 Okay, I think we could go ahead and start now. So welcome everybody to this special NHGRI Zoom session which was organized to give folks a chance to hear about a very special event and honor involving our former scientific director Dan Kasper. I'm just gonna make some brief remarks, turn over to Dan and then if people have questions you just want them to have a moderated Q&A session. You could put questions in the Q&A and Paul Lewis on board as well. He's gonna moderate that discussion. But one thing I would say is one of the really gratifying experiences I had since bringing Dan Kasper over from NIAMS to NHGRI when he joined us as our scientific director was really just being able to sit back as you all know a baseball fan, just sit back and watch Dan and his group hit home run after home run after home run in terms of publication scientific accomplishments and then watch the accolades come in and the honors come in and it was just so gratifying to watch and it made NHGRI just so proud to see all of those things. Of course we knew what we were getting when we brought Dan over even at that point he was a member of the National Academy of Sciences at that point since then he became a member of the National Academy of Medicine. Most recently I think many of you remember he was federal employee of the year in 2018 but he also has lists of many other honors and honorific lectures and various other accolades bestowed upon him including the Ross Prize in Molecular Medicine in 2019. But then I think completely surprising to Dan was a phone call that he'll probably tell you about that came with an unidentified number that I would have never answered the phone because I was never answered the phone if I can't identify the number but this is an example where it's probably a good idea every once in a while to take a phone call from somebody just assume it's not a telemarketer and indeed it wasn't and he learned that he had been selected for this thing called the Crawford Prize which I wanna point out to you he's gonna tell you much more about it but these prizes are not just all about science they give them out in different thematic areas mathematics, astronomy, polyarthritis and geosciences and I don't think it was something that Dan saw coming and so I think that almost made it all the more pleasurable and it came with an immense amount of pride in part because of the incredible honor and also because it comes with some money that he could actually accept ultimately we would get approval for that and it also came with a very nice trip that he was able to take to Sweden so this is so special and so novel that Dan put a PowerPoint presentation together to be able to summarize it and I know he's been meeting with various groups who are interested in hearing about this including this group assembled here through Zoom and involving NHGRI staff and I should also point out I'm sure Dan will fill in some details this whole thing all happened in the pandemic it kept getting delayed exactly when he was gonna be able to go there that's that the other so it also got drawn out over what seemed like a long period of time but it finally came to fruition and I know it was a very enjoyable and remarkably rewarding trip for Dan and we wanna hear all about it so with that I'm gonna congratulate Dan once again on this incredible honor tell him how proud all of us are and now we just wanna hear about your ticker tape parade through Sweden. Well Eric, thank you so so much for that really kind kind introduction and I have to say that with this sort of thing it is perhaps a recognition of me but it is even more so a recognition of all of the people who work with me in my laboratory and clinical team it's a real endorsement of the environment that we have in the intramural program and particularly in the intramural program of NHGRI the support that I've had over the years has been absolutely wonderful and extraordinary and I have to really start out by just giving a big thank you to you Eric and to all of my colleagues in NHGRI and across the intramural program of the NIH and more broadly too we certainly have a number of collaborators elsewhere. As Eric said, this prize was a total shock to me when it came in and basically what happened was that this was back in early 2020 when I got the call, let's see, was it early 2020? I guess it was early 2020. No, early 2021, you see, I forgot. But in any case, we were in the height of the pandemic mode at that point and I was actually doing a clinical team meeting from home it was a Wednesday afternoon and as Eric said, the phone rang and as had been the habit of my wife who's also an NIH employee and was working from home as well we got so many telemarketer calls that we would just when the landline would ring we would answer it but then quickly hang up. And so I did this like three times the person kept calling and I kept hanging up and then Margaret took over and dished out a couple of more hangups before finally realizing that this person was very persistent and must have something that they wanted to talk to us about. She actually answered the phone and it was a Dr. Dan Larhammer whom Margaret had never heard of at that point from Sweden, he didn't introduce himself and in terms of being associated with the Crawford Prize or the Royal Swedish Academy of Sciences he just said he was Dr. Larhammer and he needed to talk with Dr. Kassner soon, urgently. And my wife said, well, he's in a meeting and can I take a message and so forth. So anyway, at first I had said, well, I'll talk with him after my meetings are over today which would be like at five o'clock in the afternoon but that would be like 11 o'clock at night in Sweden. So I thought better of that and actually played hooky from the