Tips for reducing talk anxiety (2b, more responses to reader comments)

This is a follow-up to the original piece.

 

Dr. Krishna Kumari Challa wrote: Well, if you are an introvert, your brain goes haywire with the great stimulation given by larger audiences (an introvert’s mind needs less stimulation to have the same level of understanding about a situation). Controlling it is more important, according to psychologists, before thinking about the points given in the blog. Only when the stimulation is controlled you can control other things. That is why introverts try to hide behind something, look at their papers or at the screen instead of the audiences in the initial stages. They try to reduce the stimulation by doing so.
I would be grateful to you if you could give tips on how to reduce this ‘too much stimulation’ issue.

 

Hi Krishna – an excellent point! My experience with students suggests that there are surely “types”, such as those you call introverts, who dislike being the focus of attention and whose brains experience an exaggerated response that powerfully influences their bodies and behavior in public presentations and similar situations. Usually giving them help requires close observation, then developing an individual plan of practice that addresses specific behavioral symptoms – like those mentioned in the earlier post. This will take time and patience. Here, too, it can be useful to help them focus on the content of their presentation, and this is a theme to be covered in a future post. That said, I’m not a psychologist, and some types of anxiety clearly have very deep roots that need to be addressed therapeutically before any satisfying “cure” is really achieved.

But still there are things that can help: It’s crucial to try to define the parameters of the problem as precisely as possible. Are there any situations in which the person manages to handle their anxiety? Are they equally affected if they give the presentation to two or three close friends, or their lab? Is one of the issues trust: with people they know, does a fear of disapproval or a negative response disappear? If they can handle small groups, then this can become a cornerstone of practice. They need to give the talk as often as possible in such settings in a way that helps them internalize the positive effects and extend the experience to situations with larger audiences.

Personally I learned something about this through music. My first violin teacher, Lewis Hoyt, said that one of his teachers had always told him to imagine the heads in the audience as cabbages! Later he began studying through a new method which took exactly the opposite approach – enjoying the presence of an audience and fully engaging them as human beings in your personal music, work, or story. Over the long term, if one can manage it, this tends to work better than pretending like they aren’t there.

Your point about “control” reminds me of the student I discussed in point 9 of the original article – where the issue was managing all of the ideas bombarding his brain and the flow of the content. A few simple strategies to ensure that you can stay on track (point 8) and won’t get lost go a great way toward reinforcing confidence. The trick is to extend them to behaviors that are really hard to control: blushing, stammering, shaking, etc.

Each speaker needs to build on the strengths she/he has and use them to support areas of weakness. Can you tell a joke? Can you tell a funny little personal story about something that happened during the project? If some weird little accident happens, can you improvise and get people to laugh? There are lots of potential methods to change the atmosphere – disasrming a stressful situation – which can almost instantly relieve a lot of the tension. As a teacher or speaker you may have to dig deep into the rhetorical repertoire to find something that works, but there’s often something there to draw on.

A lot more needs to be said about this; I’ll keep thinking about it, and the comments on the piece have been extremely helpful in pulling out essential points for consideration. I’ll be teaching several courses over the next couple of months and will be able to report more specific examples from actual practice.

 

If you like these pieces, you might be interested in the article:

“The Dinner Party: Learning to explain your work to a general audience can make you a better scientist.”

 

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.

 

And if you haven’t yet seen the most popular post so far from this blog, check out the “God” article:  “Even God’s first paper got rejected.

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.

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.

 

Before and after: Scientific writing

Here’s another text from a young scientist who is aiming to improve her writing. The intent of publishing it here is to show other students, teachers, and scientists the kind of work we do in communications courses. Most of the time we work individually, but here the author, Ekaterina Perets, has very generously allowed me to print the version of the text she wrote before we began working on it, alongside my comments and the final version. That text was recently published in the MDC newsletter Insights. You can see it here.

Ekaterina is a PhD student in Enno Klussmann’s lab at the MDC. As she began writing her doctoral thesis, she decided to produce a version of her abstract for non-specialists. It’s a useful exercise that challenges you to put your work into a broader perspective and look at it through other eyes.

Ekaterina wrote a solid first version of the text that we worked on for several days to produce the final draft that was published. Her goal was to tell her story clearly and accurately, in a way that would make sense to non-scientists and other researchers as well.  I have painstakingly gone through the drafts again to elaborate on some of the issues that arose and her solutions. These are things that pop up all the time in my courses on science writing. They are usually more difficult to see – and solve – in your own writing, which is why Ekaterina’s willingness to share is so valuable.

Considered in isolation, most of the problems aren’t too significant. In combination, though, they make more work for a reader who is already challenged by all the new ideas. The changes build a story that is easier to read and presents information at a pace that can be digested by a careful reader.

Enno helped by providing comments along the way. A particular challenge in the text arose from the fact that the work hasn’t been published yet, so Ekaterina had to remove some passages from the first draft – she didn’t want to reveal anything that might interfere with getting her article into a good journal.

It’s always possible to do more with a text; there are still passages that could be fuller, simpler, and clearer. But that’s the way it always is. As Mark Twain said, “The time to begin writing an article is when you have finished it to your satisfaction.” Somewhere he also stated, I believe, something to the effect that publication is the only way to force a writer to stop editing his piece.

(Mark Twain also advised writers to “Substitute ‘damn’ every time you’re inclined to write ‘very’; your editor will delete it and the writing will be just as it should be,” but perhaps that doesn’t apply here.)

So thanks, Ekaterina and Enno!


I’ve used the following structure: first comes Ekaterina’s complete original text (except for the passages that were removed). As you’re reading the original, make a note of anything that you think might cause problems for her target audience.

After the full original text I go it paragraph by paragraph, identifying specific issues that came up and showing how Ekaterina addressed them in her next draft.

That new version is assembled at the end. If you’re still alive at that point, it’s interesting to read the two side-by-side.


 

FIRST VERSION

An A-kinase anchoring protein regulates metabolism and motility in cancer cells

The ability of cancer cells to detach themselves from the initial tumor site, migrate and invade adjacent tissues signifies the first step of usually fatal distant metastasis. In order to achieve this, a complex organization of multiple intracellular processes initiates. Collectively, this transition is termed EMT (Epithelial-Mesenchymal Transition) and the ultimate goal of modern cancer research is to gain further insight into EMT induction and regulation.

While breaking bonds between cancer cells and initial tumor predicts poor prognosis, many proteins inside the cell require physical attachment to other proteins in order to function. Also, certain proteins have different roles depending on their location inside the cell and the switch between these roles occurs when the protein attaches itself to one cellular structure or to another. These kinds of attachments are usually facilitated by scaffolding proteins.

One example of location-dependent protein is GSK3β. When GSK3β is in the cytoplasm of the cell or in the nucleus, it has a main role in transferring biochemical information important for cells’ development as well as EMT. This information circuit is called the Wnt signaling pathway and it has been reported to malfunction in various tumors. However, when GSK3β in located in the cellular structures called the mitochondria, it transmits information required for survival or death of abnormal cells.

In addition to being location-dependent, GSK3β activity depends on physical interaction with other proteins. Under normal conditions GSK3β remains active and can be inhibited by a phosphate molecule placed on it by one of the proteins called kinases. One example of such a kinase protein is Protein Kinase A (PKA). The scaffolding protein in charge of bringing GSK3β and PKA in close proximity to each other in order to insure the transfer of the phosphate molecule from PKA to GSK3β belongs to the A-kinase anchoring proteins (AKAPs) family. AKAPs have in common the ability to bind PKA and direct it to a particular location inside the cell. Since this AKAP is able to regulate GSK3β activity via PKA by direct binding of the two proteins, elucidating the AKAP’s exact function in tumorigenesis is compelling.

Interestingly enough, when we delete the AKAP gene in a model cell line, thereby preventing the formation of the AKAP protein, …

(Here a section has been removed)

Reprogramming of cellular metabolism is another hallmark of cancer. Back in 1929, Otto Warburg first noted that rapidly growing cancer cells rely on different energy production methods than healthy slow-growing cells. He stated that cancer cells produced most of their energy in a process called anaerobic glycolysis, in contrast to healthy cells which preferred the highly-efficient energy production via oxidative phosphorylation (OXPHOS) which takes place in the mitochondria. The advantage of glycolysis over OXPHOS is the high speed in which energy is produced. While Warburg thought that all cancer cells switch to high-rate glycolysis, recent studies have shown that this is not entirely true; only rapidly growing and dividing cancer cells use glycolysis, while non-dividing or metastasizing cancer cells, prefer OXPHOS.

(Section removed)

In summary, this research demonstrated that the AKAP is required for both migration and metabolic control of lung cancer cells. However, the direct target protein of the AKAP remains to be found. Therefore, future work will aim to answer the “chicken or the egg” question; who was affected first by the AKAP, the EMT or metabolism?

