#322      33 min 30 sec
The cost of cognition: The blessing and curse of human brain complexity

Neuroscientist Prof Seth Grant explains how genetics gave rise to the modern human brain, and how the very complexity that characterises our brains makes them vulnerable to neurological diseases that reveal themselves in mental illness. Presented by Dr Shane Huntington.

"It turns out that a lot of the schizophrenia mutations are in fact all converging onto these molecular machines in the synapse." -- Prof Seth Grant




Prof Seth Grant
Prof Seth Grant

Seth Grant established his laboratory at the Centre for Genome Research at Edinburgh University in 1994 and in 2000 was appointed Professor of Molecular Neuroscience in the Division of Neuroscience. In 2003, he was appointed Principal Investigator at the Wellcome Trust Sanger Institute in Cambridge and remained there until 2011, when he returned to Edinburgh University. He has held additional appointments including the John Cade Visiting Professor at Melbourne University (2005), Honorary Professorship at Cambridge University (2007 onward) and elected Fellow of the Royal Society of Edinburgh (2011).

The long-term aim of his research at Edinburgh University is to understand the fundamental mechanisms of behaviour and how these mechanisms are involved in brain disease. The research has focussed on the study of genes and proteins that control the synapses between nerve cells. Multiprotein machines comprising many different protein components are responsible for basic innate and learned behaviours and dysfunction in many brain diseases.

He leads the Genes to Cognition (G2C) research team and is co-leader of the Strategic Mouse Brain Data sub-project of the Human Brain Project (www.humanbrainproject.eu).

Credits

Host: Dr Shane Huntington
Producers: Kelvin Param, Eric van Bemmel, Dr Daryl Holland
Audio Engineer: Gavin Nebauer
Voiceover: Nerissa Hannink
Series Creators: Kelvin Param & Eric van Bemmel

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VOICEOVER

This is Up Close, the research talk show from the University of Melbourne, Australia.


SHANE HUNTINGTON

I'm Dr Shane Huntington.  Thanks for joining us.  Our ability to comprehend the environment around us, to adapt rapidly the changing conditions and to imaginatively express ourselves through art are all outstanding outcomes of an evolutionary process that has generated human brains of stunning complexity.  But what is it that enables our grey matter to achieve such feats?  Are these features solely the territory of human beings or do we share similar traits with other life forms?  As with any mechanism, be it electrochemical or mechanical, added complexity leads to potential problems that are correspondingly complex to resolve.  Diseases that affect the way we think and use our bodies are many and stem from a variety of causes but almost always situated in the brain.  Today on Up Close we're joined by neuroscientist Professor Seth Grant to explore how the evolution of synapses has given vertebrates like us the ability to think and learn whilst also making us susceptible to mental illness and diseases of the brain.  Seth Grant is Professor Molecular Neuroscience in the Centre for Neuroregeneration at the University of Edinburgh.  He is in Melbourne to speak at the 2014 Melbourne Brain Symposium, an event jointly organised by the Melbourne Neuroscience Institute and the Florey Institute of Neuroscience and Mental Health.  He is also delivering the annual Kenneth Myer Public Lecture as a guest of the Florey Institute.  Welcome to Up Close, Seth.


SETH GRANT

Yes, thank you, Shane.


SHANE HUNTINGTON

I think we'll start with just the role that synapses actually play in the brain.  Can you give us a description of where they fit in?


SETH GRANT

Well most people will realise of course that all organs in the body are made from cells and there's very large numbers of them but the nerve cells in the brain are very unusual compared to other cells in other parts of the body because they have specialised junctions between them which are called synapses.  Now not only do they have junctions between them but the nerve cells in the brain have very long extensions or fibres which have names like axons and dendrites.  Those long axons and dendrites have on them about 10,000 synapses per cell which means then that every nerve cell in the brain can contact as many as 10,000 other nerve cells.  Just contrast that with a liver cell for example.  A liver cell may only touch another 10 or 20 cells so nerve cells and the synapses are what make the brain different to all other organs.


SHANE HUNTINGTON

When we talk about the communication between cells, how does that actually take place?  What's occurring?  We're not talking about the exchange of chemicals necessarily are we?


