 Hello, and welcome back to Beyond Networks, the evolution of living systems. Today, we're gonna really dive into biology and we're gonna do that with a rant, a rant about systems biology and biology. What is systems biology? But before we do that, I want to quickly recap once again, what we've done so far. In the first module, I've introduced the idea that the rich and complex world that we live in, WIMSAT's rainforest affords a diversity of valid scientific perspectives. So there's always an indefinite number of different perspectives that you can take on a complex system. There's always more than one way to see the world. Perspectives are not just arbitrary points of view, they're based on heuristics that we use, clues and acceptations, remember, sort of improvised algorithms, methods that sometimes work, sometimes they don't. But they do yield trustworthy, robust knowledge in practice, although we can never be certain of our view of the world. Good perspectives are getting things right. Not everybody is just simply entitled to an opinion. In module two, I then went on to say everything including science itself is a process. And it is worthwhile to study the evolution of organisms and scientific knowledge using a process perspective for this reason. Even if you don't buy into the idea that fundamentally the whole universe is a process, you can agree that it's useful to take this perspective for the sake of gaining new insights. And this perspective, this process perspective focuses on change as the fundamental principle underlying the universe. Even if you don't quite agree that objects, things are not fundamental, you can agree maybe that this is an interesting point to take. The process perspective allows us to step outside our dominant view of organisms and the world in general as mechanistic machines. And that helps us recognize and also hopefully transcend the limitations of this dominant perspective that is, as we speak right now, limiting progress in our understanding of the living world. So to bring back this wonderful drawing by Bill Wimsat, we're in this bio-psychological thicket. Actually as biologists, we're in the sort of simpler part and the social sciences are not to be envy to be in an even more complicated area of this causal thicket where no clear levels of organization can be distinguished. And we need to make sense of this hairball of causal interactions. How can we do this to make sense in this thicket? Maybe not off the thicket as a whole, but to make sense of problems in this thicket, we need to think hard about what it is that we should focus our studies on because if there's no structure at all, we cannot understand. Remember that other diagram from Wimsat's book that I was showing. If everything is random, we probably chose the wrong variables. So what are the objects of study? What are those variables that we should choose? And in particular in biology for the whole history of biology or more or less, this has been the organism, living systems. The definition, again, when I need absolute knowledge, I don't do science, I go to Wikipedia. So what I find there is a definition of biology that says biology is the natural science that studies life and living organisms. Very simple. Otherwise it's just physics or chemistry, right? So the object, the main object of study in biology has always been an organism. But something funny happened in the history of biology over the last 100 years. So let's get into that. And that funny recent history sort of necessitated the invention of a branch of biology that's called systems biology. This lecture is part of an evolutionary systems biology master. So let's examine what systems biology is. So systems biology, again, from Wikipedia is the computational and mathematical analysis and modeling of complex biological systems. Cool, that doesn't say much, does it? What is a complex biological system? That will be the topic of the next lecture. So what does this mean? It's very vague. It's not actually, if you think about it, this definition doesn't restrict systems biology to any subfield of biology. It's not really a discipline within biology. It is more like a sort of an approach, right? The use of computational and mathematical analysis and modeling. But that used to be theoretical biology. Now, the difference some people say is that now we have theoretical biology used to make computational and mathematical models of biology, but nowadays we have data. So these models are based on more or less big data sets that we have. So let's think about this a little more. That's true in practice. This is a wonderful time to be a biologist because you have sort of new experimental methods and data available that nobody had before. So this is not enough, right? And so systems biology has become a bit of an empty shell. This sort of word, instead of saying something meaningful, it has become a buzzword, scientific bullshit. Perfect example of scientific bullshit that people use to get attention and money. Everybody's doing systems biology right now. So in what sense would I call myself a systems biologist? In what sense does it make sense to be a systems biologist? So it's not an easy question. So let's see, there are different opinions. They're very divided. So some people, this is from a review by Treveves in 2006, highly recommended reading about a very brief history of systems biology. And he says, currently, this is an age of systems. I like that. And systems structure and behavior should form the core of also student biology courses. This is exactly why I'm doing this lecture. Understanding the complexity of biological systems represents the greatest intellectual and experimental challenge yet faced by any biologists. And this is also true. It's daunting, right? Right in the introduction