 Well, thank you very much, Martin. Thank you, Karun. Last year I communicated with this group by video I didn't have the opportunity to come for personal reasons and so as some of you may know Karun is not a man to be trifled with and he said you promised to come we'd love the video But next time you have to come yourself. So here I am Karun I really wanted to do this because I think that these initiatives are really very critical And what I'd like to do in my early comments and then what I'd like to have is really a give-and-take rather than just a one One-way lecture is to discuss what I think are the fundamental issues that we're facing and I'll come at it not just from the R&D standpoint or the scientific standpoint or what I have been You know, I've been an academic and then in government and now in industry I really like to come at it from the public health and What is really happening in all of these areas worldwide and discuss it in relationship to the US India Relationship, which is really at this point a global India relationship to the extent that most of what is happening today Can no longer be limited to a geography Why is that if you really think as a scientist you realize that we've made Extraordinary progress in understanding basic biology We have actually be we've been humbled by the complexity that we have discovered in the 70s The concept of a magic bullet for cancer was predominant and we funded the war on cancer and many of you remember that and the complexity that we have uncovered through the works of genomics and proteomics and the many other Scientific endeavors that were overtaken has led us to understand That biological systems that are much more complex than what we thought they were on the other on the other hand we've also started to understand populations and populations of patients at different levels of complexity and From the genome studies from the ability to see variations across human genomes variations across regions Variations even within the same pathology within the same patient how many types of cancer do we have today? And so the second axis of what we are facing as a community to overcome the scientific challenge is Under one hand the complexity of human biology on the other hand the heterogeneity of human populations And how do you tackle that is in my view the central core issue of all of the organizations? We are dealing with that that we need to overcome Many people say well the loss of productivity in R&D is due to organizational issues too big a company companies are too big and Regulation regulation is more complicated and those are true factors But at the end of the day what I think is true is that we have we're hitting a scientific barrier and We have to find a way to overcome that barrier with a different model a different way of approaching these issues I Was at a meeting actually at bio and The bio organizes a yearly meeting of annual encounter if you will of the capital banks and venture funds and the CEOs and This was in New York. I was invited It was the NIH director and I asked the audience at that time and say how many of you and I'll ask you Think we know 80% of what we need to know to be really effective in R&D No one raised their hands, and then I said 50% no one raised their hands and I said 25% There was a bold Guy out there raised his hand and I said 15 a few more 10 well 10 Everybody so we know 10% of what we need to know and so I turned to the bankers, and I said how can you fund people? Who just admitted in? Front of you that they know no more than 10% of what they need to know I mean I you and put your money on somebody like that We would you and they did and the reason they did is fundamental and that is that from the public health standpoint If you look at the challenges of today, worldwide Every government is faced with a crisis whether it be developed governments like the US where 18% of GDP is being used for health care eating away Every other prospects of investing in education in infrastructure in more research I mean today if you look at the problems in Europe the same issue occurs but if you think it's a problem of developed economies who have Burly invested in health care. You're wrong. I was talking with minister Jane yesterday same thing in India Even though India spends 1% or one and a half percent today. The growth rate is Astronomical is going to double in the few years much faster than economic growth very very difficult to manage At the same time as we've seen an epidemiological transition So these is what I call the rocks of our issues We are facing a perfect storm of events that are very hard to for us to manage as a single institution a single country a single no one has the ability to truly encompass this given the fact that Populations today people today expect health care to be a human right They don't think health care is a privilege like they used to in the 30s and 40s and 50s You know people said well tough luck. You don't have the money to pay for a doctor or pay for medicine in the 60s things changed With the Medicare system in the US with the insurance schemes in Europe It became more of a human right Not a privilege and so we're facing tensions from the science standpoint with this sort of block Which I call the translational block Made up of this complexity and this heterogeneity whereby one size fits all is no longer possible Then we have a societal expectation Barrier which is you can no longer just expect to have you being welcomed For any drug you come up with or any new therapy because we can't afford it and it's actually bankrupting Societies and then the third one is that we're dealing with a landscape of disease That is different than what it was 30 40 years ago 30 40 years ago acute disease was the core issue today 80% of spending is on chronic diseases and it doesn't spare Emerging economies is the same thing. In fact, they have a double issue They still have the diseases of you know poor infrastructure and the diseases of the modern world all at the same