Wednesday afternoon lecture series to take his call and then learned that in fact I had won this thing, the Crawford Prize which I knew about the Crawford Prize. I didn't know that I was going to win the Crawford Prize and I was just totally dumbfounded, I must say. It was just an incredible shock when I learned about that. So anyway, so this is the story of what happened since then. I'll just start out maybe by telling you a little bit about the guy after whom the Crawford Prize is named. And that is Holger Crawford and actually the prize is named after Holger and Anna Greta Crawford and it's pronounced Crawford. There's no W in it. So to pronounce it properly it's the Crawford Prize not the Crawford Prize. And Holger Crawford was a business executive. Basically he had been raised in Sweden by a single mother. He had gone to the Swedish School of Economics where he graduated first in his class and he became at a fairly young age the CEO of some company called Akerland & Rousing which is a packaging company. And shortly after he took this job as the CEO of the company, he came up with this idea for packaging milk in tetrahedral paper containers which apparently had never been done before. And he called this the Tetra Pak and founded a company called Tetra Pak in 1950 and made lots and lots of money from Tetra Pak. And by the mid 1960s he had decided that he wanted to move on. He spoke with this guy here whose name was Nils Owal who was a physician in Lund, Sweden. This is where the packaging company was and where Holger Crawford was. And Nils Owal had this idea for starting hemodialysis. And back at that time, hemodialysis was not something that was practicable. He developed the dialysis machine and Holger Crawford underwrote the company called Gambrough that made dialysis machines. And so Holger Crawford made a lot of money from that too. So in 1980, he established this prize, the Crawford Prize. And he did this in partnership with the Royal Swedish Academy of Sciences. And basically the Royal Swedish Academy is responsible for selecting the prize winners. And here you'll chuckle, but the prize is awarded on a rotating basis and disciplines chosen to compliment those in which the Nobel Prizes Award is awarded Astronomy and Mathematics, Geosciences, Biosciences with an emphasis on ecology and polyarthritis. Now you might think that the first ones, Astronomy, Mathematics, Geosciences and Biosciences, maybe they are in the same caliber as physics and chemistry and the other things for which the Nobel Prize is awarded. But polyarthritis, I mean, granted I'm a rheumatologist, but even I would admit that that's a little bit of a stretch to have a Nobel Prize equivalent in polyarthritis. But don't look a gift horse in the mouth with regard to these kinds of things. And actually Holger Crawford had a reason for doing that and that is that he suffered from rheumatoid arthritis in his later years. And he perceived that medical progress at least back at that time in the early 1980s was not very good in developing treatments for rheumatoid arthritis. And as a beginning rheumatology fellow back at that time, I can say that that was true. So in any case, there were these prizes, the Polyarthritis Prize actually was only to be given if there was some progress in the field. In other words, it was not a regular thing that there would be a Polyarthritis Prize. They had to have a special committee that would decide that there had been sufficient progress to do that. And in fact, there was no Polyarthritis Prize for virtually the first 20 years of the Crawford Prizes because they felt that there hadn't been sufficient progress. But in any case, so the prize entails six million Swedish kronor, which is a lot of money in US dollars too. It's over $600,000. So it's a lot of money. And some of the past laureates, I won't read off all of them, but some of them that you might recognize, James Van Allen, the person who discovered the Van Allen belts, E.L. Wilson, who many of you may have heard of at Harvard, and Carl Woos, who discovered the Archaea, the separate kingdom in phylogeny. So a number of fairly prominent people have won the Crawford Prize in other fields. In Polyarthritis, actually, the first of the prizes that was given in Polyarthritis was in 2000. And the first Crawford Prize at all was given in 1982. So it was almost 20 years. And that was given to Sir Ravinder Mani and Sir Mark Feldman, who were the two individuals who first had the idea of using inhibitors of TNF tumor necrosis factor for the treatment of rheumatoid arthritis, which was a revolutionary thing and warranted a prize, whether it was the Crawford Prize or whatever, that was a major change in the field of rheumatology. And subsequently, there have been prizes that have been given with regard to adhesion molecules, cytokines, the role of HLA and environmental factors and rheumatoid arthritis susceptibility, and regulatory T cells. So that's a little bit of the background on the Crawford Prize. Just to give you a little bit of an idea of why did they think that maybe I was worthy of the Crawford Prize. Well, they gave the Crawford Prize this year, the 2021 Crawford Prize, for establishing the concept of auto-inflammatory diseases. And so some of you will say, well, what's that? So at least as we first proposed them, these are a group of disorders that are characterized by episodes of seemingly unprovoked inflammation, but without the auto-antibodies or antigen-specific T cells that you'd see in the characteristic autoimmune diseases. So sort of diseases where there's unexplained non-infection caused, not malignancy caused, inflammation, but where you don't have the usual features of autoimmunity. And we now know that these are disorders of the innate immune