Prospectively, our approach contributes to elucidating mechanisms underlying EMT and metabolic reprograming regulation in tumorigenesis and proposes this AKAP as a potential therapeutic target.


 

COMMENTS

In this section I walk through the text and comment on each issue as it arises. In classroom teaching it’s better to cluster problems of the same type and cover several examples before moving on to each new issue. This helps a student decontextualizes a problem and recognize it in their own writing. Here, for the sake of simplicity, I’ll stick to the order of the text. I’ll break it into paragraphs to discuss the overall information structure and transitions, then work through the sentence level to cover issues there.

First paragraph:

The ability of cancer cells to detach themselves from the initial tumor site, migrate and invade adjacent tissues signifies the first step of usually fatal distant metastasis. In order to achieve this, a complex organization of multiple intracellular processes initiates. Collectively, this transition is termed EMT (Epithelial-Mesenchymal Transition) and the ultimate goal of modern cancer research is to gain further insight into EMT induction and regulation.

 

I found this beginning logical; it starts with a concept that most readers are probably familiar with (“metastasis”) and moves to something that is probably new (EMT) that is crucial to the paper. Some of the sentences are dense, partly because they use words that are familiar but rather uncommon. If you can replace such words with more common terms without losing the meaning, it requires less “processing” by the reader. In a single sentence this may not be too important, but using such words constantly in a text makes it “heavier” and a bit tougher going overall.

In my own writing, I aim to compose sentences that make a point as clearly as possible, that can be understood the first time they are read, and whose structure links to the sentences that precede and follow them.

The first sentence will probably be accessible to the target audience (students and others who have no specialist knowledge of the field). It isn’t the easiest type of sentence for readers to decode because the subject (a list) goes on for a line and a half before we get the verb. There are several ways to avoid this:

Metastasis, which is usually the fatal stage in cancer, begins when...

Cancer cells take the first step toward metastasis… when they…

The sentence also contains several words and constructions that have alternates in more typical daily language: “The ability of… detach themselves (free themselves, break away from)… initial tumor site (the tissue where a cancer originally appears)… signifies (is)…” I wasn’t too concerned about this, but the phrase “usually fatal distant metastasis” compresses several ideas into a compound that is looser and will surely be easier to cope with after Ekaterina changed it to:

The ability of cancer cells to detach themselves from an initial tumor site, migrate and invade other tissues signifies the first step of metastasis, which is often the fatal step in cancer progression.

It’s always good to take out extra information if it doesn’t really contribute to the point at hand; here she has removed “adjacent” and “distant” and loosened the dense compound at the end of the first sentence by starting with a single, familiar word (metastasis) and adds a clause to provide the clarification or definition.

The second sentence begins with, “in order to achieve this,” which has unnecessary words (“To achieve this” would mean the same thing). “This” is vague because it refers to a complex process with many parts. “A complex organization of multiple intracellular processes” will be abstract to most readers, and it is dense because it compresses a sentence into a noun phrase. An alternative would be something like, “A number of complex processes within cells must be reorganized…” In the original version, again we have to wait quite a while for the verb (“initiates”), and most readers will find the sentence easier to scan with a shorter subject placed closer to its verb.

Here’s her solution:

Cells must reorganize a number of internal processes to initiate metastasis.

The next sentence starts with “collectively,” a word that’s common in scientific texts and a little more unusual in other styles. Its meaning should be clear, so we’ll leave it. But the reader must completely understand “what is being collected,” and there are ways to make this easier to scan.

I was worried that “the ultimate goal of modern cancer research” might be overstating her case: cancer is a vast field, whose ultimate goal is probably to cure the disease. EMT is surely a crucial step along the way, but other labs working on other aspects of cancer might have other “ultimate goals” and disagree. In her final version, she has toned this down.

“Initiate” and “regulate” are less-familiar than more common words such as “start” and “is controlled”, but it’s important to note that “regulation” has a particular scientific meaning. This is similar enough to the way most people understand the word that she might not necessarily want to change it. Here is her final version:

The ability of cancer cells to detach themselves from an initial tumor site, migrate and invade other tissues signifies the first stage of metastasis, which is often the fatal step in cancer progression. Cells must reorganize a number of internal processes to initiate metastasis. Collectively, the steps in this process are called the Epithelial-Mesenchymal Transition (EMT). An important goal of modern cancer research is to learn more about the molecules and processes that initiate EMT and influence the way it develops in a tissue.

 

Second paragraph:

While breaking bonds between cancer cells and initial tumor predicts poor prognosis, many proteins inside the cell require physical attachment to other proteins in order to function. Also, certain proteins have different roles depending on their location inside the cell and the switch between these roles occurs when the protein attaches itself to one cellular structure or to another. These kinds of attachments are usually facilitated by scaffolding proteins.

The connection between the introductory paragraph and this one is a crucial step along the way to Ekaterina’s complete, logical story. Her strategy raises an issue that often appears in writing about biomedical themes. When the experiments are finished and the results interpreted, it’s often possible to link something you have learned to cancer or another disease. That may have been the original intent of a project, or the connection may turn up while you’re pursuing some other question.

Either way, the claim will only be taken seriously if specific types of evidence are provided. In the type of work carried out at the MDC, this usually starts at a very basic level of a biological system, identifying a molecule, studying its activity in healthy cells, demonstrating what happens if it is missing or unable to perform its functions, and showing that the same type of disruption occurs in a disease.

This provides a logical framework to explain what you did – providing you approach things from the bottom up, from the lowest level of structure in an organism to one of the highest levels (health). But if your text starts with a disease, your entry point is high, and it’s harder to build the logic this way.

There are reasons to do so anyway: In popular science writing, diseases presumably attract readers out of a sort of diffuse self-interest: people are afraid of diseases and interested in progress toward cures. In scientific texts, diseases are often hung over a project like a big banner, perhaps to attract the attention of a wide community of cancer researchers, or to open the coffers of agencies that prefer to fund projects that will lead to real medical applications.

Whatever your reason, starting with the disease can introduce a structural problem in a story that is more logical when told the other way around. Ekaterina needs to jump from tumors and metastases to a scale that is millions of trillions of times smaller: interactions between proteins in cells. She wants to do that in the fewest steps possible so that she can start talking about her work. Her original draft uses a sort of logical slight-of-hand: she has introduced metastases and the notion that cancer cells have to detach themselves from their neighbors, and jumps to the idea that proteins have to attach themselves to structures inside cells. It’s awkward because she’s talking about things at vastly different scales, in different locations, and hasn’t provided any other logical connection between these events.

Ekaterina found a great solution to the problem by linking the two themes at a more profound level: cellular attachments and detachments depend on interactions between proteins – whether they bind to each other or not. Adding that connection makes the transition to the molecular scale much more logical:

Before a cancer cell can migrate away from its tumor, it has to detach itself by breaking its bonds to other cells, and this is generally a sign that the patient’s prognosis will be poor. The cell is usually tied to its neighbors and material in the space between them by proteins that are bound to each other; now these connections must be broken. The binding and unlinking of proteins, inside the cell as well as outside, is a general phenomenon that is crucial to every aspect of cellular life and has to be carefully controlled. Whether a protein binds to the right partner, and when and where it does so, can make the difference between life and death for a single cell or an entire organism.

A molecule’s location influences its ability to carry out its tasks, and its location is determined by interactions with other proteins that help attach it to a cellular structure or compartment. This often requires the participation of a “scaffolding” molecule which can bind to both the protein and the target membrane or structure it should be attached to; the scaffold provides a way of bringing them together.

Third paragraph:

One example of a location-dependent protein is GSK3β. When GSK3β is in the cytoplasm of the cell or in the nucleus, it has a main role in transferring biochemical information important for cells’ development as well as EMT. This information circuit is called the Wnt signaling pathway and it has been reported to malfunction in various tumors. However, when GSK3β in located in the cellular structures called the mitochondria, it transmits information required for survival or death of abnormal cells.

Here Ekaterina uses the concept of localization as a bridge between paragraphs; she just mentioned it, so readers should be able to follow her logic. Here I was concerned about the number of ideas that might be new which she introduced, and whether she had connected them to each other in the clearest possible way. Sometimes the simplest things make a text challenging to readers unfamiliar with basic concepts: What do they imagine when they read “transferring biochemical information,” and will they instantly relate it to the “information circuit” in the next sentence? The author can help by making connections excruciatingly explicit; readers who can’t follow your logic will have to invent one on their own, and rather than invest the effort, they may give up.

There are countless ways to build connectivity and make transitions. A lot of them don’t need to be as explicit when writing for scientists from your field. They are already familiar with concepts such as protein-protein binding and the logic that connects this theme to events at the scale of cells, including metastases.

