A dialog on ghosts and models in science

This is the first of several pieces in response to questions I have received about my recent lengthy article (too lengthy!) on “Ghosts, models and meaning: rethinking the role of communication in science.” Read the full article here.

Can you give me a succinct definition of the “ghosts” you’re talking about?

There are a lot of contexts in which science communication somehow fails because an audience doesn’t get the point or understand a message the way it was intended. The naïve view of this is that scientists just know a lot more about a specialized topic than people from other fields or the public. That happens, but it’s rarely the biggest issue in communication – and it doesn’t explain why people have problems writing for experts in their own field.

When I began teaching scientists to write I came across a lot of content-related breakdowns that were hard to understand. This got so frustrating that I finally decided I had to systematically analyze the problems I was seeing. That took about four years, and “ghosts” emerged as one of the most frequent and important issues.

Ghosts originate from many things: concepts, frameworks, logical sequences, other patterns of linking ideas, theories, images and so on. What unifies them is that the author has something in mind as he composes a message, and it is essential to understanding what he means – but he never directly articulates it in the message itself. He may not even be aware of it. Since it’s nowhere to be found in the message, it’s invisible; if the reader doesn’t sense its presence, or can’t easily recover it, it disrupts his understanding of what the author means.

This is true of all kinds of communication, but the natural sciences have some special ways of assigning meaning to things that really need to be taken into account when you’re planning a message or trying to interpret one. If you don’t, you’re setting yourself up for misunderstandings.

 

You mention models again and again – why are they so central to these misunderstandings?

Among the most significant and disruptive ghosts in science are various models that are used in formulating a question or hypothesis and interpreting the results. Most studies engage many types and levels of models. Scientists obviously recognize this; as Theodore Dobzhansky said, “Nothing in biology makes sense except in the light of evolution.” But there is a big difference between acknowledging this and demonstrating how something like evolutionary theory reaches into very basic practices, such as how scientists name molecules. And there’s a big invisible ghost behind Dobzhansky’s statement – something he doesn’t explicitly state but is essential to understanding what he means. Evolution itself is based on even more fundamental principles of science, so if you’re talking about the theory, you’re also talking about them. In fact, most “debates” over evolution are actually arguments about even bigger things, and if you don’t confront that level of the disagreement, it doesn’t even really make sense to discuss whether species change or go extinct or the other topics that these discussions always get mired down in.

 

What are those specific ghosts?

I think there are two, and they are so basic that they distinguish science from other ways of thinking about things and assigning them meaning. I call the first one the principle of local interactions: if you claim that something directly causes another thing, you either prove or assume that the cause and effect come in contact with each other in time and space, or are linked by steps such as a transfer of energy that follow this rule. So to make a scientific claim that a child inherits traits from its parents, you have to find some direct mechanism linking them, such as the DNA in their cells. It is directly passed to children from the reproductive cells of their parents, and it’s the blueprint that creates bodies through its transcription into RNAs and their translation into proteins.

The second principle applies this type of causality to entities as complex as organisms or entire ecospheres and declares that the state of a system arises from its previous state through a rule-governed process. And it will generate future states through the same rules. You may not know what they are, but you assume they are there, and a lot of scientific work is devoted to creating models that will expose them. If you follow this principle you can observe what is going on in a system right now and project it far into the past and deduce its previous states. This is the source of the Big Bang theory in astrophysics; it’s the basis of geology, and when Darwin applied it to life he got evolution. Extending the principle into the future is the basis of the experimental method used to determine whether your model of a system is accurate enough to work with – if something in an experiment violates predictions made by the model, you have to revise it.

Anything that violates the principle of local interactions would be considered non-scientific. That’s the case for extrasensory perception – until you can demonstrate that some energy passes from one person’s mind into another’s, you can’t make a scientific claim for its existence, so you have to look closely into whatever model of causality led you to claim it might exist. And the second principle implies that there are no discontinuities – you can’t create something from nothing. Miracles and the fundamentalist account of creation violate both principles.

If you can’t agree on these two things, it makes very little sense to discuss details of evolution that derive from them, because differences in your very basic assumptions will make it impossible to reach any sensible common ground – or even define some of the terms you’re talking about. So these principles are ghosts in “debates” on this topic, and they are the things you need to debate, providing you can do so fairly, with intellectual honesty and integrity.

 

You came up with this concept of “ghosts” while working on texts by students and other scientists. Why are they a particular problem for students?

Active researchers are deeply engaged with their models; most projects take place in a fairly exact dialog with models you are either trying to elaborate on by adding details, or extend to new systems, or refute through new evidence. This makes models very dynamic, and there’s no single reference on the Internet or wherever where you can go and find them. In biology virtually every topic gets reviewed every year or two, which is an expert’s attempt to summarize the most recent findings in a field to keep people in a field more or less on the same page. That’s the group that a lot of papers and talks are addressed to, at least most scientists think that way – and they assume the readers will have more or less the same concepts, models and frameworks in mind. Anything that is widely shared, people often fail to say – they think they don’t need to. And it’s impossible to lay out all the assumptions and frameworks that underlie a paper within it – you can’t define every single term, for example. So these become ghosts that aren’t explicitly mentioned but lie behind the meaning of every paper. The two really huge basic principles I mentioned above are rarely, rarely described in papers.

And even the details of the models more directly addressed by a piece of work – the physical structure of the components of signaling pathways, or all the events within a developmental process – aren’t mentioned very often. Those models are embedded in higher-level models, and the relationships in this hierarchy are not only hard to see – there’s no single way of explaining them. Scientists sometimes work these things out fairly intuitively as they extend the meaning of a specific set of results to other situations and higher levels of organization.

Now imagine a science student who is absorbing tons of information from papers like these. As he reads he’s grappling with understanding a lot of new material, but he’s also actively building a cognitive structure in his head – I call it the “inner laboratory, or cognitive laboratory.” It consists of a huge architecture in which concepts are linked together in a certain structure. The degree to which he understands a new piece of science depends on how that structure is put together, and where he plugs in new information. If the text he’s reading doesn’t explicitly tell him how to do this, there will be a lot of misinterpretations.

How can his professor or the head of his lab tell whether a scientist under his supervision is assembling this architecture in a reasonable way? You catch glimpses of part of it in the way someone designs an experiment, but I think the only method that gives you a very thorough view of it is to have the young scientist write. That process forces him to make the way he links ideas explicit and put them down in a way you can analyse each step. In writing – or other forms of representation, such as drawing images or making concept maps – you articulate a train of thought that someone else can follow, providing a means of interrogating each step. Most texts are pretty revealing about that architecture; if you read them closely you can see gaps, wrong turns, logical errors, and all kinds of links between ideas that a reader can examine very carefully.

The problem is that in most education systems in continental Europe, in which most of the scientists I deal with were educated, writing is not part of the curriculum. Whatever training they have is done in all sorts of ways, and the teaching is usually not content-based. Instructors use all kinds of exercises on general topics, but that learning doesn’t transfer well to real practice. Why not? Because when you write about a general theme, your knowledge is usually arranged very similarly to that of the teacher’s and any general audience. In your specialized field, on the other hand, your knowledge is likely to be very differently arranged, and that’s where the ghosts start to wreak real havoc on communication.

 

So ghosts aren’t just things that scientists leave out of texts – they’re also phenomena that arise from the reader or audience…?

Absolutely – they arise from differences in the way a speaker and listener or a writer and reader have their knowledge organized. That can happen in any kind of communication, but in science it’s actually possible to pin ghosts down fairly precisely. In political discussions or other types of debates there aren’t really formal rules about the types of arguments that are allowed… But if you know how meaning in science is established, you can point to a specific connection in a text or image and say, “To understand what the scientist means, you have to know this or this other thing.” Again, since neither of you can directly see what’s in the other’s head, a reader may not guess that some of the meaning comes from very high levels of assumptions, or a way of organizing information that you’re not being told. And some have been digested so thoroughly by scientists that they’re no longer really aware that they are there.

