University Professor Ferid Murad "Bio Innovation" At Gw Global Forum-Seoul, March 17, 2012

University Professor Ferid Murad "Bio Innovation" At Gw Global Forum-Seoul, March 17, 2012 - Online Custom Essay Writing Service

University Professor Ferid Murad "Bio Innovation" at GW Global Forum-Seoul, March 17, 2012

well thank you I'd like to thank President nap for inviting me to participate in this forum I found it really quite interesting usually I attend scientific readings but this is a little bit differently they kept learning a lot more actually I've been asked to consolidate two lectures that usually take me about an hour each and that's the relationship of academic medical research and Industry how these programs can collaborate and interact together and it can push this all down into 15 minutes. that's really an important difficult task but I'll do my darkness I'm a clinical pharmacologist I had trained to both in medicine in basic science I've had positions all over the country Virginia Stanford Texas northwestern but I've also while I've spent most of my career in academic medicine with primary appointments in the department of medicine and joint appointment that joint appointments in the basic science departments I spent about ten years in industry as a corporate officer and vice president of pharmaceutical research and development and as you heard from steve lerman of helped colleagues co found several biotech companies what i want to do is to tell you about what's happening today in the excitement of biotechnology academic research and how they all need each other to make this technology move forward the biotech industry was born shortly before I went to Stanford in the late 1970s when Stan Cohen in her boyer on a napkin in a restaurant one night decided that they could take genes and express them in bacteria for recombinant technology that was the birth of Genentech and of course the biotech industry just flourished as a result of that for the past 25 or 30 years today we can express all sorts of genes in all sorts of systems not only bacteria but in mammalian cells and even plants and has a great deal of potential the research interest that I've fallen in love with for my entire career has been cell communication cell signaling how do cells talk to each other how does the brain control your kidneys or your gastrointestinal tract or your heart rate these organs release molecules that we call messengers and the first slide is going to show you a list of a typical list of such messengers it's not a complete list by any means but these are molecules that today we call hormones Auto codes paracrine substances growth factors cytokines and the pharmaceutical industry has taken advantage of these molecules from this research information that came largely from academic programs to create products and it's just a partial list and what companies have done is not only take the native compound but modified its structure to prolong its half-life its distribution in the body and even made analogues that block their activity for diseases where you're making too much of these molecules such as some of the cancers or endocrine disorders. this is an example of sort of what I do I take these molecules and I figure out how they regulate the bio chemistry and biology of their target tissue to cause a biological effect and we've looked at lots of biological effects we've looked at smooth muscle relaxation regulation of blood vessels airway smooth muscle GI smooth muscle secretion and excretion and the intestinal tract we're now looking at stem cells and how they differentiate we're looking at cancer cells and how we can prevent them from growing and they're very interesting to sort out all this biochemistry. while I'm a clinical pharmacologist and have done clinical search I really prefer to look at the basic biochemistry of these pathways because I think it's a goldmine of information and by understanding some detail how these molecules communicate with tissues we can take the pathways into sect out molecular targets and discover new novel pathways and new novel drugs and that's what I do. I do clinical research with mostly basic research and often it's always related to some medical disease with the understanding that at some point it could result in an interesting and important medical product the industry to develop drugs in the past often took molecules off the shelf administered them to an animal to look at a biological effect whether it was lowering blood pressure decreasing heart rate some biologic effects and if the animal had in effect in head didn't die or didn't have a toxic event this was a promising molecule that perhaps could be developed into a drug and the pharmaceutical companies would take these compounds make analogue. they had longer half-lives they could be formulated administered in various ways intravenous or oral or whatever and it was a very slow tedious and very costly processed it discovered drugs when Boyer and stand con came along with their recombinant technology this opened the doors now for a entirely different approach for Doug drug discovery which we call rational drug design now we look at the detailed biochemistry in tissues and by identifying the pathways of communication in the biochemical pathways we can take those enzymes in proteins and pull them out and screen them against libraries huge libraries of compounds sometimes these libraries are thousands or even hundreds of thousands of I know one company that screened a million compounds against one of our targets that we were interested in to find a drug that's now in clinical trials for pulmonary hypertension in premature babies. it can be done it's a lot faster however once you get that lead compound you have to come back and modify the chemistry to make sure that the half-life is adequate but it's not going to be toxic it's more potent and the rule of thumb is that the more potent a molecule is the less