Even in this type of communication, however, the writer has to be intensely aware of the logic that connects ideas to each other and the larger story; at that point you can make an intelligent decision about each transition. Is a connection really implicit, from the text? Would there be anything wrong with making it explicit? When giving someone directions to a party, it’s usually better to give too many directions than too few – within limits. If everyone you’re inviting lives in town and is familiar with the same landmarks nearby, you won’t need to start with a map of contintental Europe. In the same way, a scientist doesn’t need to be told that your body is made of cells.

As always, the amount of information and logic you choose to present should be guided by a realistic guess about the knowledge of your intended audience. Ekaterina added more linkage and rearranged some of the points within sentences to produce this version:

One example of a protein whose activity depends on its location is a molecule called GSK3β, which has been found to malfunction in various tumors. When GSK3β is in the cytoplasm or the nucleus, its main role is to transmit information needed during cells’ development and for the regulation of EMT. In these two locations, the main function of GSK3β is mainly to send signals along a molecular “information circuit” called the Wnt signaling pathway. But GSK3β can also be found within other cellular structures called mitochondria. There it transmits information along a different route, with different effects: the signal helps determine whether abnormal cells survive or die. Both locations and signals play a role in whether cancer cells grow, survive, and metastasize. They may only be able to do so by interrupting the signals that GSK3β normally transmits to other proteins. Therefore, ensuring that GSK3β is in the proper location and functions correctly is probably crucial in cancer prevention and treatment.

 

Fourth paragraph:

In addition to being location-dependent, GSK3β activity depends on physical interaction with other proteins. Under normal conditions GSK3β remains active and can be inhibited by a phosphate molecule placed on it by one of the proteins called kinases. One example of such a kinase protein is Protein Kinase A (PKA). The scaffolding protein in charge of bringing GSK3β and PKA in close proximity to each other in order to insure the transfer of the phosphate molecule from PKA to GSK3β is a member of the family of A-kinase anchoring proteins (AKAPs).

Here there are clear links to the previous paragraph (GSK3β and localization) and Ekaterina connects this to a topic introduced earlier: protein-protein binding. But within the paragraph, it’s not always immediately clear how each new idea arises from the previous one – at least until you have read the whole sentence. The first sentence, for example, ends with protein interactions, a theme also taken up in the next sentence – but only after the introduction of a new idea (phosphorylation), and the link between the two ideas comes at the end. The reader has to wait for the author to close the gap. The alternative is simply to change the order of information within sentences to get a better flow.

English permits great flexibility in the arrangement of phrases within sentences. Word order can be used to establish (or at least support) the logical flow and to transmit other kinds of meaning. Each sentence is like a story that begins somewhere and takes us somwhere else, and the next sentence can start right at that point and move on.

That is much more difficult in a language like German, where sentence structure is much more rigid: putting almost anything before a subject requires an inversion that pushes the main verb all the way to the end – so you often have to process entire sentences to grasp their connections. German readers are used to this and may, fundamentally, be better at it.

Ekaterina’s native language is not German, but she has used this type of sentence structure. To represent the problem symbolically, an arrangement of ideas is probably easiest to follow if it looks something like this:

A – B; B – C; C – D… etc.

If a sentence contains three pieces of information as Ekaterina’s does, this may be harder. But the arrangement in the first two sentences look more like this:

A – B – C. D – B – A

(A = localization. B = activity. C = protein interactions. D = phosphorylation. B = activity. A = interactions)

Rearranging this to create a more linear storytelling structure would change this:

In addition to being location-dependent, GSK3β activity depends on physical interaction with other proteins. Under normal conditions GSK3β remains active and can be inhibited by a phosphate molecule placed on it by one of the proteins called kinases.

….to something like this:

GSK3β’s activity depends on both its cellular location and its direct physical interactions with other proteins. By binding to a protein called a kinase, for example, it acquires a chemical tag called a phosphate group. This has an important fact: it inactivates GSK3β and switches off signals when a message has been received.

It’s not easy to carry this approach through to the end of the paragraph, because most of the sentences convey more than two ideas. That means shuffling and combining them in other ways. And a linear structure isn’t always appropriate: it’s good when describing a sequence of events, or when “zooming in” from a general idea to a specific one. Sentences that introduce lists, however, would be structured differently.

Suppose Ekaterina had introduced the topic this way: “In different cellular locations, GSK3β interacts with different sets of proteins and has different functions.” If examples follow, the clearest structure would be to construct the information the same way: “In the cell nucleus, GSK3β binds to specific proteins as a way of transmitting signals… In the cytoplasm it functions the same way. But when it is located in structures called mitochondria, …”

Ekaterina’s found a different solution that has the same effect: within sentences, the order of ideas reflects the logic that connects them:

GSK3β’s location and activity are the result of interactions with other proteins. When GSK3β binds to a molecule called Protein Kinase A (PKA), for example, PKA transfers a chemical tag called a phosphate group to it, which switches off the signaling activity of GSK3β. The tag can only be transferred if the two molecules are brought into direct contact, a process that is arranged by scaffolding proteins such as members of the family of A-kinase anchoring proteins (AKAPs).

This brings Ekaterina directly to the heart of her project. At this point the reader has been introduced to all the main players in the story, and now she is going to guide us to the specific question she is asking and the way she chose to pursue it.

 

Fifth paragraph:

AKAPs have in common the ability to bind PKA and direct it to a particular location inside the cell. Since this particular AKAP is able to regulate GSK3β activity via PKA by direct binding of the two proteins, elucidating the AKAP’s exact function in tumorigenesis is compelling.

Here there is another dense cluster in the first sentence: “A-kinase anchoring protein (AKAP) family,” which she will loosen in the final draft. In the second, “have in common the ability to” is awkward (and grammatically suspect because a phrase is interposed between the verb and its object).

The third sentence is interesting for another reason. It seems to fit the principles we have covered – it begins with points that have already been introduced and then builds a link to the overarching topic: the development of tumors and metastases. This raises a different issue related to information density. “Since the AKAP is able to regulate GSK3β activity via PKA by direct binding of the two proteins” combines several pieces of information that the reader has learned moments ago. That integration is important, but readers will only understand it if they have digested what they’ve learned. It’s a bit like introducing someone to three new words in a foreign language and a new grammar rule, and then immediately presenting him with a sentence that combines them all. He may understand it, but you shouldn’t expect him to.

Here’s how Ekaterina loosened it up:

AKAPs share a common feature: the ability to bind PKA and transport it to a particular location inside the cell. This means that the AKAP not only interacts with both GSK3β and PKA – it also directs them to specific locations in the cell. That’s interesting because PKA also has many roles in the development of tumors.

In the new draft she decided to expand on this by reminding readers of a point she had raised earlier:

Now three molecules are bound together: the AKAP, PKA and GSK3β. This puts PKA close enough to transfer a phosphate group onto GSK3β and block its activity. Since both of these molecules have been implicated in the development of tumors, it makes sense to wonder whether the AKAP, the protein that brings them together, might also have a role in the disease. If so, we would probably expect to find a disruption of the normal activity of the AKAP, but its functions in healthy cells have been unclear.

 

Sixth paragraph

At this point Ekaterina has introduced the main question of her research, which is something like this: “Are the cancerous effects of GSK3β sometimes related to the fact that it is in the wrong place and/or its ability to interact with important partners such as PKA? And if so, could defects in the AKAP be responsible?”

Her thesis project required breaking this question down into smaller parts, designing experiments to address each part, and then assembling the results into a satisfactory answer. In the sixth paragraph she introduces part of the experimental strategy:

Interestingly enough, when we delete the AKAP gene in a model cell line, thereby preventing the formation of the AKAP protein, …

She hasn’t explicitly explained the rationale for this experiment – which any scientist will understand, but what about non-specialists? There’s an easy way to make sure they get the point:

A common method to discover the function of a molecule is to remove it from cells where it is normally found and observe what happens to them. We did this with the AKAP by deleting its gene in a line of cells that we use as a model in the lab, which left the cells incapable of producing the AKAP protein. We discovered that its removal affects a number of processes that are specifically involved in metastasis and other aspects of the development of tumors.

Next Ekaterina confronts a technical problem: She can’t describe some of her experiments or present the results until they have been published in a scientific journal. Giving away too many details, even in the MDC newsletter, would be grounds for the rejection of her paper by a journal – which typically refuses to publish work that has already appeared.

Her solution is to address the reader directly and frankly, explaining why she doesn’t go deeper into the project:

For the details you’ll have to wait for the paper. For now we can say that the silencing of the AKAP affects the behavior of other proteins that play crucial roles in signaling, EMT, and also cell metabolism, the process by which cells produce the energy they need. Cancer cells have different energy needs than healthy cells, and the reprogramming of cellular metabolism is another hallmark of cancer.

