no tool to predict how the patient is going to respond, favourably, partially, not at all or adversely. And we manage to kill a good number of patients with adverse reaction. Innocently because we don’t have a tool to predict. Probably the most notable reaction that you know is sensitivity to penicillin. I am sure that you all know whether you are sensitive to penicillin. But what else? Do you know anything else about your sensitivity? I bet you that almost none of you knows anything about your other sensitivities. And I also can tell you that there is not a compound on this planet, let it be from plant, animal, nature or people... Someone that walks on the face of earth is not sensitive to it. But how do we know? We don’t know, only by trying but we cannot try. And then people develop from mild side effects like a rash or erythema, you know, like red eruption which is nothing, to anaphylactic shock. And we see patients dying in the hospital. The power of personalised medicine is going to predict also that because we are going to predict who are the patients that are going to respond to the drug and give only those that are the responders as we call them the drug. All the others, either they are sensitive or they are not going to respond at all. Why to give them the drug? And this secret again is embedded in our DNA and then the transcriptome, the proteome, the post translational proteome and so on and so forth. And you see all the 4 reactions to drugs from favourable to adverse. And we really need to know it because this is not a minor issue in medicine. And the difference why is it so? Because we are different, we are small and big, fat and thin, male and females, living in Antarctica or in Africa, eating cabbage or eating pork. We are different people. And now we at least develop tools to approach ourselves individually. Let me go to the very last one. So it’s all in the human genome. We are developing atlas and banks and it’s all in the proteome and the transcriptome. And let me just go to the last one which are the problems that we are facing. And the problems are some technical and some ethical. The technical problems I’ll go fast. Many diseases are multigenic. Gone are the days that we have, you know, one gene, one disease. There are many diseases that are related to one gene. But metabolic diseases, diabetes, certainly psychiatric diseases, autism are multigenic diseases and we need to know the contribution of the genes? Malignancies are characterised by genomic instability. We discovered one mutation or 2 or 3. We start treatment and the genome keeps on mutating itself, developing resistance to the drugs. Human experimentation is very complicated and expensive. We cannot do experiments on humans like we do on mice. Mice are easy. They are one breed or several species. We turn on the light in the cage at 8 o’clock in the morning, we turn it off at 8 o’clock in the evening. We feed them with Chow Purina and they are nice and we cured millions of mice from cancer. But then the border between the mice and the human turned out to be almost unsurpassable. We are lacking at animal models especially for neurodegenerative and psychiatric diseases. Cost of developing of new drugs, especially the blockbuster era is gone. Because until now we treated hypercholesterolemia with Statins but now some of the patients don’t respond to it. And there will be one type of hyper-cholesterol and another type and another type and another type. And the market is going to be divided and the companies will have to develop more and more drugs for the same share market. So they are not happy about it. So you see that there are many technical issues. But for me at least as a human being the most bothering one is the bioethical problems of availability of genetic information because we are depositing at the hands of the doctor or of the bank or whoever the most sensitive information we do have. We believe that it’s protected from leakage. And remember this information is also predictive on your future diseases in a way and it’s awfully sensitive. And it turns out that it’s going to be impossible to protect it. You know whatever we do... A couple of Israelis working in the Broad Institute develop an algorithm to identify people by name just from snip analysis of relatives that deposited their information in Google and other data banks by names. So they know how to... It’s nothing hackers, nothing about crime, nothing about breaking the law. It’s a science paper that just came up recently. And you see genetic privacy is the ability to identify individual from their anonymous genome sequence using a clever algorithm and public data base threatens the principle of subject confidentiality. And there are people that are going even further and said: “Be prepared for the big genome leak.” So first of all we still don’t know how to deal with it. But above it, above the confidentiality lie problems that have nothing to do with confidentiality. And I think that I will not go into numerous details. I’ll just tell you a story that you all know but may not know all the implications. And this is the story of this beautiful woman, Angelina Jolie. She came up a few weeks ago telling the whole world that she has a gene, she’s a carrier of a gene called BRCA1. It happens to be an ubiquitin ligase, another element in the system that we discovered. And this mutation carries a susceptibility for both breast cancer and ovarian cancer. And she made a decision to remove her 2 breasts and in 3 months also to remove the ovaries. And it was very nice of her to do it, very courageous because it encourages other women to do it. But it really pinpoints to the main problem in my opinion of personalised medicine. First of all she left a major problem behind. And that’s the problem of her daughters. So for herself she solved the problem. Because she is married and she has daughters, adopted daughters, her own daughters. But what a 16 year old daughter or 20 years old daughter that is going to college and dating a boyfriend is going to do with the knowledge that she is a carrier or may be a carrier or that her mother is a carrier and she has the potential to be a carrier? And will she check it or won’t she check it? And if she checks it and found positive, what is she going to do about the boyfriend, about the children, about her future? Well the future is not as gleam as I described it because it’s always like that the diagnostic technology is preceding our ability to treat them and to handle them. And in the future we shall be able to exchange genes. So there is a future, it’s not like it’s all doom. But there will be an intermediate period in between that we shall be in the kind of the twilight zone, that we know what we have but we still don’t know what to do about it. And let me sum it up in one single sentence and that personalised medicine penetrates into the most sensitive layer of our very existence. And that is that we don’t know the future. And we enjoy it. Because once we know the future our internal structure is shaken. Thank you very much. Applause.

Aaron Ciechanover (2013)

Drug Development in the 21st Century - Are We Going to Cure All Diseases?

Aaron Ciechanover (2013)

Drug Development in the 21st Century - Are We Going to Cure All Diseases?

Abstract

Many important drugs such as penicillin, aspirin, or digitalis, were discovered by serendipity - some by curious researchers who accidentally noted a "strange" phenomenon, and some by isolation of active ingredients form plants known for centuries to have a specific therapeutic effect. Other major drugs like the cholesterol reducing statins were discovered using more advanced technologies, such as targeted screening of large chemical libraries. In all these cases, the mechanism of action of the drug were largely unknown at the time of their discovery, and were unraveled only later. With the realization that patients with apparently similar diseases at diagnosis – breast or prostate cancer, for example - respond differently to similar treatments, and the clinical behavior of the disease differs from patient to patient, we have begun to understand that the mechanistic/molecular basis of what we thought is the same disease entity, is different. Thus, breast cancer or prostate cancers appear to be sub-divided to smaller distinct classes according to their molecular characteristics. As a result, we are exiting the era where our approach to treatment of these and many other diseases is “one size fits all”, and enter a new era of “personalized medicine” where we shall tailor the treatment according to the patient’s molecular/mutational profile. Here, unlike the previous era, the understanding of the mechanism will drive the development of new drugs. This era will be characterized initially by the development of technologies where sequencing and data processing of individual genomes will be fast (few hours) and cheap (<US$ 1,000), by identification and characterization of new disease-specific molecular markers and drug targets, and by design of novel, mechanism-based drugs to modulate the activities of these targets. It will require a change in our approach to scientific research and development and to education, where interdisciplinarity will domineer and replace in many ways the traditional, discipline-oriented approach. Entry into this era will be accompanied also by complex bioethical problems, where detailed genetic information of large populations in developed countries will be available, and protection of privacy will become an important issue for health authorities.

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