Aaron Ciechanover (2015) - The Revolution of Personalized Medicine: Are We Going to Cure all Diseases and at What Price?

Good morning. I'm not going to tell you about the ubiquitin system, you might better hear the lecture of Avram. So in order to avoid duplication I'll tell you on something else, which is the revolution of personalized medicine. Mostly its historical roots and bioethical implications which are extremely interesting. So where are we? We are here. So as you can see, people are dreaming to cure all diseases. The question is whether this dream is realistic. And if we are thinking of it in the terms of the previous century, in the 1900, people didn't die of cancer. The reason was that they didn't live long enough to get cancer, because cancer is a bonafide age-related disease. People didn't get Alzheimer's or Parkinson's, again, because these are age-related diseases. So with the marvels of the 20th century with antibiotics, and vaccination, and imaging, and development of medicine, and science and technology, we have extended our life span for an average of 50 or 55, to around 80 or 85, which is amazing. If you think about it, the old Greeks, and the old Egyptians, 4,000 years ago, lived on the average 25 to 30 years. It took about 4,000 years without any significant step that we can point to, to extend lifespan by about 20 years, from 25, 30 to 50, and then within one century, actually it was in a half of a century, we extended the lifespan from 50, 55 to about 80, 85, and we can pinpoint what happened. So again, it's vaccination, antibiotics, and medicine, and imaging, and understanding diet, and the sewage system, and so on and so forth. So there are many factors that contributed to it. And with it, we're also paying a price for this launch, and the price are those degenerative diseases, this whole set of diseases. Whether it's slow degenerative diseases, or vascular diseases, or cancer. These are all degenerative diseases when the systems, the body systems cannot compromise any more with external stress or any other stress, and they kind of surrender. So whether in the future is lifespan still extended, and we are still uphill, and we believe that people that are being born today will live maybe 10 or more years longer than we do. We may experience new diseases that are not on the surface yet, though people believe that we are more or less seeing the horizon of the extent of diseases. Not the treatment, not the cure, but at least the extent, but really, nobody knows. If we think of where medicine is going today, medicine is going in mostly three directions. One direction that I'm going to talk about is the classical direction, is drugs, development of new drugs, and we'll talk about it in a minute. Another direction is devices. We're kind of not thinking of it, but if we think about the last 20 or 30 years and the big achievements of medicine, those are devices. Think about imaging, think about CAT scan, think about MRI, functional MRI, we can now follow the activities in the brain. We can give a problem to solve to a man and a woman and see, during the process of solving the problem, what areas in the brain are lighted up, and the difference in the thinking process. So it's really marvellous. We heard the lecture, two days ago on entering the brain via imaging, and seeing really the actual activities of the brain. So imaging, but it's not only imaging, it's organ, it's joint replacement, it's stents, it's valve replacement in the heart. So devices is one direction, and that has to do with engineering, mostly with engineering. Another direction is regenerative medicine. So it can be either to regenerate the whole tissue or stem cells. We are taking a tissue that was degenerated, you know, if we are talking about Parkinson's disease, the substantia nigra pars compacta cells in the brain. And we are able to take either adult cells and reprogram them. Or we can take embryonic cells and program them, a priori to differentiate to the desired cells. And it can be for treatment of various diseases, from Parkinson's to diabetes. We hope we shall be able to generate Langerhans islet cells that will be sensitive to glucose level and secrete insulin accordingly and to cure diabetes, and so on and so forth. So this is another direction. So one direction is devices, another direction is regenerative medicine. The third direction, as I mentioned at the beginning, is drug development. So let's talk a little bit about drug development. In the drug development, we can think of about three revolutions, or we can divide it into three time windows. The first time window is the era of incidental discoveries. People didn't really look into what they found at the end, but it happened that they found probably the most useful and impactful drugs that we know in the pharmacopoeia. Think about aspirin. Aspirin actually was known for 4,000 years, it was known to the old Egyptians from the willow barks that grew along the banks of the Nile river. When they chewed the leaves of the willow, it tasted very bitter, but the Egyptians noted that this extract has a pain alleviating characteristic. So it could alleviate pain, it took 4,000 years, to the 19th century, for Charles Gerhardt, and Buchner, and others, to purify the active ingredient, which was salicin. Then it took Eichengrün, and Felix Hoffmann, that you can see there at the top, to