Metabolism is another theme she wants to introduce because it has an important role in her thesis, and she finds a great way to do so using history:

Back in 1929, Otto Warburg first noted that rapidly growing cancer cells rely on different energy production methods than healthy slow-growing cells. He stated that cancer cells produced most of their energy in a process called anaerobic glycolysis, in contrast to healthy cells which preferred the highly-efficient energy production via oxidative phosphorylation (OXPHOS) which takes place in the mitochondria. The advantage of glycolysis over OXPHOS is the high speed in which energy is produced. While Warburg thought that all cancer cells switch to high-rate glycolysis, recent studies have shown that this is not entirely true; only rapidly growing and dividing cancer cells use glycolysis, while non-dividing or metastasizing cancer cells, prefer OXPHOS.

This is a good storytelling because it gives readers a character to latch onto. By placing her project in a historical context, she is also saying more, by implication: her work addresses an issue so fundamental in cancer research that it has occupied scientists for nearly a century.

All along the way Ekaterina confronts important decisions about the amount of information a reader really needs to get the gist of her work. Here she decides to introduce two types of metabolism that she names without going into much detail; it’s enough to contrast them based on the sites in cells where they occur and a parameter that is related to cancer (speed). I recommended sharpening the contrast by expanding on the idea in this sentence:

The advantage of glycolysis over OXPHOS is the high rate at which energy is produced.

Here’s what she came up with:

This link was discovered back in 1929, when the German scientist Otto Warburg became the first to note that rapidly growing cancer cells rely on methods of energy production that are different than those used by healthy, slow-growing cells. He stated that cancer cells produced most of their energy in a process called anaerobic glycolysis. Healthy cells, on the other hand, favored a type of energy production based on a process called oxidative phosphorylation (OXPHOS), which takes place in the mitochondria. The difference has to do with speed and efficiency: glycolysis produces energy at a very high rate, while OXPHOS is geared toward efficiency, and is more sustainable over the long term. While Warburg thought that all cancer cells switch to high-rate glycolysis, recent studies have shown that this is not entirely true; only rapidly growing and dividing cancer cells use glycolysis. Non-dividing or metastasizing cancer cells prefer OXPHOS. When you read the paper you’ll see how we demonstrated the AKAP’s effects on metabolism and how we interpret them in terms of the dysregulation of metabolism and EMT.

(Section removed)

The reader has to guess how this might relate to her project, but some clues are available: OXPHOS takes place in the mitochondria, which is one of the sites where GSK3β is found… Hmm…

Now all that’s left is to sum up. The conclusion is crucial because it gives the author a chance to put everything back together, to show how she has answered the scientific question posed at the beginning, and to frame the story she wants the reader to remember it. Here’s what she wrote for the first draft:

In summary, this research demonstrated that the AKAP is required for both migration and metabolic control of cancer cells. However, the direct target protein of the AKAP remains to be found. Therefore, future work will aim to answer the “chicken or the egg” question; who was affected first by the AKAP, EMT or metabolism?

Prospectively, our approach contributes to elucidating mechanisms underlying EMT and metabolic reprograming regulation in tumorigenesis and proposes the AKAP as a potential therapeutic target.

The main changes she ends up making have to do with phrasing, word order, and making sure her logic (which would be clear to any scientist) will also make sense to readers less familiar with buzzwords like “elucidating mechanisms” and “potential therapeutic target.” She gets rid of clusters like “contributes to elucidating mechanisms underlying EMT and metabolic reprogramming regulation in tumorigenesis.” By now most of those terms will have confronted the reader, but the conclusion is the last place you want the text to get dense.

A lot of questions remain: other proteins directly affected by the AKAP have yet to be found. The project raises a “chicken-or-egg” question, in which EMT is the chicken and metabolism the egg: which process does the AKAP influence first? Our approach should contribute to understanding the mechanisms that produce some of the changes in these processes that are observed as tumors arise from healthy tissue and then become metastatic. And it hints that the AKAP might make a therapeutic target. This would be useful because AKAPs have features that might permit fine-tuning their effects with drugs. By doing so, it might be possible to alter the behavior of GSK3β in one location, where its activities contribute to disease, without affecting its healthy functions.

Below I provide the final version. As Ekaterina lives with this text, she’ll find that she could come back time and time again and improve it with editing. It’s a writer’s curse – to recognize weaknesses in old texts that have been published and you can no longer change. The important thing is what you learn when you mak the effort.


 

FINAL VERSION

Can a small A-kinase anchoring protein play a big role in cancer? A report from the lab bench

The ability of cancer cells to detach themselves from an initial tumor site, migrate and invade other tissues signifies the first stage of metastasis, which is often the fatal step in cancer progression. Cells must reorganize a number of internal processes to initiate metastasis. Collectively, the steps in this process are called the Epithelial-Mesenchymal Transition (EMT). An important goal of modern cancer research is to learn more about the molecules and processes that initiate EMT and influence the way it develops in a tissue.

Before a cancer cell can migrate away from its tumor, it has to detach itself by breaking its bonds to other cells, and this is generally a sign that the patient’s prognosis will be poor. The cell is usually tied to its neighbors and material in the space between them by proteins that are bound to each other; now these connections must be broken. The binding and unlinking of proteins, inside the cell as well as outside, is a general phenomenon that is crucial to every aspect of cellular life and has to be carefully controlled. Whether a protein binds to the right partner, and when and where it does so, can make the difference between life and death for a single cell or an entire organism.

A molecule’s location influences its ability to carry out its tasks, and its location is determined by interactions with other proteins that help attach it to a cellular structure or compartment. This often requires the participation of a “scaffolding” molecule which can bind to both the protein and the target membrane or structure it should be attached to; the scaffold provides a way of bringing them together.

One example of a protein whose activity depends on its location is a molecule called GSK3β, which has been found to malfunction in various tumors. When GSK3β is in the cytoplasm or the nucleus, its main role is to transmit information needed during cells’ development and for the regulation of EMT. In these two locations, the main function of GSK3β is mainly to send signals along a molecular “information circuit” called the Wnt signaling pathway. But GSK3β can also be found within other cellular structures called mitochondria. There it transmits information along a different route, with different effects: the signal helps determine whether abnormal cells survive or die. Both locations and signals play a role in whether cancer cells grow, survive, and metastasize. They may only be able to do so by interrupting the signals that GSK3β normally transmits to other proteins. Therefore, ensuring that GSK3β is in the proper location and functions correctly is probably crucial in cancer prevention and treatment.

GSK3β’s location and activity are the result of interactions with other proteins. When GSK3β binds to a molecule called Protein Kinase A (PKA), for example, PKA transfers a chemical tag called a phosphate group to it, which switches off the signaling activity of GSK3β. The tag can only be transferred if the two molecules are brought into direct contact, a process that is arranged by scaffolding proteins such as the members of the family of A-kinase anchoring proteins (AKAPs).

AKAPs share a common feature: the ability to bind PKA and transport it to a particular location inside the cell. This means that the AKAP not only interacts with both GSK3β and PKA – it also directs them to specific locations. That’s interesting because PKA also has many roles in the development of tumors.

Now three molecules are bound together: the AKAP, PKA and GSK3β. This puts PKA close enough to transfer a phosphate group onto GSK3β and block its activity. Since both of these molecules have been implicated in the development of tumors, it makes sense to wonder whether AKAP, the protein that brings them together, might also have a role in the disease. If so, we would probably expect to find a disruption of the normal activity of the AKAP, but its functions in healthy cells have been unclear.

A common method to discover the function of a molecule is to remove it from cells where it is normally found and observe what happens to them. We did this with the AKAP by deleting its gene in a line of cells that we use as a model in the lab, which left the cells incapable of producing the AKAP protein. We discovered that its removal affects a number of processes that are specifically involved in metastasis and other aspects of the development of tumors.

For the details you’ll have to wait for the paper. For now we can say that the silencing of the AKAP affects the behavior of other proteins that play crucial roles in signaling, EMT, and also cell metabolism, the process by which cells produce the energy they need. Cancer cells have different energy needs than healthy cells, and the reprogramming of cellular metabolism is another hallmark of cancer.

This link was discovered back in 1929, when the German scientist Otto Warburg became the first to note that rapidly growing cancer cells rely on methods of energy production that are different than those used by healthy, slow-growing cells. He stated that cancer cells produced most of their energy in a process called anaerobic glycolysis. Healthy cells, on the other hand, favored a type of energy production based on a process called oxidative phosphorylation (OXPHOS), which takes place in the mitochondria. The difference has to do with speed and efficiency: glycolysis produces energy at a very high rate, while OXPHOS is geared toward efficiency, and is more sustainable over the long term. While Warburg thought that all cancer cells switch to high-rate glycolysis, recent studies have shown that this is not entirely true; only rapidly growing and dividing cancer cells use glycolysis. Non-dividing or metastasizing cancer cells prefer OXPHOS. When you read the paper you’ll see how we demonstrated the AKAP’s effects on metabolism and how we interpret them in terms of the dysregulation of metabolism and EMT.

