 So in 1972 there was a young MD called Stanley Prusner who was working in San Francisco and in particular studying a disease called Kreuzfeld Jacobs disease that we know very little about at the time. And what he tried to do is try to isolate the disease agent which is very common because you thought it was a virus and just like COVID in that case you would like to at least isolate its RNA they wouldn't do sequencing in those days but that would at least prove that it was a virus. But no matter how much work he did and everything he couldn't isolate this RNA. In fact what rather kept happening is that this was came back with impurities and everything and no matter how hard he tried to isolate it he just found proteins in the solution. And this even went so far that he almost didn't get tenured because he felt that his research was failing. But what Stanley eventually realized was that this was in fact a disease agent and it's common to some other forms. There is a disease called Kuru in New Guinea that had to do with some tribes that were still practiced cannibalism and there is a disease called Scrapy where it comes to sheeps in particular when they eat other sheeps. So what he was able to show that this disease agent was in fact proteins and he coined the term protein similar virus they call it a prion which was quite controversial at the time because obviously we know that anything that infects us it would be either a bacterium or a virus. We don't have proteins carrying disease because proteins would be digested in our stomachs or something right. We have entire systems to take care of this. The amazing things with prions it turned out that the immune defense wouldn't really set off. So the immune defense would not try to fight this disease agent because it appeared to be a natural protein that would occur in our bodies anyway. What Stanley Prusner realized was that this is a type of proteins that somehow builds it plaques. So over very long term times some proteins apparently aggregate so they associate to form much larger things until you can really see them in the microscope and that was common both for Scrapy, Kuru and the Scroidsville Jacob disease. He published this in 1982 a decade later and as a result he got the Nobel Prize in Medicine for this in 1997 I think it was and you might have heard that if you roughly at the same time we had this so-called Mad Cow disease which is another example of a disease caused by prions. So we know a little bit more about this today. What most of these disease agents have in common is that they have a protein that can exist in two forms and I'm well aware that I'm contradicting everything I said. Remember at the start of this lecture Amphinsus dogma the thermodynamic hypothesis that the natural state of the protein is determined by physics so how can we have two states? Well imagine that the world looks this way. We have some sort of free energy landscape with several very deep wells and when this first the protein folds I end up in this well here. This is a beautiful well I'm going to be stable almost forever I will be stable for 50 years whatever but technically it's not the global minimum of free energy it's just a very very good minimum in free energy. Now remember about kinetic stability if we have lots of things there in nature that should select for this in particular natural selection but we tend to have kids by the time we're 30 so even if this will eventually lead to disease in my body natural selection is not really going to select against that if I've had a chance to have offspring before this sets in and historically over billions of years we used to die much younger than we did today so there's not really going to be any natural selection factor fighting this and of course in general this starts to sit in gradually and it would only hit us by the time we're 80 or something so it shouldn't really matter. That is true apart from some sort of genetic effects and everything the other dangerous things if these proteins are now very stable maybe just maybe under some conditions they could move over to this super stable free energy minimum here that really is the global free energy minimum that would have different properties it would be better so it's more stable it's even too stable there but it's not functional so in this case we would have that the functional state is the second lowest while under some conditions we could go to a dysfunctional state even later and that's what happened in this particular protein so there's a protein where we have the native functioning state here and it's exactly the same sequence but under some conditions some of these helices turn into a beta sheet there's a very stable beta sheet remember how I said about beta sheet formation times it can take forever this is so stable that even the normal enzymes we have to digest proteins I think can't break this apart and that will lead to some scary things what if I now take this protein and eat it well my stomach enzymes can't break it and some small fraction of this protein might even make it out into my blood beta sheets as we will see next they have a tendency to aggregate with other beta sheets so if these proteins also aggregate you can kind of get a process that catalyzes more formations of these and then you would effectively have this that we're having something small that's growing into plaques normally this wouldn't matter right because this starts building up by the time we're 80 or so and when I'm really feeling the symptoms here I'm 100 I'm not going to die from this but if you're a 20 year old eating hamburgers or again practicing cannibalism or sheep what might happen is that this build-up process could happen much earlier in your life and then suddenly 15 or 20 years later you would start having very severe neurological disorder and it's in fact it's so bad that people even died from it that is what led the entire british industry to abolish the practice of taking cows that were dead and taking well all the remnants of it including the nerve system and brain and feeding that to other cows and when they got rid of that the spread of quartz filled jacob's disease in the uk pretty much ceased completely so this is a very important memento mori it is dangerous to assume too much in almost all cases amphism was right the global minimum of free energy is the native state of our protein but as the second last concert of this lecture before closing there are exceptions and those exceptions can lead to very scary things in terms of disease this is likely also component in many diseases such as Alzheimer's and everything but we simply know too little about protein aggregation and some of you might end up studying that and having very successful careers