eLife Episode 37: How human handedness happens

31 March 2017
Presented by Chris Smith.

In this episode we hear about helping people with paralysis to communicate, how exposing mice to nicotine can affect their sons, scaffold-building parasites, the origins of human handedness and plain-language summaries of research.

In this episode

Brain computer interface helps paralysed people to communicate

00:33 - Brain power

Sensors on the surface of the brain help paralysed people to communicate

Brain power
with Jaimie Henderson, Stanford University

Damage and disease affecting the brain and spinal cord are devastating. A person never recovers their lost function because the central nervous system has very limited abilities to repair and regenerate its tissues. So scientists are turning to technology to creative more effective assistive devices for patients with neurological disabilities, and they’re getting better all the time. Chris Smith heard how from Stanford University's Jaimie Henderson...

Jaimie - So, what we were trying to do with this paper is to demonstrate the ability to type using brain signals and in fact, create a system that allows people to move a cursor on a computer screen and to type at anywhere between approximately 4 and approximately 8 words per minute which is a factor of between 2 and 4 faster than what's been demonstrated before.

Chris - How would that compare with say, me or my smartphone if I'm tapping out a text message?

Jaimie - I would say, the average person probably performs somewhere in the 12 to 19 words per minute range. So we’re beginning to approach that range, but we’re still probably about half of what you can type on a cell phone.

Chris - But critically, you are doing this without a person needing to move a muscle.

Jaimie - That’s correct. This is all done through reading out brain signals and translating them into movements of a cursor on a computer screen.

Chris - Before you tell us why the competition are doing less well than you are, how does it work?

Jaimie - We began by implanting a tiny sensor on the surface of the brain. The sensor is 4x4 mm. It’s about the size of a baby aspirin with 100 probes that penetrate just into the outer layers of the brain. These pickup signals from the neurons. When those signals are read out, there's an amplifier that mounts on the top of a device called the pedestal which attaches to our research participant’s skull and protrudes through the skin. We attach a cable to the top of this, we run those signals out, amplify them, digitise them, and put them into a computer where they can be decoded. We can then use our computer algorithms to understand what the brain is trying to do, what sort of movement the person is trying to make and decode that and display it on a computer screen.

Chris - How long does it take after you put this into the person’s brain for them to learn to think along the right lines to achieve meaningful control?

Jaimie - We found that our research participants are able to get control of the cursor fairly rapidly. It’s pretty intuitive. People usually pick this up within several days and become very facile with it in several weeks. The reason for this is that we’re basing our decoders on tuning of the brain cells. So we asked our participants to imagine or attempt a movement of their opposite arm. We then pick up the signals from those brain cells which are tuned to the particular direction of movement. So, if I imagine for example moving my arm up into the left, certain of those brain cells will increase their firing rate or will be more active with that movement whereas certain other brain cells will decrease their activity. Each probe of the array that we’ve implanted can pick up signals from one or several brain cells. By decoding the tuning of each of those brain cells, we can then predict what a person is attempting to move and use that to move a cursor.

Chris - People have been eavesdropping on the brain’s motor circuits and using them to drive devices in this way for a really long time. I mean, this is not brand new – the approach you're taking, is it? So, what is the novelty here?

Jaimie - There are actually several innovations that we use to achieve this level performance. One is real time system design and real time programming. This allows us to very rapidly feedback cursor position to our participants. So the cursor positions actually updated every millisecond. That’s faster even a 120 hertz display can display it. This very rapid feedback allows participants to rapidly acquire where the cursor and the target is and to better control it. We also use digital filtering to clean up the signal. So it’s really these innovations altogether that allow us to achieve this level performance.

Chris - What about the long term stability of the interface into the brain tissue though because for many years, people have struggled to do this with these chronic implantable devices. They find the signal degrades over time?

Jaimie - Well unfortunately, that is still a problem. We do see signal degradation over time although one of the participants in the study had had the implant for approximately 3 years at the time that we performed these research sessions. Her performance was among the best in the study.

Chris - If you ask the people who use them, what was the approval rating? In other words, how did they respond? Also, given that you're now doing this in real time, what can you do to improve this further because we’re not quite up to a teenage text rate yet, are we?

Jaimie - No, we’re not quite there yet. Participants very much enjoyed using the system. One of them said that after he had been using our system for a period of time, he went back to his old head tracking system and found it somewhat cumbersome and clunky. There's obviously still a lot of work to do. We do want to be able to type faster as you mentioned. It’s possible that by reading out the planning phase of movement – in other words, when someone is beginning to plan to make a move, it’s been shown in the laboratory that one can very rapidly decode an intended movement even before a movement can be generated. So, hoping at some point to explore that concept further.

