Should mice be used to study the human gut microbiome?

In recent years, the trillions of bacteria living in our guts have risen from obscurity to stardom. Hyped press releases claim that probiotics and faecal transplants might one day treat almost everything, from bowel inflictions to obesity. These studies often involve mice, but are these rodents really a suitable model for microbiome research?

The gut microbiome has been associated with an ever-growing list of diseases, including obesity, diabetes and even mental disorders such as anxiety and autism. Much like the Human Genome Project around 15 years ago, the booming microbiome research field has promised to deliver new revolutionary treatments, some as simple as eating a yogurt. Perhaps inevitably though, history repeats itself. After a few years of frantic microbiome sequencing and many new biotech start-ups, microbiome researchers are now having to face the hard questions: are the changes in the gut microbiome associated with certain diseases a cause, or a consequence, of the disease? How on earth can bacteria in the gut affect other parts of the body, such as the brain? What are the molecular mechanisms behind all this?

E. coli bacteria thrive in the gut.

Studies in humans can at most reveal correlations between the microbiome composition and a given disease. For example: Bob is obese and happens to have a microbiome with lots of bacteria X, but John, who is slim, doesn’t. This suggests that bacteria X cause obesity, yet, there’s also a good chance that in fact it’s the other way round: obesity might somehow promote growth of bacteria X. Or maybe this type of bacteria thrives on Bob’s diet, or it simply prefers the unique environment of his gut.

It is virtually impossible, and unethical, to perform experiments in humans to explore causal hypotheses (does bacteria X cause obesity?) and control for confounding factors like diet and genetic background. Microbiome researchers have to use the next best thing: mice. There are, however, growing concerns within the scientific community that more often than not, data from mouse can’t be extrapolated to humans for clinical purposes. Or at least, not easily.

In a new study, Jeroen Raes and colleagues at the KULeuven University, in Belgium, carefully compared the human and mouse gut microbiomes to assess the strengths and pitfalls of this model system for studying microbiome-related diseases.

“Microbiome research, notably its association to inflammatory diseases, relies heavily on mouse models […]. It is essential to know the qualities and limitations of each model to choose the correct one to test specific hypotheses”, says Sara Vieira-Silva, one of the authors conducting the study.

Can mice recapitulate the human gut microbiome?

Mice are great for biomedical research. They share most of our genes, and have similar anatomy and physiology. With the many available genetic tools, scientists can easily and quickly discover the function of literally any gene in the mouse genome, and recapitulate human disease in a controlled experimental set up. So where’s the catch? The problem is that although mice and humans share many similarities, there are also many differences.

Rae’s team performed comprehensive statistical analyses for all gut microbiomes from mice and humans published to date. These new data tell us what types of bacteria live in the gut in various scenarios (disease, diet, genetic background…), as well as their relative abundance. The team first compared the gut microbiomes of healthy humans and mice. And the differences start here.

Human and mouse guts have predominantly two ‘families’ of bacteria—Bacteroidetes and Firmicutes—but within these groups, 85% of bacteria species found in mice are not present in humans. And the bacteria found in both? It appears their abundance in the gut also varies between mice and humans; when you’ve got a lot of a certain bacteria in mouse, you may find very little of it in humans, and vice versa. The authors stress that many of these differences could simply be a result of technical limitations, like methodology or interference from external factors (diet, age, etc).

Mouse models of disease

There are over 60 mouse models of Inflammatory Bowel Disease (IBD), but none fully recapitulates the disease. Even so, the changes in the gut microbiome of patients with IBD (when compared to healthy people) are similar to those observed in IBD mouse models. For example, there is a significant reduction in bacterial diversity in both IBD patients and IBD mouse models. However, some specific bacteria species will be more (or less) abundant in mouse but not in IBD patients. The same goes for obesity models. Overall, mice fed on high-fat diet, and also leptin-deficient mice, which cannot control their appetite, recapitulate the microbiome changes observed in obese people. But there are many discrepancies in the data, again likely due to external factors that are difficult to control, at least in human studies.

The conclusion? Well, mice are not people. Raes and colleagues warn microbiome researchers that extreme care should be taken when trying to extrapolate findings in mouse to humans. They should also make bigger efforts to standardise their protocols for animal handling and data analysis, and to share mouse models to eliminate any genetic variability that might skew the data.

“Most limitations of murine [mouse] models for fundamental microbiome research can be overcome by methodical study design and statistical testing: either eliminating or keeping track of possible confounders (e.g. diet variation, genetic background) and testing for their influence on the results”, says Vieira-Silva.

Nevertheless, the authors conclude, when it comes to understanding the causes and molecular mechanisms behind human disease, mouse models seem to fit the bill. “Although the mouse microbiota composition is not identical to the human's, most mechanisms of microbiota-host interaction will be shared between mice and humans” concludes Vieira-Silva. “Mice models allow us to study these mechanisms with direct controlled experiments, towards the ultimate aim of providing therapeutic solutions.”

Reference:

Nguyen T.L.A., A. Liston & J. Raes (2015). How informative is the mouse for human gut microbiota research?, Disease Models , 8 (1) 1-16. DOI: http://dx.doi.org/10.1242/dmm.017400

And edited version of this article was published in Lab Times on the 24-02-2015. You can read it here.

'One fossil can overturn anything' Interview with Jenny Clack

Now happily living on land, our Devonian ancestors tried many ways to get out of the murky waters. Jenny Clack has been studying the water-to-land transition of vertebrates for many decades. Her discoveries broke dogmas and rewrote textbooks. 