Some of the most interesting ghosts appear when you try use someone’s description of a structure or process to draw a scheme or diagram. I recently had to draw an image of how a few molecules bind to DNA because we needed an illustration for a paper. I thought I had it clear in my mind, but I ended up drawing it five times – each version incorporating some new piece of information the scientist told me – before I got it the way she wanted it. You learn an incredible amount that way.

A scientific text is often based on an image of a component or process that a scientist has in his mind. He’s trying to get a point across, and to understand what he means you have to see it the way he sees it – but if he leaves anything out, it’s easy to completely miss the logic. It’s like trying to follow someone’s directions… That works best if the person who’s giving the instructions can “see the route” the way it will appear to you, maybe driving it one time to look for the least ambiguous landmarks, or taking public transportation and watching exactly what signs are the most visible. And thinking it through with the idea, “Now where could this go wrong?”

 

Another thing you refer to is concept maps – you include several examples in the article. How do they fit in?

Concept mapping is a system invented by a great educator named Joe Novak; it gives you a visual method to describe very complex architectures of information. It’s extremely useful in communication, teaching, and analyzing communication problems. One reason it’s so important is that our minds deal with incredibly complex concepts that are linked together in many ways. Think of trying to play a game of chess without a board – that’s incredibly difficult, but a chess set is a fairly simple system compared to most of those that science deals with. There’s really no way to keep whole systems in your head at the same time. Making a map gives you a chance to see the whole and manipulate it in ways that would be impossible just by thinking about it.

But the real genius of this system appears in communication and its most precise form – education – where a teacher ought to understand what he is really trying to communicate, and how it’s likely to be understood by the students or audience. In most cases you’re hoping to do more than just “transmit” a list of single facts; you’re trying to get across a coherent little network of related ideas, linked in specific ways. If you do that successfully, the audience will leave with a pattern they can reproduce later. It might be a story, a sequence of events, or a metaphor – the main thing is, they have seen how the pieces are related to each other.

A great way to do this is to make a map of the story you’re trying to tell, and then make your best guess about how this information is arranged in the heads of your target audience. What can you realistically expect them to know, and what information and links are likely to be new? If you see the pattern you’re trying to communicate very clearly, and make a reasonable guess about how some type of knowledge you can relate it to is arranged in your audience’s head, you know what you have to change to get them to see things the way you’re hoping. In schools they’re teaching kids to make concept maps early on. Then before a lesson about something like the solar system, the teacher has the kids draw a map of what they think about the sun, moon, planets, and so on. After the lesson the kids make a new map – comparing the two tells you what they’ve really learned.

 

In your article you point out ghosts that come from schemes like sequences of events or tables…

A lot of scientific models consist of sequences of interactions between the components of a system. Those start somewhere and involve steps arranged in a particular order, and it’s important for the reader to have a view of the steps and that order in his mind. You’d be surprised how often scientists describe these processes in some bizarre order that doesn’t go from A to K, but starts at G, goes to H and I, then goes back to G and works backward to F, E, and D… Again, if you are already familiar with the sequence or pathway this is no problem. But if you don’t, you’re probably expecting the reader to try to assemble the process in some reasonable order. That may be possible through a careful reading of the text, but it takes far more “processing time” than a reader would need if the whole sequence were simply laid out in order in the first place.

Tables are interesting because a lot of experiments are designed with a structure that’s pretty much inherently that of a table. Say you have two experimental systems plus a control, and you apply two procedures to all of them. To make a claim about the results, you have to march through all these cases – basically a table that’s 3×2 or 2×3. Here again, you’d be surprised how many scientists’ descriptions skip over some of the cells of the table, mostly because the results aren’t very informative. Or they tell you, “Procedure A caused a 5-fold increase over Procedure B,” without telling you what happened in the control.

Both of these effects are due to a scientist’s failure to recognize the structure of the information he has in his head and is trying to present… Then he fails to present that structure in the text in a way that’s easy for the reader to rebuild in his own head.

 

You’ve said that ghosts are one component of a larger model you’re working on that reformulates the relationship between science and communication… What else is there?

A lot of the other points can be captured through an exploration of what I call this “inner” or “cognitive” laboratory of science. The really good scientists I know have a very clear understanding of their own thinking. They know the assumptions that have gone into the models they are using, and are aware of the limitations, where there are gaps and so on. That type of clarity usually translates into good communication, no matter what the audience.

One thing I found during this project that was very surprising was the extent to which writing and communication for all kinds of audiences was connected, and how addressing very diverse audiences could clarify thinking in a way that improved a scientist’s research. When you find a scientist struggling with clarity in a text, it usually means one of two things. Either a topic is not clear in his head at that moment, or it’s not clear in anybody’s head at this moment in science… That second case is very interesting because it means you can find interesting questions just through a very careful reading of a text, realizing that it’s asking you to build a certain structure of ideas. If you have difficulty, that means something. One of the basic strategies I used in working these things out was that problems are meaningful – they’re trying to tell you something about how good science communication works, or how scientific thinking works… usually both.

Speaking to a general public with really no specialized knowledge of a field can be a truly profound exercise for a scientist. It makes him interrogate his own knowledge in alternative ways. He has to come to a much more basic understanding of the patterns in his inner laboratory and apply different metaphors, trying to map that knowledge onto someone else’s patterns. Well, the cognitive laboratory is already metaphorical, based on concepts rather than real objects, and applying new patterns or metaphors to what’s in there is extremely interesting. It can suggest questions you’ve never thought of before. This means that tools that have been developed by linguists and communicators can be used as tools to crack open scientific models.

I’ve actually done this – used those tools to expose an assumption about evolution that everyone was making but wasn’t usually aware of. The assumption had never been tested, so my friend Miguel Andrade decided to take it on as a project, and put a postdoc on it. The results were really interesting, showing that there were a lot of cases where the assumption didn’t hold – and we got a published, peer-reviewed paper out of it. That was three years ago, and in the meantime I’ve been involved in a number of similar projects that have had a similar outcome. A communicator who pursues questions about meaning and language has a different set of tools to understand how ideas are linked in scientific models. You’re freer to apply slightly different metaphors and patterns to ideas; you may be more rigorous in perceiving assumptions; metaphors and other tropes help you see cases in which people are reasoning by analogy rather than strictly adhering to the system at hand.

So these ideas aren’t just a way to help people plan and communication better – although they certainly help in those tasks. In fact they are much more fundamental in scientific thinking. Understanding these relationships between communication and science is a pathway to doing better research, through a better understanding of its cognitive side. I’ve noticed recently, for example, a lot of cases where the way people are thinking of complicated processes is drifting away from the language they use to describe them. The language is conservative and it may be hard to adjust. But that will be essential as the models these fields are using move forward and become so complex that our minds – and our language – may not be truly able to capture them.

 

 

 

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The Bible of Elazığ: a backroom to a parallel universe

Bizarre, serendipitous adventures in science communication

Part one

This incredible story goes back a few years and adheres as closely to truth as memory and my notes permit. I have changed some names, for reasons that will become clear. It began a few months after I had finished a book called The Case of the short-fingered Musketeer, which concerns the heroic efforts by physician/scientist Friedrich Luft and his lab to discover genetic mechanisms underlying essential hypertension. I covered that story in the book, as fully I could. But except to a few close friends, I’ve never recounted the extraordinary events that happened in its aftermath.