Paternal nicotine exposure protects male offspring against a range of other drugs

06:21 - Like father, like son

Exposing male mice to nicotine can make their sons more resistant to nicotine and other drugs

Like father, like son
with Oliver Rando, University of Massachusetts

Our realisation that epigenetics offers our offspring an opportunity to adapt on a timescale far faster than a genome message can change, has give us new insights into the basis of number of diseases. Take diabetes and hypertension, for instance, which are more common in the offspring of parents with metabolic syndromes themselves. But are the epigenetic changes that underpin these altered disease risks a highly focused response to one component of an adverse environment, or a more generalised genetic alarm signal whereby the body alters its resilience against a range of potential threats. Speaking to Chris Smith, Oliver Rando thinks it’s the latter...

Oliver - Over the last decade or so, it’s become increasingly clear that the environment experienced by a father can affect the health and the behaviour of his children. Many of the environments chosen include dietary regimens or stressors that affect many aspects of a father’s health. In this study, we wish to understand whether or not fathers tell their children much more specific information about the world they saw. To do this, we chose to use nicotine, both because nicotine is a commonly used drug in human populations and so, this will be relevant to human biology. Also because nicotine has a very specific molecular function which is that it binds to a receptor. And so, we could ask whether or not children are specifically more or less responsive to nicotine and only nicotine, or whether or not children become generally drug resistant or generally anxious, or something of this nature.

Chris - In other words, is there a very specific in type programming for a certain stimulus and a certain outcome or is there more like a molecular tripwire here where a range of things can sound the alarm and it then puts in play a whole range of responses and it wouldn’t matter what tripped the tripwire. You'd see the same range of responses.

Oliver - That's an excellent way to put it. We do this in inbred mice. One of the reasons to use inbred mice is, so that all the mice have the same genomes. We treat pairs of male mice. Half of them are exposed to nicotine. They're drinking water actually. The other half consume a control solution. We then take those mice and we allow them to mate with females then we take the male mice away so that they don’t directly interact with the children. And then we analyse a variety of behaviours and phenotypes in their children.

Chris - What trends emerge?

Oliver - So, quite a few things don’t change in the children. They don’t become grossly more or less sensitive to nicotine. However, the children of nicotine-exposed fathers become more resistant to toxic doses of nicotine.

Chris - This is like a sort of defence priming. If your parent has been exposed to X then you are now primed to encounter things like X and defend yourself against them.

Oliver - That's correct. that’s certainly how it seemed at first. The next part of the study was to ask whether or not the children are primed for X or whether or not the children are primed for a broader range of things. to do this, we also exposed the children to cocaine and much to our surprise, even the children of fathers exposed to nicotine, those children became more resistant to cocaine as well. So that now tells us that even though fathers were exposed to one drug, the children become more broadly resistant to toxic levels of drugs.

Chris - We’re using this term “children” and that could mean male and female. Was there a difference between the male and female offspring? Do they both respond in this way or is it just one of the two?

Oliver - We only see the sons exhibiting changes in their resistance.

Chris - Interesting. So how do you think that’s being passed on then?

Oliver - Well, we have no idea. We haven't done any molecular work on the sperm which is of course the likeliest place for this information to be. In other types of paternal effect system, so in other experiments where we treat males with different environments and look at the children, we are very keen on the idea that small RNAs are the carriers of the information about the environment. But in this particular study, we did not look in the sperm at all.

Chris - Let’s explore why do you think this effect exists at all?

Oliver - It certainly can be construed as being adaptive. By “adaptive”, I mean useful for the kids. If fathers are exposed to nicotine, their children become more resistant to this toxin. So that’s certainly something that you can imagine being evolutionarily advantageous. Why their children become more resistant to multiple toxins, I'm less confident in speculating about, but at least in the case of when the fathers are in an environment where there's lots of nicotine about, the children will be better suited for that environment.

Chris - Obviously, these are rodent studies and we’ve got to be cautious about translating them to humans. What would be the implication then if you have a child growing up or developing in an environment where the father is being exposed to various chemicals? What might be the implications for that child’s own use of nicotine or exposure to nicotine subsequently?

Oliver - In the mouse model, we did look at self-administration which is a model for addictive behaviour. We saw no difference in the self-administration of nicotine in this offspring. But it cannot extrapolated to humans particularly well because mice are notoriously bad model for nicotine addiction because the half-life of nicotine is much shorter in mice. So while we have no evidence that it would affect predisposition towards smoking, studies in humans will need to be done to really make sure that that’s true.