A lot of questions remain: other proteins directly affected by the AKAP have yet to be found. The project raises a “chicken-or-egg” question, in which EMT is the chicken and metabolism the egg: which process does the AKAP influence first? Our approach should contribute to understanding the mechanisms that produce some of the changes in these processes that are observed as tumors arise from healthy tissue and then become metastatic. And it hints that the AKAP might make a therapeutic target. This would be useful because AKAPs have features that might permit fine-tuning their effects with drugs. By doing so, it might be possible to alter the behavior of GSK3β in one location, where its activities contribute to disease, without affecting its healthy functions.

 

The dinner party: Learning to explain your research to a general audience can make you a better scientist

Nobel Prize winners customarily deliver two talks about their work during the official award ceremonies in Stockholm. One is a scientific statement about the research for which they have won the award and their perspective on its importance to their field. The second is the “banquet speech,” aimed at a more general audience. These banquet speeches are often remarkable examples of scientific communication and are the best refutation of the idea that it takes convoluted language to express complex ideas. Clarity is, in fact, a much harder art to master.

After interviewing a number of these exceptional people, I have become convinced that the connection between excellent science and clear communication is no accident. What links them is a style of thought that always manages to “see the forest for the trees:” the choice of just the right experiment, at just the right time, which suggests an important new model or clarifies an existing one, resolves some important debate within a field or establishes an entirely new direction for research.

Contrast this with another type of “banquet speech,” a dinner party at which someone asks you about your work. Well, what you did today was try for about the 50th time to get an experiment to work. As you fumble for an explanation, you realize that the person you’re talking to has never heard of the things you’re working on and lacks a real understanding of basic concepts like genes, signaling pathways, and transcription factors. You’re lucky if they’ve heard of the type of cell you’re working on, and why on Earth would somebody care about the biology of a worm?

You’ve been at your project so long that it’s often hard even to see the tree, let alone the forest, for all the leaves. At some point you notice that the person who asked the question has a glazed look on his face and is drinking a lot of wine.

Is there an easy solution? And if it’s true that excellent science and good communication go hand in hand, can you become a better scientist by improving your communication skills? After many years of helping researchers develop their writing and presentations, I think the answer is a resounding “yes”. While communications courses are often lumped into a broader category of “soft skills,” they ought to be regarded as central components of a scientific education. In some countries that is the case, but other educational systems – particularly in mainland Europe – scientists receive little or no help in learning “a skill that is inherent to every field,” to cite writer and educator William Zinsser.

Very few of us have the kind of mind that quickly and naturally sorts information into a clear structure and – on the first try – translates our thoughts into the linear form of language, in a way that allows a reader or listener to reconstruct complex ideas. (An amazing exception is Barack Obama; look at the word-for-word transcripts of his Presidential debates and compare both the conceptual structure and syntax of his answers with those of other candidates.) But even professional writers don’t normally have to get everything fine the first time. It’s usually fine to start with a rather scrambled draft and recover or introduce structure in revisions.

Even when you’re finished, however, there is no guarantee that your text will be suitable as a “dinner speech;” this requires something more. Explaining your science at a dinner party requires a certain style of thinking that is a sort of worst-case scenario for other communicative situations. It can be made easier by preparing properly for the task – a process that is equally important and useful when communicating with experts. That process is crucial both to successful communication and successful science.

* * * * *

Most biomedical research is devoted to working out the exacting details of some biological process. Experiments generally aim to answer a very specific question, but both the question and any answer you might receive only make sense in the context of an intricate set of assumptions and models. Most projects aim to validate a particular hypothesis, or extend an existing model to a new situation, or refute it. You may be applying a new technology to quantify something that couldn’t be measured before, or using a new tool to explore a set of data. Whatever your project, it acquires its meaning through a particular type of dialogue with what scientists already know as they try to expand current knowledge to fit a new situation, or venture into unexplored territory.

Students absorb a number of models during the course of their studies, usually becoming so familiar with a framework of ideas that certain patterns become habitual, stylized, practically subconscious, and thus “invisible”. For example, the connection between DNA, RNA and proteins is so common that scientists use the same name to identify three different types of molecules, in different species, and switch comfortably back and forth between them as they discuss their functions in model organisms and humans. Along the way they often completely lose a listener who does not have the relationships of these molecules firmly in mind.

Subconscious models and structures may create obstacles as you do science because a scientist might not fully comprehend the architecture of assumptions on which an experiment is based in the first place. This might make it difficult to understand results that run counter to expectations. Does the problem lie with an experimental setup, or the way a model has shaped a hypothesis, the model itself, or some far more general assumption? It may be impossible to decide without a very clear understanding of the relationship between a question and much more general structures of thought.

Even the most fundamental links between ideas in a field may be unclear to non-scientists and hinder communication at a very basic level. When this is likely to happen, the underlying frameworks need to be exposed and articulated. This suggests a strategy for communication that can work with a range of target audiences. Below I will describe one means by which we achieve this in science writing and presentation courses.

The first step is to force students to articulate a precise scientific question as clearly as possible. Take, for example, the following: “What small molecules could disrupt the binding of a protein to a transcription factor, and what chemical/structural features permit them to do so?”

As a grammatical sentence, this can be decoded, to a certain degree, by any native speaker – but its meaning to a scientist depends on both knowing particular facts and relating them to a much broader base of knowledge. The two go hand in hand. Defining a “transcription factor” requires placing a type of protein into the context of a larger story about cell structure and behavior. “Binding” and “structural features” have to do with the chemical subunits of molecules, the three-dimensional arrangement of atoms in these subunits, and how this architecture influences a protein’s activity.

To give a sense of the meaning of this question to a non-specialist, a researcher needs to relate it to a hierarchy of more general questions, models, and “stories” that scientists agree on. There will be several possible approaches, because any given question is usually embedded in different types of schemes. For example, the interaction between two molecules is part of a “chemical” story about the features that allow them to bind. Another type of story has to do with biological functions. Transcription factors usually are usually the penultimate steps along “biochemical signaling pathways.” These information routes through the cell usually start with a stimulus at the cell surface, trigger a signal that is passed from one molecule to the next, and then alter the transcription factor so that it moves to the cell nucleus. There it docks onto DNA and changes the pattern of active and silent genes. All of these pieces of information need elaboration – the scientist’s job in a communication exercise! – and below is an example of how it can be done.

Either type of story can be converted into a hierarchical “tree” that starts with the specific form of the question and links it to higher-level themes. Each step in the list below represents a way of connecting the specific question to a more general question or a larger story:

• What chemical/structural features determine whether a specific protein can bind to a specific transcription factor?

• What proteins can bind to this transcription factor, how do they change its behavior, and what genes does it go on to activate?

• How do molecular signals or environmental factors change gene expression patterns?

• How do cells respond to changes in their surroundings during development, the onset of a disease, stress, or some other situation?

• What are the basic components of our bodies and how do they influence our lives and our health?

This process of moving from the specific to the very general provides a structure for extending the meaning of findings both “horizontally” (to other molecules and processes with similar structures and functions), and “vertically” (to more basic principles of living systems). It also provides a system that can be used when dealing with a particular target audience. Everyone is probably interested in the last question, which involves very basic aspects of life and our bodies. This provides a level at which you can “meet” the listener and guide him or her into the story in a structured way, as a sort of dialogue headed for more specific questions and answers.

After stating that you’re trying to study life by understanding its basic components – molecules – you can point out that our bodies begin as single cells that differentiate. This usually happens through a process by which cells receive molecular signals from their surroundings. Those signals begin at the cell surface and are passed along from molecule to molecule inside the cell, until they reach a transcription factor. The role of this protein is to activate new sets of genes, changing the components of cells, and thus giving different types of cells new structures and functions. The aim of your work is to understand what characteristics allow a molecule to activate the transcription factor. Why is this interesting? Well, one reason is just to learn basic things about cell functions and fates. And of course diseases often disrupt signaling pathways, and your work may help explain why this happens – as well as suggest points at which therapies can intervene.

This description simply moves upward through the tree, from the general to the specific, and it provides a structure for the story. The information will need to be enhanced, broken down into “digestible” bits, and compared to things that the audience is familiar with, using metaphors and other tools. But at least you have told a story that is logical and gets to the point – what you have actually done, and its relevance.