of this course I was saying. So we have been hiding in this sort of oversimplified version, fake version of reality. And reality is much more complicated than that. And now is the time to tackle this reality. Well, this is a very sort of enthusiastic view of systems biology. It's the right time to do this. It's a completely different way to do biology. Others are a bit less impressed. So here is Ronald Plaster, famously saying in an interview in the journal, Current Biology, I think it was Plaster used to be the head of the Fiberich Institute in Utrecht and also the Dutch minister of science for a while. A very important influential person. He says, he's an experimental biologist, by the way. He says, what makes discoveries by watching, working, checking these systems biologists? They sit around at the computer. They want to be Darwin, but do not want to waste years on the beagle. They don't travel around the world and see things. They don't collect the data carefully and analyze it. They want sex, but no love, icing, but no cake. Systems biology is scientific pornography, quite harsh. So what do I think? I think both of these people have a point. It is the most exciting sort of time to do systems biology if we fill it with some sort of meaning. But at the same time, we are running the danger of being overwhelmed by bullshit, which is not sort of concerned with, you know, finding any insight, truth or wisdom, but only concerned with the career of those people using a buzzword to promote their own science. So another quote from Travavas here. Systems biology is currently undergoing enormous expansion, so that's not controversial. But there seems little awareness of either the history of systems biology or the behavior of systems that make them science studies. So this is interesting. And this is an indicator for bullshit here because nobody who uses this term virtually nobody can explain to you why the system is supposed to be an interesting object of study. So we're still focusing. For example, if we do omics, genomics, proteomics, whatever, we're still focusing on individual interactions and we're sort of aggregating those into big networks. But in what way does that mean that the system in itself that other level of looking at biology is meaningful, is important? What does that mean? We have to explain that. Also, and this is very important in this quote, systems biology is not just five years old. It's not just 20 years old. How old is it? Most people are not aware how long ago systems biology was invented. Here, Konopka textbook, systems biology textbook from 2006, he writes, albeit systems biology exists for over two millennia, it has enjoyed a spectacular rejuvenation in recent years. It has been around for 2,000 years. Oh my God, what does that mean? What does that mean? Does he have a point? He does have a point. And for that, we have to take a very, very quick tour into the history of biology. The first thing I want to point out is the whole background in front of which we're discussing this is a certain attitude towards life and whether universe, matter is a life or not. Remember the discussion of white heads, panpsychism and his philosophy of the organism which we consider crazy today. But for most of human history, this was not crazy at all. So for most of our human history, we have considered our world alive. We had an ontology of life. Remember the ontology is what we consider real. For example, before modern times, animism was the main sort of metaphysical system or religion that people use to frame their worldview. It comes from Latin, anima, breath, spirit, life. And this again is a quote from Wikipedia. It is the religious belief that objects, places and creatures all possess distinct spiritual essence. They're not words you often hear in a scientific lecture. Potentially, animism perceives all things, animals, plants, rocks, rivers, weather systems and human handiworks and perhaps even language words, utterances as animated and alive. And this, it's a very recent thing, only about 2,700 years ago that we have the first evidence that humans stepped out of this school. And it starts with the first pre-socratic philosophers. They start to doubt, but a lot of them, here's Thales of Miletus, who is considered the first Western philosopher ever in history. And he used to sort of, was striving for sort of general principles to explain the world. He thought everything, the foundational principle of everything was water, which is very strange today. But he also thought that magnets were alive because they could move iron around and he has a quote, we only have fragments of this work. He has a quote where he said, everything is full of gods. What did he mean by this? He had a view which is called hylozoism and that's the philosophical point of view that matter is in some sense alive. So this is no longer a mythical or religious view. He argued from a philosophical point of view that since the magnet had agency, it could move things around, it needed to have a soul. And the soul was completely, it wasn't something, it was very in this world, not anything transcendental at the time, but sort of a principle that was imminent in our material world that we live in. So these first philosophers also, Anaxemines, one of his Thales students, he thought that the soul-giving principle was air, not water, but the same thing. He believed that the fundamental sort of substances that made up the world were in some way alive and also aware. He fast forward 700 years, wait, 400 years, not 700 years, to what can be considered the first biologists. This may come as a surprise, but Aristotle was really interested in biology. He and his student, Theophrastus, left Plato's Academy in Athens for years and moved to the island of Lesbos where they studied