Toxoplasma assembles an actin scaffold inside cells to coordinate parasite replication

12:26 - Combatting toxoplasmosis

The Toxoplasma gondii parasite builds a scaffold inside human and other animal cells to help it multiply and cause disease

Combatting toxoplasmosis
with Marcus Meissner, University of Glasgow

At first glance, a parasite caught from a cat litter tray doesn’t sound like it should have much in common with malaria. But malaria is a close relative of Toxoplasma gondii; and the discovery by Glasgow’s Marcus Meissner, that, when toxoplasma grows inside our cells, it assembles a communications network that synchronises the growth of the parasites, could reveal a new way to combat both bugs. Chris Smith heard how...

Marcus - Toxoplasma is a single-celled organism. It’s a parasite that can only live inside other cells. It is commonly infecting cats, but it also is carried by other warm-blooded animals including us, humans. Amazingly, up to one-third of the UK population is actually chronically infected with this parasite. Meaning, once infected, you will carry this parasite within yourself for the rest of your life mainly as tissue cysts in your brain but also in your muscle tissue.

Chris - How do most people pick it up?

Marcus - There are two major routes for the information. One is directly from the cat, eggs are shared with the faeces of the cats up to 2 million a day. The other route is via eating undercooked meat.

Chris - Once a person picks it up, what happens then?

Marcus - Then the parasites starts with an acute infection which is usually harmless for most people. It’s like a common cold or flu-like symptoms. However, then the parasite differentiates into persistent forms and these form tissue cysts in the brain and in the muscle. And so, the medical importance is for immune-compromised people where the immune system breaks down, there, the tissue cysts reactivate and it can cause encephalitis and brain damage. The other problem is, if a pregnant person gets infected for the first time. the parasite can cross the placenta and infect the embryo and that can cause heavy organ damage.

Chris - What have you been trying to find out about it?

Marcus - It’s obviously already important to study it for its own right as a human pathogen, but it’s also a very good model system for other parasites of the same family, the apicomplexans which includes malaria. What we wanted to find out is how the parasite actually invades the host cell because in order to survive, the parasite has to invade a host cell – in case of malaria, that’s our red blood cells – and also how the parasite replicates inside the host cell. So we focused our attention on a protein called actin which is scaffolding protein found in many different cells. However, in these parasites, no one knew if this protein can actually form a scaffold. We found a new way of imaging this protein inside the cells and found a really amazing network that is formed between individual parasites in the cell which the parasites use to communicate with each other to exchange material and to make sure that they have a synchronised cell cycle. Meaning, that all parasites replicate at the same time.

Chris - So, we got this situation where this parasite gets into a cell, whether it’s malaria or in this case, toxo, and once it’s in the cell and it starts to grow or replicate, it’s orchestrating this scaffolding which is connecting the replicating or growing progeny together, both chemically and physically. That seems to play a big role in how they grow and develop.

Marcus - Yes, that is correct. so we find for example that if we disrupt this scaffold, the parasites are sort of crippled. Meaning, they cannot really finish their replication cycle and you end up these parasites that cannot leave the host cell anymore. So they are trapped inside the host and that is of course a way to interfere with the further transmission of the parasite.

Chris - Just before we come on to what the implications of that might be, what was the imaging technique that you use to enable you to see what these parasites were doing inside cells like these?

Marcus - The trick was really that an antibody can be expressed in the parasite that binds to the scaffolding protein, only then it makes a scaffold. This antibody gives a fluorescence signal and then using super-resolution microscopy, they could make a 3D model of the scaffold and using time laps imaging, meaning, we made movies of the behaviour of the parasite, we were able to identify material that is transmitted or transferred in between the parasites.

Chris - Do you think it’s something as simple that if all of the parasites replicate or grow in a cell at the same time, then they're going to be able to share the resources that they're making at the same time, and that’s a very efficient way because you’ve got a big job lot of what you need, all in one place at one time, you share it all out, and you can grow much more effectively?

Marcus - That is actually one of our hypothesis. At the moment, we were able to detect and describe the network but we are not really 100 per cent sure yet what is the exact function of the networks. So, we don’t know the mechanisms yet.

Genes are asymmetrically activated on the two sides of the spinal cord early in development

17:52 - Left handed, or right handed?

