eLife Episode 12: Why we don't (often) bite our tongues

The neuroscience of chewing, sleeping sickness, the proteins that move molecules around cells, skin cancer, and the open access movement...
10 June 2014
Presented by Chris Smith


In this episode of the eLife podcast, the neuroscience of chewing, African sleeping sickness, skin cancer, and an ancient protein complex called TSET. eLife editor-in-chief Randy Schekman also shares his thoughts on scientific publishing...

In this episode

Why we don't bite our tongues too often
with Fan Wang, Department of Neurobiology at Duke University Medical Centre

Brainstem jaw motor circuitsWhy when we speak or eat do both sides of our jaw move? Chris Smith put this question to Fan Wan from Duke University Medical Centre, Department of Neurobiology.

Fan -   So, the question we had in mind is, how do we use our muscles in our face and mouth in a highly coordinated manner?  For example, when you eat banana, your tongue is trying to position the banana between your teeth and your teeth are chewing it down.  Once it's grinded into a mushy bolus, you're automatically using other muscles in your throat to swallow it, without much effort.

Chris -   And I suppose that the additional complexity is that these are muscles that are paired because you've got one set on one side of your face, one on the other and they've got to move together in order to move your jaw symmetrically.

Fan -   Yes, exactly.  So, mammals have their jaws, a lot of them fuse in the midline.  So, if you try to chew on one side, the other side automatically also move together.

Chris -   So, one therefore has to ask, do they work in that coordinated way because there are connections between the nerves that supply those individual muscles at the level of the brainstem where those motor nerves originate?  Or are there signals coming down from above higher centres up in the brain which are activating them together so that you get a coordinated movement?

Fan -   Precisely.  So, we actually took a relative naive approach.  We wanted to see what neurons are connected to the different motor neurons.  So, we use a virus that can infect from the muscle and to the motor neurons that sort of supplies the muscle, controls the muscle.  And then the virus can replicate itself in the motor neurons then jump to other neuron that connect to these motor neurons.  So, while we did such studies for the jaw muscles and the tongue muscles, when we labelled the neurons connected to one group of motor neurons, we found those neurons also send axons to another additional group of pre-motor neurons.  What we find are the pre-motor neurons have one branch connected to the left side of the jaw muscle.  The other branch connect to the right side of the motor neurons that control the right muscle, thereby, providing a simple solution to synchronise the left and right side.

Chris -   So, does this mean then, if I were to go in and deactivate those pre-motor neurons which are effectively the coordinators of this movement on one side of a brain stem, just if I deleted them or took them away.  Animals should still be able to activate the muscles co-ordinately on both sides of their face because the other side would nonetheless turn on the right groups of motor neurons in the right order.

Fan -   Exactly.  I think that's our prediction.  We're actually trying to do the exact experiment that you just proposed.

Chris -   Probably the most important question of all, have you discovered why we do or don't bite our tongues?  Sounds like a slightly fastidious question, but actually, it's an important one because tongue movements are very highly coordinated with chewing movements, aren't they, because otherwise, we would be lopping off our tongues every time we had a meal.

Fan -   Exactly.  There are two aspects.  Neurons that control the motor neuron of our tongue sticking out are always simultaneously controls at the door opening motor neurons.  In a sense that when you're sticking your tongue out, you are obligated to open your jaw.  And that is a simplest mechanism to ensure you don't close your jaw but bite to your tongue.

Chris -   What have you actually found though that is genuinely new here?  Because when one goes and looks at a patient who's had a stroke, medical students and doctors look at the patient and ask them to say, raise their eyebrows or smile because this can distinguish between whether they've got damage to the lower motor neuron or the message not getting through from above.  It's well-known that if you damage the brain stem, the motor neurons, you will be paralyzed on one side of the face.  But if the upper motor neuron is damaged, you can still nonetheless make these symmetrical bilateral movements.

Fan -   Good point, yes.  So especially in the brainstem, it seems there are

promoter neurons.  A lot of them do have bilateral projections although it's a ipsilateral or one side sort of a concentration, a bias.  Previously, people find are, you can stimulate one side of the cortex, this is done in animals, and then you can initiate bilateral synchronised movement of the jaw.  However, when you cut the midline of the brainstem, you will lose this ability to synchronise the jaw movement.  You need some sort of connections across the midline at the brainstem for bilateral synchronised jaw movement.

Trypanosomes - the parasite that causes sleeping sickness keeps one step ahead of its host.