animals in Aristotle's case and plans mainly Theophrastus's case around a lagoon on the island of Lesbos. Contrary to his reputation that he was an armchair philosopher and never did any experiments, Aristotle dissected eggs, animals, and all kinds of things to understand better what he was seeing. And the best thing is that he looked, he was a systems biologist, look at this. He says in his book, The Politics, the whole is something over and above its parts and not just the sum of them all. So this quote, the whole is more than the sum of its parts, goes straight back to Aristotle. He was looking at living systems and was considering them what he called a substance, something fundamental that is moved by some sort of, he called it form and was made out of matter and had a dynamis dynamic. So very interesting view and I recommend there is a one hour BBC documentary on this narrated by Armand Marie Lera who also wrote a book about this called The Lagoon which tells you much more about Aristotle's biology and maybe gets rid of some of the prejudices that you may have against his biological insight. Of course, he got a lot of things right wrong. He thought that we were thinking with our hearts and not with our brains. He thought that the egg of the mother doesn't contribute anything but nutrition to a baby, et cetera, et cetera. But remember that he was the first to really do experiments in biology and he lived more than 2000 years ago. So this idea that seems so strange today that substances are a life, organisms are substances that are fundamental parts of the universe. Life is a fundamental ingredient of the universe. This view continued right through the Middle Ages and it was only challenged of course by Descartes and his clockwork universe which we could call an ontology of death. So suddenly you cannot overestimate the influence of Descartes on philosophy, on humanity's world. He was the first in human history to make this really radical switch from saying, hey, there is no soul in the material world. It's separate in this different world, right? And by saying the whole material universe works just like a machine. This was a revolutionary step at the time. And that's just a few hundred years ago if you think about it. So we switched from an ontology of life to something that you could call an ontology of death, an inanimate material world. And so now the problem is no longer to explain why something dies, but the problem is to explain how come something is alive. How can you be alive? How can you be conscious in such a universe? Of course Descartes escaped this question by inventing his dualism that is still troubling us today. We fast forward again, biology at the beginning for several hundred years in fact remains pretty immune to this. So you have 18th century biology, Linnaeus here with his famous taxonomy of plants remains largely organismic, centered on the organism. It couldn't do anything else. They had no methods. They had the microscope. So Manley Winhoek and Robert Hook especially looked at small organisms and we could see more. We could see the cellular structure of organisms and all that. There was very little sort of way to dissect decompose the organism into its molecular parts, of course. So for practical reasons, mainly biologists remained organismic biologists. And this is very important if we go to the 19th century in Darwin's theory of evolution. Darwin's evolutionary theory is 100% organismic. What is being selected are organisms that survive or die. The struggle for life is central to his theory of evolution. This is an organismic theory where organisms that behave, that grow, that do all kinds of things, are central to the theory. And so we have, so that this focus on the organism survives the switch from a living to a sort of non-living material universe without much of a problem. So the decline of this view comes pretty late. Even vitalist ideas, if you consider people like Henri Berkson as Alain Vital, late 19th, early 20th century. And then experimental biologists like Hans Striege who in the early 20th century were still propagating vitalist views. Vitalism survives into the 20th century, why? Because Driege became a vitalist not because he was some sort of fuzzy, mythical thinker, but because he couldn't explain his regeneration experiments. He couldn't explain the regenerative capabilities of frogs and sea urchins. Based on the mechanistic theories, on the physics of the day, that were propagated into biology through the School of Willem Rues and Wichlungsmechanic Developmental Mechanics, for example. The research program that said everything is just a clockwork and we're gonna study development embryology in this way. This didn't, the experimental results that Driege got from separating sea urchin last few years and then seeing those grow into separate embryos, this self-regulating capacity of the embryo that starts with completely, we take a part of it and it regenerates itself. Completely went beyond his imagination and his sort of vitalism was one where he didn't invoke some sort of mystical force or immaterial spiritual force, but he suggested that we need to extend physics with additional principles. So he introduced this principle of Entelechi, he called it. Going back to a term that Aristotle coined, by the way, that was sort of an additional principle to the thermodynamics that we already knew that made living systems special and alive and capable to regulate. They both interestingly died in 1941, which you could consider the final death year of any sort of influence, mainstream influence of vitalism in biology, but this sort of struggle between mechanism and vitalism left a lot of biologists dissatisfied. And in the early 20th century, there was a big movement that was in the philosophy of