To put things into context, the research carried out by Fred and his group involved a family of farmers living in Northern Turkey. They suffered from a genetic disease that was thought to be unique at the time, but over the course of the project Fred’s group uncovered a number of other families around that globe that are affected. People suffering from the hereditary condition called Bilganturan’s syndrome have very short fingers and toes, a short overall stature, and amazingly high blood pressure.

One unusual aspect of the group’s research was that the Turkish family had been actively involved in the project for many years, which made their perspective an important part of the story. When I told Fred I wanted to write a book about their work, he decided to mount a new trip to visit the family on the Black Sea. I tagged along on a week-long expedition, where the scientists collected samples that would eventually lead to the solution of the family’s unique condition. Later we paid a visit to a Nihat Bilganturan in Ankarra, the physician who had written the first paper about the family’s disease in the early 1970s. He was an amazingly colorful figure whose work had taken him to the US, Saudi Arabia and around the world – I’m still hoping that a massive autobiography that he was working on will be published someday.

Those two visits represented my entire experience of Turkey when I set out to write the Musketeer book. That obviously wouldn’t do: so much of the tale revolved around crossing cultural and societal borders, and two of the main characters were young physicians whose Turkish parents had immigrated to Germany in the 1960s. One branch of the family affected by the disease had moved to the Stuttgart region. To have any hope of realistically portraying their thoughts and their lives, I carried out extensive interviews with many of them – usually through translators. But I still needed more.

Living in Berlin brings you into daily contact with many such immigrants and their children, from all walks of life. Whenever I could I began engaging these people in conversations, in hopes of improving my understanding of their situation. One of those chance encounters led to the wild and unexpected adventure I’ll describe here.

* * * * *

For ten years I’ve had a small apartment near the S-Bahn station in Pankow, not one of the glamourous areas of the city. The steady rise in rents is a sign that things are improving, but the cafés and shops in the neighborhood have had a hard go of it. Just as you get to know the regulars, a place changes hands.

The corner near my place used to be occupied by one of those night shops you find all around Berlin. Mostly run by Turks or other immigrants, their main source of income is a flow of pedestrians who stop by for beer or cigarettes, then step outside to smoke and drink. They bring their empty soldiers back inside, collect the refund, then buy the next round. The city hadn’t yet toughened up on indoor smoking, so there was a perpetual cloud emerging from a back room where they had a row of computers that people could use to surf the Internet. It was handy if you needed a late-night e-mail fix, but hard on the lungs – and you certainly didn’t want to watch the surfing habits of the denizens that hung out there.

The place was run by two middle-aged Turkish men who would chat the ear off anyone who expressed an interest in their home country. When they found out about the book I was writing… Let’s just say they began considering themselves key, confidential informants on every possible topic. I had long reached the saturation point by the night somebody broke in and absconded with their computers, upon which the place passed into the hands of a younger generation of German Turks and a new set of informants.

I didn’t see the original owners again until about two years later, when I was at the Friedrichstrasse in Berlin, running late for some appointment. I ran up the steps to the S-bahn and arrived on the platform just as the doors of the train were closing. I jammed my way in, sat down, and tried to catch my breath. When I’d recovered enough to take in my surroundings, I noticed a short, hefty guy with bristly white hair sitting across the aisle, staring at me. I couldn’t place him until he came over to sit down next to me. It was one of the original owners of the shop.

The first thing he said was, “You’re a scientist, aren’t you?”

No, I said, but I certainly knew enough of them.

“We need your help,” he said.

* * * * *

Such moments of serendipity happen in Berlin all the time, and there’s no predicting what will come of them. You meet people by chance, talk about nothing in particular, and then run into them a couple of years later when your lives have entered a new phase.

Ali, as I’ll call him here, was cagey about the topic on his mind. The first step was to exchange cell phone numbers. Maybe we could meet in a day or two down by the Yorckstrasse? It sounded like a small adventure; how could I possibly refuse?

So the next Saturday I took the S-bahn to the station south of Potsdamer Platz. Ali collected me on the platform and led me down the stairs, then on a long walk farther to the south down a boulevard lined with trees. We turned east and walked a hundred meters more where he stopped, opened an unmarked door, and gestured that I should enter. Inside was another world: a Turkish tea shop.

I hadn’t noticed them before, but in certain neighborhoods you’ll find many such doors; at any moment they might open to reveal a cluster of men, reading newspapers and drinking tea and arguing about impenetrable topics. Here there were four or five guests sitting around a table, engaged in the usual activities under the drone of a television set mounted on the wall. It was tuned to one of those strange dramas that had been perpetually running on the TV in the restaurant of our hotel in Turkey: a melange of soap opera and family story in which people would shout at each other; someone would unexpectedly burst into tears, followed by the sudden appearance of a gun. An utterly foreign dramaturgy that was impossible to follow if you didn’t know the language.

As we entered the shop, conversation broke off abruptly and the heads of the men turned to rake me with a suspicious, penetrating stare. Ali said something that seemed to appease them; after a comment or two they turned back to their newspapers. A young man emerged from behind a counter and, without asking, served us black tea in small, glass cups. The tea was steaming hot and had to be taken in small sips. We chatted about something; I don’t remember what, but it was nothing meaningful.

What am I doing here?

After ten or fifteen minutes of this, Ali stood up. “Come,” he said, and gestured toward a door behind the counter. We passed into the back room, a combination between office and storage room, with a desk littered with papers, stacks of boxes, and an ancient leather sofa creased and stained by ages of wear. There was a rust-encrusted bicycle leaning against one wall. Ali moved some stuff off the sofa. “Sit,” he said, and I sat down on the sofa, sinking in deep. Now really wondering what I was doing there.

My host sat down at the desk and shuffled some papers around. He got out his cell phone, scowled at it a while, and punched in some numbers. An excited conversation. He hung up and smiled at me. “You want some more tea? I’ll get us some more tea.” And he left.

Ten minutes later he returned with tea and another Turkish man who hadn’t been outside – tall, thin, balding, with black horn-rimmed glasses. Mehmet, let’s say. We sipped and once again, talked about nothing in particular for a while. The newcomer asked about my work, in a way that suggested I was being cross-examined. To turn the tables, I asked about his work.

“I’m a lawyer,” Mehmet said.

Mysteriouser and mysteriouser.

* * * * *

This was the first of five or six meetings that eventually took place in that tea shop near the Yorckstrasse or another nearby. Each time I had the feeling I was undergoing some sort of test, and each test I passed unlocked a bit more of an incredible story. Later I understood that the people I was meeting had very good reasons for their extreme caution and distrust of strangers. But at the time this all seemed like a bizarre symptom of a cultural code I didn’t understand – especially since they had approached me for help, rather than the other way around.

It was the third meeting, I think, when they asked me if I had any experience with “very old things.”

What kind of old things?

Very old… objects.” Mehmet’s eyes were glued to my face.

“Old” could mean almost anything – historical? archeological? paleontological? I had nothing like professional experience in any of those domains, but if he was talking about something truly ancient, I’d at least gotten my feet wet. As a high school student I’d joined a month-long paleontology trip across the state of Kansas, which culminated in the discovery of a dinosaur near Lake Wilson. Then at the university I’d fulfilled part of my science requirement with classes in archeology. The high point of that period was a year in Bordeaux, where alongside an intensive program to become a French teacher, I’d taken a year-long course in prehistoric art. Most weekends the professor would take us on expeditions to the caves of the Dordogne, where we’d stand under glowing painted figures of animals or follow a herd of mammoths that had been engraved on the walls of the twisted corridors. Once we spent four hours walking through the grotte Rouffignac carrying only lanterns, which was as near as you could get to the experience of a prehistoric sculptor who had followed the same route 30,000 years ago. For some reason those ancient artists rarely depicted humans; when they did, the images were usually tucked away in nearly inaccessible corners of the caves. At one point the guides lowered us students down into a hole on a rope, one-by-one, to bring us face-to-face with a drawing of a human head.