system. The autoimmune diseases are more disorders of the adaptive immune system, whereas the auto-inflammatory disorders are more disorders of the innate immune system. And I'll explain that a little bit more as we go along. Just to put it in some sort of historical perspective, actually in the early 1900s, Paul Ehrlich, who was an immunologist, one of the founders, I guess, of the field of immunology and who won the Nobel Prize in Medicine back in, I think it was 1908, proposed that there could be no such thing as autoimmune diseases or diseases where the immune system would attack the host because the immune system is so potent that it would be fatal. And he called that idea horror autotoxicists, the terrible things that would happen to the host if the immune system turned on the host. By the 1950s, it became clear that in fact there were autoimmune diseases and that in fact diseases like lupus and rheumatoid arthritis and thyroiditis in those diseases that you could actually develop antibodies against your own tissue and have real pathology and not necessarily die from it, although some people obviously would die from that. And then in 2000, another 50 years later was when we proposed this concept of autoinflammatory diseases. So it's taken a while for this concept to evolve. In terms of how it happened for us, and this is boiled down to one slide, there's the three stages of discovery that I'll mention to you. The first stage was from 1989 to 1999 and that was the time when my research group was trying to and ultimately did find the gene mutated in familial Mediterranean fever by positional cloning. And at that time, at least in the world of rheumatology there was a lot of skepticism about the genome project. And in fact, of course there wasn't even a genome institute at least initially when we set underway. And the idea of familial Mediterranean fever which is a relatively rare disease where patients have a recessively inherited disorder where they get recurrent fevers and arthritis and severe abdominal pain and sometimes severe chest pain and can develop kidney failure from it. It was thought that that was sort of not a very relevant disease to be studying. And so some said that we were using an unproven method to study an irrelevant disease, but we persisted and ultimately did find the gene. And it turned out that that gene encodes a protein that had not been known before and turns out to be sort of the prototype for a number of other proteins involved in inflammation. And then a couple of years later, we kept seeing patients with unexplained recurrent fevers and we found that there were some of them that didn't have mutations in that gene. They had the mutations in another gene, the TNF receptor. And so we called that condition TNF receptor associated periodic syndrome or traps. And then at that point, the light went on and we figured that, well, there's two of these diseases both of them inherited disorders in which patients have recurrent fevers and inflammation and no auto antibodies. And so this is the basis for a new family of diseases. And so we proposed this idea of auto inflammatory disease. And then during the epiphany stage, which sort of began at the point where we figured that out, we started to sort of refine the concept of auto inflammatory disease and to think about all of the other diseases besides the ones that we had described that might fit under the rubric of auto inflammatory. And so we had a long list, we published a paper with this long list of diseases that we thought were auto inflammatory. And then within a year after that happened, another group in San Diego, Hal Hoffman's group in San Diego discovered the gene that's mutated in a couple of those diseases that we said were auto inflammatory and were somehow related to FMF and traps. He found the gene that's mutated in a couple of those diseases. And lo and behold, that gene encodes a protein that has a domain that is in common with the FMF gene. And so actually there was a connection there. And what's more through work that was going on in basic science at the time, that gene encodes a protein that's a regulator for IL-1. And so we and other people had the idea of treating these patients with those diseases with IL-1 inhibitors and it was miraculous. These patients, some of whom had terrible disease, children with one of the variants of it who developed meningitis, aseptic meningitis. They go blind, they go deaf, they developed intellectual disability. A lot of them die in adolescence. All of a sudden it was like their inflammation went away. We have kids that started on IL-1 inhibition at that time who are now graduating from college. It's incredible. It makes you believe in molecular medicine. So that's the second phase, the epiphany stage. And then the third stage, we say a little bit whimsically is the horror auto-inflammaticus stage. So rather than horror auto-toxicus, horror auto-inflammaticus stage. And so that's from 2009 to the present. And given the wonderful advances in genomics and DNA sequencing and all of the things that we can do, now we have like over 50 auto-inflammatory diseases. We recognize now somatic mutations can cause auto-inflammation. So really just a lot of fun. So it's been great. And whether there was a Crawford Prize or not, I've had a wonderful time doing all of this. And so there was a Crawford Prize. And ultimately we ended up going to Sweden, my wife and I, and actually we brought along some of our families on both sides of the family in late April. And so because of all of the postponements with the pandemic, they had saved up actually four Crawford Prizes to be given at the same time. Usually they do one at a time on a rotating basis each year as a different discipline, but they