time with Populations there are six seven times what they used to be 50 years ago And so we have it we are the core of this and this is where the US in the Chamber of Commerce Really comes in why because if you believe what I said It is going to be very important from the scientific standpoint to recognize one thing We have made great progress in understanding biology, but we have not made great progress in understanding Disease biology and even less so in what I call the emerging disease challenges of today It would be Alzheimer's disease neurodegeneration Cancer what you name it. We don't really know the fundamental causes second that means that we will have to get much closer to human pathology and pathogenesis in disease populations Which means a completely different model of research and innovation which is no longer the linear model We have some bench experiments And then we go to the bedside and then the bedside to a population population to society I mean patient groups to society that model is over and we cannot Therefore use an R&D model that is closed in it has to be open and it has to be open in a way That is scientifically rigorous to have an understanding as early as possible of the human population Which is heterogeneous at the same time the new tools are here I mean genomics is extraordinarily powerful the cost of genome sequencing has come down We can certainly look at different pathways in tumors today with very small samples We're looking at single cell sequencing single cell proteomics the explosion of knowledge should really pay off But at the end of the day we're in the race in the race between this dragon of health care costs Which is really bankrupting? Governments and being scary on the population who says I may not have the Science and innovation and technologies that will preserve me from having Alzheimer's disease at age 70 or diabetes with Comorbidities remember it's a pandemic and on and on so as a community We really have to come together and I was discussing yesterday number one Whatever happens you need a level playing field and a transparent approach to these issues Number two we need much closer partnerships in what I call the pre-competitive space It is not possible even for NIH. I used to say Even NIH does not have with 30 billion dollars of research does not have the skill set or access or understanding of all their needs that needs to be understood in what we do therefore at the end of the day the pre-competitive space needs to be enriched access to what I call translational capabilities or a wider group Worldwide so that we can do what we call you know Bill chain calls it big data analysis so that we can in fact extract knowledge directly from The species were here to treat humans not mice in the lab So I'm being facetious. We need obviously very good basic research, but it's not sufficient today no research project can succeed with a comprehensive Multidisciplinary approach that comes from different fields of science will be regulatory or population science or basic biology or biochemistry They need to come together and you know I learned one thing The strength and power of a multidisciplinary team is not determined by its best members But it's determined by its weakest link So we need to work on finding what the weakest link in and that's what we at Sanofi Say we need to reinvent R&D. We need to have it based on very strong You know rigorous principles of translational medicine as we know it and people we can discuss what that is Based on open innovation in a multidisciplinary environment where you can access in a network basis to the best people in the world The best people anywhere to come and participate It also requires a really a public private partnership approach There is no way that we will understand disease heterogeneity and reclassify these diseases Without participation by patients by academic institutions by scientists by government with proper regulations That are based on trust and transparency So that's a pre-competitive space that we need to build worldwide Last but not least is the sense that you need to build on your strength and you need to really understand what those strengths are And in the case of US India, I went to India several times and had quite a bit of interactions there when their last October It's really interesting. I can tell you what the one single word that I remember from my trip which I learned there And I learned it in Bangalore from a this was the biological science institute that is being built there and somebody was telling me about The the filtration of water. There's a system that has been developed there That allows you basically on-site filtration at very low cost And I said, well, that's interesting. You said it's this in in in the in the world We need to come up with the and promote the concept of frugal innovation And you know, it's very true frugal innovation can be applied to many systems And one of the most impressive one was actually the innovation. I saw there in healthcare delivery and There are good reasons for that. I mean the cost of labor is completely different but still when you went to the hospitals were and I'm Dr. Shetty The surgeon who created this hospital created a system where they can basically perform cardiac surgery On a huge number of patients at a tenth of the cost that would be applied in the US Systems implementations what I call operational research. That's an area where I find India to be extremely Creative and extremely positive, you know, extremely able to in fact teach the rest of the world how not to do what we did Which was to build huge infrastructures for acute diseases, which are no longer the problems of today The use of mHealth the use of eHealth. There's a university that has four million students with electronic health electronic education basically so I think in in in the car in the concept of healthcare innovation and The area of healthcare innovation. I see that as being strong the second area is innovation We work clearly with emerging