SETH GRANT

Well these specialised junctions, these synapses are the place at which chemicals are exchanged between the two cells.  They send signals to each other.  They talk to each other.  The best known examples of that are what is called neurotransmitters and I think many of your listeners will be aware that there are chemical neurotransmitters, they may have heard about them in the context of different medicines or diseases, they've been known for almost a century but these chemicals are released from the ends of the axons and they then impinge upon the synapse membrane on the other neuron and that activates those recipient neurons to then discharge an electrical activity which then traverses the long fibres between that cell and the next.


SHANE HUNTINGTON

This seems like an incredible evolutionary step to have been achieved at some stage in the history of biological life on the planet.  How far back do we go and still find these synapses?


SETH GRANT

It's a very interesting question because if one looks into the fossil record you'll discover that large multi-cellular animals first appeared about 600 million years ago.  If you go back into older sediments you won't find any large fossils, you'll only find single celled organisms but then when you look carefully at those very first organisms it's strange that in a very short space of time it's clear that there were animals with nervous systems so not only did multi-cellular animals originate quickly and abruptly in the fossil record but it would appear that something as complicated as the nervous system turned up extremely fast and we have very good reason to believe that the synapses in those ancient organisms were super sophisticated.  That is because when we examine jelly fish for which we can find fossils about 600 million years of age, if you look at the jelly fish today they have very sophisticated nerve cells with all kinds of different neurotransmitters and ways of regulating each other so it's always been a bit of a puzzle, why did and how did those neurons arise and those synapses arise so quickly after the very first animals?


SHANE HUNTINGTON

Now there are many parts of biology where when we break them down we look at them, we can see that nature seemed to just get it right a long, long time ago and continues to use those evolutionary steps to this day.  How much have the synapses actually changed from these early versions you talk about?  Are we still essentially walking around with similar structures to what you might have found in an early dinosaur?


SETH GRANT

Well this very much depends on how you look at it and I'd like to sort of cast your mind into one of two frameworks.  One is what I would call the traditional neuro-anatomist framework and you must appreciate that the synapses were discovered in the last part of the 19th century by neuro-anatomists who were staining the cells in the brain.  They could see the junction between the nerve cells first described by Ramón y Cajal and for that and other contributions he won the 1906 Nobel Prize.  But those synapses and that neuro-anatomical view have really dominated our thinking even to the present day but it's only been within the last decade or so where molecular neurobiologists, people like myself have been able to ask how and when did synapses first evolve from a molecular perspective?  This is where we come to an answer to your question.  As it turns out, the molecules that are synapses that perform all of those specialised jobs of communicating and releasing chemicals and sensing chemicals, all of those molecules actually evolved before there were any fossilised animals.  They arose in single celled organisms three billion years ago and for a couple of billion years these synapse molecules were only in unicellular organisms that were swimming around in ponds and [the] sea and in those cells they were sending their environment as well.  In other words the molecular machinery of synapses was invented a very, very long time before animals.


SHANE HUNTINGTON

It sounds very much like the drive for those cells to be produced was in no way related to what we think of now as the ability to think.  It was completely a response to the environment at the time.


SETH GRANT

I like to look at those unicellular organisms and say they're thinking too but they're thinking probably about the same things that we think about and there's often said that all animals if you could speak to them would probably all want to talk about food and sex and that is also true for these microorganisms because much of the time these molecules and sensors are there specifically for them to sense their environment, sense food, sense each other, communicate and mate and breed.


SHANE HUNTINGTON

Now let's break one of the synapses down and you can choose your animal of choice here as to which one we look at.  What are they actually made of?  What components would we find if we pulled them apart?


SETH GRANT

When you take synapses out of the human brain and we'll talk about that species since I think your listeners would be mostly interested in humans, you can do so by taking a biopsy out of the cortex of a human who's having a brain operation and take a very small amount of that tissue and you can separate out the synapses and then with a detergent and salt solution you can solubilise all of the proteins that are within them in the same way that you solubilise proteins when you're washing the dishes at night and scrubbing them off the plates after you've eaten a steak.  You can solubilise those proteins in a solution and then you can take that solution and place it into an instrument called mass spectrometer.  This instrument will measure the molecular weight of all of those proteins and using reference information we can identify the names of those proteins and indeed even the genes that encode those proteins and so produce a comprehensive molecular parts list of the synapse.  We call that parts list the synapse proteome and in humans we found that the synapse proteome consists of about 1500 different proteins each encoded by a different gene.