had saved up mathematics, astronomy, polyarthritis and geosciences all to be done at the same time, which was wonderful because it really then did make it like it was a smartest board of science that we were going to over at the end of April. So we flew over to Sweden, actually we flew to Denmark and then you take a car across the bridge to Sweden. And we did that on a Friday evening. And I forget what it was, maybe the 22nd or something like that of April. And got to this place here that you can see called the Grand Hotel of Lund. So we checked in to the Grand Hotel of Lund on Saturday. Now Lund is actually a beautiful historic city. This is the inside of a cathedral in Lund, which is almost 900 years old at this point that you can see if you visit Lund. But actually I wasn't visiting the sites of Lund because I was under strict restraints because of NIH travel policy. And so as it turned out, the events of the Crawford days started on Monday. I flew over on a Friday because the Crawford people said I should be there on Saturday, but actually they didn't have anything for me to do in terms of events. They thought that maybe one would want a tour Lund. But I had to have meetings scheduled for the Saturday and the Sunday so that it could justify my being there. So I contacted this guy, Frank Wohlheim, who's a rheumatologist in Lund, who's writing a book on his mentor, Jan Woldenstrom, who's since passed away. The Woldenstrom of Woldenstrom's macroplobulinemia. It's kind of blood cancer. And so we met on Saturday night to talk about this biography of Woldenstrom that he's writing. And then I had some other things I had to do for a rheumatology meeting in Florida that I had to log on to from my hotel room. So in any case, my family went and toured Lund and I talked with Frank Wohlheim, which was very nice. He's a delightful guy. But in any case, and then Sunday evening, we had a family dinner. And as you can see, there actually were a lot of family members that took us up on the offer to go over to Sweden. So we had a big dinner on Sunday evening. And then the next morning was the beginning of the proceedings, the Crawford Prize lectures and whatnot. So this was being held in the grand auditorium of the Lux Building at Lund University. And here I am before the actual lectures began and I'm there with Richard Holmdahl and Ole Kempke. And they were two members. Ole actually is the chair of the committee that chooses the Crawford Prize winners in polyarthritis. They're both rheumatologists at the Karolinska Institute in Stockholm and actually are also members of the committee that chooses the Nobel Prize in physiology or medicine. They were very impressed with the NIH, let me just say, because they remarked upon the letters that they had to write indicating that, in fact, the money that I might get was not for giving a couple of lectures at this meeting, but in fact was in recognition of my work. But they certainly were impressed that the NIH has a real set of standards with regard to that. And just parenthetically, I'd like to thank Ellen Ralfus for helping to move things along with regard to that process and Leonard Ross for everything that he did to help move the approval process along as well. In any case, once we had some coffee, then we had a series of lectures. So the first of the lectures was by Enrico Bombieri from the Institute for Advanced Study in Princeton. He gave the mathematics lecture. And for those of you who actually want these slides, you can have the slides and then you can click on the link and you could actually listen to Professor Bombieri's lecture. But let me just tell you that it was very complicated and I don't think that there were many people in the auditorium that understood very much of what he had to say. He's a very nice man, I must say that, but I didn't understand a lot of it. He talked about his work on prime numbers. A lot of his work over the course of his career has been on number theory. And he is a very prominent mathematician. When he was a young man, he won the field medal, which is another big prize in mathematics. I'm not gonna go through. I tried to think of a little snippet of his talk that I could just play so that you could get a sense of it, but I failed. I just couldn't come up with anything. This slide simply shows the beginning of his lecture. He graduated his lecture in 1859, the epoch-making paper by Riemann on the Zeta function in the period, blah, blah, blah. But in any case, it was something anyway. So then the second prize was the astronomy prize. And that prize was awarded to Eugene Parker. This was actually the 2020 astronomy prize, as was the mathematics prize that was for 2020 as well. And so this went to Eugene Parker, but unfortunately, Eugene Parker, who was a professor emeritus at the University of Chicago, passed away about a month or so before this event happened. And he had been in ill health anyway. So instead, the person who gave a lecture in place of Eugene Parker was this person here, Nikki Fox, who is the director of the NASA Heliophysics Science Division, and very considerable person. And it was really an enjoyable lecture to listen to. You can see that she's got this T-shirt on that is the Parker space probe. She actually is the person that's in charge of the mission. They launched a space probe to measure various radiation coming out of the sun. It orbits the sun between just outside of Venus and then on the other side around the sun. And it goes in successively smaller orbits so that eventually it will burn up, but at least right now it's still functioning. But I thought that it would be fun at least to listen to her a little bit in terms of some of the things she had to say. So as the introduction said, I am the director of NASA's