Jenny Clack's passion for palaeontology began at a young age, but unlike most children, Clack found dinosaurs “rather boring” and was instead fascinated with weird older creatures from the Devonian era, over 360 million years ago. After completing an undergraduate degree in vertebrate palaeontology, Clack worked for about seven years as a display technician at the Birmingham City Museum, until she finally had the opportunity to do a PhD with Alec Panchen at the University of Newcastle upon Tyne (UK). Clack’s talent quickly got noticed, and during her PhD she was offered a position as an assistant curator at the Museum of Zoology of the University of Cambridge (UK). At Cambridge, Clack had an insight that would transform her career and her life. During an arduous field trip to Greenland in 1987, she found spectacular remains of Acanthostega, a tetrapode (four-legged vertebrate) that would overturn decades-old theories. Clack was the first woman in her field to become a fellow of the Royal Society, won numerous distinguished awards and is currently a professor and curator of vertebrate palaeontology at the Museum of Zoology of the University of Cambridge.

When did you know you wanted to be a palaeontologist?

Clack: I was always interested in natural history generally, and as quite a young child, from the age of seven or so, I collected plants and fossils. And certainly by the age of ten I was interested in palaeontology and rocks, and I used to borrow books from the library. I would read geology books and books on fossils and natural history instead of what my teachers would want me to do, which was to read novels, of course. Throughout school, I was always interested in natural history and decided that I wanted to do zoology degree, and went to the University of Newcastle upon Tyne. One of the reasons for choosing Newcastle was because it had a programme in palaeontology as part of the zoology degree. It was just the idea of these ancient creatures... I was always interested in the earliest stuff, rather than dinosaurs. I had a series of volumes of a children encyclopaedia that had sections on various periods from the Palaeozoic, and they were really my inspiration. I wanted to know about the very old fishes and early animals, like the amphibians that were described in those days. When I got the opportunity to study at university then obviously I decided that’s where I wanted to go. But it wasn’t straightforward by any means.

What was it like for a little girl back in the 1960s to pursue an academic career? 

Clack:  It was more that the teachers obviously knew that I was interested in that kind of thing. I remember one of the teachers in junior school identifying me as an “academic type”, even though I had no idea what that meant at the time. Certainly, my parents always encouraged me to do whatever it was I wanted to do. They took me on holidays to places where I mind find fossils and other elements of natural history. […] My career has been a bit of a complicated path because I didn’t go into palaeontology professionally after my degree. I did a Museums Study course, and then worked seven years in the City Museum in Birmingham. And it was only when I had the opportunity to do a PhD that my career really started.

How did you eventually get into academia?

Clack: It was partly encouraged by the museum itself because they allowed people to do three weeks of private studies per year and my mentor-boss at the time was very supportive of this. So, I got back in touch with my old mentor, Alec Panchen, in Newcastle and asked him whether he had any projects I could work on, and in fact he did. He directed me to a specimen in a museum in Bradford that was a Carboniferous tetrapode. To cut the long story short, I took that specimen to his lab and worked on it for the three weeks, during which time I found that there was quite a lot more to the specimen than anybody had realised. And then Panchen said I could probably get a PhD from that material; he applied for grants and got it.

Was it at this time that you decided to focus your career on the fish-to-tetrapode transition?

Clack: I was interested in the same sort of field that Panchen was, which was Carboniferous tetrapodes, so it was a natural expectation that I would study something of that nature. And indeed, the PhD started that ball rolling. While I was still doing my PhD, I applied for a job as an assistant curator at the Museum of Zoology of the University of Cambridge and much to my surprise they offered it to me. This would not happen today. There is no way someone who hasn’t finished their PhD, has got no published papers and has no reputation would get that kind of job. Now, you would have to have a postdoc, at least. I had the museum qualifications and the research background that they were interested in. I fit the bill I guess [laughs]. And it wasn’t until some years later that the opportunity to look at the Devonian material came about. 
After I had finished my PhD in 1984, I wondered what on earth am I going to do next? I didn’t have any very clear ideas. My colleague Andrew Miller said something will come up and indeed it did! It turned up in a drawer in the Earth Science Department across the road. This was a drawer full of Devonian material from Greenland that a former student there had collected without realising what it was, or its potential importance. And from there we got the expedition to go to Greenland in 1987 and collected more of this material, which turned out to be extremely important. A very lucky break indeed.

Fossil remains of Acanthostega.

What exactly did we learn about the water-to-land transition from your discoveries of Acanthostega?

Clack: There were two major discoveries. The first one was about the story we had been told that, as soon as these creatures came onto land, they developed the capacity to hear air-born sound. And it became clear from the work I had done in my PhD, and the work on Acanthostega, that this couldn’t possibly be the case. The story of the origin of terrestrial hearing became much more complicated and it was corroborated by people from other palaeontology groups. But probably the most widely known discovery was that Acanthostega had eight digits in each limb. That was a real surprise. It took a little while for people to believe that this was the case because the dogma was that there were five digits in primitive tetrapods. And here we had an animal with eight digits on each limb! 
We then discovered that a Devonian tetrapod that had been known for decades called Icthyostega had in fact seven digits on its hind limb, and this complemented what we had known about a Russian animal from the Devonian, which has got six digits. All of a sudden it became a pattern of multiple digits in the earliest tetrapods with limbs. This changed the idea of how limbs evolved and what they evolved for. If you look at the old books from the 1940s, for instance, you get an idea of what they thought a proto-tetrapode looked like, and basically it looked like a fish that has got legs with five digits on, and it’s making forays onto the land. But actually our work suggests that the animals already had limbs with digits before they ever came out of the water. So, it kind of turns the story upside down.