SHANE HUNTINGTON

I'm Shane Huntington and you're listening to Up Close.  We're discussing synapses with neuroscientist Professor Seth Grant.  Seth, my understanding is the synapse you'll find in a vertebrate is more complex than what you would find in an invertebrate.  Given the origins you've spoken about why is there that disparity?


SETH GRANT

That has turned out to be a very interesting observation and we first made that observation in 2008 and we did so by analysing the protein composition of synapses in the mouse and compared them with those in the fly.  We discovered that there seemed to be many more proteins in the mammalian synapses compared to these insect invertebrate synapses.  And this was a little bit of a puzzle because the neuro-anatomists who look at the cells and stain the cells and look at the synapses couldn't see any difference between those synapses and it was largely thought that the synapses were really not very different at all between invertebrates and vertebrates but it turns out that they're molecularly much more complicated in vertebrates.  We looked into this in quite a bit of detail and we found that the mammalian synapses had two or three times as many proteins as did the invertebrate synapses.  We were a bit puzzled by this because nobody had ever expected that to be the case.  In fact some people said they didn't even believe it but it turns out that it's correct and we now know the explanation for the increase in this complexity.  We found that not only do humans and mice have many more synaptic proteins but in fact all of the vertebrates that we have examined have many more proteins than all the invertebrates as a general rule.  The question becomes how and when did that come about and it's quite straight forward to work this out because since all of these different vertebrates have this big increase in the proteins and we know that those vertebrates diverged from one another in the fossil record as much as 300 million or 400 million years ago.  We can deduce then that the evolution of this increase in complexity must have occurred about 400 million or 500 million years ago.  This is where our work converged with another very important discovery made by scientists who were sequencing the genomes of very simple vertebrates.  They found in the same year that we found that there were many more proteins in the synapses, the genome scientists discovered that there really was a very profound event that happened in the very earliest vertebrates.  It was that there was an ancient invertebrate and one of its offspring had a gene mutation but it's the biggest mutation of them all, it produced a whole extra entire genome.  In other words every gene was duplicated.  It's called a whole genome duplication.  So this animal and its offspring had an extra entire genome and not long after that, I say not long, it may have only been 50 million years but one of its offspring had a second entire genome duplication so now you have one duplication followed by another producing four copies of the genome.  This animal had as many as four of every single gene as its invertebrate ancestor had. And what is so surprising is that it was this one animal that gave rise to all of the vertebrates on the planet today.  As a result of those two rounds of whole genome duplication vertebrates have been endowed with extra copies of all of the genes and that includes extra copies of these synapse genes and that is why there are so many more proteins in the synapses of the vertebrate compared to the invertebrate.


SHANE HUNTINGTON

Seth, people have obviously heard about the enormous computational power of the human brain.  How do the synapses fit into the production of that power that we have?


SETH GRANT

I like to think of it like the internet.  When we think of the internet and its computational power we think of all of the different computers that are connected by all of the different wires and when you think of the internet you don't really think of the wires and the cables as doing much in terms of computation, you think about at those computers where it's all happening.  Now in the brain it's very much like that as well because it's in the synapses where a lot of computation actually occurs and it is because the job of the synapse is not merely to pass a message from one cell to another, it certainly does that and that is important but that's not the only thing it does.  It also sits there and analyses the information and it does so because there are little molecular machines inside synapses sort of like little computer chips and they sit there and they listen to the signals, they process the signals an then they modify the nerve cell so as to change its properties.  In fact it is that ability to do that that is responsible for laying down the learning and memory traces.


SHANE HUNTINGTON

Now whether we're talking about something like the space shuttle or the intense coding that goes into a super computer complexity always seems to mean there's just that much more that can go wrong.  Is this rule followed in the case of the synapses?