Where you start in the hierarchy depends on your best guess about the level of prior knowledge of your audience. If you have overestimated what they know, and start with a point that is too specific, you will lose listeners right away. When talking to biologists, on the other hand, you can assume that they already understand basic concepts like signaling pathways and their effects. They may not, however, be familiar with the specific pathway you are interested in, the molecules that are involved, or its particular biological functions. At this point you can start close to the end, with the second question in the list above.

I’ve often heard students “throw in the towel” when they try to explain their work to non-specialists: “To understand what I’m doing, you’d have to have a complete course in molecular biology.” Again, using the example of a transcription factor, it’s probably enough to discuss how a molecule is related to the activation of different sets of genes, that this changes populations of molecules in a cell, and those in turn change a cell’s form and functions. You don’t really need to explore what happens next – alternative splicing, or the many other levels of post-transcriptional regulation – to get the point across.

If you’re talking to biologists, going too far in the other direction and explaining a point like, “Cells respond to environmental stimuli” would seem silly. Saying something far too general such as, “I’m trying to cure cancer,” when what you’re really doing is studying a particular transcription factor, would be equally ridiculous. Of course your work may have implications for a disease – note all of those sentences that typically come at the end of the discussion section of a paper: “So this study suggests new potential targets in the development of rational therapies in the treatment of cancer.” But it doesn’t explain the real scientific relevance of what you have done.

* * * * *

Communication is most effective when you regard it as a dialogue rather than a one-way transmission of information. The hierarchical tree suggests a dialogue structure in which you begin with a question that your target audience might really ask, or at least be interested in, and then guide them to the particular point you want to make. It also helps you make logical decisions about what information is necessary – and especially what isn’t! – in making a particular point.

There are many more elements in successful communication – including the use of powerful images and metaphors that capture the essence of a particular biological entity or process. Metaphors are crucial as scientists learn about their field and try to convey complex ideas to their colleagues. But the first step in convincing scientists to develop their communication skills depends on showing them that even the “dinner party talk” can improve their science.

The link lies in connecting the general to the specific, in relating a piece of work to a hierarchy of models and stories in which it is embedded, and here is the connection between doing better science and communicating it well. It is an essential strategy in the courses I am developing. It is always wise to clearly articulate the models and mental structures upon which a particular piece of work is based; these relationships tell you how far a particular result can be extended to other molecules, processes, or biological functions. They are equally useful in developing strategies to communicate science to just about anyone. Nobel laureates understand this very well, and we can all learn something from their example.

Conducting a really juicy interview

I wrote this in response to a question posted in the Science Writers group at Linked in. There are some interesting discussions going on there; if you haven’t joined, jump over for a look. One of the members asked:

“How do you come up with the best questions during the interview? What do you watch for to pursue in your line of questioning?”

I’ve found that a really good interview requires a combination of excellent preparation and free-thinking as things go along. In the preparation phase, one needs to get as familiar as possible, of course, with a scientist’s work – which can be a challenge if you have to deal with people working on a wide range of topics and disciplines, technologies, etc. In biomedicine that’s pretty much always the case these days. Have a look at the person’s CV, paying particular attention to their recent publications, but also go back and look at their earlier work. A lot of scientists have a “red thread” of interest – something they started working on long ago that has remained a sort of “Leitmotif” over the years. Watching how such themes develop can give you a good impression of where they are headed. Most people are working on something really exciting right now that they haven’t published yet but have hinted at in their recent work, and I always like to try to tease those themes out of them. They won’t tell you the details, but they might give you a general sense of where they are going with a topic. If they’ve written any reviews recently, be sure to read them. Check out any “news-and-views”-type articles that may have been written about their recent projects. If they haven’t published a recent review, read a couple by other authors.

Most scientific papers deal with very specific questions, often applying some new technology or approach, but the thing that makes them really interesting is the fact that they are usually examples of a broader principle. A project may test an existing model, or aim to develop a new one, and great scientists are always aware of the connection. If you can get this broader sense of the “meaning” of a project and ask the person about it, he or she is usually willing to talk at this level of things. A lot of Nobel prizes have begun with very specific experiments, but the researcher knew that they were tightly connected to a hierarchy of larger and larger models; a single experiment might shake a whole branch of knowledge or open an entirely new path for investigation.

Never be afraid to ask for clarification if you don’t understand something, or the logic behind what the person is saying. A lot of times scientists will talk about what they are doing but forget to explain why they think it’s so important – getting to that point is a must…

Some basic questions to keep in mind: Why is this work important? Why is this the right time to ask this particular question; why haven’t people asked it before, or what has prevented them from answering it before? Why did the scientist choose this approach/technology in trying to answer it? Did something happen during the project that was really unexpected or surprising? Did it change his or her view of some fundamental process or mechanism? What new questions do the results suggest?

And I always throw in a couple of wild cards: What’s your “dream” experiment? If there were no limits in the resources or manpower at your disposal, what would you do next, and why? What’s the most exciting paper you’ve read from your field in the last few months?

Watch for the “gleam” in a researcher’s eye – when he or she gets excited, and follow that wherever it goes. It usually means you’re close to something that motivates them to keep doing a job that can be difficult and frustrating. Tapping into that source of motivation often gives you a strong sense of why a theme is so important right now.

If you can get answers to these questions, your interview will have real “meat” in it – you’ll be giving your readers unique insights into the state of the art of a topic, where it’s headed, and what they should be watching for in the near future. It will also give them a broader appreciation for a person’s work and a scientist’s field. All of this will help when you have to edit the piece for publication – when you have to finish off those incomplete sentences, reconnect thoughts, etc. Pay attention to the person’s individual speech and style and edit the piece so that it reflects the scientist’s personality.

One last point: try to make the finished product something that a researcher’s colleagues, and not just non-specialists, will enjoy reading. Science communicators often have a unique opportunity to spend some quality time with people who are important in their fields. I always think of myself as a stand-in for the reader – I get to go to lunch with this famous person. Not everybody gets that chance. Try to give the reader this sense of a personal encounter with one of today’s “great minds.”

More on this topic later.

Before & After #1

These texts were produced by a student taking part in the “Writing Labs” that I regularly offer at the MDC. These individual workshops give students a chance to write about science for a nonspecialist audience. Usually I have the students write two short articles: one regarding their own research, or a project closely related to it, and another regarding work they are less familiar with. Generally they have more distance from the latter paper and do a better job. It’s a good exercise that has a lot of secondary pay-offs: not only do students develop general writing skills, it helps them structure their thinking about their own work and present it more clearly. More on that later.

Finally, I’ll publish some of their work on the blog so that they can rack up “publication credits.” If you want to make a career in science communications, you need to be ready to show some examples of your work. We’re developing other places for students and scientists to publish such pieces. (See, for example, http://www.scienceinschool.org/ – the magazine for science teachers I helped develop while at the EMBL.

This is the “unfamiliar research” article from a student who very generously allowed me to publish both versions of her text on the site.

I haven’t included the “work” stage, where we analyzed and restructured the content, fixed grammatical errors, etc. First I’ll let the texts speak for themselves.

If you’re interested in doing such an exercise, or knowing more, get in touch!

“BEFORE” text

Aging: one protein,
multiple molecular defects

While we all look to reverse the signs of aging, scientists have been for long trying to pinpoint the molecular mechanisms behind it. A two people work in Science, 19th of May 2006, by NIH researchers Paola Scaffidi and Tom Misteli, have identified an important player that, solely, could lead cells to aging-associated defects.

As society pressurizes for long-lasting young-looks, teenager stamina and increased life-spam science tries to come up with solutions for this first-world problem. Developments in aesthetic and plastic medicines and increased awarenessess in anti-aging food diets have been helping the most concerned preventing premature aging and minimizing the aging signs. Although many theories have been proposed by scientists of how molecular mechanisms are disrupted throughout one’s lifetime, we are far from understanding the source of the problem. In this paper, Scaffidi has revealed that Lamin A, a protein located at the nucleus envelope (structure separating the DNA packed nucleus from the cytoplasm) participates in the aging process by disrupting relevant cellular functions.

The authors have compared skin cells from normal aging individuals with premature aging HGPS (Hutchinson-Gilford progeria syndrome) disease patients. HGPS is a rare disease that leads to premature dead (mid teens, early twenties). Growth defects are accompanied with accelerated aging processes such as hair loss, atherosclerosis, wrinkled skin, etc. The genetics behind this disease is a mutation in the Lamin A gene, an integrative constitutive of the nuclear envelope. This structure is responsible for the organisation of chromatin (DNA and proteins called histones) and regulation of gene activity (usually “off” when associated with the lamina).

