Dr. Nicole King and Dr. Seth Grant join Cold Spring Harbor Laboratory's David Micklos to discuss the evolution of complex, multicellular animals. Remarkably, the molecules that have driven brain evolution, are the same molecules found in simple unicellula

Dave Micklos: I'm Dave Micklos. I'm here with Nicole King and Seth Grant, and we're talking about how organisms become more complex. Nicole, you're interested in a group of microorganisms that border on the edge of multi-cellularity. Could you tell us what that organism is and what you found out about how unicellular things can potentially become more complex. Nicole King: Sure. We've been interested in understanding how the first animals evolved, and it turns out that the most important first step was the acquisition of multi-cellularity. That is, how is it that ancestral organisms that were strictly single-celled evolved the ability to have cells remain together in a coordinated way, so that their functions actually were synergistic as opposed to competitive. It turns out what we're learning is that much of the genetics, the molecular machinery that allows the cells to interact cooperatively, evolved early in the single-celled organisms for other functions, and then were co-opted to serve functions of allowing cells to communicate and adhere to each other. So it's this exciting example in which all the equipment was there, and then it had to be activated in a particular way to allow the cells to become multi-cellular. And that's the earliest step of the acquisition of complexity on the road to becoming a complex multi-cellular animal. Dave Micklos: And just tell us some of the major classes of molecules that were present in unicellular organisms that were needed to, say, build an animal. Nicole King: Sure. So we think of 3 or 4 particular functions that are required to have a stable and complex multi-cellular organism. And these are molecules that are required to hold cells together, adhesion genes, molecules that allow cells to communicate, and these are signaling molecules, and these typically are receptor on one cell and maybe a secreted protein from another. And then in terms of having cell differentiation, there needs to be ways to allow different sets of genes to be turned on in one cell versus another, so these would be transcription factors; proteins that bind to special places on the genome to turn genes on and off. And the final class of genes are those that are on the cell surface and allow the cells to attach to a secreted matrix called the extracellular matrix. And we find representatives of all of those types of components in the single-celled choanoflagellates. These are the organisms that are the closest living relatives of animals. Dave Micklos: Now Seth, you work on a similar problem, but put a finer point on this. So Nicole has found that some of the elements needed to become a multi-cellular animal were present in single-celled organisms, and you found a similar thing with the nervous system, so if you could say how that relates to Nicole's work. Seth Grant: Well it relates very closely because the brain is considered to be the most cellularly complex organ known, particularly the mammalian brain, made of a billion nerve cells, and if one examines how those cells connect to one another you'll find exactly the kinds of molecules that are important that Nicole has just told us about. And in evolutionary comparisons of the molecules that are found even in the human brain, and the junctions between those nerves cells, you will discover that it is those adhesion proteins that Nicole mentioned, as well those that interact with the extracellular matrix, and also the signaling proteins, and these are amongst the key components of the junctions called synapses between nerve cells. Dave Micklos: And just if you would tell us a bit about the experiment that showed why that was so, that that machinery or that toolkit had been developed over a period of time. Seth Grant: I think the background to this is that everybody thinks of the brain as a super-specialized organ, which it is, specialized for behavior, and behavior is the interaction with the environment. And what we did was to study the composition of these junctions between nerve cells, called synapses, and we did this using a special kind of biochemistry. And what we found was a large number of proteins in mouse synapses. And when we examined where they came from in evolution by comparing the genes that are found in the mouse to those that are found in the organisms such as those that Nicole and others have studied, we found much to our surprise that a very large proportion of synapse proteins are found in animals that don't even have any nerve cells at all; in fact they are only even made of single cells. And it is this sort of machinery which is at the ancestry of the synapse, and thus our mental processes. Dave Micklos: If you try to relate what a single-celled or a colonial organism like yours does to thinking, what would be some of the analogs of what these proteins are doing in the single-celled organism versus our brain? Nicole King: Well I think that one of the things we forget about single-celled eukaryotes is that they're living in a complex and ever changing environment, and so one of the things that these single-cells need to be able do is to interpret and respond to many different types of cues. And so many of the types of molecules we've been talking about are probably used in a way that allows them to determine [that] over here there are a particular type of bacteria that we like or over here there might be some pathogens, it's too cold here; it's a variety of different environmental cues. So those are the types of challenges that single-celled organisms face. Now my understanding in the brain is that part of the source of complexity is the ability to send and interpret many different types of stimuli, and some of the complexity, if I understand correctly, comes from the very different types of receptors and signaling molecules that are interacting. And so recognizing and appreciating that the basic machinery for the molecules that underlie complexity in the brain actually evolved very early, and understanding that they probably evolved in order to allow a seemingly simple organism [to] deal with a very complex environment might help us understand some of the evolutionary foundations for the evolution of something as insanely complex as the brain. Seth Grant: Yeah, I would go one step further and just return to an observation that was made in the 19th century by a scientist called Lloyd Morgan. And he pointed out that all animals need to respond and interact with their environment - perhaps obvious - but he pointed out that the mechanisms that may be found in single-celled animals may be the same kinds of mechanisms that exist even in humans. And this was supposed back in the 1890s. And I think one of the beautiful things is that we've now found that there is a unity, a sort of common origin, to those molecular principles, and they are deeply rooted in the origins of multi-cellularity, which pertains to the most complex organ, the brain. Dave Micklos: Now you've both have used the term 'toolkit' in talking about the proteins that are needed to do things, so if you'd comment just on what you mean by a toolkit, and what you mean by a toolkit. Nicole King: Well I think that the idea here, and the toolkit is a catchphrase for thinking about the structural molecules that underlie the biology of an organism. So we talk about proteins, and then within proteins we talk about protein domains which are interlocking modules, each of which has an independent function. And so you can say, for this given organism it has this suite of structural molecules. Now the toolkit can be implemented in different ways, and so the regulation of how genes and proteins are enacted is a different question. So we can say, "All of these components, these tools, are available. Now how are we going to use them; what are the directions?" And so by having a more sophisticated set of directions you might have a more complex biology, even though the same tools are in place in the two different scenarios. Seth Grant: Yeah I think of the toolkit - which is the proteins, it's the proteins who after all do everything, even though they're encoded by DNA - but it's like a LEGO kit: you get a small LEGO kit when you're a young child, and it has these nice colored blocks of different shapes and you can build all these wonderful things. And you love it so much that next time Christmas comes around, you get an even bigger set with all these extra bits and pieces, and that's essentially what one has got with these higher, greater multi-cellular animals; you get a bigger molecular toolset. In the case of the nervous system, the molecular toolset that all of us vertebrates have is actually much bigger; it's the giant LEGO set as opposed to the little one, which all of the insect and other simpler organism cousins have. And that's why we have much more sophisticated nervous systems, because we can build much bigger things with our enormous LEGO kit.

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