likely it will be toxic if it's very selective for a luckier target but it takes very organized groups of people with lots of different disciplines to pull this off not only do you need biologists and pharmacologists and physiologists and cell biologists but you need chemists you need toxicologists to put this whole story together to create a product it's very time-consuming it's very expensive that it's a lot faster in my opinion than doing it the old-fashioned way by putting chemicals and animals that took forever often 10 15 20 years to create a product now we can find important potential products within a couple of years but we don't know if they're going to be useful and applicable in human studies once we get to that point but before I get into this I want to point out a couple of concepts that some of you are aware of it some of you are not if you have a product that's going to be a billion dollar a year sales for every month you'll lose time in getting that product on the market you've lost 80 million dollars 80 million dollars paisa for an awful lot of research in medical research there are many drugs that are billion-dollar markets there are some drugs that are 10-15 billion dollar markets like the statins. time saved is very important you want to get there as fast as you can and to do all the appropriate research to get that product out there effective and safe another point is that it's impossible to see toxicity in your preclinical studies in your animal studies or even in your first phase 1 or phase 2 studies in the clinic with these compounds if the incidence of toxicity is less than 1 percent if it's a tenth of a percent of the patients that get toxic injures the liver into the kidneys whatever that means you have to give it to a thousand patients to see one event. sometimes you'll never detect toxicity until it's on the market and been given to a few hundred thousand patients and when you get to the market at that point and you run into a really nasty toxic effect and you have to take it off the market its cost you hundreds of millions of dollars. you know what that to happen. what you want or molecules that are highly selective hopefully with low toxicity and very effective and potent and the targets that you're aiming for toxicity is an impossible thing to predict it's probably the most difficult aspect of pharmaceutical development of drugs you can make them discover them make them more potent do lots of tricks with them but to predict that they're going to be toxic tour not is almost impossible until you do those studies in enough animals or enough fissures I often tell technology companies being developed by some of my colleagues and friends that low tech is faster cheaper and probably more profitable high tech is very high risk but if the biggie if you win then you can hit a huge market with big margins but it's a very high risk it's been estimated that less than one to ten percent of the products that go into the clinic are likely to finish the clinic and be approved for marketing a small percentage I think the odds can be better than that if you're really clever with a good research team you can get there faster with more success rates my success rates that we're really quite high because I really think about research very seriously I feel very comfortable with clinical medicine as well as basic research. our success rates I think we out of 17 products in the clinic only one really failed all the rest is quite well when engineers build bridges and skyscrapers they do all of their homework they think about the project from start to finish the same has to be done in medical research is the target that you're going to aim this acts of molecular some medical disease is it an important one is that a disease that requires some novel therapy where the current therapy is not sufficient or totally doesn't exist you have all the resources to pull it off you have the staff do you have the equipment is the intellectual property safe intellectual property is not just a single patent but if the fence of patents that protect all that technology and all the analogs and all the nuances of that approach. that other companies can't invade your technology and come a log and tweak the clock molecule and make a little bit different and enter your market who are the competitors how far along are they often very difficult to predict because industry doesn't publicize this research it doesn't tell you what it's doing because it will provide clues to the competitors. the only time you see companies publishing data this is often the case in biotechnology companies because they're looking for funds and promotion to attract interest but in the big pharma companies they only publish when they've killed the project or they're about to market it and they want the publicity to influence the medical doctors to use the product. you often don't know what they're doing is the product going to go for an orphan disease in orphans eases when there are less than two hundred thousand patients requiring that product some cancers some genetic disorders if it's an orphan disease drug you give fast track it through the FDA for your clinical studies and you get more rapid approval to get it to the market what's the realistic market projection I've learned from my experience in industry that marketeers are very good at predicting markets once they have gone into the same market again with a related compound they're very precise about what they think it'll sell how many patients will take it etc if it's a novel approach in a novel disease where they don't have experience they're not very good at it frankly and I've had many arguments with the marketing staff and senior management companies say you're wrong and I feel that I know more about the potential market size and profit margins and they do the other question is how far can you take it you have the funds and resources to really take it all the way through