Handedness has its origins in the spinal cord

Left handed, or right handed?
with Sebastian Ocklenburg, Ruhr University, Bochum

One striking things about humans is the fact that 90% of us, when handed a pen or a tool, will use it with our right hands. And this is not a modern phenomenon. Cave paintings suggest that our ancestors tens of thousands of years ago were also inclined to use their right hands for specialist tasks. Chris Smith wanted to know how this happens...

Sebastian - My name is Sebastian Ocklenburg from Ruhr University, Bochum in Germany. The question I'm really interested in is, how does handedness develop? We know that in the population, about 90 per cent of individuals are right handed but it’s still completely unclear what determines whether somebody is left handed or right handed. The defining theory for the last couple of decades has been that handedness is determined by a single gene but we know from genetic research in the 2000s that this is very unlikely. So in the 1990s, a researcher named Peter Hepper had the theory that handedness might not be determined by the cortex but by the spinal cord because it was found that embryos already show a right handed preference for motor movements during a developmental phase in which the spinal cord is not connected to the motor cortex.

Chris - What did you do then to try to see how the spinal cord might be arriving at that situation of that right hand sided dominance in order to be future right handed?

Sebastian - One of the major theories about development of handedness is that gene expression asymmetries might play a role here. so, this is what we look at. We try to find genes that were expressed asymmetrically in the spinal cord. If there are expression asymmetries, that might be an explanation for behavioural asymmetries later in life.

Chris - How did you study that?

Sebastian - So, we looked at tissue samples from the spinal cord, from human foetuses obtained from a gynaecological clinic. Those were from week 8, 10, and 12. So we looked at genes now, they were expressed on the left and right spinal cord. We also performed epigenetic analysis. So we looked at asymmetries in gene methylations and expression of micro-RNAs.

Chris - So what you're saying is that the genetic code may well be the same in an individual who’s right and left handed but you can actually change how turned on or turned off certain genes are, and also, the epigenetic markers which are added to the genes could be different on the right and the left. That could account for the handedness even though the genetic messages are the same.

Sebastian - Exactly. So, we think this might be one of the reasons why previous researchers have found so few results when looking at genetic variation exactly that of such processes might switch on or switch off, or modify gene expression which then leads to variation in key structures in the central nervous system that modified the behavioural phenotype. You cannot see that from just looking at the genetic variation.

Chris - Was that clear? Could you see that there was a difference in the way the genes were being turned on and how much they were turned on on the right versus the left?

Sebastian - Yeah, we found that these processes are very much dependent on the time point where we look at it. So if you look at the time point where the foetuses show this right side preference for the first time to see a huge asymmetry in gene expression also in these epigenetics processes which gets less and less the further it proceeds in development.

Chris - Now famously, in his book Right Hand, Left Hand, Chris McManus who did literally write the book on left handedness since about the 1980s, he highlights in that book that asymmetry begets asymmetry. In other words, just because you were found an asymmetry in the gene expression in the spinal cord, something must produce that asymmetry in the first place. So what do you think or how do you account for the fact that you’ve got this difference in the expression of gene patterns on one side of the cord versus the other?

Sebastian - So that’s probably the biggest open questions I want to address in my research in the future, which environmental factors actually trigger these epigenetic processes. I can really say I have a good clue at that right now. Some people for example suggests stress might play a role. Some other please suggested that intrauterine hormonal environment, for example, testosterone level. But it’s really something that we will have to look up in follow up experiments. I cannot really answer that right now. I'm sorry.

Plain language summaries

23:14 - Spread the word

Plain-language summaries are making research more accessible to broader audiences

Spread the word
with Sarah Shailes and Stuart King, asst Features Editors, eLife

Each month we try to devote at least one of our interviews to consider some of the wider impacts of scientific practice and scientific life. Recently we’ve looked at the impacts of the positive result bias, how women fare in science and whether science is losing its best young talent owing to funding shortfalls. This month, with the help of assistant features editors Sarah Shailes and Stuart King, Chris Smith considers eLife itself and the role of its research digests. And if you’re not sure what a digest is, Sarah can explain...

Sarah - eLife digests are plain language summaries of research articles. We’ve been including them in research articles since their general launched in 2012. They always start with some background information about the area of his research and they’ll setup the kind of research question that the authors of research article we’re trying to address with their research. and then they’ll talk about the main findings of that research and then they’ll go on at the end to talk about the next steps and the relevance to the research.

Chris - How long are they?

Stuart - The average digest is 347 words. I know that because we recently looked back but the range would be about between 200 and 400 words.

Chris - That’s on par with a news piece that you'd see in a newspaper.