06:01 - Eczema prevents skin cancer

The immune response triggered by eczema may reduce the risk of skin cancer

Eczema prevents skin cancer
with Fiona Watt, Centre for Stem Cells and Regenerative Medicine at King's College London

The issue of eczema and whether it's linked to skin cancer is controversial, KCR Scientist Esther Hoste and Fiona Watt spoke to Chris Smith about what they have discovered...

Fiona -   There's been a long debate about whether or not people who suffers from allergies have an altered risk of developing cancer.  Looking at the figures, I would say for every study that suggests the positive correlation, there's one that shows a negative correlation, and one that shows no effect at all.  But nevertheless, it is of interest because there's a very strong inviting concept that harnessing the immune system in some ways can be a useful way of treating cancer. Trypanosomes

Chris -   Why should there be a relationship between dermatitis and skin cancer?

Fiona -   In theory, if you believe that the immune system is involved positively or negatively in tumour formation, then we know in eczema that the immune system is on red alert and that's why you have scaly and itchy red skin.  It's quite natural to expect that in that situation, you would have an altered response to insults that would cause cancer.

Chris -   And so, hypothesis would be, if you have an immune system on red alert, that it should be more vigilant towards any cells that are trying to become cancerous and delete them, but then is not a flip side of the coin that an immune system on red alert is going to cause more inflammation.  We know that sustained inflammation is in and of itself a risk factor for cancer.

Fiona -   Yes, absolutely.  So, when we setup the experiments, we were completely divided about what the outcome would be.  We genuinely did know what to expect.

Chris -   Esther, you work with Fiona on this project.  How did you actually do the study to try to unpick which of those two outcomes it was going to be?

Esther -   Because the human system is very difficult to study because atopic dermatitis or eczema is a disease which has a relapsing and remitting nature which we had to shift to an animal model to study the importance of the atopic phenotype on skin carcinogenesis.  Because people that are suffering from atopic dermatitis are often treated with immunomodulatory drugs and that actually will clearly hamper our conclusion.  So, we created a mouse model in which there are three proteins lacking that play an important role in epidermal barrier function.

Chris -   Does the absence of those proteins then trigger an atopic state in your animal model?

Esther -   Yes, so if you knockout those three proteins, what you get is you get an increase in certain immune types while other immune types are actually reduced.  And phenotypes that we see are actually, they exhibit hallmarks of the active state of atopic dermatitis.

Chris -   So, this gives you an animal where if you were to look at the skin, you would see characteristics very reminiscent of atopic dermatitis in a person.

Esther -   Yes, that's right.

Chris -   And so, you can be reasonably sure that you've got a faithful model there in which to then test the rates of cancer development.

Esther -   Yes, I think that's one of the biggest novelties that we used for the first time.  An animal model in which the epidermal barrier is clearly defective and has also an immune component which really mimics the disease.

Chris -   And then what about the skin cancer side of things because animals don't develop skin cancers over their lifetime like a human does necessarily?  So, how did you mimic that?

Esther -   Yes, so in order to induce tumour formation in these mice, we make use of two chemical components.  One is a component called DMBA that actively induces mutations in H-ras which is a very important protein in tumour formation.  If you just applied DMBA agents, mice don't get tumours.  But if you promote the tumour genesis with another component that is called TPA, you start to get tumours.

Chris -   And so, if you then do the obvious experiment which is, you do this in mice that have the deficient skin barrier so they're mimicking atopic dermatitis, eczema, versus animals that don't have the deficient barrier so they're like a person who doesn't have eczema.  What's the difference in rates of skin cancers in those two groups?

Esther -   What we saw is that the mice that has atopic dermatitis, they're highly resistant to skin tumour formation.  So, they develop much less tumours.  There were also mice that did not develop any tumours at all while the control mice, all made tumours.

Chris -   Quite striking findings there, Fiona.  How do you actually account for this and what do you think the implications more broadly are then?

Fiona -   I think in terms of the basic biology, the important point is the skin has a defective barrier in our model that is linked to increased cancer resistance.  We believe that that is because the immune system helps to insure that cells with cancer's mutations are expelled from the skin.  So, that's the key conclusion from our findings.

Trypanosomes - the parasite that causes sleeping sickness keeps one step ahead of its host.

11:46 - How trypanosomes sidestep immunity

How the parasite that causes sleeping sickness keeps one step ahead of its host.