Heliophysics Division. And as such, I get to actually manage and look after a lot of missions, 20 that are actually up in orbit right now and another 14 that are in development, all of which are really studying science that was driven by Dr. Eugene Parker. And so Heliophysics is indeed the study of the sun, our closest star, everything from the very, very center of the star all the way out to the very edge of its influence and indeed beyond. And so here you see a very familiar looking planet, the Earth, and you can see that our magnetic field is protecting us from all of this stuff coming from the sun. If we go up and I take you to the poles of the sun, you can look down on the poles and you will see that atmosphere starting to spread away in a spiral shape, that spiral known as the Parker spiral because of course Gene predicted that would happen. Then we go to the very edge. So this is now the very edge of our sun's influence. This is where the solar wind stops and it meets interstellar space. This is yet another prediction of Gene Parker that in fact our solar wind would form a protective cavity around not just our planet and our star but our whole solar system. So as we are orbiting around the Milky Way, the solar wind actually protects us from the vagaries of interstellar space, from particles, from dust, from cosmic rays coming from us. And so we have a pretty nice life here because of the solar wind. But in 1958, using, and this is in Gene's own words, he solved four lines of algebra. That is how Eugene Parker described finding the solar wind. He actually said to me, all I did was solve four equations. So he solved four lines of algebra and it was all predicated on the Beerman study of the comets, which was so beautifully described to us. Beerman was actually visiting Chicago and he was meeting with John Simpson, who was Gene's boss at the time. And he presented exactly what you just saw, that the comet tails were always pointing away from the sun. And he actually said, well, there must be something moving out, it's some sort of, he called it corpuscular radiation. Now John Simpson kind of dismissed it out of hand and said, maybe something comes out occasionally, but it's not coming out all of the time. And he also cited a famous scientist at the time, Sydney Chapman, who had said that much like the Earth's atmosphere, the sun's atmosphere would be static. And so John Simpson had dismissed everything but he passed all the work onto Gene Parker and said, see what you think about this. So Gene studied it, he solved his four lines of algebra and he came up with different sort of solutions for these four lines of algebra, five of which were physically not possible, but the sixth one was. And I'm actually going to, I don't usually use notes, but I want to make sure I get this quote right because I love this. This is from a paper by Cain in 2009. So Gene Parker went to John Simpson and said, John, Beerman is right and Chapman is wrong. So John Simpson said, Eugene, what is your basis for saying this? Well, my calculations show that the sun's atmosphere is not only not static, but it's highly dynamic. And with millions of degrees of coronal temperatures, the whole place will be boiling and some flow would come out sometimes more, sometimes less, but never zero. And I, Eugene Parker, would like to call it solar wind. So John Simpson said, so what do you propose to do, write a paper or something? Gene said, well, yes, unless the university prohibits it. John Simpson replied, no, no, no, no, we're very open-minded here. Do what you like, publish what you like, but for heaven's sake, don't put my name on it. Wonder if he ever regretted that. So several journals did indeed reject this paper. But luckily, an editor did intervene. But one of the referees went so far as to actually say, if you're going to publish in this area of science, you might wanna go to the library first. And Gene told me this and he said, oh, Nicky, that was the nice review. So fortunately, the editor was Chandra Sacar, who was also at the University of Chicago. And he really kind of enjoyed the controversy. And he said, Eugene, I think this is a ridiculous idea, but I don't wanna see it killed, so I'll publish it. And certainly, Gene got a lot of, maybe ridicules too strong a word, but a lot of pushback and a lot of goodness, what is all this about from colleagues. But then just a few years later in 1962, the Mariner II spacecraft on its way out to Venus did indeed sense the exact solar wind that Gene had predicted. And so the rest is kind of history. But one of my favorite comments that Gene made was, if you do something new or innovative, you should expect trouble. All right, well anyway, moving on, then I gave my talk on auto-inflammatory diseases. You've already heard at least the essence of it, here I am delivering it. This is just a slide that is a note actually that I wrote on the very first patient that I saw with familial Mediterranean fever as a fellow at the NIH in 1985. Then eight years, eight years, 12 years later, when we found the gene for FMF by positional cloning, just a schematic of how we went about doing that. The fact that the gene in fact encodes what was then a novel protein. And of course, everybody very happy to have made it to that point. And I want to add that with the advent of the NHGRI or as it was called the NCHGR at that time, it really made a big difference for us in terms of being able to find the gene. It turned out that the N-terminal 90 or so amino acids that protein form a domain that's found in some 20 different proteins that are involved in the innate immune system. And then shortly thereafter, a couple of years thereafter, we, after we found the gene for FMF, we didn't know about this domain right