to introduce it to the market with startups that's unlikely it's been publicized that the big pharma companies can spend hundreds of millions of dollars I've seen some numbers a billion dollars to develop a product I don't believe that I think the numbers realistically are in the two to three hundred million dollar ranch I can tell you that in biotech companies you can get products on the market after 30 million 50 million a hundred million dollar investments. it is doable but you've got to know that you've got to raise that money at the time you need it to move to the next milestone in your clinical development program and you don't want to raise all that money up front because you dilute yourselves. you raise it as you go and you hope the investors are there the next time you need to go back to the trough and raise another 10 or 20 million dollars now let me turn to my research with nitric oxide that Steve lerman briefly referred to some years ago I was interested in how hormones and drugs regulated smooth muscle motility contraction relaxation and we accidentally discovered that an important drug nitroglycerin which was known to cause smooth muscle relaxation in lower blood pressure it had been used for more than a hundred years to treat angina pectoris but not knowing how precisely it worked we discovered that it was a prodrug or precursor that was converted to nitric oxide in the body that was a novel concept of free radical a gas was now going to be a messenger molecule to mediate the effects of an important drug and we subsequently learned that not only is it mediating the effects of drugs the thought that I called nitro vasodilators that it was also a natural product in the body that regular that mediated the effects of lots of other hormones and messengers in all sorts of tissues we publish these results in 1977 that's the reason I went to Scott Stockholm but it turns out today 34 35 years later there are a hundred and thirty thousand publications in the field of nitric oxide research and in a very popular area in medical research leading to lots and lots of novel drugs and I'll review this for you briefly we know that in blood vessels this is a cartoon of a blood vessel with the endothelial lining on the left hand side of the slide smooth muscle compartment on the right hand side of the slide if you take all of your blood vessels in your body and put them back to back they'll go around the earth two and a half times it's a huge organ the endothelium is a single cell thick like an inner tube in your tire and this is talking to the underlying smooth muscle to regulate the function of the smooth muscle right here in red at the top of the middle and it's nitroglycerin which forms nitric oxide to regulate the production of another messenger molecule cyclic GMP and I'm not going to go through the biochemical cascade I don't want to get into too much detail in you you but the ultimate effect is that it relaxes the smooth muscle by influencing the modification of the actin myosin filaments that's flied together back and forth by D phosphorylating myosin the filaments slide apart and relax when it phosphorylates myosin they come together in classical traction there are drugs such as a skill calling on your transmitter greater keinen histamine that will also cause relaxation but only if the endothelium is intact and that's because the receptors that recognize these molecules are only found on the endothelium and not in the smooth muscle and when that happens the endothelium makes nitric oxide is a messenger that moves across to the smooth muscle to cause relaxation there's a disorder called endothelial dysfunction patients with hypertension diabetes atherosclerosis tobacco use and probably obesity have blood vessels that do not make enough nitric oxide. consequently the blood vessels and those patients are constricted restricting oxygen delivery and nutrients to the tissues down straight we know now that because of this endothelial dysfunction we can now come up with some new approaches to treating these diseases to supplement the therapy with antihypertensives or insulin treatment of diabetes etc this is a partial list out of these hundred and thirty thousand publications that are out there to show you how this whole field of biochemistry and biology can be utilized now to develop a lot of drugs for lots of other diseases we know that nitric oxide is a neurotransmitter in the brain it plays a role in the gastrointestinal tract that regulates the heart it regulates the kidneys it participates in inflammation in the joints it probably plays a role in Parkinson's disease and Alzheimer's a lot it regulates genes it can regulate stem cells and to differentiate into various cell types. it's got lots of promise now for rational drug design and development and there are compounds being developed that will mimic these pathways or block these pathways one of the compounds you are all familiar with it's become a sort of a street drug it's viagra the nerves in the blood vessels of the penis release nitric oxide is a neurotransmitter to cause relaxation of the blood vessels to fill with blood viagra enhances the effect of nitric oxide that's how you it works in a wrecked I'll dysfunction there are other applications in pulmonary hypertension in premature babies their blood vessels in their lungs are very constricted if you let them inhale a little nitric oxide they dilate those blood vessels they stop shutting blood right to left the hypoxic belt blood and the systemic circulation is improved they're no longer blue babies. there are lots of other potential applications in this whole field and that's what I do I really look for new ways to treat important problems we now have some interesting data with cancer we think we can treat some important cancers by manipulating the nitric oxide cyclic GMP pathway thank you very much for your attention you

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