SETH GRANT

It certainly is and this I think is really at the root of answering one of the most puzzling and ultimately important questions about the complexity of the nervous system.  If you ask yourself what happens when it goes wrong the nervous system goes wrong by producing a very large number, hundreds of different diseases.  Now the question is, why is something that is so complex as the nervous system also vulnerable to so many different diseases?  The answer goes back to this very simple story about how the genome became complex through these genome duplications.  On one hand we had the extra genes giving us a more complex and diverse molecular machinery which gave us a more complex and diverse set of behaviours and that is a wonderful thing for the vertebrate to have but it comes at the price.  The price is that those extra genes are places of vulnerable and mutations can damage any gene at any time and those extra genes are therefore the place at which those mutations occur. And we find then that many of those new genes that arose in the vertebrate when they go wrong are responsible for a very large number of diseases afflicting humans and indeed other animals.


SHANE HUNTINGTON

How much of this is happening early in life?  Because when we're talking about evolution the real key to passing on effective sets of genes is during the procreation years of a species.  Now in humans most of us have done that by age 40.  How much of these problems that you see with synapses are occurring after that age and hence are not really being knocked out of the evolutionary tree as a result?


SETH GRANT

Well the important thing to understand is that mutations in DNA are the engine of evolution.  Every time a cell divides there are mutations, changes in the DNA sequence that occur in the offspring of the parent cell.  There is about a thousand million nucleotides in the DNA sequence of humans and every time a new single cell human is conceived there's probably as many as about 100 new mutations.  They're called de novo mutations.  Every child that is born will carry some new mutations that the parents did not have and if they're unfortunate enough to have one of those mutations hit square in the middle of an important gene that encodes a synapse protein then they may well result in having some kind of mental illness.


SHANE HUNTINGTON

A lot of your experimental work has been done with mice.  We've talked about a variety of different species and vertebrates, non-vertebrates and so forth.  How similar are the synapses in mice to humans and can you track directly across when you do these particular measurements?


SETH GRANT

We looked at that a few years ago and we did it by directly comparing the synapses of mice and humans using molecular techniques.  We isolated all of the proteins out of human synapses from patients who were having brain surgery, we used a small amount of their tissue and also the same type of approach was used to isolate synapses from the mouse brain and we looked at all of the different proteins in great detail.  We compared their sequence of the amino acids, we compared the sequence of the genes and we found something that was rather surprising.  Despite the fact that mice and humans have evolved from a common ancestor about 90 million years ago and of course we appear to be very different in terms of size and a few other physical characteristics, it turns out that the synapse proteins of mice and humans have remained extremely similar to one another.  They haven't changed very much over those 90 million years.  In fact if you compare the extent that they have changed with other proteins, in fact even other brain proteins or other tissue proteins, you find that the synapses proteins have not changed as much as these other ones.  Now why might that be?  Well it's certainly not because mutations don't occur in those genes, they occur as much in synapse genes as indeed any other set of genes but the reason the proteins haven't changed as much is that natural selection appears to have not permitted those changes to be transmitted into the population.  In other words, the conservation of those proteins is because they're doing some very important functions in organising the structure and the physiology of brain synapses.


SHANE HUNTINGTON

You're listening to Up Close.  I'm Shane Huntington and my guest today is neuroscientist Professor Seth Grant.  We're talking about the role played by synapses in the brain.  Seth, in order to make this work valuable from looking at mice you need to be able to test both their personality and their behavioural traits.  How do you go about doing that with a mouse?