I came out of my reverie, and realized that I was tired of whatever game Ali and Mehmet were luring me into. If they wanted my help, it was time to let me in on what was going on.

“What kind of objects?”

They gave each other a long glance. Finally Ali said, “A cousin of mine, in Turkey… found some things. Very old manuscripts. We would like to know what they are.”

“Where are these things?”

“In Turkey,” Ali said. A pause, and another glance. “But they have pictures.”

He didn’t have them now, he said. But he would call his cousin, who might be able to send some. “Maybe you can come back tomorrow.”

* * * * *

Finally catching a glimpse of the pictures took two more trips to Yorckstrasse and two more visits to the back room, then an invitation to dinner in a Turkish restaurant. There we were joined by a third man whose name I never learned and whose relationship to this strange band of “relatives” – as was the case for Ali and Mehmet – never became completely clear. Later I found out that the term “cousin” was being used in the broadest possible way. And that my new-found acquaintances were playing fast and loose with some of their facts. But they’d succeeded in hooking me with a story and drawing me into an adventure that was just beginning.

Ali finally resolved some issues with the Internet – his “relative” was only willing to provide the images on a secure server for the shortest possible time. The first time we tried to log on – from another shop with Internet access – they had already been deleted. The second time we could scroll through a few of the photos. There was a thick brown book wrapped in some kind of warped leather, and a few shots of inner sheets of parchment containing drawings and line after line of a very odd script that resembled nothing I’d ever seen before.

It was impossible to say anything from images alone, of course. But I had to admit that the thing looked old – amazingly old.

The manuscript was 105 pages long, completely legible, and the images were stunning and incredibly intriguing. There were several crosses, in styles I didn’t recognize. Another image represented a snake, curled in an S-like form followed by the strange script. Its tail was curled around what looked like an infant.

Later they told me that the images had been examined by an expert. If his analysis was to be believed, the book was a Bible, although no one had been able to decipher the text. From the images they believed it to represent a part of the New Testament.

And one of the initial pages with a cross held a notation – written in what the expert claimed was a recognizeable dating system. If their interpretation was correct, the book dated from the year 232 CE.

Unbelievable. Especially given the fact that the oldest extant New Testament manuscript anywhere in the world – except for a few fragments – dated from the third or fourth centuries CE!

What to do? Armed with a few images that they were finally willing to part with, I decided to hit the libraries and talk to scholars from the fields of ancient manuscripts and Biblical history. It was immediately clear that a true Biblical manuscript even remotely that old would be a momentous, Earth-shaking finding.

All of this had dropped into my lap completely by accident, but if there was anything to the story at all, I had to pursue it.

The story continues in Part two, coming soon.

Tips for reducing talk anxiety (part 2a, first feedback from readers)

Wow! The article on performance anxiety is getting a lot of traction; thanks very much for the feedback and I’m hoping for a lot more. (See the full article here or just scroll down if you’ve landed at the blog main page. Click here for a list of other pieces devoted to teaching and training.)

Two readers have provided tips that I include here with a couple of comments:

From Jennifer Kirwan, the head of the Metabolomics Unit at the Berlin Institute of Health, come two pointers:

Two tips I was given years ago when public speaking:

1)      Never ever use a laser pointer or wooden stick. Instead, use powerpoint animations to circle or otherwise highlight the point of interest. Not only does this eliminate the issue of shaky hand syndrome, but it also serves to engage your audience more as frequently people have to struggle to see the laser dot on the screen, especially when it’s moving.

2)      Many people tend to find they blush when faced with public speaking. We were advised if we have this problem to wear clothes that cover our shoulders and avoid low cut clothes. It makes the blushing less obvious and, if you are less worried about people seeing you blush, you’re less likely to start.

Great points. A couple of remarks:
To 1: It’s absolutely true that the spot from a laser pointer can be hard to see – especially under certain lighting conditions and on some slide backgrounds. And a pointer can be terribly distracting in the hands of speakers with that awful habit of drawing really fast circles around the thing they want you to look at. (…which may be an unconscious strategy they’ve adopted to hide trembling – or the effect of a major caffeine overdose). And the pointer is often a lazy person’s way of compensating for a slide that’s crammed with too much information, or whose design is unclear and hard to scan. (And, of course, if the audience is looking at the laser dot, they won’t be looking at you.)
Caveats: Some people (including me) aren’t very fond of PowerPoint. I’m not as fanatical about this as other people (including the peerless Edward Tufte), but they make very good points. It’s crucial to map out content and your message before you choose the template for each slide and the talk in general. When you do, you’ll often find that none of the templates really fits. Most people do it the other way around. They pick some template, or simply start with the default that some other user set up long ago, and try to fit their information into it. This can impose a structure on the message that doesn’t fit it at all, and you may not even be aware of it.
But for anyone who does use PowerPoint, or another system with similar animation features, Jennifer’s advice has some clever added benefits. Picking spots to animate or highlight will force you to plan a rhetorical path through the information on the slide – those points represent the key landmarks in this chapter of your story. Defining that path can help you distinguish important information from unnecessary details, showing you things that can be left out. (General rule: leave out as much as possible, and then a little bit more.) Animations can also help during your presentation. If, God forbid, you do have a blackout, the next highlight will point you back into the story.
Even so, I would always have a pointer on hand: you may need it for other reasons. Someone may pose a question that requires you to return to a slide and focus on something you haven’t anticipated; you may need to point it out for the rest of the audience. Secondly, something can happen that makes you abandon your original plan. If time gets short you may need to skip things
Suppose, for example, the topic of the last speaker overlaps with yours. You  may want to build a bridge between the talks that you hadn’t anticipated: “The previous speaker addressed this question at the level of the transcriptome. At the level of the proteome, however, we didn’t see any upregulation of pathway components – as you can see here, and here.” (Since the focus of your talk is slightly different, you hadn’t highlighted those particular molecules.)
To 2); I really like Jennifer’s second point about using your wardrobe to cover blushing. That makes great sense.
(Although in my personal case, I’d need a different strategy, being the kind of person who rarely bares his shoulders or exposes much cleavage during a talk. Maybe I could wear a bright scarlet suit that made my face look pale, or go to the Solarium and get a mild sunburn beforehand, or blind the audience with my laser pointer, etc. etc. … Sorry, Jennifer, I couldn’t resist.)

The second comment came from my friend and former colleague Alan (aka Rex) Sawyer, and is interesting on several levels: cultural, pharmacological, and rhetorical:

I needed this advice 25 years ago while preparing for my first paid gig as a counter-tenor soloist (Friedenskirche, Handschusheim, Johann Sebastian Bach, BWV 4, “Christ Lag in Todesbanden”). But what broke the ice as I went on stage was that the stagehand had failed to provide a seat for me. The audience laughed good-humouredly, which totally banished my case of nerves as it got the audience on my side. Later I got a top tip to eat three bananas about an hour before going on stage. Bananas contain trace quantities of a natural beta blocker. The effect is subtle, but it really works.
To that I can only say: if you’re already taking beta blockers, consult your physician before eating bananas; otherwise you may be comatose when it comes time to give your talk. Wait several hours before operating any heavy equipment. A laser pointer is probably safe.
And don’t get confused and eat three watermelons by mistake. The effects might resemble those of another pharmaceutical product: reports claim that a substance called citrulline in watermelon acts as a sort of natural Viagra. Although you’d probably have to eat an awful lot of it to experience the effects. And at that point, you might not want to walk onstage to give a talk.
If you like these pieces, you might be interested in the article:
If you’d rather enter the bizarre, twilight world where science collides with humor, check out the Devil’s Dictionary of Scientific Words and Phrases, or the text of a talk I gave in Oslo in 2015, plus everything else in the categories “Hilarious moments in science communication” or satire.