How trypanosomes sidestep immunity
with Christopher Batram, Department of Cell and Developmental Biology, University of Würzburg, Germany

Trypanosomes, the organisms that cause sleeping sickness, are extremely difficult to eliminate from the body partly because the organisms frequently shuffle the antigens that they express on their surfaces, so they present a moving target to the immune system.  How this antigen shuffling trigger is achieved though is a mystery.  The University of Wurzburg's Christopher Batram has found that when the bugs activate a new antigen, they use an epigenetic system to shutoff the expression of the old one. TrypanosomesHe explained this to Chris Smith...

Christopher -   African trypanosomes which cause the sleeping sickness in humans evade the host's immune system by expressing markers on the said surface that are recognised by the immune system.  They have a huge family of this marker genes in the genome, but only one is expressed at any given time.  Nothing is known about the mechanism of how this is achieved, how just one marker is expressed at any given time and the other ones remain silent.

Chris -   Do the parasites, the trypanosomes change those markers at various points in order to make themselves look different, give themselves a chemical facelift if you like, so the immune system finds it hard to recognise them?

Christopher -   Yes, they periodically switch the expression from one marker to another.  It's not known how they do these switches.  So, the problem you've got is, how do we turn off a very big group of genes?  Leave just one active, but then periodically, totally mix things up and select a gene from the inactive group and suppress the one that was turned on.

Christopher -   Exactly.  The question was, how do trypanosomes activate a new antigen and how they de-activate the previously active one?  One possibility is that the active one could first be silenced before a new one is activated.  There's a little problem with that because silencing the active gene by RNAi causes a cell cycle arrest the cells eventually die.  So, we hypothesise that this could be the other way around.  A previously silent gene is randomly activated and thus, this is causing the deactivation of the active one.

Chris -   I see.  So, a new one switches on and it's the process of switching on the new one that in some way, turns off the existing one.  In this way, you've always got a surface marker gene active, so you won't go into cell cycle arrest, but you don't turn off the existing one until you've got a new one ready to go.

Christopher -   Exactly.

Chris -   What experiments did you do to then workout whether that was the case?  Did you put some kind of marker into one of the genes and then turn it on with another to see if that marker does what you would predict it would?

Christopher -   Yes.  So, we introduced a second surface marker gene into a different genomic context which we can inducibly express by adding a chemical.

Chris -   And when you turn on that second gene, does the first gene switch off as you would predict it would?

Christopher -   Yes, it does.

Chris -   How did you then unpick that?  So, do you know what the new gene coming on is doing to the transcriptional system for the first marker gene to make it shut down?  How's that being achieved?

Christopher -   So, this remains unknown.  We know that it depends on histone modifications.

Chris -   So, that's interesting.  So, rather than it, directly shutting off promoters or something, it's doing it via a modification of the histone.  It's doing it epigenetically.

Christopher -   Yes, exactly.  That is the case.  We did the same experiments with the knockout cell line in which histone methyltransferase was deleted.  When you over expressed the second gene of these cells then the endogenous gene was silenced, but not the whole transcription unit.

Chris -   So, you over expressed just the surface antigen gene for the second surface marker and this had this shutting down effect.  So, there must be something intrinsic to that antigenic signal which is activating this epigenetic modification apparatus.

Christopher -   Yes.

Chris -   How is it doing that?

Christopher -   We don't know.  That's the big question we are challenged with now.

Chris -   Would you like to speculate because you must have some theories as to how it's doing this?  What do you think is going on?

Christopher -   It could be that the initial spike of the production of two surface antigens could relay a signal to the silence machinery in order to maintain this monolithic expression.  So, one possibility is that there's a signal coming from the endoplasmic reticulum, folding proteins so-called chaperon or something like that, but we have actually no idea.

Chris -   This could be very important, this mechanism because one of the big problems with sleeping sickness, trypanosomiasis, is that it's very hard to rid the body of these bugs, the immune system can't get a handle on them because they evade immunity.  So, if we can find a way to clog up their system and stop them shapeshifting themselves in this way, maybe the immune system would gain the upper hand and eliminate them.

Christopher -   Exactly.  This is the future goal - to get more insights into this mechanism, how the transcription unit is silenced.  When we can trigger this chemically, then we can get rid of the parasites, maybe.

A protein complex called TSET sheds light on the evolution of trafficking pathways.

17:10 - Finding a missing link

A protein complex called TSET sheds light on the evolution of trafficking pathways.