Is it the number of digits alone that tells us that, or some other features as well?

Clack: Acanthostega had a number of primitive features. One of those was the proportion of [the bones in] the forearm, of the radius to ulna to each other. In most tetrapods, the ulna is longer than the radius, and that’s true to almost all tetrapods, and most fossil ones as well. But in the fish, from what tetrapods were supposed to evolve, it’s the other way round: the radius is much longer than the ulna. And that was the condition in Acanthostega. It seemed to us that the limb elements of Acanthostega were showing us what the primitive condition was like for limbs in general. Also, the fact that the digits were variable in number through these early tetratpods, suggested that the function of the digits in the limbs was quite different from what we assumed. It’s a paddle basically.

You also discovered new features in Icthyostega…

Clack: We discovered that Icthyostega is a really enigmatic animal. We’ve known this more or less since it was discovered, and the more we found out about it, the weirder it looked. It’s got some features in which some limbs elements, like the humerus, are more primitive than that of Acanthostega, and yet other aspects of the anatomy of Icthyosthega suggest it was more terrestrial than Acanthostega. Acanthostega seems to be almost certainly entirely aquatic, but Icthyostega has a really robust front limb that looks as though it could at least raise the front body off the ground, whereas the hind limb is a paddle and points backwards towards the animal’s tail. 
We worked out how this animal could move using information from synchroton CT scans of the limbs and reconstruction software that can help you find out how the limbs actually worked in 3D. It turns out that Icthyostega didn’t walk in a conventional manner. It looks as though one of the possible modes that it used would be a source of crunching motion, with the two front limbs together and the hind limbs acting as breaks or supports, but not actually producing any power on land. They were used to propel the animal in water, so for walking or for moving on land it used its front limbs, sort of pulling it along. And in the water it used its hind limbs as paddles for propulsion.

How did the first terrestrial animal walked?

Clack: We don’t really have enough information to be sure about that, but people now have been using the same sort of software and techniques to look at Acanthostega in the same way. But being very much aquatic, it’s obviously not going to be comparable in terms of what it was doing. The implication is that there were lots of different experiments going on in locomotion and we have only looked at the tip of the iceberg, in terms of the information that we’ve got, which is so limited. For example, in 2011, scientists published some track ways that were found in Poland that pre-date the Devonian tetrapods we had found by about 15 millions years. We don’t know what made those track ways, but we know it was made by an animal walking supported by water and using its limbs in an alternated fashion […]. So there were some animals around at this early stage that were using this pattern of locomotion, but we don’t know what they looked like because we don’t have any body fossils for them. 

What does it take for a palaeontologist to take on an ambitious expedition like your expedition to Greenland?

Clack: Again it was a series of lucky breaks. The material from Greenland at the time belonged to the Danish government. The material from Icthyostega, for example, was all in Copenhagen. I got in touch with the then curator of the Geological Museum in Copenhagen and told him about the material I had found in the Earth Sciences Department. And the quality and amount of that material convinced him that there was a lot more to be found. So he got in touch with the authorities in Denmark and the Greenland Geological Survey (as it was called then) and they happened that year to be setting up a 3-year project in the very area that we wanted to go. We managed to jump on the bandwagon, their expedition, using their facilities and transport arrangements, to get our expedition together. And the funding came to a large extent from our museum in Cambridge, and a certain amount also from Copenhagen and the Karlsberg Foundation. That’s how it was funded. We did try the Research Council in the UK but they weren’t interested.

Have there been other findings throughout your career that got you as excited as when you found Acanthostega?

Clack: Well actually, the project that I’m working on now which is now half way through. The Tw:eed Project is a consortium looking at what happened at the end of the Devonian. As the story goes… Devonian was the age of fishes, and at the end of the Devonian, quite a lot of them got wiped out, there was a mass extinction. The cause of it isn’t clear, but it seems to have been something climatic. The period after that, for 15 to 20 million years, was an almost complete blank in the fossil record, certainly for tetrapods but also for almost everything else as well. [...] The problem was that after that period of 20 million years, when we begin to pick up fossils of tetrapods again, they were extremely diverse. There was a huge variety of tetrapod forms, from small ones the size of a mouse, to other ones that were three or four meters long. So how did they get there? What happened after the end of the Devonian that allowed them to do that? We knew nothing about how these things became properly terrestrial. And it all happened in that gap. 
This gap was first identified by an American palaeontologist called Al Romer, so it’s called Romer’s gap. There were a few specimens from the period of this gap known from Nova Scotia, although nothing formal had been published on those. And I published a paper in the early 2000s on a complete specimen of a tetrapod from the middle of this gap that had been found in Dumbarton, in Scotland. In subsequent years, some of my colleagues have been looking at the appropriate sorts of sediments in the borders region in Northumberland, in Scotland, for the rocks of this age. They found some material, and it’s that material that we are beginning to work on, and we’re also finding a lot more. We have found numerous fossils of tetrapods, several new sharks, new lungfishes, all sorts of things. We’re beginning to get a handle on how terrestrial features or adaptations in tetrapods could have arisen.