acetylate it. The acetylation was necessary in order to remove the bitterness, but not to affect the pain alleviating characteristic of aspirin. Now, what is aspirin? You probably think that aspirin is used rarely nowadays in order to reduce pain, and to reduce fever, and so on. Actually, aspirin is the drug that has been used the most out of all the drugs that have ever been produced by the pharmacopoeia. The current annual usage of aspirin is 70 tonne metric of the drug in the world. And actually the utilization of aspirin is being increased as we are talking. The initial use of aspirin was for inflammatory diseases. The first use was for rheumatic arthritis, you see the patient there. I don't have, or, there is one, wonderful. There is a laser pointer here. You can see here the inflamed joints. It was used actually by Felix Hoffmann to treat his father that contracted rheumatic arthritis, which is a debilitating inflammatory disease in which patients are suffering severe pain and inflammation of the joints. They cannot button up, they cannot cut the food, they cannot dry themselves after a shower, basically they're paralyzed. It's a very severe disease, and he wanted to alleviate the symptoms, the pain, from his father. He synthesized acetylsalicylic acid in his basement, gave it to his father, and low and behold, not only the fever and the pain went away, but also the inflammation went away. So he surmised that he discovered not only an anti-fever drug, but also an anti-inflammatory drug. The mechanism was discovered much later on. It inhibits the synthesis of inflammatory mediators like interleukins, but I don't want to go into it. But what happened later, it was discovered that there is a linkage between chronic inflammation and cancer. So people that are suffering chronic inflammation, even subclinical chronic inflammation, that they don't notice, even, that they are inflamed, it can be breast cancer, or bowel inflammatory disease, develop along the years, following many years of chronic inflammation, they develop cancer. People surmised that if they will suppress the inflammatory response, they will, in the long-term, prevent cancer, which turned out to be true. And aspirin is being taken these days by millions of people worldwide, as a chemopreventive drug to prevent cancer. Mostly colorectal carcinoma, which is one of the most common malignancies, both in men and in women. Then another connection to aspirin was discovered that aspirin is an anticoagulant, it can prevent blood coagulation. So, another cohort of millions of people joined the crowd, and those are the people that suffered heart attack. And as you know, heart attack is coagulation of blood in the coronary arteries, the arteries that lead blood to the heart muscle itself. Here you can see, it's not President Clinton, it's somebody else that suffers a heart attack. People that had suffered from heart attacks are put on anticoagulant, and in most cases, some aspirin, or aspirin alikes. You can imagine that between prevention of cancer, and prevention of a second heart attack, we are talking millions and millions of people that joined the crowd in using aspirin. And the development of aspirin cost nothing, it's an old Egyptian discovery that just improved a long time, so it was completely coincidental. Another coincidental drug is penicillin. I will not go into details, it's Sir Alexander Fleming, and later on Sir Ernst Chain, and Howard Florey. Alexander Fleming was a British microbiologist. He grew bacteria over a dish. Here you can see the smear of the bacteria. And he forgot, simply forgot, a petri dish over the bench for several days. When he came back, a spore of fungus that was in the air fell on the rich nutrient agar, and grew to generate a colony. You see here the white colony in the middle of the fungus. Typically, what I would have done, if I would have seen it in the lab, I would have taken the dish and just trashed it, because it's contaminated. But Alexander Fleming did not trash it, and what he noticed, he noted that there is a halo. There is no pointer, okay. So you will use your imagination. If you look at the white spot, you will see that around it there is a halo to which bacteria don't grow. They don't reach all the way to the border of the colony. He surmised that the colony of the fungus secretes a material that he called anti-bios, against life, therefore the name antibiotics. The fungus secretes it in order to protect itself from the bacteria from coming close. This opened the whole field, it took 10 more years for Sir Ernst Chain and Howard Florey to purify the active ingredient, which turned out to be penicillin. Penicillin was already used in World War II, and saved the lives of hundreds of thousands of patients, and then later on. But it also gave the idea to people that other fungii may secrete other antibacterial agents. Selman Waksman found streptomycin, and so on and so forth, and there became an avalanche. Now we can synthesize them, we don't need the bacteria anymore. It opened the whole field, and again, serendipity. So we are talking about drug development, complete serendipity. The second era is the era of screening. We are still in the era of screening. We'll go quickly through it, I bring you one example. Chemistry brought us many chemical compounds, millions of compounds are available in libraries that belong to families. People