Tips for reducing talk anxiety (part 1)

This is part of a series of articles on the blog (a few already published, more in the works) devoted to didactics and the communication of science (and other things). I am currently working on a handbook that includes ideas such as these and explores in depth the myriad problems of presenting content. More pieces to come on that.

The tips given here are related to performance anxiety and represent just a sample of things I’ve learned from my own excellent teachers, from my experience in training lots of scientists and other types of speakers, from my own experiences in public speaking, and from the process by which I completely eliminated my own stage fright when performing as a musician (yes, it’s possible – and that’s when the fun and the real music begin!). In the courses I give we always find a way to adapt these principles to individuals and their problems.

Please help me by contributing your own experiences and tips, so we can build a useful, very practical resource that will help as many students and teachers as possible! I will add your points to the list and mention their sources!

The first step in learning is to identify any barriers that exist – to define the problem as clearly as possible. So it’s crucial to carry out some self-exploration: you need to carefully study your own body in situations of fear, anxiety and stress.

These mental and physical techniques require practice, and they work best if you imagine yourself as concretely as possible in the environment you will face when giving a talk. Visualise the room – ideally, visit it ahead of time, and maybe go to another talk there. Sit toward the back and listen. If you can’t visit the room, then imagine various scenarios: a large classroom, an intimate seminar room, a packed auditorium, an almost empty auditorium.

Next close your eyes and imagine the moment before you are invited to speak. Imagine someone getting up and introducing you; you’re sitting there and will be headed onstage in 30 seconds. Find out if possible whether you will be standing or sitting down; imagine the size of the audience you will be facing, mentally prepare for a moment where the beamer doesn’t work and needs to be fiddled with, if the microphone suddenly doesn’t work, etc. Have some strategy for “vamping” the time, with a joke or some other device that engages the audience. (“While we’re waiting, I’d like to conduct an informal survey about a question of tremendous scientific relevance: Where does that stuff in your belly button come from, anyway?” There’s actually a very interesting study out about this… )

  1. Nervousness is usually accompanied by various physiological and mental symptoms, and here the goal is to deal with common and specific symptoms such as stress and tension, a nervous voice, a wavy pointer, and blackouts. By removing these symptoms you can trick your body into thinking it’s comfortable, and the cognitive issues often fade along with them. But there are clear strategies for dealing with blackouts, too.
  2. The first step is to try to replicate the condition of your body when you’re nervous, by imagining you’re in the situation, or remembering the feelings you had the last time.
  3. Anxiety is usually marked by muscle tension in very specific parts of your body. The first goal is to be aware of their positions and consciously relax them. My own technique is very simple: I totally relax my ankles, letting go of all tension in my ankles and then my feet. When I do this – and it’s true for most other people as well – it is very hard to maintain tension anywhere else – in my back, my vocal chords, etc. Try it – totally relax your ankles, and while doing so try to make a muscle tense in your back, or your arms. If it’s difficult, that means you can use this approach as well. If not, you need to find some other part of your body that you can deliberately relax and thus force yourself to relax the stressed muscles as well. Stand up and relax your ankles. This should be the first thing you do after you’re standing at the lecturn or whatever, and you’ll have to practice remembering to do it.
  4. Remember that the first 30 seconds or so of a talk are less about the content than about the audience learning to listen to your voice and style. If you realize that, then you realize that it’s also a time that you can use to get comfortable. First of all, BREATHE. Then speak SLOWLY and CLEARLY and have a clear strategy prepared to invite your listeners to engage with you right from the beginning. This is something you have to practice as well – people are usually most nervous at the beginning of a talk, and that’s when they usually talk the fastest. Additionally, for predictable reasons, they tend to say the highly technical terms they are most familiar with the fastest – and these are just the words that need to be spoken the most clearly and distinctly. Practice the beginning of your talk with a metronome or by slowly pacing around in a way that forces you to slow the rate of syllables as you speak. You’ll have to practice this a lot of times until you instinctively start slowly rather than with the rush of nervousness.
  5. Engagement #1: try to engage the listeners at the very beginning. Before you speak, look around at some of their faces and smile. If you’re not fixed to a podium or a position at the front, move toward them, as if you’re in a more informal setting.
  6. Engagement #2: if possible, start off with a real question that interests you and has motivated the work, if you can find one that’s general enough to be grasped by the entire audience. Why? If you’re lucky, they’ll actually try to come up with an answer in their own minds, or focus on the question. This immediately draws the audience into the content, rather than a focus on you and your behavior. At that point you’ve engaged them in the subject matter. If they really try to answer the question, they’ll think something like, “Oh, that’s interesting; I would have tried to do it this way…” and you’ll immediately have set up a dialogue that will continue throughout the talk and will provide plenty of good feedback at the end.
  7. Engagement #3: Rhetorically speaking, most data slides are also shown to answer specific questions. (“Does protein A interact with protein B?” Well, to find out, here’s what we did. You see the results here, which provides the following answer…) Unfortunately, most speakers don’t realize that this is what’s happening. They use the ANSWER to the question as the title of the slide, and often start trying to explain the answer before clearly presenting either the question, the methodology, and the results. This confuses the rather simple story-line inherent in the slide. It can also disrupt the talk as a whole because an answer (end of slide) usually stimulates the next question (beginning of next slide). You don’t have to make all the titles of your slides questions, but you should realize this is what is going on (and actually, why not do it?). It has the benefit of gluing separate slides together in a smooth story. And it also can stop a big problem that occurs if the order of information on a slide is different from the order you are using while speaking. When that happens, people are trying to read and listen at the same time, are getting different information from those two channels, and probably won’t remember anything.
  8. Boiling a talk down into a big question and many sub-questions can have a huge effect on anxiety when you’re worried about content blackouts. All you need to remember (or have on tiny cards in your hand) are the questions. You know the answers – that’s what you’ve been doing for the past 100 years. The question-answer method serves to create a real dialogue that engages the public and also an outline of your talk.
  9. Practice other specific performance problems that you are aware of. The first step in finding a cure is to identify what has been disrupted at the right level (it’s just like practicing music that way). A while back I had a student who was having what looked like blackouts during a talk. Later he explained that they weren’t blackouts – instead, every idea was bombarding his brain at once, and he couldn’t figure out where to start. I suggested a method by which he put up a slide and practiced fixing his eyes precisely on the thing he would talk about first, then moving them to the next thing, and so on. The very next day he gave a talk in front of 400 people without a single glitch or “brain freeze.”
  10. Shaky voice. If your voice quavers or trembles while you speak, the problem may be tension in some part of your body (see number 3 above). Often there is another problem, especially (but not only) if you are speaking in a foreign language. You may be pitching your voice too high or too low, which puts tension on your vocal cords and that will extend into your face and throat and shoulders and then the rest of your body – and then you’re doomed! This often happens in a foreign language, where people sometimes choose a “base pitch” (the tone – in a musical sense – at which you would speak if you were talking in a monotone) that is at the wrong place of the spectrum. This is really likely to happen if you subjectively consider your voice too high or too low (to be “sexy”) and try to place it differently. How do you know the right base pitch that your voice should have? A friend who has become a well-known speech pathologist gave me this tip. Go to a piano, and find the highest and lowest keys that you can comfortably The appropriate ground tone for your voice should be between the half-way mark and a third of the way from the bottom of this range. If you try to speak at a pitch that’s too low, you’ll experience the “creaky voice” phenomenon. If your voice is too high, in general, you’ll strain your vocal chords and eventually get hoarse or lose your voice. If either of these things happens to you anyway on a regular basis, you may be pitching your everyday voice too high or low. Also try different volumes of voice. You may arrive in a big room with no microphone, and you’ll have to project. Aim your voice at the person in the back, without shouting at the people in the front row. Your diaphragm and vocal cords have the potential to cause all the air in the room to vibrate and communicate your message. Singing teachers know the secrets of projection. I don’t, but it has a lot to do with breathing deeply and comfortably, and not tightening your throat or larynx.
  11. Shaky pointer syndrome. The reason a pointer shakes is because of tension in the muscles that control your arm and hand. The solution is to let your shoulder hang, without any muscular activity from the back or upper arm, and imagine that all the weight is on your elbow, and that it’s sitting on a table. Now use only the muscles you need to raise your forearm (preserving this feeling of all the weight in your elbow) and aim the pointer at a spot on the wall. Let it remain on the same point for a while. If it shakes, there’s probably some tension still in your upper arm (it’s really hard to make the forearm tense if your upper arm and shoulder are relaxed). Once you can hold the point relatively still, try moving it back and forth in a horizontal line. Here, too, you should imagine that your elbow is resting on the table, taking all the weight from your shoulder, and you’re just sliding your forearm back and forth.
  12. Those nerdy, highly technical slides… Although most scientists tell me that nowadays, most of the talks they give are to mixed, non-specialist audiences, you’re bound to have a few slides that are complex or obscure and you won’t have time to teach people “how to read them.” Example: I’m working with scientists who are developing mathematical models of biological processes, and at some point in their talks they want to show the real deal – math and formulas. They know a lot of people will be intimidated by this, but they still need to show the real work. On the other hand, they don’t want people to “tune out” and give up on understanding the rest of the presentation. At this point what I recommend is to say something like, “Now my next slide is specially made for you math nerds out there; the rest of you can take a short mental vacation and I’ll pick you up in just a minute on the other side.”
  13. Imagine the “personality” you’ll project when you become the leading expert in your field. Pretend like you’ve given the talk a hundred times to enormous success, and now you’re on the lecture circuit, giving it to audiences that think you’re the Greatest and are eager to provide input and their own ideas. How will you look up there? What kind of voice will you have? What types of rhetorical devices can you use to project “modest authority”? When a musician has practiced and practiced a piece for months, and gets stuck, sometimes all you have to do to make the next big step is to imagine what it will sound like when you play it a year from now. If you can imagine that, as concretely as possible, usually the next time you play it will be much closer to that vision. The same thing goes for giving talks.
  14. Criteria for success… If I give someone directions to a party, there’s a simple test that reveals whether I’ve done a good job or not – whether they arrive on time, on the right day… What’s the equivalent for a talk? (Pause while you think about it a minute…) The best answer I’ve heard is this: Imagine you leave the room and there’s somebody waiting outside who says, “Damn! I really wanted to hear that talk; what did he/she say?” At that point a member of the audience should be able to give the person a short summary, and it should fit two criteria: 1) the speaker would agree with it, and 2) most members of the audience should give very similar answers. As a speaker, how do you ensure that this happens? Well, the most obvious way – which few people really ever consider – is to close your talk by saying this: “Now imagine when you leave the room, there’s somebody standing outside who tells you, ‘Damn, I really wanted to hear that talk; what did he/she say?’ Well, here’s what you should tell them…” And then sum it up in a nice little package that’s tight enough to be remembered, with a clean, predictable story line. Remember you’re not trying to simply communicate single facts! You’re trying to answer a question – which you have to be able to articulate very precisely – and you need to explain the meaning of that question in terms of models and concepts that you share with the audience. You need to put information into a structure that can be grasped and remembered, in a way that holds the attention of the audience and engages their intelligence. This means you have to provide information in a relational, coherent structure – and if they don’t share your background and models, you’ll have to provide it. If you do that, you’ll get the kind of smart questions and feedback you’d like, the kind that will help you improve your thinking and your research.