biology, but also in biology itself. These were practicing biologists that tried to dissolve this tension between mechanism and vitalism. And these researchers were spread all over the world. They communicated in a worldwide web of snail mail interactions and visits to each other. So you had William Emerson, writer in the U.S., John Scott Haldane, Edward Stuart Russell, Woodger Henry, Joseph Henry Woodger, Joseph Needham in the U.K. And here in Vienna, of course, you had the founders of systems theory and systems biology, arguably historical founders, Paul Weiss, who I will quote extensively in the next lecture, and Ludwig von Bertalanfi, which will also encounter again. So these people came up with a theory that was pretty influential in the 20s and the 30s of last century. And it was called Organicism. And it was sort of the last big movement in biology that was really focusing on the organism. So the mechanists, not just in embryology, but also elsewhere in biology, were pushing against, they were saying, they were the solution to vitalist problems. But the organisms, so both of them agreed, the mechanists and the organists, that it was not okay to sort of invoke any sort of non-naturalistic, non-material forces. So they were ontologically materialistic. They also said all the organismic processes are physical chemical. There's no magical voodoo going on and vitalism is not okay. So, but there were differences obviously. So while mechanism focused in the 20th century more and more on the gene, as the sort of prime objective study in biology, Organicism focused on the organism, as its name says. Mechanism was this reductionist sort of push, reductionist approach and the agency and also the principle of inheritance was saw at the genetic and later at the molecular level. While Organicism saw was more holistic in systems level and saw agency and inheritance as a property of a whole living system. Mechanism stressed the importance of composition. What are the genes that underlie different traits? So what is the genetic architecture of a trait? While Organicism stressed the importance of organization. We'll come back to that a lot in this lecture. And lastly, Mechanism either thought the mechanists thought biology was ultimately reducible to physics and chemistry or some like Ernst Meyer, who we'll talk about as well thought that biology is irreducible not because of the biochemistry of the organism but because of evolutionary principles such as adaptation by natural selection. He thought those kind of things you cannot reduce below the level of what biology is studying. While Organicists said no, biology is irreducible because living systems have a particular organization. They're not made up of anything that's not physical or chemical but they are organized in a different way than non-living systems, okay? So this was not some sort of fringe thing. It was a very, very, very mainstream important movement. It's almost entirely forgotten because what happened during the 20s and the 30s of last century, these two things happened. Genetics was invented for real. I know Mendel came up with the first genetic experiments in the 19th century but genetics was rediscovered at the beginning of the 20th century and then Thomas Hunt Morgan and his Drosophila lab at Columbia University and then a Caltech set genetics to a completely new level. And then of course, as the century went on the chemical structure of DNA was discovered and we have molecular genetics today. And also in evolutionary biology, Fisher Haldane, who by the way was the son of Charles Cobb Haldane, the organist. And also Sewell Wright and other people started to reduce. So first merge genetics and evolutionary theory and then reduce evolutionary theory to the level of genetics. So here are the two pillars of what I would call the molecular genetic dark ages. And I don't want to disparage the sort of methodological and experimental success we've had during that time. But this is a lecture about concepts. Conceptually, those are two rather narrow disciplines. They are very sort of strictly reduced to a specific perspective. They're not very diverse and this is exactly what we want to get out of here. Okay, so let me briefly describe those two pillars. One, the modern evolutionary synthesis unifies evolutionary theory and genetics, as I said already to the exclusion of embryology, they said. This is too complicated. We know that trades grow during development but that's probably not important for evolution on an evolutionary time scale. They focus on change of allele gene frequencies in populations. The modern evolutionary synthesis assumes a straightforward mapping from genotype to genotype. I wrote here phenotype, genotype to phenotype. So you can study the evolution of the phenotypic evolution at the genetic level because the mapping between those two is fairly straightforward. Phenotypic evolution is treated as an epi phenomenon of genetic evolution. For this reason, you can just derive it basically if you understand genetic evolution. And the modern evolutionary synthesis extrapolates phenomena at the population level, population genetics and micro evolution to macro evolution over evolutionary time scales without providing any evidence that the same sort of explanations apply. The second pillar of the molecular genetic dark ages of course is molecular biology. And that includes its predecessor genetics and classical genetics and the omics extension of it that we have today. So these disciplines focus on the molecular components of living systems. So they zoom in away from the organism down to the molecular components. It assumes some degree of genetic determinism like genetic programs to justify that you primarily look at the genes again. So these are philosophical justifications that the