away. But shortly after we found the gene for FMF, we found the second gene and proposed this concept of auto inflammatory syndromes. A year or so later published the paper in which we suggested that perhaps these two diseases, familial colder to carrier and Muckel-Wells syndrome were somehow related to familial Mediterranean fever. It turned out that then a year after that, Hal Hoffman and San Diego showed that in fact, the gene that's mutated in those two diseases share that N-terminal domain with the FMF protein that in turn led to the insights with regard to IL-1, and this is the publication in 2006 of the paper in which we showed that in fact, IL-1 inhibition is absolutely transformative for patients that have the neurologic manifestations of this condition. And then the two flavors of immunity, adaptive immunity where T and B cells are the major players, the receptors somatically rearrange and mutate and the autoimmune diseases are characterized by high-titer autoantibodies or antigen specific T cells and the innate immune system, which was just beginning to be recognized at the time that these auto inflammatory diseases were popping up. And in the innate immune system, myeloid lineage cells are the major effectors. The receptors are hardwired in the germline genome and the auto inflammatory diseases show inflammation, unprovoked inflammation, but without the autoantibodies or antigen specific T cells. Then with the cost of sequencing coming down dramatically, this is an NHGRI slide, we were able, and many others were able to find additional diseases, discover additional diseases in which there are mutations in genes that encode. Either structural proteins in the innate immune system or regulatory proteins in the innate immune system. In this particular case, discovering mutations in the ADA2 gene and children that have recurrent fevers and strokes, that led subsequently to the discovery of TNF inhibitors as a way of preventing strokes in these kids, which was really a big deal at that time, Mandy Umbrello led those studies. And then this is just a list of the various genes and diseases that we've discovered over the years, at least the ones that we've had a major role and there's 16 of them all together, 14 of them actually are diseases that didn't exist at the time that we started, that were recognized as just a part of doing this work. These are all monogenic diseases. And then there are a number of genetically complex disorders where we've also been interested in defining some of the susceptibility loci. So that was that talk. And then the last talk of the day was Andrew Noel. And Andrew Noel is a professor of natural history in the Department of Earth and Planetary Sciences at Harvard. And he got his Crawford Prize in Geosciences for the work that he had done, characterizing the first three billion years of life on Earth and its interactions with the physical environment. And that was a fascinating talk as well. So basically, he started from the standpoint of going back as far as you could in the fossil record of animals and then trying to figure out, well, what was life like on Earth before those fossils were developed? And so I'll just play a little bit of his talk for you. I'd like to take just a minute to put that animal record, in fact, the animal kingdom in perspective in both time and space. And if you look at that diagram in the upper left, it represents an effort by my friend Ron Milo in Tel Aviv and his colleagues to quantify the amount of biomass in different groups of organisms. And once you can see what they come up with here is that a majority of the biomass on this planet is actually plants with bacteria next and then fungi, then archaea, another group of microorganisms distinct from but organizationally similar to bacteria and then protozoans and algae and the little box in the corner is animals, much less than 1% of all the biomass on this planet. It turns out that plants actually cheat in that if you go outside and actually look carefully at one of the trees that surrounds us, you'll find that more than 90% of its mass is not living tissue. Wood does not become functional until the cells that created it die. So if you only include the living tissues of plants, then we live in a bacterial world with plant second and animals are still a very small part of it. Then let's go to the diagram beneath that, which is what's called a universal phylogeny. It is an attempt using molecular sequence comparisons to build really a genealogy that depicts the evolutionary relationships of all life. Uncontroversially, it suggests that there are three major categories of life, the bacteria, the eukaryotes, which are organisms like ourselves that have a membrane-bounded nucleus and then a group only really discovered to be distinct in 1977 called the archaea, which is organized in a simple way like a bacterial cell but is in fact quite distinct. That diagram shows the eukaryotes as being a sister group to the archaea through work done over the last seven years, some of it done in Sweden. We actually now think that the eukaryotic cell represents a merger between a recently discovered group of archaea and some cells from the bacteria. In any event, the reason for showing this is that no matter how you look at this set of genealogical relationships, all of the animals, both living and in the fossil record, reside on one small distal branch of the tree. And the inference from that is that there must be a deeper history of life than that represented by animal fossils. And that deeper history would be largely microbial. Then finally, if we look at the right-hand diagram, it's simply a geologic timeline. The oldest evidence for animals that we have from the fossil record goes back about 575 million