companies and we have three projects already active with excellent collaborations Last but not least is that you know India has a great combination of engineering talent scientific talent As I said in biological sciences. It's really rising and it is that multidisciplinary that really needs to be made use of at To the maximum extent possible So I said that I would not give a big speech, but it's already a big speech So I'll stop right here and I'd love to take give and take and questions and comments if allowed Martin Leah says inspiring speech. Thanks. My question is with open innovation How do you distinguish between? Find looking at diseases and trying to understand say how to make that disease clinically feasible versus identifying new targets and ways to To to treat the disease which becomes more of a proprietary issue Right, so I think it's a central question fundamentally, I think understanding disease pathogenesis is is frankly a common good, right and it's done Clearly it has to be done with new approaches new methods and sometimes what you find is what I tell my Academic colleagues when I was a Hopkins. I had the patience. I didn't have the tools The industry had the tools, but not the patience and so we have to find different ways of understanding that but frankly that the the world is going to To pick the target should be your choice and to develop the appropriate modality To it to address the target is your choice now clearly We are not able to address all the targets. We know we are not able to stratify the targets We think are important and we have no real quick way of demonstrating the validity of a target So target validation is important. That's what we have the consortium with, you know NIH Francis Collins and we have we're working and collaborating there I think it's going to be you know something that we need to work on but I still believe innovation and Modalities, I mean are you going to use RNAs DNA, you know Natural products, that's your innovation. That's something no one else can do and really with the consolidation of the industry worldwide Fewer and fewer entities are able to do that globally And that to me means that we absolutely have to use a not a Paramidal system of innovation but a network system of innovation just like other industries have done I mean you look at my iPhone. It's 95% network. It's not built by Apple. Yes You talk about the population different communities and there is a difference depending on their ethnicity and Geographic situation their whole genome is different from one area to different. How do you see the collaboration of? Industry and academia they are in such situation Right, so it's the issue of heterogeneity and variation now I make it an issue because it's really relevant in the disease Context but really frankly when you study it the variation is not as large as what we thought In fact when you look at the genomic evolution It's clear that all of the human population outside of Africa has come out of 10,000 individuals And so it's actually not as much variation as we think but there are really Individual variations in specific enzyme systems specific categories specific, you know founder effects I know it was I'm not a geneticist, but Clearly we need to study that better and understand it because naturally you'll say well I'm different in China than I am in India and I'm in Europe But I think we need to have the science for that so in diabetes for example, we do know that Patients in China and Japan get diabetes sooner and at lower BMIs than the Caucasians We know that in America when we see the differences between South Americans and North Americans in terms of diabetes acceptability We're still in the process of knowing this but that I think requires an international effort by nature by definition I mean you can't really do it unless you have a complete collaborations and cooperation around around the world on this And it's happening. I mean I'm very optimistic actually that it's you know Happening with the collaborations within the research consortia that we have we have the thousand genome project Which is a worldwide project at NIH, but also collaborating with everybody You just heard the announcement of the Beijing Beijing genome Institute the NIH Sanger to look at those So it's going to take a few years, but I think it's it shouldn't be exaggerated because I think people a lot of times think You know we're so different. We're not that different outside You know from one region of the world to another but there are significant difference. I mean there and you know the issue of alcohol Metabolism for example is a very well-known one which was discovered several many years ago Where there is an enzyme deficiency in the Asian population that clearly needs to be taken into account when you do this But I think that mapping needs to occur and what is occurring? Hi, good morning. Yeah, so I had a question relative to the R&D investments by pharmaceutical and biotech companies in India Just recently I was reading an article that over the last couple of years looks like there has been reduction in the investment funds by the large pharmaceutical companies in India and And I'm wondering that is there a correlation Between that and the last couple of years of sort of a slow economy in India. Just wanted to get your perspective on that So I think there are two two responses to this one is a macro global phenomenon And then one may be a more regional one the at the macro level what you have isn't is is essentially the patent cliff Which really eliminates 250 billion dollars of revenues worldwide Which you have to take into account. So what I've learned and I you know I'd love to go from one world to another and learn something. I've learned that when you look at your You know efficiency of your operation you realize that you can't not spend Infinitely infinite amounts of R&D money while at the same time your sales are expending. So there's been a contraction I would say worldwide of spend on R&D and you can