 Welcome to our science show. Today we will be discussing the Nobel Prize in what is called Physiology and Medicine and we have with us Professor Satyajit Rat to discuss what does this Nobel Prize mean. It has been given to somebody called Paavo Swante as you probably know by now or Swanto Paavo who is finished. What is he? We will ask Satyajit on this as well as the discoveries that he has made for which he has been given the prize. It is also interesting. This is a solo prize which is rather unusual in today's day and age. Satyajit, first question to you because we thought there were three prizes. One for chemistry, one for physics and one for medicine. Now this is physiology or medicine. So what does this prize really mean and what is it being given the prize for physiology or medicine or both? So you raise an interesting question and the proposition matters because it is not even physiology and medicine in amicable coexistence. It is physiology or medicine as two clearly separate entities and a straightforward interpretation for this is that the prize is intended for something that makes a difference to human health by large. So because The idea of Nobel that it should be for human benefit, the whole Nobel Prize itself. So it is in that sense that basic discoveries that matter at least can be plausibly argued to matter for some contribution to human health are treated as physiological discoveries. The more direct discoveries of medicines and penicillin and so on and so forth are obviously treated as medicine and the tension between fundamental science where mechanisms are worked out and this engineering and medicine field where interventions are worked out is very clear with that proposition of physiology or medicine. It is an interesting issue that you are talking about because in this prize it has also been mentioned that it is work on archaeogenetics identifying Neanderthal or Denisovan genes, archaic friends or relations of ours in human terms, human family terms that it might have contributions to looking how we look at health today. How seriously do you take this or is it a little bit of a stretch to make the connection that you are saying is the basis for giving such a Nobel Prize? So I was in fact going to refer to precisely that but before that if you will permit me there is another a set of the Nobel Prizes in general not just physiology or medicine in particular that I think it's useful for us to think about which is they're supposed to be given for a discovery. They are not intended as a recognition of a lifetime body of work. They are intended for a singularity. So now if we put both of those together that there is an implication for human health and that there is one discovery for which this prize is being given and we put that together with the other unusual features that you've pointed out. One, Swantepabu is a Scandinavian, not an American. Two, he's been given a solo Nobel Prize and if you now read the citation that is on the Nobel Prize's website to pretend to itself and to us that these two artificial constraints set in their context. Number one that it must be for one discovery and number two that it must have some connection to human health are in fact fulfilled by Swantepabu's work when in reality his work transcends both of those what I considered trivial constraints. Narrow boundaries. So shallow boundaries. On that background let me respond to your quick question. So the straightforward answer that is cited on the Nobel Prize committees as in support of this self-justification rationalization is that we as today's human beings who are one species, Homo sapiens or Homo sapiens, sapiens depending on how you which side of a number of arcane boundaries you sit on. Clearly in the past 50-60,000 years or less have interbred significantly with closely related but distinct humanoid lineages namely the Neanderthal and the Denisovan. Now the health connection that has been claimed is, oh look, here are two examples. The Denisovan lineage has provided at least some of us as today's human beings with a version of a gene that allows better comfortable survival at high altitudes. The Tibetan Nepalese etc. argument. The Neanderthal, oh look, many versions of genes related to as it happens my field which is the immune system have come to us from the Neanderthal lineage. Now truth to tell, all that this says to us is, oh, isn't understanding biology and history interesting but the Nobel committee is making this out to be a connection to human health and that relates much more directly to the artificial boundaries of the Nobel Prize rather than anything directly to human health or to the surface. So you know coming back to the science discussions and I think what we see here is that it seems that Swantepabu has made very significant contributions over a period of time to be able to take what would be degraded genetic material found from samples which are very old contaminated by other bacteria and able to recover from this the genetic material of interest and this has two parts to it. One part of course is that how to quote unquote purify the ancient DNA, how to create copies of it so that you can then look at how the material should be analyzed and so on. So that is one is the purification, concentration, recovery of the ancient DNA, other is of course the mathematical part of it checking out the lineage. So if we separate the second part which is not his strength, his strength is really the it seems the first, the that part seems to be his strength. What are the basic things that it did and where would you put it? I know that is going to be difficult for you because these are areas which are so rarified for most of us that we won't understand most of it anyway. Well paradoxically I think that the proper response to your question will be that what Swantepabu has done over a 30 year, 35 year period of systematic, focused, dedicated work is entirely understandable to all of us. Let me take your first question, part of it is the technicality of getting out ancient DNA from semi-fossil bones where all sorts of other DNA from people who have handled the bones, DNA from microbes, DNA from animals in which along with which those bones have lain, all of that needs to be separated. Now one component of that is there is no real way of getting a pure physical DNA sample. You will always have contamination. The really important contamination to avoid is the closest contamination, which is us. So, the really important contamination to avoid is not the bacterial, the microbial and the bear and the tiger and the wolf contamination because those can be separated during the mathematical handling of the sequences. They are so separate. They are clearly separate. What cannot be easily separated is human-like DNA because then you don't know whether purchase of reading come from that original material or from somebody who handled it as a scientist thinking about his next dinner. It's you who is reading it. Is it your contamination or is it the sample? Exactly. So, all of us will understand that what you really want is not some earth-shaking, innovative, disruptive technology. What you want is systematic, obsessive commitment to standard operating