 Welcome to MOOC course on Introduction to Proteogenomics. In last few lectures you have heard the technologies perspective, how technologies are evolving, in which way various technology platforms from the genomics and proteomics have contributed for the big data sciences. Today we have a clinician who is going to talk in a very different manner the kind of gap which we see from the clinicians perspective, what should be the questions right questions to be asked and the technologist who are generating data set. So, so far we have studied various diseases in context of big OMEX data, but today the speaker Dr. Sachin Jado will talk to us towards the patient based studies and being a researcher he is also providing the links between research and societal requirements. Our next speaker Dr. Sachin Jado, he is the chief of department of hematology, pediatric oncology and bone marrow transplant division at Fortis Hospital in Bangalore. Dr. Jado will provide the perspective of patients and society as they were and observe them closely every day. He will take us to a journey of how concept of cancer originated, what all limitations, clinicians and researchers faced during early times and how close are we now in terms of understanding various diseases. So, I hope today's talk will take you on a very different journey and eliminate you and challenge you with the thought process, how to design a right clinical study and which way OMEX sciences, OMEX technologies could at least try to fill the gap. So, let us welcome Dr. Sachin Jado for his talk on clinical considerations for OMEX first part. Do you even want to listen to a doctor because you are here for something else right? This is would you would you I mean you have to say yes, do you want to listen to a doctor? How many of you would rather be somewhere else just get over with this? I would assume it is a yes. I am assuming I will move on to the next question before the answer comes in. So, no seriously would you even want to listen to a doctor? How many of you are actually graduates and how many of you are in graduate studies? How many are actually in PhD? And how many are on clinical projects? So, I will tell you why I am asking this question because we have a couple of basic science research projects going on and the rule that I have created which is very uncomfortable for PhD students is before they start the project they will work in the ward for a week with us. Just like you would wish that the doctor comes to your lab so that you can have an intelligent conversation. I truly believe that for you to make effective scientific discoveries you need to understand the population which will ultimately benefit. And the first time we did this with the first batch of PhD students they were with us for a week it was a breast cancer project. They were in the OPD, they fell to the lump, they saw the lady crying, they went to the operation theater and then took that sample and for them it was you know then you have a face to that tissue. And then when they went back and they said you know amongst the four women that lady rapidly growing tumor the cells are growing in cell culture very rapidly. And it makes such a big difference because then you come full circle. And that is kind of what I am trying to do today I am a clinician like I said I do not understand what you do although I interact with researchers and try to do something sensible those are my conflicts of interest. And I belong to this department in Bangalore we are five doctors bunch of other clinical guys paraclinical people rest of our oncology colleagues and some administrative colleagues. What do we work for? Why do I do my job? Why are you doing your PhD? What do you think? What do you think? Sorry? First society come on here you are not thinking of society. Why do we do it? Why do it? For your satisfaction? Own satisfaction so let us see what we have here. So yeah you are right. So that is the first thing for personal goals. It really is because if it does not delight you you will not endure the gruel of coming at night and you know all of that not being there for social events etc. So of course usually it is personal goals and it is either I am working today to finish my experiment I have a medium term goal I have to finish my PhD postdoc is that right? I want to avoid conflict with my boss I just want to do this today all of us need to earn a livelihood as well very important some of us work for this reason I do that sometimes because I can comfortably say I am busy and and avoid some marriages right? I do not know if you can do that nobody questions me but then there is this other thing with sometimes we think of this sometimes all of us think you know what we have to do something something that will create an impact every once in a while and quite often when we are in this kind of situation we think because normally it is the usual rigmarole but then all of us think when we are outside our usual job that well we should do something new publish something create an impact and maybe impact lives trust me this is what we are going to focus on today I will essentially take you through a story of where clinical oncology was how much time it has taken us and how we are rapidly moving ahead in understanding what is actually happening to our patients so we look at the impact of your work on the lives of patients and these are patients that we deal with on a daily basis you may not encounter them but trust me it is important I will restrict to the kind of work that we do I do not understand solid tumors I do not understand cardiology we restrict ourselves to blood cancers and bone marrow transplantation for today's discussion so how did this whole concept of cancer originate right how did doctors in the past think that well I have five kinds of patients and this person has something else this person has a fever with lymph nodes this person has lymph nodes with no fever maybe this is something else maybe it is not an infection so how did this originate we can only go back to Egyptian mummies right we do not know anything beyond that these are very well preserved human bodies and tuberculosis have been discovered in Egyptian mummies