hear it I mean you look at the news closing that center closing this center. So that's one cause and if you look at the numbers I don't know what they are, but I would say 20 25 percent. Maybe Mari Can tell us my Maki knows very well this global trend of reducing R&D expenses to match the The revenues which are you know every country in the world right now is seeing a decrease in total bill for drugs because a Generification of drugs us minus 3% so it's it's really happening in that way The second trend is this the trend of going away from the model of what I call corporate R&D Empires and what I mean by that is if you looked at the 60s and 70s every corporation in the world had their What I've called their prisoner R&D corporate Structures, so you had IBM with the IBM research center and Xerox park and so on people have realized that that's a way to Sure way to kill innovation Bell labs and so on so they've gone away from that now today in every industry except pharma Except pharma which has had the luxury of being able to sustain these you know completely Inward-oriented research systems, so you have a de-investment then because of the changing of what I said you go to open innovation So investment is made more into a flexible way, and you reduce a lot of infrastructure As far as India is concerned. I think that's part of the global phenomenon and some Perhaps some issues we talked with the minister about you know in in in clinical research We we are we have to tackle the issues of liability adverse events and so on In early research, we really have to tackle the issues of intellectual property And make sure that the partnerships that we have are protected in terms of what the investments are So it's complex, but by and large there's been a Reduction of R&D expenses in the industry globally, and you're seeing that everywhere Following up on your theme of using the Xerox park analogy Is it part of the issue at pharma that the therapeutic area categories themselves are still too big rather than having the Infrastructure of an oncology franchise You know a lot of the successes are coming from biotech companies innovations that have a subset of that So is in fact that's that the next step of Efficiency you know I'm not from the industry. I came out of left field So I'm not the best person to talk to I'm new to this and and I came out of academia and government And I really had no idea about how the industry worked. I did externally But once you get in you realize that you know, it's like everything else. I had total confidence that the problem was simple like Everybody has when they tackle a new problem till they get the details and So so what I think you need to separate the issue of R from the issue of D So when you look at the issue of R of you know innovation breakthroughs new methodologies new technologies and so on If you are a big organization that has an R and a D you have to feed both things And if you are successful in R in one period of your history then you start funding your D Which by definition forces you into a cycle which defunds are where is our occurring it occurs outside Why is that is that bad? No, I think it's good It's what happened after the Baidol Act in the US and many other like Legislations, so I think what you see is that early creative activities are best distributed in where they where it occurs I mean frankly if you're locked in into a concentration camp called a corporate R&D in the middle of Nowhere you will be productive for five or eight years and ten and then you have to support D You have to fund the project. You're successful now, so it's it's not a phenomenon. That's inherent to being small or large It's inherent to the cycle of R and D in my opinion I'm not the expert, but that's my feeling and I think you need to break that cycle because frankly Small size or large size is not the other problem. Actually if you look at data Molecules coming out of biotech are no more likely actually less likely to be successful than molecules coming out of Corporate research in the current sense, so it's not that is not the answer I think but I think focusing is another topic that people come about and say, oh, why don't you just do oncology? the problem with that that I see is that oncology research is evolving it does appeal it does track to immunology does appeal one and If you have orthodoxy you are killed you're dead because no new ideas will come from the transverse cross-fertilization, so the question to me is and at the deeper level if Indeed the structure the molecular structure of the pathways that lead to a disease process are modular enough That they don't appeal to you know cross regulation nervous system immune system and so on but then you're right But I don't think that nature is like that I think nature is cross-interactive the immune system response the the nervous system response the vascular system response So I think you should be in my view Driven by by the ability to cross-fertilize Distribute the research to where is happening work with the innovators, but D is different D is discipline D is performance D is Absolutely, what makes us trusted by regulators that you have to do this and and you have to Manufacture in a way that you're confident that you are really producing something for the patients that is trusted drug discovery pipeline is drying up Most of the diseases are grouped as chronic diseases now There is a serious concern about adverse drug reactions today's in today's world about chemical pharmaceutical drugs, which we have I'm sorry. I couldn't hear what you're too close to the Resonance, yeah, okay. Okay. I said the drug discovery pipeline is drying up all of us. No, it Most of the diseases are grouped as chronic diseases Adverse drug reactions of pharmaceutical drugs is a serious concern all of us are aware of it So my question isn't it a time to rethink the way we are going the direction we are to take Isn't it time to have a more holistic thinking on health care and drug development? Why can't we think of