The last points relate to content, which will be the subject of more articles very soon.

ALL of these points require practice – numerous repetitions while mentally imagining the real-life situation as it will feel, as closely as possible. You may always feel anxious before or during a talk; it may never go away. But most people can deal with the symptoms, using strategies like these, and that makes all the difference.

Two final points: First, remember what it’s like to be in the audience when a speaker is really nervous. Everybody is rooting for him or her – they’re on your side! Take comfort in that and try to engage people in the sense that “you’re all in this together”: you’re inviting them to think about an interesting question with you, rather than waiting for them to throw rocks (or shoes) at you.

Secondly, you’ve got to be engaged in the content. Even when you think your story isn’t that great or sexy, or leaves lots of questions up in the air – well, that’s what most science is like, folks! Remember that you’re presenting something that has an inherent interest to a lot of scientists. And negative results are useful as well because they can save your colleagues a lot of time; it will prevent them from following the same old leads, time and time again, without realizing that other labs have tried and failed and been unable to publish their results. Closing off blind alleys is a great service to scientists everywhere – it’s a key step toward progress by forcing people to rethink and revise the basic models they are using.

These are some of the very basics I’ve learned through experience in many performance situations of my own as well as working with a lot of students with different problems over the years. I have learned a lot from the fantastic teachers I have had the privilege of studying with (and continue to do so in the life-long process of learning). I also absorbed a lot from a fantastic book about performance anxiety, whose focus is music but every bit of it is applicable to public speaking, which I highly recommend here:

The Inner Game of Music
Overcome obstacles, improve concentration and reduce nervousness to reach a new level of musical performance
Barry Green with Timothy Gallwey (co-author of the Inner Game of Tennis)
London: Pan Books, 2015.
ISBN: 978-1-4472-9172-5

At Amazon, also available on Kindle

For other articles on science communication teaching, click here.

An animal that runs on hybrid fuel

Research highlight from the MDC – a great story from Gary Lewin’s group in the current issue of Science

 

When oxygen gets scarce, the naked mole-rat throws a metabolic switch to draw energy from fructose rather than glucose

The naked mole-rat, a rodent native to Africa, can survive with little or no oxygen far longer than other mammals. The secret lies in its metabolism: in addition to the basic system by which animals generate energy from glucose, naked mole-rats have a backup system based on fructose. This discovery comes from Gary Lewin’s lab at the Max Delbrück Center (MDC), in a collaboration with the groups of Michael Gotthardt (MDC), Stefan Kempa (MDC and BIH), and Thomas Park (University of Illinois in Chicago), as well as scientists from several other countries. The work is published in the April 21 edition of the journal Science.

Oxygen is so essential to life that a very short deprivation is fatal to animals. Their cells need a constant supply to drive the chemical reactions that produce energy from food. In ancient times, cells evolved a form of metabolism that used the sugar glucose as a source of fuel and the high reactivity of oxygen atoms to extract its energy. This process was so efficient that glucose-based metabolism could fuel the bodies of humans and even larger animals, and it has been maintained over the course of evolution.

But life in a harsh environment can alter even very basic aspects of an animal’s biology. Long ago, something drove the ancestors of the naked mole-rat underground. There the rodent’s biology and behavior began an evolutionary dialogue with the extreme conditions it encountered. This led to some highly unusual adaptations. Naked mole-rats are insensitive to some forms of pain, and have lifespans that exceed 32 years – ten times the norm for most other rodents. Only one or two cases of cancer have ever been detected in the species. And now MDC scientists have discovered that the animal can go with little or no oxygen for extraordinary lengths of time.

Such characteristics have attracted the interest of scientists around the globe – including neurobiologist Gary Lewin. Over several years, his laboratory has gained deep insights into the biology of pain by comparing the nervous system of the naked mole-rat to that of mice and humans. Upon learning that the naked mole-rat could cope with little or no oxygen, he was immediately intrigued – and his lab was well prepared to pursue the biology behind this unique attribute.