Stuart - Yes. So they're short complete articles on their own basis. So we do take a number of the articles and we share them on a separate site called medium. We do that to reach a different audience who aren't all day reading the research articles.

Chris - What's your motivation for doing this, Sarah?

Sarah - Our main motivation is that we want to make findings of research papers more accessible to a broader range of people. That includes other scientists from other fields of research. I'm a plant scientist by training and when I try and read a neuroscience paper, I find it very hard. There's all sorts of jargon that I don’t understand. By using much more simple language, active language, so talking in terms of processes happening as opposed to kind of using lots of nouns and sentences, it really helps people who aren't specialists to get hold of that information and use that. We try and aim digests to be accessible to people who are sort of towards the end of their school years and adults who are interested, and motivated in science.

Chris - Why should the journal do this because you could argue it’s for scientists and scientists know a lot of these words anyway?

Stuart - One of my major motivations is because we’re an open access journal, all of our research articles are freely available to read by anyone. So adding the digest then is part of that, and that the audience could be anyone and they can access and read, and understand the content. If you want your research to have an impact in the real world, you need to reach beyond the academic community. A digest, although it’s a small summary, it’s a small step towards doing that. One of the other motivations for us doing this is that we get the authors of the research article involved in the writing.

Chris - But you haven't always done it like that there, have you?

Sarah - I mean, we’ve always produced digests but when we started, digests were written by us and by freelance writers who were reading the manuscripts, working out what the important messages were from the paper from that. A couple of years ago, we started asking the authors of research papers to answer some questions for us in more plain language and that’s really helped us. It highlights what authors think is the main message of their research. That’s been great because we get different voices coming through in the digest because everyone thinks about research in different ways. But it’s also been great in that when we send draft to digests to the office to check. They’ve made fewer changes because actually, what we’re sending them is something much more similar to what they’ve seen before. I think we’ll end up with something that the authors are overwhelmed or happy within the end.

Chris - More importantly, what do the audience think as the rule of any medium is, give the audience what they want?

Stuart - That’s just something that we’d look into relatively recently. The end of the last year, we conducted a survey of current digest readers and we had over 300 responses. Overwhelming, I think the response was very positive. Most of the audience are scientists but we are also reaching non-scientists as well, and that’s an audience we’re probably looking to engage more with. But on the whole, both scientists and non-scientists alike finds the digest that as we currently write them useful, good structure, good language, so we were very pleased with the results actually.

Chris - What about other journals because lots of journals do go down the same path, so they're offering a similar sort thing, similar synthesis of what you need to take away from this paper?

Sarah - Yes, so we’re working on the series. We found about 50 journals that actually produces plain language and reason. I wouldn’t be surprised if that’s in all of them. One of the things that strikes me about them is there's such a variety out there. they're written in different styles, at different lengths, they're aimed at different people. So some organisations for example, the journal Autism are particularly targeting their summaries at patients and their families.

Chris - Do they think this is useful?

Stuart - Definitely. One of the articles specifically looked at this exact issue in patient involvement and how plain language summaries can help that. So, HDBuzz is an organisation that covers the latest research in Huntington's disease and they found that those families who are affected, finding out about the latest research provides them with real hope to deal with these conditions happening in their families. I think it’s a strong motivator for the researchers involved.

Chris - So isn’t that what are newspapers for?

Stuart - Yes and no. So another organisation that’s looked into this is Inspire which is a collection of disease related social networks. They found that patients and their caregivers look into a range of different sources. Over half of them are looking at general articles. But the slight issue with general articles, it’s not written for them. It’s written for other scientists. It often doesn’t quite give them the context of what it means for them and how close it is potentially to a treatment. Newspaper articles on the other hand might over emphasise that. They’ll focus too much on that and get the headlines, compounds XQ as cancer that’s often grossly always implied. Another organisation looking to tackle this is Dr. Media based in the Netherlands and it’s been inspired by the exact conversations, patients coming to their doctors asking for guidance on what a newspaper story means to them. They work with clinicians to produce this content because in one to one consultations, you're only working with one patient but by making it accessible online, they can reach so much wide audience.

Chris - Were you surprised by what you found?

Sarah - Yeah. I think we were pleasantly surprised. Our biggest fear when we went into the survey was that we’d find that no non-scientist were reading eLife digest.

Chris - And then you'd be out of a job.

Sarah - Yeah. It would feel like the aim with them was being missed really. So the fact that there are non-scientists interested and motivated enough to find them was really nice and reassuring I think.

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