Lamin A was also found to be mutated in normal aging cells. Scaffidi showed that, like in HGPS, the nucleus presents an irregular shape, abnormal amounts of proteins associated with the nuclear envelope structure and an accumulation of DNA errors by disruption of repairing mechanisms (upon each cell cycle, where mother cells generate two daughter cells, the DNA is checked and repaired by appropriate mechanisms). As researchers revert these phenomena’s by inhibiting the mutated Lamin A protein version, it opens new avenues for the research of therapeutics against mutated Lamin A.

Using HGPS as a model system seems to be helping scientists figuring out clues into the normal aging mechanisms. As the scientific knowledge on aging grows, the players are slowly being unravelled raising a robust set of potential targets which usefulness, solo or in a cocktail, could be further explored.

“AFTER” text

On growing old:

From a wrinkled cell nucleus
to the symptoms of aging

A protein that is mutated in an extreme rapid-aging disease also shows defects during normal aging processes

Most of us would like to enjoy a long-lasting youthful appearance, the stamina of a teenager, and an increased lifespan. The causes of aging lie in molecular processes within our cells which scientists have been trying to pin down for a long time. In a paper in the May 19, 2006 edition of Science, NIH researchers Paola Scaffidi and Tom Misteli identify an important protein that, on its own, seems to lead to age-associated defects in cells.

Developments in plastic surgery and “aesthetic medicine,” as well as an increased awarenessess of the contributions of diet, have played the largest role in preventing premature aging and minimizing its symptoms. Scientists have proposed a number of theories to account for the way molecular mechanisms are disrupted throughout one’s lifetime to cause aging, but we are far from understanding the real sources of the problem. Now Scaffidi and Misteli reveal that a single protein participates in the process by disrupting a number of important cellular functions.

Their work focuses on a protein called Lamin A. It is found in nearly every human cell and makes up part of the nuclear envelope, a membrane that surrounds the DNA in the cell nucleus and separates it from the surrounding cellular compartment called the cytoplasm. As well as giving the envelope a regular shape, Lamin A helps organize DNA in the nucleus and control the activity of genes. It binds to strands of chromatin (a mixture of DNA and the proteins that are attached to it), which usually keeps nearby genes “switched off.”

The authors came across Lamin A when comparing skin cells from normal aging individuals with those of people who suffer from a type of extreme premature aging called HGPS (Hutchinson-Gilford progeria syndrome). HGPS is a rare disease that leads to premature death in a patient’s teens or early twenties. Those with the syndrome suffer the symptoms of accelerated aging such as hair loss, atherosclerosis, wrinkled skin, etc. Several years ago scientists discovered that patients with this disease have a mutation in the Lamin A gene.

Scaffidi and Misteli now show that Lamin A is also mutated in normal aging cells. As in HGPS, the nucleus presents an irregular shape. They also found that that cells produce abnormal amounts of proteins associated with the nuclear envelope structure. Additionally, the cells display an accumulation of DNA errors by disrupting mechanisms involved in DNA repair. (Normally, each time mother cells generate two daughter cells, the DNA is checked and repaired by appropriate mechanisms.) The scientists inhibited the mutated version of Lamin A protein by providing cells with a healthy version. This procedure reversed the defects caused by the mutation. So the work opens new avenues for research into therapies that target mutated forms of Lamin A, which might correct – or at least slow down – some of the problems associated with normal aging.

This makes HGPS a model system that may help scientists figure out normal aging mechanisms. As our scientific knowledge on aging grows, new molecular players are being identified, revealing a set of potential targets whose usefulness will be explored in further work.

Reference:

Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging. Science. 2006 May 19;312(5776):1059-63.

The Kansas Creationists vs. the Evolutionary Atheists

Leaving Flatland and its flawed debate

Note: This article is being published in under the same title in the current edition of the magazine Occulto. Hodge, Russ. “The Kansas Creationists vs. the Evolutionary Atheists.” Occulto Issue e, Summer 2013, Berlin. Edited by Alice Cannava. ISSN 2196-5781. pp. 64-85. You can obtain a printed copy of the journal at  http://www.occultomagazine.com

My daughter was leaving Germany for a year to explore the American half of her genome. Rather than the liberal Kansas town where I went to school, she was headed for the southern half of the state, colored deep red on political maps. “You’ll be fine if you don’t discuss politics, religion, or guns,” I advised her. “Or Charles Darwin.” His name alone provokes a strong reaction in my home state, as I found out after writing a book on evolution.[1] Everyone has an opinion and you don’t have to pass a test before you jump in to a scientific debate, giving it the character of a barroom brawl. The topic leaves few Kansans sitting on the fence. Maybe because we use a lot of barbed wire.

Barbed wire was patented in 1867, nine years after Darwin and Wallace foisted evolution on the world. Out on the prairie, farmers began fencing up their lands, threatening the culture of cowboys and cattle drives. In 19th-century Kansas, barbed wire caused a far greater ruckus than evolution, although the debates didn’t drag on long because the two sides were well armed.[2] In Europe the theory caused more consternation, but discussions were fought with hot air rather than hot lead. Nor did the Bishop Wilberforce run a cattle stampede through Thomas Huxley’s garden. You could destroy a farm that way, but it didn’t work with intellectual property.

Barbed-wire fences broke up the prairie and metaphorically divided the population over deeper issues:  Would all the unsettled land be sold? Who had the right to use it? There seemed to be two clear sides, but only by leaving Native Americans out of the discussion. Tribes had diverse views of the relationship between people and land that would have added more dimensions to the debate.

Spatial metaphors are a type of trope – a wide range of rhetorical devices whereby words are used in unusual ways, often to describe one thing in terms of something else.[3] They are fundamental to the way we think, learn, and communicate. Tropes do not simply rename things, but rather combine complex networks of associations that correspond at some points and diverge at others. They often remain hidden as we communicate, causing misunderstandings that are hard to figure out. They have a powerful influence on the way we think, especially when we don’t realize they are there. Some are so basic, stylized and routine that we limit our imagination and the ability to see things in other ways. People often transfer the wrong properties of a trope to its target, expecting two systems to behave the same way and missing the differences.

Some tropes are obvious in everyday language, making them fairly easy to detect and analyze – take, for example, the old adage, “Every debate has two sides.” It reduces many issues – whether over barbed-wire fences, science, or “red-blue” divisions on a political spectrum – to the shape of a coin, implying that you have to choose. But most topics are far more complex. Why not think of a shape with more sides – perhaps six, like a dice, or a ball that can come to rest on any point and is easy to nudge to another?

But the two-sided model completely dominates the way most people think of debates about evolution: as if the world is firmly divided into two camps, science and religion, entrenched and fighting a war. The real situation is more interesting: Most religious denominations accept evolution, and many scientists have religious beliefs. But things got off on the wrong foot in the very first public forum in 1860, where religious fundamentalists saw the issue as a battle between universal truth and everything else, and they have controlled the form of the debate ever since. It’s too bad: fundamentalists have discovered no new facts to support their position in all of that time, while evolutionary science has made extraordinary progress. The theory is a scientific idea and should be discussed that way, rather than being hijacked and carried off to the foreign land of theology.

Even if it’s a bad metaphor, scientists could take more advantage of the coin. You could print competing hypotheses on its two sides: “Species arose through a long process of evolution,” versus “Species were created over a six-day period about 6,000 years ago.” Every day this coin is flipped by geneticists, chemists, physicists, doctors, geologists, paleontologists, mathematicians, informaticians, and researchers from other disciplines. They find new ways to test it all the time. There ought to be plenty of evidence for a sudden burst of creation 6,000 years ago, or at least evidence to debunk evolutionary theory, but the coin lands with Darwin’s head pointing up every time. Even the strongest beliefs haven’t flipped it over. That doesn’t stop people from hoping it will land, just once, on the other side. But prayers can’t make evolution go away, or even improve the health of the royal family in Britain.[4]

The two-sided debate has become such a social institution that people forget it’s a trope, just one of many ways of looking at things, and take it to represent something real. When that happens tropes move into a cognitive underground where they powerfully influence our thoughts, discussions, and perceptions of many things, and they become devilishly hard to get rid of. It’s hard to imagine that these stereotyped collisions between religious fundamentalists and scientists will go away.

Even so, I think the debate is about to change. The cause won’t be a miraculous conversion of the entire planet to some form of religious fundamentalism, or a mass exodus into atheism. Instead, I believe that science is on the verge of a conceptual revolution that will completely discredit simplistic debates. For a long time now words like “species”, “genes” and “natural selection” have been tossed back and forth, as if we are talking about the same things. I am not sure how fundamentalists think of these scientific concepts, but scientists have been steadily changing the sophisticated tropes and models that underlie them. A common vocabulary has masked a much deeper conflict; we are not at all talking about the same things.