SETH GRANT

This is a really interesting issue because I think everybody will be aware just by even looking at little cartoons in magazines of mice doing mazes and things and doing mazes of the kind that humans actually never do. And for many, many decades scientists have used rodent specific mazes and they have tried to extrapolate from the behaviour of rodents in those mazes to some aspects of human behaviour but there's a lot of reasons why that extrapolation is really not well founded.  So there was an important breakthrough made by Cambridge scientists about 10 or 20 years ago who decided that they would take on computer technology for testing psychological functions and take them on from pen and paper tests with humans.  They produced essentially psychological tests on a touch screen just like an iPad so images would be presented on the iPad and you would be asked to remember something or the location of a particular image and do all kinds of psychological tests measuring your ability to learn and do complicated types of learning.  And that was adapted into humans.  And then some scientists took those iPad tasks and asked the question I wonder if rats and mice could actually do this if we sort of put an iPad effectively in the mouse cage and every time it does the right thing we'll give it a little snack as a reward.  And lo and behold mice and rats are extremely good at doing these things so it turns out that you can use the same psychological test or something very similar to the human psychological tests in rodents.  And so recognising that we now had a means of directly testing the same components of learning and memory and other aspects of cognition in mice and rats simultaneously we wanted to take it to the next step.  We decided that we'd like to ask this question, are the genes that are controlling synapses in mice doing the same thing in humans?  And we made some mice where we genetically engineered them to have a defect in a gene, a gene called DLG2 and these mice showed particular learning impairments in their little iPad touch screen tests.  And then we collaborated with some clinicians who had some patients with a DNA mutation just like the one in the mice, it was in the DLG2 gene and they tested them on the iPad touch screen tests. And lo and behold they found that they had the same psychological impairments.  In other words this gene was doing the same thing to our behaviour as it was doing to the mice.  This tells us something really interesting.  It says this gene has been doing the same thing for the last 90 million years.  And here's the punch line.  That gene I'm talking about is a gene which is at the root of patients who have schizophrenia.  Some patients with schizophrenia have a mutation in this gene and therefore we can say that schizophrenia is a very ancient disease, it started to arise before humans, it occurs in mice but perhaps more important is that the mouse can now be used as a model through which we can test and try to discover new drugs to treat schizophrenia.


SHANE HUNTINGTON

Seth, it is exciting to think that we have this direct link between the genes in our own bodies and these problems with the synapses and the problems that result from that like schizophrenia.  What does this mean in terms of treatment?  Are you able to effectively switch these genes off or are we back in that game where we don't know the real activities of those genes across the entire, you know, body that we have?


SETH GRANT

I think we're on the verge now of knowing enough about this molecular machinery to start to develop entirely new ways of finding drugs to treat schizophrenia and other mental disorders.  The drugs that are presently available haven't really changed much for several decades and they were developed in an era when the molecular basis of the nervous system just simply was not understood but now we know all of the molecular parts lists, we can look at the sequence of those proteins, we can look at the types of structures of those proteins and we can decide which ones are important and we can now identify completely new classes of drug targets.  To give you some ideal. Virtually every drug that is used to treat nervous system disorders operates on neurotransmitters but it is only a small fraction, maybe about five per cent of all of the proteins in the nervous system that have anything to do with neurotransmitters.  There's about 90 per cent of other molecules which represent new potential drug targets so I think there's really a wonderful frontier now for the translation of this basic science through new drug assays and new discovery methods.


SHANE HUNTINGTON

Presumably knowing that I have the gene that can potentially lead to schizophrenia, the key word there being potentially, what other factors have to be in play?  Is this similar to other diseases where we know a person, their environment for example is critical to the onset of that disease?


SETH GRANT

I very much like that question because you're really putting your finger on one of the deep and unanswered problems in nervous system diseases and in fact other diseases for which there is a genetic basis and the problem can be expressed really very simply.  Why is it that if a single celled embryo contains the DNA mutation in it and throughout the entire lifespan of the individual that mutation is present but why is it that the disease only starts at a certain time?  For example schizophrenia typically begins in young adults in their 20's but they have that DNA mutation from the moment they're conceived.  Why don't they develop the disease when they're five or twelve or ten?  Why is it at 25 that it starts?  Why is it that other diseases start at a very characteristic age?  You will not find an answer to that from any scientist I know, and we simply just don't know the answer.  There's something very interesting going on there.  There's some general principle that we are as yet unable to understand.


SHANE HUNTINGTON

Presumably with the, as you said earlier, very large number of diseases that can be caused by problems in the brain we have a range of different genes that we need to look at, how far through that list have we gone?  You mentioned schizophrenia.  What other diseases have we managed to get a better handle on as a result of this sort of work?