reason that both of these pillars focus on genes is not scientific but philosophical. You have to keep that in mind. We'll come back to this point in our later discussions. The organism is nothing but the sum of its molecular parts. So if you figure out all the molecular parts if you do omics, you measure a sequence, everything suddenly the meaning of life will come at you. No problem. It treats molecular mechanistic explanations privileged. So a mechanistic explanation here means at the molecular level. It is heavily positivist, reductionist and physicalist in its philosophy. So positive this we're not gonna go into this very much but it's sort of, you know when a molecular biologist says, I don't need any philosophy because I have facts. That's basically a caricature of positivism and reductionist because of course you get rid of the organism by zooming in to its components. So biological order in this view and this is important to understand is completely accidental. There are no sort of general rules or patterns to be discovered. So it's just one thing after another. So what you have to do is a lot of natural history and you have to study every organism in its own peculiar history. There's no point of doing theory really in biology to a large degree. So, and this is why these two sort of pillars have obscured a lot of the conceptual work and are now making conceptual work in biology really difficult actually. This is one of the main problems that we have. So here's to sum it up, Francois Jacqueau one of the smartest molecular biologists of the 20th century. He exuberantly, 1970, the statue within a beautiful book he says, today we no longer study life. This is no spelling mistake, life with a capital L in our laboratories. This is not a regret. This is, he's thrilled about this. We don't have to worry about life anymore. Remember, biology is the study of life, I thought. At the same time he says, or four years later in another book, the logic of living systems. Every object that biology studies is a system of systems, beautiful quote, object, biology studies objects. No, we should study processes. And also, what are those systems of systems he's talking about? It's systems all the way down. But these systems are no longer the sort of systems where the whole is more than its parts. These are machine systems, cogs that work together. It's an utterly mechanistic view of biology. So how did we get there? It's because this sort of research program, reductionist, genetic, mechanistic has been hugely successful in terms of the new methods and the experimental sort of results that produced over the 20th century. And so this has obscured the fact that it's ontology and also its ontology is wrong and its epistemology is very limited. So it only is one out of many, many different perspectives. And now we're at a point where we can come back the sort of methods we have developed through this sort of excursion into the realm of the molecular world. We have generated methods and also data sets that allow us to go beyond this perspective. So the term systems biology comes up the first time in a book chapter contribution by Mihailo Misarovitch, one of the best theoretical systems biologists that you probably never heard of, still living today and has taken the biological world in a revolution probably from about the year 2000 onward. And this is a reaction to come back to why this is happening. This is a reaction as Erasmus Winter writes in his wonderful entry about systems biology in the Stanford Encyclopedia of Philosophy. Systems biology can be interpreted as a response to the limitations of research strategies, investigating molecules and pathways in isolation. We've hit the wall, we don't understand life. We don't understand systemic thinking. We can't control these living systems with this approach. Synthetic biology is struggling. It doesn't work like electrical engineering and so on and so forth. Okay, so this is why we're discovering, why we're inventing systems biology, which as the Institute for Systems Biology in Seattle on its website proudly announces is based on the understanding the whole is greater than the sum of the parts. So this deep insight, visceral insight that the people around Leroy Hood in Seattle have made is 2000 years old and has only been obscured during the last 80 or 100 years or so. And what we're doing here with systems biology is rediscovering biology as it always was in one way but with a new set of eyes because we have all these new tools, eyes and hands. We have all these new conceptual and experimental tools nowadays that we can use to go beyond what was possible before. So to summarize, systems biology is important but it's not a new thing. And also basically it is about the organism. Here, a few examples of a bunch of beautiful organisms and organisms of course are the quintessential systems. If you talk about systems, organisms are a beautiful example. We're gonna define what systems are a bit more closely in the next lecture. To wrap up for today, in summary, systems biology, we discovered the biology of the organism, nothing else. And to anybody who had an awareness of the history of these lost wisdoms of the past would not have been surprised that this is the time where this is happening. But at the same time, we have to look at what's happening in systems biology today and ask, are we really serious here? Or are we just expanding the good old strategy of genetic reductionism? With our technological capabilities and use it as a larger scale. So let's examine very carefully in the next lecture what I mean when I talk about a system. And then we'll go on and introduce tools to understand systems in a way that takes this concept series. Thank you very much for listening. I hope to see you next time. Bye now.