So it is possible to find fossils from the Romer’s gap...

Clack: Yes, that’s right. Our idea is that this particular formation called the Ballagan Formation, which has been known for many years and was described as the Scottish cement stone series, is not commercially viable. There’s no coal and no decent limestone. In the 19^th century a lot of the carboniferous fossils were found by miners, and that’s how we knew they were there. But because nobody has been looking for commercially viable rocks, nobody has found anything, and because nobody has found anything, nobody has looked. It’s a sort of self-fulfilling prophecy until you get somebody with the determination to say, well they got to be there. And indeed, it turns out that they were.

Do you think that a multidisciplinary approach is important for palaeontology, or is it just a trend?

Clack: This seems to be increasingly the case, yes. […] In the 1970s and 1980s or earlier, palaeontologists tended to work by themselves, just looking and describing the animals. They were doing some fieldwork to find new stuff too, but definitely that was “one person, one fossil” kind of thing. But now collaboration is the key word because different people have different skills, and with all the new techniques that are coming forward you need collaborations to get all those skills together. And certainly I’ve collaborated with people from the Royal Veterinary College for example, and people from the synchroton facility in Grenoble. You just can’t work by yourself anymore, and this particular project was really perfect for this kind of collaborative effort.

How has the development of modern instrumentation (isotope analysis, computer modelling, X-ray computed tomography) changed the field?

Clack: Now we can think of asking and answering questions that would have seemed impossible 10 or 15 years ago. We can ask new questions about how things work, what that might mean, and how the animals developed. And, of course, you’ve got geologists on one side, and then you’ve got technicians, and people doing developmental biology on modern creatures to look at how things could relate to what the fossil record is finding. These collaborations are increasingly common. Developmental biologists and Evo-Devo people are constantly coming to us and asking what we see in the fossil record, and how could this fit with what they’re finding. It’s really encouraging. […] Quite a few people are interested in compiling large databases and then interrogating them; what fossils came from this region, how many species are there in these various time slots and what does the phylogeny tells us. That’s all very well but one fossil can overturn any of that. You still need the data and that’s why it’s so encouraging also that more people are going out and finding new stuff all the time, finding new localities and new areas of the world to explore. And at some of the localities people thought were wiped out, they go back and find new material there, so there’s a wealth of stuff. And of course, communication is so much easier than it used to be.

What is the palaeontology of the future?

Clack: Oh, who knows? If you look at the Society of Vertebrate Palaeontology website, they have their programme for their annual meeting which was in Berlin this year, and the diversity of talks is just stunning, where do we go from here? Well, I think we still need to be fuelled by new material, but that new material can overturn anything that I said! 50 years ago we thought we knew everything about fossils and Palaeozoic vertebrates… no we don’t know, it has been completely overturned since then and there’s no doubt it will be overturned again in the next 50 years.

How can we change the way scientists are perceived by the public? 

Clack: The media like to portrait science as rather esoteric, let's say. BBC tries to do a good job, but I think they have very stereotyped ideas about science and they think the public can’t cope with uncertainties. The message needs to get across that science is about questions and not about answers, and that’s hard to communicate. 

What do you love the most about being a palaeontologist?

Clack: Solving the puzzle, interpreting difficult material, and I think it’s probably one of the things I’m best at. I also quite enjoy writing the papers. I don’t find writing difficult, as I know some people do.

What big exciting questions remain out there for palaeontology, and which ones would you really like to see answered?

Clack: In terms of vertebrates, some of the big questions now are: what’s the origin of vertebrates? How do we get limbs from fins? How do you get fins in the first place? How do you get jaws and teeth, where are they coming form? That’s the sort of thing we can relate to modern developmental genetics as well. Where we can find links with other disciplines it’s really important. If you look at the limb bones of the carboniferous animals, in many cases they’re quite different from those of modern forms. How do we get terrestrially capable limbs? Which bits have to be modified so that you can bear weight? What muscles do you attach and how do they develop?

How would you explain to someone in one sentence that it is important to fund and encourage more palaeontology research?

Clack: It’s a bit like learning History, you know what use is History? What use is the Arts? People don’t seem to ask those questions, but what use is Palaeontology? Oh, that’s no use is it? Well it’s a cultural exercise, it expands the mind, it tells us where we came from and it puts us in our place. It’s all part of the evolutionary story. It’s not like a biomedical science where you want to help people, or invent some kid of drug or something, it’s mind expanding blue skies, learning about the world.

What is the fossil of your dreams?

Clack: I would like a sequence of strata with exceptionally well-preserved soft tissue representations of Devonian forms so that we could find out what sort of reproductive strategy they used. It’s what we call a Lagerstätten, like the Burgess Shale where we can actually see soft tissue preservation of early tetrapods. 


References:
Pierce S.E. & John R. Hutchinson (2012). Three-dimensional limb joint mobility in the early tetrapod Ichthyostega, Nature, DOI: http://dx.doi.org/10.1038/nature11124

Clack J.A. (2002). An early tetrapod from ‘Romer's Gap’, Nature, 418 (6893) 72-76. DOI: http://dx.doi.org/10.1038/nature00824 


Image credits: Museum of Zoology, University of Cambridge. Portrait, Chris Green, Department of Zoology, University of Cambridge.

An edited version of this interview was published in Lab Times in print on the 24-11-2014.

The secret for a longer life? Kill your unfit cells

If you had the choice, would you like to live until you’re 130 years old? New research in fruit flies shows that manipulating a single gene can extend their lifespan up to 60%, suggesting that living well into your hundreds might become a reality in the foreseeable future.