protocols that are adhered to rigorously with containment, with spacesuit handling and with what engineers will call QAQC protocols, quality assurance and quality control protocols where every step is tested and monitored for contamination. So, that's what he set up. A lot of that is actually engineering, is containment engineering. So, it's not as if he as a molecular biologist and a biochemist had any particular insights into that. What he had was this fundamental biologist's vision that if we could do that, we would have a data resource of immense significance to a whole range of fields and he committed himself to creating laboratories, protocols, systems, processes and the whole culture of scientific investigation in his institution that would allow clean sequencing from highly contamination prone and confusion prone material. This he did on the one hand. So, in a sense, it's the truly insightful visionary program director because simultaneous he saw the other half which is that when you want to sequence really small amounts of DNA, you need the sequencing technologies and sequencing technologies have three separate components to that. One is his own, which is the actual sequencing technology, the DNA biochemistry, but the other is machines, hardware and the third is the software and the software that both goes into the sequencing and even more the algorithms that in complexity achieve the status of informatics science in analyzing them. And he built seamless connections as the biochemist molecular biologist with the hardware technologies that are being generated for human genome sequencing and the informatics that computer scientists have been developing over decades. So, this is truly a Nobel Prize for a person who held the image of an extraordinary resource with major possibilities for understanding a certain way of being human and worked for 30 years in putting disparate program components together into a whole. And all his colleagues across the world who have worked in this field acknowledge this fundamental contribution and it is in this contribution that it's actually a recognition of a lifetime of dedicated focused yet multidisciplinary extraordinaire work. The leadership as well as the vision so to say and and it's also interesting because when you talk about clean rooms as we know the need for clean rooms also is there for instance in electronics when you manufacture chips. So, the technology is there across a set of disciplines and therefore it's not that it's just been created for the laboratory in which case it might have been much harder and also again similarly for the lineage calculations parsing out the various trees. So, to say all of this again is something which is comes from different fields have application over a variety of other fields as well. So, the technology or the tools to do this analysis also is there. Absolutely. So, let me for people who are listening to us thinking what is the Nobel Prize about? Let me on this background point out what the Nobel Prize is about. Yes, I think the other part which you need to point out or the part that you need to point out what the hell did he get it for? The Denisovans, Neanderthals, you mentioned them, how did you bring this together? But here's the issue. There was slow recognition in the 80s when Pablo began his work that the more and more genetic code we sequence of today's creatures, I'm not saying human beings, creatures, bacteria were being sequenced and disease causing as well as environmental bacteria were being recognized to have relationships with each other that were deeply informative in terms of how they spread, how their lineages evolved, people who are listening to us will recognize that over the past three years of the pandemic, the virus lineages, the virus variants that are emerging, how they become dominant, where they come from, what their relationships are to each other, that we do. You can now imagine that this is true of other viruses, other bacteria and of animals and of plants and of human beings. It's important for us to understand the history of Earth's living systems. What Pablo realized is that what was being done then was sequencing today's creatures, today's organisms, the genetic code of today's organisms and he realized that while that's invaluable, that's today's. It allows us to make guesses and inferences about what might have happened in the past, it does, but those remain guesses and inferences. But he said to himself, being a good Scandinavian, coming from frozen bloody cold cultures where material degrades much more, biological material degrades much more slowly than it does in places like India, particularly Peninsular India where I'm sitting. He thought to himself, what if one could sequence ancient remnants of biological material? Basically, what if one could sequence the genetic code of a frozen mammoth? That was done easily. But then he became aware that if he could do that with fossilized bones that were found in cold enough conditions that some DNA was still available, especially dry, cold conditions, which means temperate and subarctic caves, which is why both the Neanderthal and the Denisovan sequences come from subarctic caves. It would be enough DNA and if only he could fish it out with good technology, with good sequencing and with good informatic analysis, that would not be today's sequences. That would be sequences from 50,000 years ago. That would be sequences from 70,000 years ago and that put together with today's sequences would cast an entirely more granular novel and different light on both human and animal histories. And his greatest successes with the Nobel Prize's preoccupation with humans was with the Neanderthal caves where cousin lineages to humans, mainly the Neanderthal humans and in the Denisovan caves in Russia, where another cousin lineage, the Denisovan lineage, were entirely sequenced. And the thing that became completely evident as a, oh, wow, moment was that our DNA today contains both Neanderthal and Denisovan genetic contributions. And that means, number one, that over long periods of time, we have interbred extensively with Neanderthal and Denisovan lineages. This is not one pair of happy people going out there doing their thing. This is quite extensive contribution of genetic code through cross meetings over a long period of time. And that those genetic contributions of Neanderthal and Denisovan lineages were subject to evolutionary pressure leading to, as the Nobel committee has pointed out, the realization adaptation to high altitude environments was made a little easier by Denisovan versions of certain genes. Adaptation to many infections was made easier for us by Neanderthal versions of certain genes. All of this comes out of Pablo's work on ancient DNA, identification, isolation, sequencing, analysis, and understanding. And that is why the Nobel committee has identified his singular contribution as the field of paleogenomics. Thank you very much for being with us. This is all the time we have today for our discussions on Pablo, Svante, Pablo's Nobel Prize and what does it mean for us and for our knowledge. Thank you very much for watching this leak and do join us for other discussions as well.