going back to nature? Maybe focus on more on botanicals like India and China have India has a strong base of Ayurvedic medicines China TCM is there for thousands of years. We have been taking care of health of people over there So isn't it time for the you know pharma industry to really focus on natural products more and maybe specifically on botanicals, please That's a tough question. It's a good question I think people treat themselves the way they see, you know, we're human beings and human beings have a certain relationship to their expectations and beliefs and you know traditional medicine has been here for years and Centuries and thousands of years it benefits from an evolutionary selection process Just like natural products have been naturally selected by evolution. So I think you need to look at that I don't think you should discourage it. I don't think you should is the end the sole solution I don't think we should close our labs and go to translation to traditional medicine So we should learn from each other. Artemisthen is a good example Venkristin is a good example I mean, there's no question that co-evolving biological systems are going to learn from each other and you need to study that We did a study and with the University of Hong Kong in China You know in China you have a component of traditional Chinese medicine, which is ubiquitous and you see it everywhere So you ask the typical question is the PKPD is same from one to the other and we found that no In fact, if you get one from the northern region, it's actually very different than one from the other region And then we did genomics of the particular Component and we found that in fact only in a region that came only in one particular region in a particular environment with the right genome did you find the effect So we can help with these methods and integrating these methods to improve in fact Chinese or traditional Ayurvedic medicine, but it's not the only solution I Funded a company with a with a venture fund here in Boston to Ignite the potential of natural products Why because we had a genomic technique that allowed us to read the DNA of these natural organisms in a way that would be more predictive, but I don't think the regulator it has The ability to say well just concoct this and milling and I'm going to regulate that very easily In the US it's a herbal is excluded from the regulators for reasons that are simple You cannot actually guarantee lot-to-lot reproducibility nor genomic identity nor PKPD Thanks, so as long as we haven't gotten there. It's very difficult for me to see how you would improve on that on what we know today It's a complex answer, but it's a great question Thank you very much Really really elegant presentation. I'm really enjoying this discussion I have a question which is really knowledge pertains to India But even to the United States setting and what I call the multiple myeloma problem So just in two a two year two thousand, you know, we didn't have any drugs that they cost it about thousand dollar or so Then came Valkade and the price went up and now the couple of more drugs have been approved And our patients are living four years longer And they're given chronically right and that's just one example in oncology and I know Raju is Sharing a panel discussion later on, but I want to take get your take on that So how do you reconcile with their reality not only for this country, but getting I mean India? 250,000 dollar for a drug it just Beyond the ream of just the very top Maybe 15% even How do we reconcile that with the other reality which is the tough study which is showing to bring a drug an oncology drug at least to a market it takes 1.2 to 2 billion dollars because the success that failure rates are so high So unless we spend 1.2 to 2 billion dollars, we cannot come up with a drug And if we come up with a drug we need to recuperate that cost would cost 250,000 even half a million dollar by the time for orphan diseases So How do we how do we do this for not only India, but even here? And the second related question is with the genomics we are finding out that there almost every disease is becoming an orphan disease 5% of lung cancer have certain mutation 1% of this cancer So they're all turning into orphan diseases and therefore the drug costs are going to be a lot more similar to the Genzyme model, the Sanofi model now so This is a very large question, and I know Raju and others will be discussing this, but Since you've been an industry in academia and government, I wanted to take get your take on that It's a it's a very important question. We discussed it this morning actually It's called stacking, you know because you have multiple drugs which are designed as if it was one drug one disease one patient Today we know that cancer is not one cause. It's multiple causes acting at once And so combination therapies are going to be very important actually if you buy the argument that I gave that one biology is complex two is heterogeneous and two is three is cross talking between immunology and and and you know Epithelial development, whatever you talk I mean if you combine these three you realize that there isn't the disease that you're going to be able to treat with one drug And so at the end of the day, you're going to have this mechanics. I don't have the answer So let me say it's an important question I don't have the answer But I think there may be ways to think about it in the sense that yeah, well this orphan disease idea Frankly if indeed we have common pathways of disease, let's say, you know Driver mutations in cancer. Well, we maybe do a study and find that it is really relevant in breast cancer But then you do a genomic expression study and you find that is the dominant driver mutation in 10 other cancers Well, the regulators will have to sort of help us and say, okay how do we use this compound in Renal cancer or in lung cancer and this is happening clinically so you have diagnostics companies That are trying to do trials of the basis of what I call disease