Dying of old age is a strange thing. Why does our health decline just because we’re old? Although the answer might at first seem obvious or simple, it really isn’t. There are countless theories of ageing, a few popular even outside the scientific community. Take ‘superfoods’, for example. The miracle properties credited to these antioxidant-rich foods stem from the free radical theory of ageing—older cells produce more of a toxic form of oxygen that gradually poisons them. Antioxidants like vitamin C or D counteract this deleterious effect and prevent ageing (and the appearance of wrinkles), superfood advocates claim.

A common denominator in these theories is that we age—and ultimately die—because our cells deteriorate with time (for whatever reason). As tissues and organs mount up more and more of these damaged cells, they begin to malfunction and eventually stop working. This raises an interesting assumption. What if we could get rid of these unfit cells and keep only the healthy ones? Would we live longer?

Jeanne Louise Calment had the longest confirmed human lifespan
on record (122 years and 164 days).

It’s well known that sick cells such as cancerous cells, are eliminated by our bodies, either by immune cells or by committing suicide. However, our ‘old’ unfit cells are still healthy enough to bypass this quality-control checkpoint. Or so it was thought. A few years ago, Eduardo Moreno and colleagues at the University of Bern, Switzerland, showed that healthy but less fit cells are also culled from tissues, by a mechanism they called “fitness fingerprints”. Each cell has a molecular fingerprint on its surface that tells its neighbours how healthy it is. When a given cell has a fingerprint that is worse than its neighbours', it kills itself. But the researchers didn’t know the importance of this cell elimination process for the organism. For example, would we age faster if those cells could not kill themselves?

To answer these questions, Moreno’s team genetically engineered fruit flies to control a newly found gene essential for marking unfit cells for culling. “If you put an extra copy of this gene you have better selection of the [unfit] cells, they are eliminated faster and therefore the animals can live longer”, says Moreno.

When the gene, which Moreno named azot, was removed from flies, they became sick and died prematurely. On the other hand, flies with an extra copy of the azot gene lived up to 60% longer.

Previously, only caloric restriction had been shown to prolong lifespan to such an extent in flies. In fact, reducing the amount of daily calorie input increases longevity in flies, nematodes, fish, mice and rats (data from studies with primates remain controversial). Could it be then, that starved flies with an extra copy of the azot gene live even longer? Indeed, these flies lived about 80% longer, Moreno’s team showed. In human time this would be equivalent to living up to 150 years!

The question remains whether these findings could be relevant for our species. Humans have the azot gene, in fact most organisms do, so potentially it should be possible to increase life expectancy in people by altering azot protein levels.

“You could start thinking of how to manipulate these mechanisms with drugs, for example, to treat ageing or diseases like neurodegeneration or myocardial infarction,” says Moreno, “I’m totally convinced it will be possible to delay aging and prolong lifespan in humans.”

Would we want to live longer though, if we spend most of our life old and sick? “Our long-term challenge will be to understand the biology of aging to address problems associated with steadily increasing life expectancy, such as metabolic disease and neurodegeneration”, says Martin Denzel, a researcher at the Max Planck Institute for Biology of Ageing in Cologne, Germany. With this in mind, Moreno’s team tested whether the long-living azot flies remained healthy as they aged. When the researchers looked in these flies’ brains, they found that their neurons accumulated fewer ageing cellular markers. Azot not only prolongs lifespan, but it also delays ageing.

In the future the team wants to understand what azot is actually doing. This gene encodes for a protein of unknown function, but the researchers know that when “the azot gene is activated, it triggers the normal cell death apoptosis pathway”, Moreno concludes. The team will also investigate the function of azot in mice, and collaborate with medical doctors to see if the azot-dependent cell elimination pathways are present in ageing-related diseases like Alzheimers.

“I have high hopes that eventually basic research into the aging process will yield treatments that extend the span of healthy living and that improve the quality of life in advanced age”, Denzel explains. “However, it will take a lot of additional work to investigate if this mechanism might be beneficial in mammals.”

Reference:

Merino M., Jesus M. Lopez-Gay, David Buechel, Barbara Hauert & Eduardo Moreno (2015). Elimination of Unfit Cells Maintains Tissue Health and Prolongs Lifespan, Cell, DOI: http://dx.doi.org/10.1016/j.cell.2014.12.017

This article was published in Lab Times on the 23-01-2015. You can read it here. 

Why do some people see ghosts?

For most people ghosts and spirits are part of the imaginary, but a few are truly convinced they can sometimes feel a strange presence near them. These individuals are not experiencing a paranormal phenomenon—they’re having an illusion. Schizophrenics, for instance, consistently report hearing voices or feeling someone—a ‘shadow’ or a ‘man’—close to them. Scientists have long known that illusions have a neurological cause, but they haven’t managed to pinpoint exactly how they are triggered by the brain.

Now, Olaf Blanke and colleagues have not only mapped the brain regions responsible for the ‘feeling of a presence’ illusion in neurological patients, but they have also developed a robot that tricks healthy people into sensing a ‘ghostly’ apparition. This work may shed light into what causes hallucinations in schizophrenia, and help design new therapeutic approaches to treat this psychosis.

 

Credit: Alain Herzog, EPFL.