said now we have also disease models, we can imitate cancer or cholesterol accumulating cells in tissue culture. We have millions of compounds, let's match the two, and let's just screen. So we shall take, without understanding the mechanism, without having any mechanism in mind, we shall take millions of compounds, automate it, and throw one by one by one by one by one over the disease model that we have, and see whether one can prevent whatever phenomenon we are studying. And indeed many very useful drugs were developed by just what I call brute force screening. One of them is a very famous drug, it's statins. Statins are cholesterol biosynthesis inhibitors. Again, the drug is a very useful drug, and it's being sold, unlike penicillin, that the patent expired, and unlike aspirin, that never was patented. The last year's sales of statins were 40 billion dollars, 4.0^9 dollars. It's a huge, it's probably the number one blockbuster in the pharmacopoeia market. Statins were first discovered by Akira Endo, a Japanese pharmacist. They decided to set the model for cells that accumulate cholesterol, and he screened the library of natural products. So he collected the library of natural products that were collected from fungii and other Japanese plants, 10,000 of them. He screened them and he discovered one drug that was inhibiting cholesterol biosynthesis. And then in the early 70's, not too far away from us, only 45 years ago, the first statin showed up in the market. Meanwhile it was improved and improved, and during the years statins became extremely useful drugs to prevent immobility and mortality from heart attack. Accumulation of cholesterol, you see here, the plaque in the coronary artery. You see the section of the artery, and you see the white material, the white fat, that is accumulating and accumulating and accumulating, and at the end occludes the entire lumen of the coronary artery, and the patient succumbs to a heart attack. What we call a myocardial infarction in the clinical jargon. So this was screening. We are now moving to the new generation of drug development, it is called the generation of personalized medicine. Actually in the language of Lee Hood, the father or the prophet, he's not really the father or the prophet of this revolution, is the four P's revolution. So it's not only personalized, but it's also predictive, preventive, and participatory. We shall try to, very briefly, within the time frame, we have to give you an idea of what it is, and the reason why we are moving. What was wrong with screening? We can keep on screening and screening and screening until we shall cover all diseases. The problem is that we are screening for disease models, we are not screening for human beings. If you are looking at human beings, it becomes much more complicated. If we take a group of human beings, let's say today, that have prostate cancer, or breast cancer, or Alzheimer's, or any disease, and we send them to their way with the gold-standard treatment, any gold-standard treatment. If it's prostate cancer, let it be surveillance, or irradiation, or prostatectomy. If it's breast cancer, let it be mastectomy, or lumpectomy, taking the lump away, doesn't matter, the gold-standard treatment. And we send them away, and we follow them for five years. We see that within five years they split into two, well, roughly into two. One group survives the disease, it depends on the disease. There are some diseases that nobody survives, unfortunately. And some are deteriorating, despite the fact that they had the same disease, so-called the same disease, and they got the same treatment. So they really diverge into two extremes. Some afer five years are completely cured, back happy to their families. Some are dead, some are still deteriorating, and now they're going another treatment, and another line of defence, and another suffering, and another and another and another until they succumb at the end. What is it, that despite the fact that they have the same disease and the same treatment, they behave so vastly different? The are two reasons: One, they don't have the same disease. We think they have the same disease, but the molecular base of the disease is different. So despite the fact that the woman may have breast cancer, the breast cancer of woman A is different than the breast cancer of women B, C, D, and E. And second, they themselves are different. We are very different from one another. Actually, we carry very little in common. We have two legs, and two eyes, and some genes are in common, but if you think about it, even blood we cannot transfuse to one another. We need to check the blood type. We can have A, or B, or AB, or O, and we can have plus and minus. Not to talk about kidney transplantation. That we have to search one in 10 million in order to find somebody that will match me. It will be my identical twin, but that's a miracle to have an identical twin, that's awfully rare. But think about how different we are in the HLA system, in the immune system, in our composition, we are very different. Not talking about eye colour, hair, intelligence, weight, everything, we are very different from one another. Therefore, why should we assume a priore that the same disease, that we shall behave the same as far as disease course is concerned. Well, it was convenient to classify diseases according to the disease, and to