years, but our planet is more than 4.5 billion years old. And so the question that I'll address today is what can we learn about this long interval of Earth history that precedes the advent of large fossilizable animals? Okay, let me then finish up then. The punchline, of course, is that we actually can reconstruct the deep history, both physical and biological, of our own planet. And now in the last 20 years of other planets as well, that there are not only reconstructable histories of life and environment, but clearly life and the environment have interacted through Earth history. And so that major biological transitions both track and I think help to drive environmental changes in our planet's history. And this is something that continues. These are just four panels of changes just during the age of animals over the last 500 million years. Most of you know that Earth is characterized by plate tectonics. So the actual geography of the Earth changes through time. This is what the Earth looked like about 250 million years ago at the time of that great mass extinction that Daniel talked about. And it's about as different from our present Earth surface as it can be that nearly all the continents are amalgamated into a supercontinent and there is a global ocean that's more than a hemisphere in extent. We know that atmospheric composition continues to change in particular the amount of carbon dioxide has changed through time. We know that climate has changed through time. This is just a drawing of what the Earth looked like 20,000 years ago when you have ice extending south in North America to about Long Island covering Scandinavia, things like that. And there's a series of ice ages through time. And every once in a while, bad things happen on short time scales. This is 66 million years ago here, two dinosaurs out on what will surely be their last date. And there's looking at this thing going on, which in fact, as many of you know, was an 11 kilometer bolide that crashed into the Earth in the Yucatan Peninsula and precipitated a major extinction. And one has to point out that we are not living in a static time ourselves. In fact, the evolutionary present is on a geologic time scale, a time of very rapid environmental change. I love these diagrams put together by a guy named Jim Barry at the Monterey Bay Aquarium. This is not the amount of CO2 in the atmosphere, but the rate of change of CO2 over the last 400,000 years. It's boring, it's boring, it's boring, it's boring, it's boring, it's boring. And then the industrial age starts and it gets really interesting. Here is the pH, rate of pH change in the ocean. It wiggles around and again, this is the phenomenon called ocean acidification, that the pH of the oceans has changed dramatically. And that is really the context that in which we and our children and grandchildren will live. And I think that by incorporating the lessons of Earth's past, perhaps we'll be wise enough to deal intelligently with its future. Well, hopefully so. So that was the last of the lectures for the Crawford Prize Symposium. I then went out to dinner with some of the people from my lab, from the early days of the lab, at least a number of them. So Mike McDermott, who was involved in the identification of TNF receptor mutations and traps. Ivona Aksentyevich, who's been with our research team for nearly since the very beginning. Ilone Pras, who was also one of the early fellows who is now the head of a genomics institute in Tel Aviv and his wife, Orit, and Elaine Gremers. The next morning then, so this was really a lot of science that we had during this event. We had a set of four parallel symposia having to do with the topics that each of the prize winners had. So there was a symposium in polyarthritis, a symposium in the geosciences, a symposium in mathematics, and a symposium in astronomy. I'll just play you a short clip from beginning in polyarthritis. Good morning, everyone, and welcome to the Krapfel Prize symposium in polyarthritis. And the theme of today is auto-inflammatory diseases. My name is Hans Eldegren. I'm Secretary-General of the Royal Swedish Academy of Sciences. The mission of the Royal Swedish Academy of Sciences prioritized four areas. The first two is to support science for policy and to influence the policy for science. The other two is that we want to be a meeting place for science and also to promote and award scientific excellence. It is the two latter aims that we are here for today. The Academy's two most prominent prizes are the Nobel Prize and the Krapfel Prize. We awarded Nobel Prize in chemistry and physics and the prize in economy to the memory of Alfred Nobel. We awarded the five Krapfel prizes in astronomy, biosciences, geosciences, in mathematics, and that's of course the reason we're here today in polyarthritis. I hope that you will find this symposium rewarding. I really wish you a great day. I know it will be followed by a dinner tonight, so there will be plenty of opportunity to talk to each other today. And by that, I leave the word to Professor Olle Kempe who will introduce the prize winner. So have a nice day. All right, well, I've already been introduced so you don't need that. And my talk, which was to a more specialist audience, dealt with some of the more recent things that our research group has done. I won't go through those in detail with you, just to flip through the slides of my talk anyway. And then there were eight other speakers that spoke. This was a day long symposium. Molym Camphie talking about the inflammasome. Harold Burkhart talking about psoriasis and its relationship to auto inflammation. Yannick Crow talking about the interferonopathies. Nils Landergren talking about autoimmune diseases as a counterpoint to auto inflammatory