In 2006, Blanke showed that he could induce the feeling of a presence in an epileptic patient by electrically stimulating a particular brain area—the temporoparietal junction. This region is involved in integrating body-related information from our senses and movements, and is often overactive in schizophrenic patients. But he found something even more interesting: the presence always mirrored the patient’s body position and movements; if the patient was sitting, the presence was also sitting and so on. “The presence was a duplicate of the patient, as if the patient’s body was recognised as another agent”, says Giulio Rognini, a collaborator at the Ecole Polytechnique Fédérale de Lausanne. “The body sensory information, which is not well integrated by the brain, is attributed to someone else.”

The researchers suspected that electrical stimulation of the temporoparietal region somehow disturbed integration of the patient’s sensory and motor information—her brain got confused and misplaced the bodily signals to the presence. To test this hypothesis, the team needed to be creative.

“The patient studies show that when there is no appropriate integration of the body sensory signals, then the feeling of a presence can occur, so we tried to do the reverse process: we perturbed the sensory motor system to see whether we could induce the presence”, says Rognini. And what better way to do this than with… a robot.

In their new study, Blanke and colleagues asked 12 blindfolded healthy participants to stick their finger into a ‘master’ robot and then move it around. The ‘slave’ robot, which was touching the participants’ back, mimicked the movements of the master robot either simultaneously, or with a slight delay. In the first condition (simultaneous touch), the participants felt as though they were touching their own back. This is already a strange illusion, but what happened when the slave robot poked them with a slight delay relative to the master robot is even weirder. About a third of the participants felt like someone else was touching them. Not the robot, but just ‘someone’, a presence. This illusion was short lived, but according to the participants’ description, it was very vivid and also a bit creepy.

“30% [of the participants] reported without asking them that they had a feeling of a presence. This is already very strong because in this field of body illusions, it’s very rare to find somebody that reports the illusion without being asked” says Rognini, who is senior author in the study.

The team also mapped the brain regions that trigger the illusions in several neurological patients. As expected, electrical stimulation of the temporoparietal, but especially the frontoparietal brain regions, induced the illusion. And again, most patients reported that the presence mimicked their movements.

 

Lesion overlap analyses revealed three brain regions involved in the feeling of a presence illusion: temporo-parietal 
and fronto-parietal cortex (© Current Biology)

The feeling of a presence is mostly associated with epilepsy and schizophrenia, but healthy people can also feel ‘ghosts’, especially during periods of extreme stress or physical exhaustion. Many mountaineers report they sometimes feel someone climbing with them, even though there was no one around. “If you’re walking and doing repetitive movements over and over again, your brain loses control over your movements because they’re not informative anymore”, says Rognini. “Your actions and the consequences of your actions can be misinterpreted, and together with low oxygen conditions in high altitude, this could give rise to feeling of a presence. But this is completely speculative.” The researchers are planning to test this hypothesis by trying to exhaust people in treadmills, and then check whether they are more prone to experiencing the illusion. They are also developing an fMRI-compatible robot to induce the illusion while the participants are being scanned.

“The next steps are about understanding the brain mechanisms by putting the subjects in the scanner, and then try to investigate how this phenomenon is perceived in schizophrenic patients to try to set out a therapeutic strategy or a way to better understand this psychosis,” says Rognini.

Herta Flor, director of the Institute of Cognitive and Clinical Neuroscience of the University of Heidelberg (Germany) says “Disturbed body perception is a core feature in several mental disorders, such as schizophrenia or borderline-personality disorder. To be aware of the underlying neural mechanisms might not only help to understand clinically altered behaviour in patients, but may lead to innovative treatment approaches.”

Reference:

Blanke O., Masayuki Hara, Lukas Heydrich, Andrea Serino, Akio Yamamoto, Toshiro Higuchi, Roy Salomon, Margitta Seeck, Theodor Landis & Shahar Arzy & (2014). Neurological and Robot-Controlled Induction of an Apparition, Current Biology, 24 (22) 2681-2686. DOI: http://dx.doi.org/10.1016/j.cub.2014.09.049

An edited version of this article was published in Lab Times on the 19-12-2014. You can red it here.

Seeds of change?

Plant science is probably one of the least appreciated fields of life sciences, and yet, perhaps no other research area has produced as many technological advances beneficial for society. In an open letter released last month, 21 out of the 27 most cited plant scientists in Europe pledged decision makers to back plant research, which they feel is currently threatened by lack of funding and global public and political opposition to genetically modified organisms (GMOs).

“In comparison for instance with biomedicine and fields with technical applications, plant science is not well funded, and that’s particularly true when it comes to funding from Horizon 2020”, says Stefan Jansson of Umea University (Sweden), who coordinated the letter.

Credit: © chaiyon021 - Fotolia.com

In the open letter the scientists recall the fundamental role of curiosity-driven plant research for a sustainable society and to “deepen our understanding of nature”, and they warn decision makers that without their support—financial and political—the Horizon2020 goals to “tackle societal challenges” and “to ensure Europe produces world-class science” will not be met.  

Besides asking for funding to be maintained or, if possible, increased, they demand that plant scientists must be allowed to perform field experiments with GM plant varieties, and that Europe must “promptly” authorise new GM crops that have been found safe by the European Food Safe Authority (EFSA).

They claim that in most European countries, “permits to perform field experiments with transgenic plants are blocked, not on scientific but on political grounds”. And the few field experiments that do go ahead are often vandalised, wasting years of work and public funding.  To make matters worse, the scientists say in the letter, the ongoing de facto ban on approvals for new GM plant varieties in Europe has not only been damaging for applied plant science, but it has also increased the competitive advantage of agrochemical corporation giants like Monsanto; publicly funded scientists and small companies just don’t have the means to go through expensive, and sometimes decade-long, approval procedures.