tumors have been discovered so that is the oldest tissue specimen that we have but the oldest recorded case is about 1500 BC and at that time of course nobody knew it was cancer treatment no concept of treatment patients just got comfort care and died right and that description that we have 1500 the tumor whoever was the physician tried to chop off the tumor you can imagine no anesthesia right because they probably thought it is a lump and it is growing so let us just remove it we do not know what it is then theory started coming up after many more years and rather centuries so about a thousand years later Hippocrates the guy who guides our practice he first started writing a lot of things and he wrote about many many things and amongst that he also said that there is a reason why we fall sick and he felt that we have four fluids in the body and if these fluids are imbalanced then we get one sickness or the other if bile goes up this happens if that goes up that happens etc imbalance between the four fluids well he had his theory he really did not have the opportunity to test his theories right but he had his theory like Freud had his theories right and he thought it was imbalance and this theory of cancer actually went on for 1300 years there are four fluids imbalance in the fluid something happens but there were problems with this all of us know that it is not the quantitative increase or decrease in blood and phlegm etc it is something that is happening within that fluid that actually causes a problem and phlegm and bile they probably do not cause cancer but they are affected by cancer so if somebody has a liver tumor or a cholangio carcinoma then the flow of bile will be affected bile does not cause but you know Hippocrates did what he could do he did some I mean he tried to do biopsies but it was not allowed for religious purposes poor guy couldn't do anything but he had some theories which stood the test of time until somebody else came up with another theory and you know doesn't really work this was you know this was supported through the 17th century again problems I am not going to go into the details of these and then Muller said that no no no no it is not fluid these are cells and the problem is with the cells and you can see it is that late it is that late that people realize that is because of cells right it took so many years so the fluid phase if you can call it that endured for 2200 years until somebody figured out it's not the fluid it's the cells in between the fluids right and then you have this poetry by by Omar Khayyam I don't know if anybody has read Rubaiyat and he wrote long long ago that I am sick and tired of doctors and saints I talked to them they give me theories it's junk I go to meet them and I come out from the same door it's bogus right he was frustrated which was understood because nobody knew it and then more and more theories came up somebody thought chronic irritation which is correct in some patients etc and worker was amazing you know he thought that cancer comes from normal cells and irritation of the cell turns it malignant but he was overconfident his king had a laryngeal ulcer he thought this is benign we don't need to operate the king actually died of metastasis and this was probably one of the first doctors who was you know they actually said that he has committed medical malpractice but that's fine you know he had a theory he tried to follow it and he messed up whatever he was accused of malpractice as time went on people thought it's a cancer it spreads with the parasite but slowly people started showing that cancers metastasis not through the parasites but actually through the fluids in the body this is where the era of clinical expertise starts I mean it has been there from the beginning clinical expertise but until here people said okay there are cells and they spread but nothing much more can be done because you can't biopsy you really can't biopsy because it was not known it was not allowed so all that you could do is see what you can listen to what you can and feel what you can make your diagnosis find out is it a TB is it a cancer what is it is it an abscess what's happening and make your best judgment and treat until people started doing autopsy series they started cutting up dead bodies and what's happening so sequential patients having similar signs and symptoms let's do an autopsy let us look at the lymph node and the spleen under the microscope let us see what is happening still you are not allowed to touch and biopsy and living person so you can only do post humorous work and you can't really diagnose a patient who's standing in front of you until that fellow dies right but then there is recorded that about 30 40 years later biopsies were allowed again anesthesia was not common so you can imagine what happened and then you go ahead 25 odd years Dorothea Reed amazing lady brilliant gets a one year fellowship pathology fellowship in Johns Hopkins in that one year in the lymph node she finds some different cells and says hey this is different this is a different kind of lymphoma and that's a different kind of lymphoma and later on this was called Hodgkin and that was called non-Hodgkin lymphoma right brilliant lady but she was a lady so she was not given faculty position she gave birth to a child had to leave her hospital walk off just imagine how faster our knowledge would have grown had Dorothea Reed been allowed to stay on in Johns Hopkins and do more work on lymphomas it still takes 50 years for somebody to classify lymphomas 50 years and even then Rappaport can only divide lymphomas in three subsets he didn't really understand that there are 50 60 70 different kinds of lymphomas and at that time there was no concept that lymphocytes are T and B people just knew there are white cells lymphocytes that they can be divided was not known and when that was known 20 more years later the first proper classification came which was refined but until this point you can imagine 2001 is when I first passed my MBBS so until I passed my MBBS lymphoma diagnosis was based on how the cells look under the microscope that's it restricted to your sensory perception nothing inside