say, Or, "The men have prostate cancer, or peptic ulcer, or Alzheimer, or heart attack." It was very convenient because that's all what we knew. But now we know that it was an awfully naive, an over-simplistic picture. And now the picture is changing. Why? Because we developed tools that enable us to look much deeper into the disease, and the tools are mostly... It started with the genome, with the unravelling of the human genome in 2000 when it was published first. But now it goes further and further, because above the genome there is the transcriptome, and the microRNA, and above them there are the proteins, and above the proteins there are the post-translational modifications of the proteins. Let it be acetylation, amidation, oxidation, ubiquitination, phosphorylation, whatever it takes. And above it there are the metabolites, the metabolon. So basically we are approaching now a time, the genome is the easy part, the semitropics, we can now, from the first genome that cost almost a billion dollar and took seven years, we are now approaching a time that we can do a genome within half an hour, or an hour, at the price of a few hundred dollars. But the genome is not the secret, because we need to go above the genome in order to understand what's going on. But the technologies are developing in parallel, we are already well deep into proteomic analysis, post-translational modifications, and so on. We are still far away from getting a picture, but the ideal picture at the end will be that we shall have a profile of the patient, of the individual patient, therefore we call it personalized medicine. And for this personalized medicine, also the other P's are derived. It's going to be preventive, because if we know that somebody has some mutation, we may be able to do something about it, either to direct behaviour, or to start the prophylactic treatment, or to do something, or maybe to edit the gene, using CRISPR/Cas technology. So it's going to preventive. Together with preventive it's going to be also predictive, because we are able to predict. And the last one, and the more, I don't want to say the more important, but equally important, is the participatory one. I'm going to talk about it, I just want to tell you what is participatory. Participatory means that the patient is going to play a major role in the decision making process relating to his or her fate. Gone are the days, I remember studying medicine in the 60's and 70's, medicine was an awfully patronizing profession. I remember the statement, or the imaginary statement, "Trust me, I am your doctor." Gone are those days. The patients are much more educated. The internet is there, and the decisions related, and I'm going to show you an example to their fate, are going to be much more complicated than there used to be. So what happens is the following: Without going into too many details, the mirror of medicine is going to flip by 180 degrees from the disease to the disease within the context of individual patient. First we are going to profile the patient. And then, only we are going to tailor the treatment. I'm going to show you briefly one example, and that's breast cancer. You can see a biopsy of a breast cancer, I'm not going to go into details, at the very lower left corner. You can see two different women, let's say that the left one is woman A, the right one is woman B. You can see that the right one can be stained, immunohistochemically with something, with an antibody. I can tell you to the oestrogen receptor, while the left one cannot. Well, there is nothing staining, we did stain, but we don't see anything. So the right one has a mutated oestrogen receptor and the left one does not. You see already two women, the same phenotype, the same breast cancer, completely different mechanism. One has something that we still don't know, the one on the left side. The one on the right side has something that we could diagnose, it's a mutation of the oestrogen receptor. And we can treat her with Tamoxifen, which is anti-mutated oestrogen receptor. And the same can go to progesterone receptor, and the same can go to another receptor, the EGF receptor, that we can treat with a receptin, which is an antibody, that will lead to aggregation, to clustering of the mutated receptor on the cell surface, sending it to ubiquitination and degradation. So already, you see, just in one sentence I already engulfed four different women. A woman with a mutation in the oestrogen receptor, in the EGF receptor, in the progesterone receptor, and then, the worst, the triple-negative. The one that doesn't have any of the three, and apparently is the most aggressive. And the prediction is that there will be 40 different types of breast cancer. And we should be able to profile them by first sectioning, so-called, or analysing the profile of the patient. So that's what personalized medicine is all about. It's over-simplified, but nevertheless. Let me just now go to the very last point. And the very last point are the bioethical implications. We have had many blocks on the roads to complete the map, and so on and so forth, I don't want to go into it because of time limits. Let me just go to the very last point, and that's the bioethical problems of availability of genetic information. I just want to highlight two points by giving you two different examples. One example is me, myself. It's not real, luckily it's