“Every approval of a [GM plant] variety is enormously expensive, complicated and unpredictable, so no one ever tries nowadays”, says Jansson.

GMOs in Europe

This opposition to GMOs can safely be called epidemic. Lobbying by environmentalists and widespread popular resistance to GMOs has held back the use of GM plants in agriculture globally, but only in Europe the situation seems hopeless. A single GM plant is currently commercially cultivated in the EU— the MON810 maze produced by Monsanto that carries resistance to European corn borer, and which is cultivated in Spain, Portugal, Czech Republic, Romania and Slovakia. A de facto ban on GMO approvals has kept GM plants off the fields and out of our fridges for over 10 years. Environmental activists often associate GM crops with the ‘big bad wolf’ agrochemical companies, but in fact Monsanto and Syngenta have pulled out from the European market all together, so effectively the only people affected by this ban are farmers and plant scientists.

(March agains Monsanto, Vancouver, Canada, 2013. Credit: wikipedia)

“European agriculture is lagging behind when it comes to development, yields and so on. So every year the rest of the world is improving more than we’re doing here”, Jansson says “Unfortunately it’s because we’re not allowed to use the right technologies”.

The extreme position of France

This anti-GMO fever has changed the face of plant research in some European countries. France is an extreme example. It’s a national joke in France to say that all political parties, from far left to far right, agree on one thing: they’re religiously against GMOs. 

The radical resistance to GMOs in France began in the late 1990s amidst a growing anti-GMO mood that was quickly spreading worldwide. Ironically, back in those days France was at the forefront of the plant biotechnology field, and large consortium initiatives such as GENIUS and GISBiotechnologiesVertes (formerly known as Génoplante) received generous public funding. In fact, the first ever field experiment with a GM plant variety was performed in France in 1986, and for a decade, France ranked second only to the United States in the number of these experiments with GM crops, and they triggered no public protests. However, in just a few years the number of field trials in France plunged from over a thousand (in 1998) to only 48 (in 2004), and over half of these were eventually destroyed by activists. So what happened?

As the mad-cow disease and beef hormones scandals shocked the world in the mid 1990s, people began to become very sensitive about what was in their food. And exactly around this time, the Monsanto’s Roundup Ready soybeans controversy exploded. Not surprisingly, this promising new GM technology didn’t go down that well with the public. As Greenpeace promptly launched its first campaign against GMOs in 1996, a very influential French environmental activist named José Bové started a strong anti-GMO movement that conquered the French public opinion: from Parisian “bobos”, to journalists and even scientists, everyone seemed to hate GMOs, and politicians just followed the trend. 

The French Environmental Minister at the time, Corinne Lepage, began introducing laws to ban cultivation of GM plant varieties, and all subsequent governments, regardless of their political views, continued this anti-GMO policy. Activists that destroyed GM crops and research labs were prosecuted but got away with light sentences or amnesties. For instance, in 1999 protesters led by Bové completely destroyed a greenhouse for experiments with GM plants at CIRAD, a research centre for agriculture and sustained development in Montpellier. After a long and highly publicised trial, Bové was prosecuted to 6-months in jail, but the then president Jacques Chirac eventually “pardoned” four months of that sentence.

“They [the activists] are protected by the justice, they’re not really condemned. The laws were relaxed by the courts. It’s easier for these persons to get a meeting with the Minister of Research than for scientists,” says Georges Pelletier, president of the Scientific Committee of the French Association of Plant Biotechnology and former head of the Department of Plant Physiology of INRA (French National Institute for Agricultural Research).

Because of this strong public aversion to GMOs, and of the heavy administrative burden and expensive greenhouses required for testing GM varieties for agriculture, plant scientists in France have dropped their arms and simply “lost hope”, says Pelletier. Now, they use GM technologies only for basic research, and then adopt classical breeding methods to obtain the desired plant variety, or otherwise they perform field experiments with GM plants abroad.

“Nobody is growing GM crops outside anymore, after a while you understand the message”, says Brigitte Courtois, a researcher at CIRAD who is trying to obtain rice plants resistant to flooding by classical breeding, and who got some of her plants destroyed by Bové. “My main worry is that one day we’ll not be able to do any breeding because of this narrow vision.”

CIRAD and INRA, the largest public agricultural research institutions in France, have reduced the use of GM technologies in applied plant research to nearly zero. Once a leading country in plant biotechnology, France plant scientists in public institutions are now forced to work almost exclusively on fundamental research.

“The pressure on the scientists continues […] so in a way these people are also more or less destroying the science. They put pressure on the scientists hoping they will change their research”, Pelletier says.

Communication breakdown

(Credit: Acrylic Artist/Morguefile.com)

Since Monsanto’s Roundup Ready soybean scandal, activists don’t seem to be able to distinguish the agro-industry sharks from applied plant research, or in fact any plant research, so public and political resistance to plant biotechnology and innovation persists, and plant scientists suffer the collateral damage.

“I have stopped talking about [my work] with my friends. Even educated friends with the same background in agronomy, they all feel that there are other options, like organic farming […]. For me this is associated with the fact that people have no contact with agriculture anymore, they’re urban people who know nothing about how to grow a plant”, says Courtois.