characterization panels and this is something that you know Martin, you know We've been talking about is how R&D has trying to say the advances in diagnostics platforms Platforms not one test at the time to better characterize disease processes will actually help us and potentially create not the 1% 1% 1% 1% but it could be 1% of breast cancers 1% of lung cancers 1% and at the end of the day it makes a Tunnable economic situation if I may finish The so therefore at the end of the day if you analyze it all the way to its end points The perfect state 10,000 years from now Is when pharmacopia Is a mirror image of disease biology I? Don't think we know what that is but at the end of the day that's where we have to evolve and whether or not it's a you know a Epigenetic control of some kind that is common to many diseases or a driver mutation or something. I don't know but frankly stacking of costs is another issue which is socioeconomic and I think we have to come up with a Global understanding of what is the value of a medicine we cannot have a Human rights approach to health care without a value to it and the problem right now is that there is a huge Change I was in the UK last week and I talked to the folks at You know we do nice and do the studies and they say oh, it's a quality. It's a quality adjusted life here and in in the UK it's the average cost of I mean average per capital income $40,000 or whatever it is and I said you know I mean it sounds good But I don't think a quality of a ten-year-old is worth the quality of a 90-year-old and You have no correction for that So how am I going to be motivated and how you're going to value the quality of ten-year-old a 20-year-old a 30-year-old in the US you know with the advances in Cardiovascular care we reduce mortality and morbidity of cardiovascular coronary disease by 70% and stroke 70% Are you going to value the quality of that as? $40,000 no in many in many instances we've created economic value Which has been evaluated at 2.5 trillion dollars why because instead of dying at 40 This population is dying now much later and is having Alzheimer's disease But has been productive for the 25 years that they were stayed alive. So is it really a Good approach a smart approach to say we have one measure. It's applied systematically and so on now on the other hand I would agree that no measures is worse than a bad measure But I think a bad measure that can be improved over time is going to be necessary to address that problem Elias, I wanted you to sort of comment further on the lesson that you learned in India last fall You talked about frugal innovation, right? We Understand that if one is challenged that is to disrupt what we're doing We need to ask ourselves. How do we get from a therapy? That is $10 a hundred dollars a day to something that is a dollar a day or a diagnostic that is not Not not ten dollars, but a dollar or even ten cents Could you just comment further on how you view this now if you come back and how India might play a role in Helping us disrupt what we do because the only way to get to that level of Efficiency or frugality is to change what we do. Yeah Yeah, it relates to the two two categories one is what I call operational research impact or implementation research I mean they're doing things that no other Country is doing, you know when you look at some of the health care systems and the utilization of technology This example in Bangalore is remarkable. There's another one. I saw for eye disease. It's almost like a Outpatient driven fast turnaround systematic use of the best resource there which is Labor Cost that is low so it's frugal in the sense that that is applicable to India But they've explored they're exporting this they they built a hospital model Which costs you ten million dollars for cardiovascular? Interventions and they're exporting it to to one of the Caribbean countries so that's the kind of things where it's operational research is sort of Getting rid of what we know is Badly designed in our system so you get through an invasion by Excluding the or or engineering out all of the non-value added steps of the system And that's one thing that you can do the second is what you said about okay How do I get a one dollar something rather than a hundred dollar system? Most of the cost is not really related to to the compound and interferes with the patient when I was at Hopkins I studied that and I said why are our costs going so high in the US is the opposite situation Technology in in innovation is actually a small component of the cost the larger component of the cost is health counts personnel people and if you look When you looked at the files in the 1980s 70s at Hopkins What was the number of FTEs interacting with the patient you found that it was max three? FTEs it was the doctor the nurse and today it's 19 FTEs because you have the radio radiology the pathology the this and that and the other and these 19 really out of cost 80% of costs in the US is is really a Labor cost issue the one trillion dollar that we expand more than Germany on an equal basis is due to Administrative issues 300 billion dollars of insurance and and trend billings and counter billings protective medicine for and you know from lawyers and so on 60 billion and the rest of it is basically health care Is cost of labor so frugal innovation is going to be different different environments And I think you need to really get there and say yes We will provide maximum value at minimum cost was the risk was the cost benefit And we're not doing that very well as a country as an economy as a cause an industry I don't have a solution to tell you I would do this tomorrow, but look at antibodies I mean the fact is we're looking for methodologies where the yield instead of being one gram per liter is going to be 1215 grams and on and it's happening. It's there at that point you start thinking well Maybe I could find ways of having a bigger volume and so therefore you need price going down, but I don't have a solution Thank you