Linking oxygen deprivation to a unique metabolic system

Oxygen deprivation was clearly connected to the animal’s biology, lifestyle and environment. “Naked mole-rats huddle in huge, underground colonies of up to 280 individuals,” Lewin says. “This means that they continually experience sharp declines in levels of oxygen and dramatic increases in carbon dioxide. Without adaptations, this would be just as deadly to the naked mole-rat as it is to other animals.”

Most organisms on Earth are suited to the surface atmosphere, composed of about 21% oxygen and only tiny amounts of carbon dioxide (about 0.04%). Reducing oxygen to about 5% is fatal for a mouse within about 15 minutes; total deprivation causes fatal damage within about a minute. The naked mole-rat, however, can cope with as little as 5% oxygen and high levels of carbon dioxide for hours on end with no apparent distress or ill effects. And amazingly, it can survive at least 18 minutes without any oxygen at all.

“Under these conditions the animal enters a sort of suspended animation,” says Jane Reznick, a postdoc in Lewin’s group and a lead author on the current paper. “It falls asleep and its heartbeat slows to about a quarter of the normal rate. When oxygen is restored the heart rate rises, and the animal quickly wakes up and goes about its normal behavior.”

This hinted that some backup system was protecting its heart and brain – two organs that are highly sensitive to oxygen in other species. Without it, their cells cannot produce energy and rapidly suffer fatal damage.

Hitting the stop button on an assembly line

There had to be some fundamental difference in the naked mole-rat’s metabolism. To find it, the scientists enlisted help from the MDC’s Metabolomics Unit, headed by Stefan Kempa. His team uses advanced technology to capture global and quantitative snapshots of cellular metabolism. Their methods reveal the presence of tiny metabolites: molecules that are created through the processing of fuels like glucose. Networks of enzymes break glucose down into small products that move through the metabolic pipeline, generating energy along the way.

“These experiments are a bit like hitting the ‘stop’ button on an assembly line,” Kempa says. “If you were to do that in a factory, then look at partially assembled pieces and the bits that were tossed out, you’d get an idea of what was being built, and how it was constructed.” Further experiments traced the remnants of the sugars as they flowed through an alternative metabolic route that generated energy without consuming oxygen.

Comparing mouse and naked mole-rat tissues under conditions with and without oxygen revealed some curious differences. In naked mole-rats, oxygen deprivation triggered a shutdown of cellular energy factories called mitochondria. In the mouse they continued to operate but quickly malfunctioned – mitochondria need oxygen to run.

But the most startling finding had to do with the sugar molecules found in the animals’ blood and tissues. Overall, naked mole-rats had a lot less glucose than mice, which hinted that other sugars might be providing an alternative source of energy. During oxygen deprivation, there was a significant rise in levels of other sugars. Naked mole-rats had more sucrose – and truly stunning was the amount of fructose, which had skyrocketed.

Can tissues run solely on fructose fuel?

Could the naked mole-rat be using fructose rather than glucose as a source of energy? The two sugars weren’t that different – even our own bodies make use of fructose-based metabolism, although this only happens in the kidney and liver. These organs have an enzyme called ketohexokinase, or KHK, which can trim fructose into a form that can be plugged into the energy production line. From that point on the modified fructose, called F1P, is handled like glucose. Since the subsequent stages of processing don’t require oxygen, it wouldn’t be absolutely necessary in a metabolic system based on fructose.

“In humans, fructose metabolism occurs only in the kidney and liver because they’re the only tissues that contain KHK,” Lewin says. “We found that brain tissue from the naked mole-rat contained high levels of F1P – suggesting that KHK was at work – but only under oxygen deprivation. This told us two things: that their brains might really be using fructose as a source of energy, and that the switch only happened when oxygen grew scarce.”

The evidence for fructose metabolism was accumulating, but so far it was all indirect; the next step would be to determine whether the animals were actually using the alternative source of fuel. First the scientists performed experiments using brain tissue to test whether neurons could function if they were deprived of glucose and fed exclusively on fructose. While an hour of this treatment severely damaged the cells of mice, naked mole-rat neurons continued to show activity. Experiments carried out in Michael Gotthardt’s group showed even more dramatic results for the naked mole-rat heart, which could beat just as well when supplied with fructose as it could using glucose.

“This was proof that fructose can replace glucose as an energy source in the naked mole-rat brain and heart,” Reznick says. “It helps explain how these organs – and the animal as a whole – can recover from long periods of oxygen deprivation.”

A two-part system for switching to alternative fuel

Cells can only use fructose as an energy source if they can absorb it from their surroundings. This requires a protein called GLUT5, which snatches fructose and draws it into the cell. In mice and humans, GLUT5 appears in kidney and liver cells, but other tissues have almost none. It’s another factor that restricts fructose metabolism to the kidney and liver in humans and prevents it from serving vital organs such as the brain and heart. In the naked mole-rat those tissues – and most other cells – have at least ten times as much GLUT5.

“This gives the naked mole-rat a two-part system that allows it to survive long periods of oxygen deprivation,” Lewin says. “Throughout its body you find both the GLUT5 transporter and the KHK enzyme that converts fructose into a usable energy source.”

Fructose metabolism has been encountered in human diseases including malignant cancer, metabolic syndrome, and heart failure. This hints that there might be some link between the naked mole-rat’s metabolism, its resistance to cancer, and possibly even its extraordinary lifespan.  Only further research will tell – but the current study provides an interesting new handle on such questions.

“It’s important to understand how these unusual animals make the metabolic switch without any obvious long-term damage to their tissues,” Lewin says. “We might learn something about how our own cells attempt to cope with situations in which they are deprived of oxygen, such as strokes or heart attacks. Our work raises questions about the biology of fructose metabolism that will ‘fuel’ research for years to come.”

 

Russ Hodge

Thanks to Jana Schlütter and Martin Ballaschk for comments on an earlier draft.

Reference:

Thomas J. Park1, Jane Reznick2, Bethany L. Peterson1 , Gregory Blass1 , Damir Omerbašić2, Nigel C. Bennett3, P. Henning J.L. Kuich4, Christin Zasada4, Brigitte M. Browe1, Wiebke Hamann5, Daniel T. Applegate1, Michael H Radke5,10, Tetiana Kosten2, Heike Lutermann3, Victoria Gavaghan1, Ole Eigenbrod2,  Valérie Bégay2, Vince G. Amoroso1, Vidya Govind1, Richard D. Minshall7, Ewan St. J. Smith8, John Larson9, Michael Gotthardt5,10, Stefan Kempa4, Gary R. Lewin2,11 (2017): „Fructose driven glycolysis supports anoxia resistance in the naked mole-rat.“ Sciencedoi:10.1126/science.aab3896

1Laboratory of Integrative Neuroscience, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America; 2 Molecular Physiology of Somatic Sensation, Max Delbrück Center for Molecular Medicine, Berlin, Germany; 3Department of Zoology and Entomology, University of Pretoria, Pretoria, Republic of South Africa; 4Integrative Proteomics and Metabolomics, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany; 5Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany; 7Departments of Anesthesiology and Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America; 8Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom; 9Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, United States of America; 10DZHK partner site Berlin, Germany; 11Excellence cluster Neurocure, Charité Universitätsmedizin Berlin, Germany

Breaking the temperature barrier

With an advanced ERC grant, Thoralf Niendorf’s group will aim ultrahigh-field MRI at a critical, yet largely unexplored dimension of life

 

Temperature is one of the most rigidly controlled aspects of life, as seen by the very narrow range maintained in the tissues of warm-blooded animals. The heat briefly rises through fevers and inflammations as a part of immune responses to infections. But there has been a major obstacle to exploring this crucial dimension of life: scientists have not had a method to alter temperatures within living tissues.