But in other countries, there are some signs that if the public does listen to the researchers, they are more positive about the use of GM technology to tackle societal problems. At Rothamsted Research (UK), one of the world’s oldest agricultural research institutions, extensive information about their field experiments with GMOs is available online, and researchers make an effort to engage with the public to explain their research. The results start to show: while a couple of years ago protesters attacked (but not destroyed) a GM field trial at Rothamsted, the ongoing field experiment with Camina plants that produce omega-3 oils hasn’t been at all targeted.

“When we discuss our work with the public the general feedback is that the people are interested in what we are doing and more positive towards the use of GM technology in trying to address research questions and provide potential solutions to agriculture and food production challenges”, said Rothamsted’s researchers in a statement to Lab Times.

It is difficult though for plant scientists to get the message across to the public; if they’re not allowed to cultivate GM plants, how can they show their benefits for agriculture and society? And if the public doesn’t see those advantages, the lobbyists continue to put pressure on politicians to ban GMOs. It’s a vicious circle.

“All the new environment-friendly varieties that actually have been produced over the years, if they’re just in the drawers of the scientists and never been used in practical agriculture, then its much harder to convince society about the value of what we’re doing,” says Jansson.

Politics vs science

The date for the release of the open letter, at the end of October, was chosen carefully. The new European Commissioner for Public Heath and Food Safety, Vytenis Andriukaitis, took office on the 1^st of November, and just a few days later the European Parliament voted on a Commission’s proposal to give power to individual member states (MS) to ban GMOs in their territory.

This proposal was initially meant to be a compromise to unblock the over 10-year-long gridlock on GMO authorisations. Currently, any GMO approval in the European Union (EU) first needs to go through a thorough science-based evaluation by EFSA, and then the Commission drafts a proposal to either ban or authorise the new GMO according to EFSA’s recommendation. The proposal finally goes to the Standing Commission—made of politicians representing EU governments and public authorities—and they have the final say. If nine or more countries are against the Commission’s proposal, the approval is blocked. This has happened systematically for over a decade.

“When it comes to pharmaceutical industries, for instance, it’s not the politicians that make the evaluations whether the drug is dangerous or has side-effects or not, it’s the scientific body that does that”, says Jansson.

Anti-GMO countries like France have stalled the system by using spurious scientific arguments to ban GMO approvals, and applicants are either forced to spend years on end doing more and more safety tests, or they have to go into long and expensive legal battles to overturn the Commission’s decision (or lack of thereof). Inevitably, companies trying to commercialise their GM plant variety in Europe give up, while publicly funded researchers don’t even try.

This de facto ban has worked well for anti-GMO countries so far, but ironically, because of the countless scientific studies they’ve imposed, a huge amount of scientific evidence has accumulated showing that GMOs don’t pose any risk for human health or the environment. Anti-GMO countries are running out of arguments.

As a result, in an unprecedented move, thirteen countries formally asked the Commission to give MS the “flexibility” to ban EU-authorised GMO crops in their territory. Even though this would in theory go against the single market principle, in June 2014 the Commission approved a compromise proposal granting that request, but preventing MS from banning EU-authorised crops based on health or environmental grounds. This was a painful and much-negotiated compromise that could have worked. However, amendments introduced to the proposal by lobbyists will effectively give countries legal grounds to ban GMOs on reasons such as “environmental policy, town and country planning, land use, agricultural policy, public policy, or possible socio-economic impacts, GMO contamination of other products, persistent scientific uncertainty, development of pesticide resistance amongst weeds and pests, invasiveness, the persistence of a GMO variety in the environment or a lack of data on the potential negative impacts of a variety”, MEPs say in a press release. So pretty much any reason will do.

The Commission’s amended proposal was approved by the European Parliament in November. The decision is not final yet, but the future for GMOs in Europe seems bleak.

“The amendments that give MS the ability to challenge cultivation on grounds of safety are worrying because they undermine the risk assessment performed by EFSA” Rothamsted researchers voice their concern in a statement to Lab Times. “Potentially, it will also make it harder for MS who do not want to opt-out to justify to their consumers when neighbouring MS are using safety as a reason to ban”.

The worry is that pro-GMO countries won’t be able to cultivate EU-authorised GM crops in their country because activists can now say “If that country banned this crop on safety grounds, it must mean it’s unsafe”, and this will put even more pressure on politicians to ban GMOs. EFSA’s science-based evaluation will lose weight on GMO approvals; the power will lie merely on politicians, and science will have little impact on future decisions to authorise or ban GM crops in Europe.

Seeds for the future

The open letter has so far not received any response from the European Commissioner, but it got extensive media coverage and excellent feedback from the research community, except in France, where researchers seem to prefer to remain quiet.

“The letter was addressed to two French scientists amongst the best in Europe and they didn’t want to sign. One of them because of the question of GMOs and application was inserted in the letter, so he didn’t want to sign. The other never replied”, reveals Pelletier.

So what’s the future for plant science in Europe?

Jansson says “It won’t disappear but it won’t flourish either. Maybe, in 10 years, there will be fewer plant scientists and they will be a little less useful for society.”

Reference:

Bonneuil C. & C. Marris (2007). Disentrenching Experiment: The Construction of GM--Crop Field Trials As a Social Problem, Science, Technology , 33 (2) 201-229. DOI: http://dx.doi.org/10.1177/0162243907311263

This article was published in Lab Times on the 9-12-2014. You can read it here.