SETH GRANT

That's also a very interesting question because it speaks to the way in which science is currently progressing.  One of the most exciting and important advancements in the last 15 years in biology and now in medicine has come through the Human Genome Project.  This project has stimulated the engineers to produce better and faster DNA sequencing machines and as a result of that you will now find that large studies are being done where hundreds and thousands of different individuals are having their entire genome sequenced.  And when you analyse that DNA sequence on a computer you can identify by comparing the sequences the genes that are defective in one individual or another individual.  As a result of all of the 20,000 or so genes in the genome, for every individual you can say these appear to have a mutation in this gene or in that gene.  So now put yourself in the position where the clinical geneticists want to find out the heritable basis of some disease or another.  They will take a large set of patients with that disease and they'll sequence their genome and one of the things they're discovering is that they come up with a list of different genes.  Why is this interesting?  Well it's interesting because for many diseases we used to think wouldn't it be great if it was just one gene that caused it, wouldn't that be nice?  And in fact there are some very important diseases that are caused by a defect in only one gene.  Huntington's disease is a nice example but schizophrenia on the other hand would appear to have mutations in as many as a hundred or perhaps even a couple of hundred different genes so if you just look at the list of those genes it's rather baffling.  You don't understand what's going on.  You know there are mutations there but there just seems to be a lot of them and if you look at the list of the genes they just look like a lot of different proteins.  How can we understand that?  So that's one area of science but this has converged very nicely with our work on the synapses because in our work on the synapses where we've looked at the proteins not only have we just found and discovered and characterised all the proteins in synapses but we have also found that within those lists of proteins that there are molecular machines which are made up of dozens of different proteins together.  And these are these molecular machines that are detecting and listening to the neural activity.  We took the information on the genes that cause schizophrenia and we asked a simple question, are those genes that cause schizophrenia, those great big long lists, is there anything about those lists that is relevant to our synapses?  And lo and behold it turns out that a lot of the schizophrenia mutations are in fact all converging onto these molecular machines in the synapse.  And that tells then a very simple story.  In the same way that your car can break down if you damage innumerable different parts so can your synapses break down in schizophrenia.  Those different mutations can now make sense.  They're converging on the synapse.


SHANE HUNTINGTON

Seth, we've spoken quite a bit about the Genome Project, it's one of the biggest science projects that's happened over the last 50 years or longer.  What sort of big science projects, big data projects are happening with regards to the human brain itself?


SETH GRANT

Well we've had to be driven by the observations themselves and it turns out as I've said earlier, that there are so many molecules in the brain that you can no longer take the sort of one gene at a time approach and you have to now use tools which allow you to look at hundreds and thousands of different genes and proteins simultaneously.  You can use DNA sequences and mass spectrometers and other instruments and new kinds of microscopes that allow us to map millions and millions of synapses with gigantic data files are all becoming the new way of doing biology.  So we're in an era now where it's imperative that we have new tools for the acquisition of very large datasets but equally we also now have to have in our laboratories experts on storing and handling those data and analysing them with sophisticated statistical methods.  In my own group for example we have a number of highly specialised computer scientists who are handling these vast amounts of data and then putting all of this data into the public domain for many other people to analyse.  This is an important new direction through which the precedent of the genome has really changed everything.


SHANE HUNTINGTON

Seth, thank you very much for being our guest on Up Close today.


SETH GRANT

Thank you.


SHANE HUNTINGTON

Seth Grant is Professor of Molecular Neuroscience in the Centre for Neuroregeneration at the University of Edinburgh.  If you'd like more information or a transcript of this episode, head to the Up Close website.  Up Close is a production of the University of Melbourne, Australia.  This episode was recorded on 15 October 2014.  Producers were Kelvin Param, Eric van Bemmel and Dr Daryl Holland.  Audio engineering by Gavin Nebauer.  Up Close is created by Eric van Bemmel and Kelvin Param.  I'm Shane Huntington.  Until next time, good bye.


VOICEOVER

You've been listening to Up Close.  We're also on Twitter and Facebook.  For more information, visit upclose.unimelb.edu.au.  Copyright 2014, the University of Melbourne.END OF TRANSCRIPT


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