diseases. Elaine Ramers talked about her work on the genetics of bedchats disease, Claudia Kemper from NHLBI talking about intracellular complement. Ian and Bryson talking about napriphage activation syndrome and lymphocyte cytotoxicity. And Jean Laurent Casanova who many of you may think of as being more of someone involved in immunodeficiency diseases, which he is, but actually he has also a fairly significant interest in the auto inflammatory diseases as well. And this is just a picture of the people that I showed you earlier on the dinner photo a few slides ago. And then the third day was actually the day of pomp and circumstance. And so we can go through this relatively quickly. This was held in the assembly hall at Lund University. Here's a picture of my wife, Margaret and me. Beforehand, they made us rehearse so that we would do everything according to schedule. They had books that each of us would sign. There was a book for the mathematics prize. This is Dr. Bombieri signing that. The children of Eugene Parker signing in his memory in the astronomy book. Here I am signing in the polyarthritis book and actually revealing that I don't have nearly as much air on top of my head as what I usually think. And then here is the Crown Princess Victoria who is the person who gave out the awards talking with Ebba Fisher who's the granddaughter of Holger Crawford and the chair of the Crawford Foundation Board. Then just a photo of some of the various people that were involved in this. This is Dan Larhammer, the guy that I was hanging up on at the beginning of the story and Hans Ponce Elegren who you saw a moment ago. Then just some of my colleagues waiting for this to start. And this is the last of the photo snippets, a little bit of the pomp and circumstance of the award ceremony. So anyway, Crown Princess Victoria gave out all of the prizes, the medals, the gold medals that went with the Crawford Prize. And then the ceremony ended. Here she's walking out with Dan Larhammer. There was a banquet then that evening, a reception after the banquet. Here's Crown Princess Victoria with me and my family. This is my son Nathan, my son Ben, Margaret of course. And then that was it, it was over. The next day we went on to Stockholm, at least in part because my family wanted to see Stockholm but I had arranged for speaking events in Stockholm as well. And so once we got there, I had a meeting actually, this was something that I was quite surprised. The ambassador asked for, because the embassy looks at all of the things for US government employees anyway, for travel and the travel permissions and so forth. And so they had seen that an NIH employee was coming to Sweden for an award. And so he asked to see me. And so I gave him a mini lecture on auto inflammatory diseases and we met at the embassy. And then I gave a talk at the Karolinska Institute. And then that was it, it was over. And finally, the last thing that some people ask me is, well, what did you do with all of that money? Well, I haven't spent it all, at least yet. But one of the things that I thought was really a good thing to do is to establish a set of awards myself that I've donated money for to the International Society of Systemic Auto-Inflammatory Diseases. And these awards are named after some of the people who are the real heroes of mine and some of the things that I've done. Jörg Chopp, shown here on the left, who was the discoverer of the inflammasome. Isabel Tuatou, who was actually one of my arch rivals in finding the gene for FMF. Mordechai Pras, who was my very important collaborator and the father actually of the lone Pras in getting samples from patients with FMF. Alberto Martini, who's in Genoa and has led a large consortium of pediatric rheumatology clinical trials. And Charleston Arello. And so the idea is that younger people in the field will get these awards named after these people that are more senior and some of my heroes from the past. So with that, it's over. And I think that we're over right at the hour. So I apologize for maybe going a little over. I guess I can make the excuse that I played all of those videos. And so that's what actually took up all of the time. But I just thought that it would be fun because it really was a smorgasbord of science. And it was really fantastic, having the opportunity to hear what these other guys were doing too. And certainly I think in the future they should actually consider having combined ceremonies again. So in any event with that, I will call it to a close. Paul, if you want to, if there are any questions I'll try to answer them or if they're not everybody can leave a little bit early for the weekend. Yeah, thank you Dan, very much. This is a fantastic, quite a royal trait, if you will. And that we're so proud of you and all the great achievements you have made and making us feel like we're among the best in science. And you mentioned, they were the Royal Academy. They're impressed by NIH. I thought they were going to say they were impressed by how many great scientists we have here. But we do have great regulations but I hope you convey that obviously we exemplify what an intramural scientist can do. Indeed, indeed. Okay, I think it's, I do have some questions but I can ask you later. I don't want to hope people Friday afternoon but this is very impressive and I think we're probably to call it a close and I'll email you with some of the questions I have. And this is a really quite an important discovery and thank you very much. Well, thank you Paul, thank you all for being here this afternoon as well. Yeah, I'm sure a lot of people sending their congratulations to you and including some here in the Q&A. Thank you very much, take care. Bye-bye. Bye-bye everybody, thank you for attending.