Finding a missing link
with Jennifer Hirst, Cambridge Institute for Medical Research, University of Cambridge

Margaret Robinson and Jenny Hirst working in Cambridge have between them, invented a new electronic tool to prove various databases, looking for previously undiscovered proteins that form complexes that move molecules around inside cells.  What this system flushed out was a whole new complex - TSET - that can trace its origins back to the first eukaryotes. They spoke to Chris Smith... TSET - Protein complexes

Margaret -   So, what we're interested in is, how different molecules find the right part of the cell.  We're interested in the machinery that the cell uses to get things to the right place.  We're especially interested in things called AP complex which stands for adapter protein complexes.  Each of these complexes is made up of 4 different proteins.  And for many years, we thought that there were 4 of these complexes and then just a couple of years ago, we discovered a fifth which took us all by surprise.  We thought, well maybe, there are even more of them out there.

Chris -   Their role is quite literally to package things up to the right place and address it to the right part of a cell.

Margaret -   Exactly.  What they do is they find molecules, they package them into little containers that can then be delivered to a different part of the cell.

Chris -   Jenny, if you want to find something and you don't even know it exists, which is what you had to do with this study, how do you do that?

Jenny -   First, you scratch your head and you try and think of some ideas, and very long conversations over dinner with my husband.  I suspected that there was something else to find.  But it was a case of putting our heads together and using some computing skills because the 5 complexes we already knew about, we knew what the family resemblance was and it was a case of figuring out how you were going to use that information to search hundreds of thousands of protein sequences, by automating it.

Chris -   It's a bit like Mandalaya for this period table that he knew there were gaps that would fit the board, but didn't have the element for them at that time and then knew where to go hunting.  So, what did this show, Margaret?

Margaret -   So, what we found was, we know that there are 4 subunits in each of these complexes and what Jenny discovered was one new member of each of the 4 subunit family.  So, we had the 4 subunits that might be used by a cell to make a whole new complex.  The next step was to find out whether these 4 proteins really were all stuck together.  And for this, we couldn't look at humans because although humans have got these 5 AP complexes, the 4 proteins that Jenny discovered with her new tool didn't all exist in humans.  They existed in plants, and slime moulds, and this weird soil amoeba.  But animals have lost 3 of the 4.  We've hung on to the fourth one, but not the whole thing - just a little fragment of it.

Chris -   Do you think there's any possibility that because Jenny's tool is mining data that's already been published by people that the undiscovered has remained undiscovered and that people just haven't published the protein sequences that were they to exist, her tool would've found them?

Margaret -   I don't think so because it's not just publications.  It's things like the entire human genome.  So, we know the sequence of the whole human genome and from that, we can predict the sequence of every protein in humans.  And the same is true with lots of other organisms including plants and these weird things like the slime mould and the soil amoeba.  So, I think that the proteins are there and the database is just a case of finding them.

Chris -   What are the implications of, now, you've got these additional proteins, admittedly not in us, what can you do with this information?

Margaret -   It's more about understanding where these important proteins that we have today, where they came from.  So, I suppose it's a leap to think, well, we're looking at something that's today in disease.  But I think it's important to know how these families evolved.

Jenny - Yes, I think it's about our understanding of the evolution of life on Earth.  Especially since this new complex predates the 5 that we already knew about, it must've existed long before the last eukaryotic common ancestor, 1.5 billion years ago.  We're talking more like 2 billion years ago and it tell a lot about how cells like our own actually evolve from much simpler cells way back then.

Randy Schekman

21:28 - Commercial science publishing is flawed

Commercial science publishing is distorting the process, argues eLife Editor in Chief, Randy Schekman...

Commercial science publishing is flawed
with Randy Schekman

eLife's Editor in Chief and Nobel Laureate, Randy Schekman explains to Chris Smith why, in his view, the present commercial system of science publishing is distorting science.  He also sets out his vision for what eLife is doing to change things...Randy Schekman

Randy -   I felt very strongly that particularly at the high end in the life sciences, young investigators felt undue pressure to publish in a very small number of venues.  Commercial journals such as Nature and Cell, and Science Magazine - these are fine journals, they publish important work.  But they artificially restrict the number of papers and pages that they publish because at least in the case of Science & Nature, they're still modelled on a print version and it's expensive for them to print more pages.  And so, they've created - I feel - an artificial commodity.  They do this frankly to sell magazines and this has - I believe - a distorting influence on the way young scholars choose to publish their most important work.  They compete for limited resources even when those resources represent an artificial commodity.  In the 21st century, it seems silly to me to be making decisions based on a print run when most young scholars read everything online.  They don't even know these journals exist in a hard copy form.

Chris -   But you are Editor in Chief of PNAS, the Proceedings of the National Academy of Sciences, another very prestigious journal.