not real, but nevertheless. I am a person of 67 years old, and I walk into the emergency room. I myself, when I was an active physician, this was what I typically saw in the emergency room in one afternoon. And so 20 men at my age of 55 to 75 walking into the ER, the emergency room, with a complaint of chest pain. Chest pain, the one thing that you have to do as a physician is rule out myocardial infarction, no heart attack. Because if there is heart attack, you hospitalize the patient in the intensive care unit. If it's nothing, let's say a muscle ache or something, you just alleviate the pain and send him back to his home. So this was what we call the differential diagnosis, we had to differentiate the diagnosis. Now, you can imagine that they are now taking a blood sample from me, and do also profiling, and they say, "Aaron, cool down. You don't have a myocardial infarction. But you do have a mutation in the gene that in 10 years will cause you Alzheimer's." Wow, Alzheimer's in 10 years? I didn't come to the emergency room to ask for Alzheimer's, I had a chest pain. But nevertheless, it came up in the examination. It came up in the examination, you know? So first question is, "To whom the information belongs?" It clearly doesn't belong to the doctor, it belongs to me, because it's mine. But then what I'm going to do with it? Now think about the implications. I'm not going to solve it, we can discuss it in the afternoon in one of our other meetings, but think about the implications. Okay, let's say that I absorb it... that in 10 years... And by the way, it's not imaginary, there is a gene which is called APOE4. It's an apolipoprotein gene that carries high susceptibility to Alzheimer's disease. It's not all imaginary, and we are going to look at another one in a minute. What do I do with the information? I come home and tell my wife, I tell my son, or my daughter? What are they going to do? Are they going to test themselves also for the gene? What do I do about my employer? Do I tell him that in 10 years he's going to have somebody that doesn't know even the way to the working place? And what do I tell to my insurance company? Are they going to increase my policy, and so on and so forth. So it's just food for thinking. Let me bring you another one, which is maybe more, will increase your appetite. This lady, Angelina Jolie. She came in two steps for us. One was two years ago, another one was few months ago. And she said that she is carrying a gene that carries a high susceptibility for both breast cancer and ovarian cancer. The gene is called BRCA I, breast cancer number one. And she decided to remove both her breasts and her ovaries. It was a very courageous declaration to encourage other women to be tested. She did it because her mother died of breast cancer, and her aunt died of ovarian cancer, and she suspected that there is something going on in the family. It is known that the BRCA I, which is, by the way, a ubiquitin ligase, I don't want to go into it, it carries a mutation, and BRCA I carries a high susceptibility for those two malignancies. And she decided to take this preventive step, pre-emptive step, and to remove a ticking bomb from her body, and to reduce the chances of being dead. So this was very courageous, except for another implication that we tend not to think of, or we do think of, and that's her daughters. Well I'm not going to her family, I'm going to the family of anyone of this woman carrier. What, again, to do with the daughters? For yourself you can take a decision, especially if you have an established family. But what you are doing with a 16 years old daughter, 21, 25, young mother, just engaged, student in the college, and so on and so forth? All right, I just want to say, to give a concluding statement, I didn't come here to frighten you. We are walking into an extremely exciting year of medicine. And there will be a solution to it. But think about the history of medicine. It's always that the discovery preceded the treatment and the cure. We are at the discovery stage. We shall manage it by CRISPR Cas, by gene editing, by all kinds of things, but we first need to identify the problem, find a way to diagnose it, and then go and treat it. This has always been, historically, the traditional way of medicine, except that now the pathway has been broadened dramatically, because by looking at the whole genome, I can look for mutations of cancer, mutations of Alzheimer's, mutations of heart diseases, mutations of kidney diseases. Until now we looked at one disease. We thought, "Okay, if my uncle had a kidney disease, and my father has a kidney disease, and my grandfather had a kidney disease, maybe I am carrying the gene." So it was like one disease. Now, the whole thing is coming like a little bit in a stormy way, but nevertheless, the hope is great that we are going to solve it. Thank you very much.

Aaron Ciechanover (2015)

The Revolution of Personalized Medicine: Are We Going to Cure all Diseases and at What Price?

Aaron Ciechanover (2015)

The Revolution of Personalized Medicine: Are We Going to Cure all Diseases and at What Price?

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 is different in different patients, 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 also accompanied 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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