Soon that may change thanks to an advanced ERC grant just awarded to Thoralf Niendorf’s group and his team, who work at the high end of magnetic resonance imaging (MRI) technology. “Every time a doctor takes an image using MRI, there’s a generation of heat,” Niendorf says. “The unknown impact of this has led to strict regulations governing the amount that can reach patient tissues. We’re hoping to take this side effect and turn it into a tool for research, new forms of diagnosis, and hopefully even therapies.”

That will require an instrument which can focus exact amounts of energy on precise, microscopic targets inside animal bodies. The group has found a way to build it: start with a new ultrahigh-field MRI instrument, then add a custom-designed array of radiofrequency transmitters to shape and focus its powerful magnetic field. The scientists have already worked out the theory and tested designs; now, with the new grant, they can build the machine.

At that point they will enter uncharted scientific territory. The first projects will involve thermal phenotyping studies – a term coined by the group – carried out in collaborations with scientists working on a range of systems. The goal is to determine whether various tissues have unique thermal properties that can be detected by MRI and might have diagnostic value. The next step will be to observe how tissues respond to highly focused increases in temperature. Disease-related processes may be susceptible in ways that could usher in new MRI-based therapies. A unique feature of this strategy would be the ability to deliver a treatment and monitor its effects simultaneously, using the same instrument.

Another part of the project will involve an ongoing collaboration with scientists in Sydney, Australia and Berlin who are building temperature-responsive polymers to deliver drugs or other molecules. These “nano-vehicles” can be introduced into the body, where they remain inactive until heated. They can be loaded with several substances which are released at different temperatures upon activation through MRI. The interest for research is that scientists could alter tissues in a step-wise manner, to control complex processes over time. And the same strategy could be used to strike a disease with successive blows, targeting different weaknesses.

“Planning this project has already drawn together a group of people with diverse expertise,” Niendorf says. “We’re excited about exploring this dimension of life in a truly interdisciplinary way. We can’t predict what we’ll find. But the fact that organisms keep temperature under such tight control hints at vitally important functions across the body.”

 

The original version of this article was published on the MDC website and can be seen here.

 

Juggling molecules while balancing the brain

Research highlight from the MDC
(visit www.mdc-berlin.de to see more highlights from MDC research)

People with a mental illness are sometimes described as being “unbalanced” or “having a screw loose.” These expressions may not be very polite, but they capture two important aspects of mental and physical health. First, organs such as the brain need to maintain an overall balance as we experience stress and engage in various types of activity. Ultimately this state depends on the functions of fundamental components in our cells – not screws, of course, but proteins and other molecules. A frenetic activity at this vastly smaller scale is required to ensure the stability of cells and tissues. While it is often extremely difficult to connect these levels of biological structure, the lab of Jochen Meier has established a new link. In a recent study in the Journal of Clinical Investigation, the group has connected a molecule called the glycine receptor (GlyR) to the operation of networks of neurons – and the way they are disrupted in epilepsy.

Jochen and his colleagues had already found an association between GlyR and brain disorders. They had carried out a molecular analysis of brain tissue from epilepsy patients. This disease is caused by an overexcitation of certain neurons, particularly in a region of the brain called the hippocampus. “We found that hippocampal cells produce unusually high proportions of a specific form of GlyR,” Jochen says. “The current project aimed to show how this molecule contributes to higher brain functions and eventually causes symptoms related to the disease.”

GlyR has one function that is clearly related to signal transmission between brain cells: it acts as a receptor for a neurotransmitter called glycine. Neurons release neurotransmitters into synapses, tiny gaps that separate them from their neighbors. These small molecules typically dock onto receptor proteins on other cells (postsynaptic) or on presynaptic receptors of the original cell. Depending on the type of neurotransmitter receptor and type of neuron, this either inhibits or promotes the signal.

The GlyR can be composed of two different proteins called alpha and beta subunits. Our genome encodes only one beta protein, but cells pick and choose between different genes for the alpha subunit. It may be combined with the beta subunit to create the GlyR; however, single cells sometimes produce GlyRs composed of alpha subunits only.

Like all proteins, the GlyR alpha3 subunit (GlyR-a3) is produced when the information in its gene is transcribed into an RNA molecule. Later the RNA is translated into protein. Along the way bits and pieces of the RNA may be removed in a process called splicing, creating proteins of different lengths, containing different functional modules – a bit like adding or removing wagons from a train.

GlyR-a3 RNA sometimes undergoes yet another change that affects its chemistry and functions. During a process called RNA editing, one letter of the molecule is swapped for another. This causes a corresponding change in the chemistry of GlyR-a3 protein and makes it work more efficiently. What Jochen’s team had discovered in epilepsy patients was an unusually high proportion of “long” spliced forms, and they also observed a swap in one letter of its chemical alphabet.

GlyR-a3 is known to inhibit the firing of neurons in the spinal cord, which can block the transmission of signals related to pain. This might mean that the form of GlyR-a3 found by Jochen’s team (the long spliced form, changed by RNA editing) was tuning down the excitability of neural networks in epileptic patients. To find out, the lab needed to observe the behavior of the altered molecule in an animal’s brain. Aline Winkelmann and other members of Jochen’s lab developed a strain of mouse in which particular cells in the hippocampus – called glutamatergic excitatory neurons – produce high amounts of this version of GlyR-a3.

Now they measured the way the change affected the animals in various ways: checking whether it affected the structure of neurons, the excitability of neural networks, cognition, memory, and mood-related behavior. Unexpectedly, they discovered that the altered form of GlyR-a3 caused an overexcitation of the system – and an important reason why.

“The long spliced form of GlyR-a3 is packed up with presynaptic vesicles,” Jochen says. “These are bubble-like packages that neurotransmitters are placed into before cells release them. Put this association together with an increased sensitivity to the neurotransmitter – and even some spontaneous activity due to the change in the receptor’s chemistry – and the neurons were prone to release more neurotransmitters. This had measurable effects on behavior: it disturbed the animals’ cognitive functions and some forms of memory.”

The study yielded another extremely interesting and wholly unexpected finding. The scientists discovered that in another type of cell, parvalbumin-positive inhibitory interneurons, higher amounts of the molecule had completely different effects on network excitability and behavior.
“Here the result was reduced network excitability, because it was enhancing the functions of this type of neuron,” Jochen says. “The change triggered anxiety-related behavior in the animals. But it did not cause any changes in cognitive function.”

A close scrutiny of the animals’ neurons and hippocampus didn’t reveal any significant changes in overall structure. In other words, higher amounts of this form of the GlyR-a3 molecule weren’t “rewiring” the animals’ brain network. Instead, they were persistently changing the overall balance of neural networks by enhancing the neuronal output.

“What we’ve done is to identify a mechanism at the level of molecules that is linked to the release of neurotransmitters and identifies two critical types of neurons that can cause an imbalance in the brain,” Jochen says. “We think this helps explain both changes in excitability of the brain network in epilepsy and the neuropsychiatric symptoms of some types of anxiety that are often associated with the disease.”

– Russ Hodge

Reference:

Winkelmann A, Maggio N, Eller J, Caliskan G, Semtner M, Häussler U, Jüttner R, Dugladze T, Smolinsky B, Kowalczyk S, Chronowska E, Schwarz G, Rathjen FG, Rechavi G, Haas CA, Kulik A, Gloveli T, Heinemann U, Meier JC. Changes in neural network homeostasis trigger neuropsychiatric symptoms. J Clin Invest. 2014 Feb 3;124(2):696-711.

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