Randy -   Yes, I was and that's actually where my opinions formed most clearly.  I saw that in spite of the success of the proceedings that investigators still preferred to publish in venues that restricted the number of papers that they published.  At PNAS, we felt that it was important to publish all the great papers that we receive.  So, we didn't have such an artificial restriction.  And yet, scholars chose not to send their best work generally to the PNAS because of the influence of a number, called the impact factor.  The number that greatly - I think - influences decisions about where the young scholars prefer to send their work because they feel review committees, Grant committees, often base their decisions on the impact factor of the journals in which work is published and these journals, particularly the commercial journals use that number shamelessly and they're advertising.  Indeed they manipulate the calculation to exaggerate the number and to give themselves even more influence in decisions about where scholars publish.

Chris -   And you're seeking to change this with eLife.

Randy -   Absolutely.  We will not restrict ourselves based on some perception of the number of citations that a paper will generate or the number of papers that we publish.  If we get great papers, we'll publish all the great papers we evaluate.

Chris -   The other key difference of course is that if you publish in those aforementioned journals, in order for me, if I send them a piece of work - as one person told me - they were grossly offended to be told by the journal to go and buy a copy of their own paper when they wanted a reprint of it because that's how these journals make money.  They're selling the science that the taxpayer funds to the scientific community.

Randy -   Absolutely.  They're in the business of selling magazines.  But the fact is, that they make money on both ends.  They make money selling magazines.  They make money on subscription licenses.  They make money from advertising.  They rely on the academic community to do essentially most of their work in evaluating the science.  We're not compensated for their services.  I think scientists have bought into this inappropriately.

Chris -   So, how would you like to see change and how will you make a difference?

Randy -   Our challenge is to capture the imagination of scholars, having a venue that they will seek out to publish their best work.  So, we have to influence young people who are at crucial career stage so that they make those decisions based on how their work is seen by the community and not based on some artificial number like an impact factor.  The other thing I want to say this impact factor is, influence, not necessarily only by the quality of the work but by whether the work is fashionable.  I'll give you an example.  Nature published two papers a couple of months ago where the authors claimed that they could convert adult cells into embryonic stem cells by a simple low pH treatment.  The work was met with great scepticism and in fact, people are unable to reproduce these results.  There was evident manipulation in the papers.  Now, people are quite suspicious but the fact is, that these papers will generate thousands of citations for Nature and so, they want profit by having published those papers even if they end up being retracted.

Chris -   You're getting behind an initiative called the OA or Open Access button.  What is that and why are you putting your name to it?

Randy -   So, it's a very interesting programme just beginning to identify when a reader has trouble getting behind the firewall of a commercial journal.  For those people who are aware of the Open Access button programme, you can automatically alert this service when you have failed to gain access to a published work because of a firewall restriction.

Chris -   But how would you use the data that comes from it in order to enact change?

Randy -   Well, I think it will be very striking to realise if, with the data that they compile, how many people are frustrated by their inability to gain access to the literature.  Commercial journals may be forced inevitably to introduce Open Access journals on their own.   In fact, I know that the editor of Nature, Phil Campbell has indicated that he sees the Open Access movement as the future.  He suggested that maybe even Nature may eventually go Open Access, but they feel that they'll be able to charge.  He suggested - for instance $30,000 - might not be an unreasonable sum to expect.

Chris -   And of course, that money would have to come from the scientist which inevitably means it would come from their grant pot, wouldn't it, the money that the taxpayer in some cases or a charity like the Wellcome Trust gives to the scientist to do their research.

Randy -   That of course is the problem and the question is, would people be willing to pay that sum of money to publish their papers.  I should tell you, there's another under Current that has taken shape in Asia that I think is quite alarming where scholars in China are literally offered bribes to publish in these high profile journals.  Last year, the Chinese Academy of Sciences issued a bulletin to its scholars, offering a cash reward of the equivalent of $33,000 for success in publishing a paper in Cell, Nature or Science, irrespective of the subject matter of the paper.  So, you could well imagine that an author, having won the lottery and published in these journals would simply take the profit that the Chinese Academy of Sciences offers to pay the fees that the journal charges for an Open Access version of the paper.  I think this is a terrible distortion in the system.

Chris -   UC Berkeley's Randy Schekman, eLife's Editor-in-Chief.  That's it for this month.  Don't forget that all of the papers we've been discussing are freely available alongside previous editions of this podcast from eLife's website that's at elifesciences.org/elife.  My name is Chris Smith.  This is a Naked Scientists production.  You can find out more about us from our website at nakedscientists.com and I'll be back next month with another look inside eLife.  Until then though, thank you for listening and goodbye.


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