is understood RNA DNA proteins everything that you have been hearing for the last 8 days 6 days 5 days was not known until 2001 the first WHO classification nothing it was only 8 years later that WHO said that you know what you can stay in bit different colors and the cells look different and maybe there are different cells and then divided lymphomas very well until then how is it how much is it spread what is happening it was all actually pretty vague to decide how to treat we had to see what is the age how much has it spread there were no better ways of differentiating different diseases because different diseases need different treatment different patients need different treatment but there was no way we didn't have a gene expression profiling until 2001 there was nothing clinically relevant right it was all very vague the way we would plan patient treatment until 2002 or so the first clinically relevant papers started coming out lot of basic science work had gone in until this paper came out and this was the first time somebody showed in what is apparently one lymphoma diffuse large visa lymphoma by gene expression profiling you can divide it into subtypes you can divide it into subtypes right clinically relevant remember and then WHO adapted this five six years later when they revised their classification etc and of course now 2006 actually early this year 2006 version of WHO classification came out and it's all about mutations it's all about mutations that the the subtypes are based on mutations you can imagine it's no more based on how it looks under the microscope it's based on your clinical genomics correct but even in that we have a problem so we'll come to that because there are multiple patients with a particular mutation who behave differently they may not respond to treatment some may respond beautifully to one cycle somebody may relapse within two months somebody may not relapse for 10 years with the same mutation so we don't really understand truly what is happening and our knowledge is growing so let's see where we have come all of us are aware of this yeah who reported it so somebody working on cancer proteogenomics needs to know this this happened 115 years after Warchov coined the term leukemia again somebody who was not a very high flying clinician sorry researcher discovered that in patients with chronic mylar leukemia one of the chromosome looks smaller than normal and this was again a landmark event because until now it was thought that chromosomes become small as a effect of disease chromosomes are affected by disease and they become small right but when novel and hunger food reported this right they realized that six seven patients of CML had small chromosome so is the disease making it small or the chromosome is chromosomal abnormality is creating the disease so this was the first time a definite gene signature was attributed to a cancer the first time a definite gene signature was attributed to cancer and as banding techniques evolved people realized it was a balanced translocation between chromosome 9 and 22 and this was the onset of the phase of our current understanding of etiology of cancer remember fluid phase parasite etc it's only here okay it's only here at this 1960 and this came as a letter to editor in science very low profile paper it's only at this point that we started understanding oh maybe it's the DNA which causes cancer right and then we move on but does this really help us in practice does it help to understand that yes this cancer is caused by this mutation do you think it helps yeah which disease how does it help okay so you can have a targeted therapy yeah that's that's the new aspirin so everybody's talking of targeted therapy you know everybody believed that we'll find mutations we'll target them and the cancer and and you know malignancy will go away etc etc but you know you're from pharmacology background and that is where genomics has failed us that is where genomics has failed us because cancer is a multigenic disorder it is not a monogenic disorder correct except some conditions one of them is acute bromelocytic leukemia AML acute myelo leukemia has various types the third type of AML is acute bromelocytic leukemia this is the mutation a balanced translocation of 15 17 and as knowledge grew it was understood that this is where the retinoic receptor is retinoic receptor and in Chinese traditional medicine Chinese traditional medicine not allopathy they would use various chemicals and they realized that if you put amongst various things if you put retinoic acid in a cell line then that leukemia cell differentiates into a normal cell it's no more a immature set it can differentiate and then clinical trials were conducted etc etc and we use this drug it's one of the best medicines like you said targeted mutation identified we understand the pathobiology give a chemical the chemical goes attacks it leukemia is practically cured in some patients others need more treatment then of course Philadelphia chromosome novel and hunger for people understood why this causes there is an upregulated tyrosine kinase what is this tyrosine kinase and then people started creating a rational drug design so I hope today you have learned that how researchers individually took almost 200 years to classify a disease like leukemia therefore we need collaborative efforts and a combined universal repository with all the data and information related to the patients for better understanding of disease and its behavior you also learned about the very first doctoral malpractice due to the lack of knowledge and understanding of a given disease which could be avoided if now we could work together looking at various type of information from the clinical perspective as well as molecular and omic data sets so Dr. Sachin Jadhav will continue his lecture and discussion about how now latest technology such as proteogenomics in hematology and BMT has really started impacting the patient care and he will give you some examples to convey his points and give you again a very thought provoking discussion about what best way we can do to bridge the gap between the data scientist as well as the clinicians thank you