Now, I believe, science is on the verge of a conceptual revolution that is changing the basic tropes by which we think of life; this new view may render the old sort of debate completely meaningless. The two-sided metaphor has always been a poor one. Discussions about evolution should finally escape this sort of intellectual Flatland and enter more profound dimensions.[5]

* * * *

Both religious and scientific explanations for the world depend on tropes and models. Scientists make specific observations and try to extract general principles that can be tested and improved. An experiment might confirm a model, or discredit it, and the results aren’t known in advance. Fundamentalists claim that some questions about life are answered in Biblical stories and others are mysteries that can’t be solved. There is no need to do experiments – which would either confirm what is already known, or the results would be ignored.

Developing large scientific models such as evolution or restricted concepts such as species begins with a lot of specific observations. Each doesn’t mean much on its own; the aim is to classify many into groups that exhibit similar general patterns. This resembles a trope called synechdoche, in which the features of individuals are transferred to the whole group. The next step is to test the pattern by applying it to new objects or situations. This creates a continual dialogue in which new observations force scientists to revise their general models. I’ll use a spatial metaphor and call this dual process “upward and downward” reasoning, which we use in everyday thinking as well. It’s the basis of learning, communication, and all sorts of judgments that people make.

Scientists recognize that errors can be made when reasoning in both directions. Upward reasoning can suffer from the exception fallacy: if the examples you start with are unusual, you may arrive at the wrong general principles. If you then apply the principles too widely to the wrong things, you commit an error in the downward direction: the ecological fallacy. Upward-downward thinking in our daily lives can suffer from the same errors and lead to problems such as racist stereotypes. So scientists continually check their assumptions and conclusions by requiring changes in models, if they aren’t confirmed by experiments. Fundamentalists deny that these types of fallacies exist in their own thinking, but are perfectly willing to look for them in science.

Understanding a scientific model requires understanding both parts of the process. To talk about a species, for example, you need to know how researchers assemble individual organisms into a group, make decisions about its common features, and apply them to new examples. I don’t know what the meaning of “species” is for a fundamentalist – if you deny the validity of the reasoning process by which scientists made up the term, you can’t be talking about the same thing.

Researchers make their models available to the world to allow them to be widely tested and ensure that they aren’t littered by a scientist’s subjective beliefs. At some point a model has been put to so many tests in different situations that people begin to treat it as a sort of “law”. Even then we know that it is a product of human thinking. Evolution is so interesting because its view of life exposes both the power of tropological thinking and its limitations, when the subject is an open-ended biological system that will always produce surprises.

Understanding this problem may affect the way we construct models in science and other systems. It will not discount the ability of current models to predict the function of a human gene by studying a related molecule in another species, or to manipulate organisms through genetic engineering. At some point, however, progress may be held back by mental constraints that may need to be understood to overcome. Science already recognizes that the problem exists: Double-blind experiments are necessary because expectations and models have an unpredictable influence not only our interpretation of data, but perception itself.

* * * *

When evolutionary theory appeared, it moved into a neighborhood of older concepts shaped by tropes and other mental models. The theory was communicated in common words and metaphors that were strongly associated with other things. It should have caused people to reevaluate a much wider set of assumptions, and it finally has – but the process has taken 155 years. At the time, the opposite happened, and the theory was forced into a network of very old beliefs.

For example, proposing that complex organisms could arise from simpler forms sounded like “progress”: a huge political and social theme during the Industrial Revolution. Many readers immediately tried to use evolution as a metaphor for race or class relations within human society, or to confirm the old, dearly-held view of man’s dominion over nature. Both efforts were doomed to failure: social models were tropes themselves, based on old notions about nature that had now become outdated. Social issues became a metaphorical battleground between old models of life based on religion and the new theory. No one realized that the real fight was happening at a meta-level of tropes. It was as if two people were playing a game, using the same board and pieces, but following completely different rules. It’s no wonder that you could never bring the game to a satisfactory end.

Now I think biology is in the process of toppling one of its central metaphors, in a way that may also have wider social effects. This is happening partly because of advances in technology that provide a much clearer view of living organisms and the complexity of their interactions with the environment. One result is to provide a sharper view of evolution, and how it differs from some of the cultural metaphors that have been holding it down. The change is appearing in bits and pieces and its full nature hasn’t been clearly articulated or even widely perceived. It will affect the way we understand humans, nature, and society. But this time we shouldn’t make the same mistake by applying the change inappropriately to other areas.

To make the case I will first provide a very brief sketch of evolutionary theory; secondly, point out a few issues that are central to it but are hard to deal with using current models; and finally, try to link what is happening to more general processes that underlie our construction of cognitive models.

In a text of this length it is impossible to properly ground all the philosophical, linguistic, cognitive and biological concepts that support its view of the role of tropes in cognition and science. Those arguments derive from a much larger conceptual framework that I will articulate in a future project. Here I will provide an application of the method to a debate that is currently, almost universally, carried out at a level that is much more superficial and naïve.

* * * *

“Evolution is so simple, almost anyone can misunderstand it,” said philosopher David Hull.[6] Darwin and Wallace drew on straightforward observations that can be made anywhere, and interpreted them in a way that is closely linked to everyday, “common-sense” ways of thinking. The complexity of the theory lies in the way they abstracted a model from these observations, then extended it far into the past to show how a few basic principles suffice to produce new species.

The outline here covers four basic principles. The most general is common to all natural sciences and distinguishes them from religion and other styles of thought. Researchers make a fundamental assumption: “We should understand states of the world that we can not directly observe on the basis of what we can observe.” This can be seen as a derivative of Occam’s razor, which in its original form has been translated as, “Plurality must never be posited without necessity.”[7]

The razor doesn’t mean that the universe is inherently simple; instead, it recognizes that views of the natural world are the product of philosophical and methodological choices, and one shouldn’t make up more hypotheses than are necessary. If a single, global force (gravity) can account for falling apples and the motion of the planets, we shouldn’t make more assumptions and suppose that each object is being pushed around by its own personal force, without evidence. By definition this approach discounts miracles such as the idea that the universe was created 6,000 years ago, in six days, which presupposes a suspension of the current forces we observe at work.

A model may posit forces that can’t be observed (such as gravity), but which have predictable effects that can be tested in observations or experiments. If galaxies are racing away from each other, their trajectories can be projected backwards in time to produce the notion of the Big Bang, or forward to produce a vision of the future of the universe. The same rationale yields an explanation for geological formations and a likely age of the Earth. Evolution is the biological equivalent, based on an observation of current life to abstract rule-governed processes that explain the origin of diverse species.

To conceive evolution, Darwin and Wallace wove three basic observations into a system that respects this fundamental principle of science. First: species constantly undergo variation. Offspring are not identical to their parents or each other (unless they are twins or clones). Variation can be directly observed in every species and is rarely an issue in popular, dualistic debates about evolution. The theory partly hinges on the rate at which it happens, which can only be determined using scientific methods; the results have been consistent with evolutionary predictions.

Most variation arises because of natural imperfections in biochemical systems. DNA undergoes many types of changes: through “spelling errors” (mutations), or when sequences break off longer molecules during the creation of egg and sperm cells. Cells can repair the damage, but material can move from one chromosome to another in a process called recombination. Other errors include duplications of DNA sequences, whole chromosomes, and in some cases an entire genome. Genetic material can also be lost. Any of these alterations can result in measurable physiological or behavioral changes in the organism as a whole – its phenotype. Such changes happen to some degree in every child; we are all X-Men.

The second observation was that some variations are passed down to an organism’s offspring through a process of heredity. The main reason is the conservation of specific DNA sequences from parents to their offspring, but some other types of biochemical changes are passed along as well. Heredity is not a deterministic system because first, each of us inherits a unique genome – we are all experiments, venturing into a landscape that has not yet been explored by evolution – and secondly, most types of behavior and many aspects of a body’s development are shaped in a dialogue with the environment.

The third factor in evolution, natural selection, is usually wildly misunderstood. Right from the start it was labeled with a misleading trope – “survival of the fittest” – that scientists have been trying to peel off ever since. It was coined by Darwin’s contemporary Herbert Spencer, a philosopher with the social status of a movie star. One of Spencer’s main interests was social progress, and he hoped that the new theory would shed light on cultural development. Religious and political conservatives seized on his words and applied their own tropes in interpreting “fittest” any way they liked – to keep humans at the top of nature, near God, or the wealthy or powerful at the top of society. They used it to justify racism and its nastiest form: eugenics movements that sought to “improve” humanity by sterilizing or killing the ill, the handicapped, prisoners, “promiscuous women,” Jews, and anyone else that those in power didn’t care for.

Darwin never liked “survival of the fittest” because he recognized that biological concepts could only be applied to culture in a metaphorical way that mangled what he meant. Finally, grudgingly, he used the phrase – probably out of the wish to appear conciliatory – but only after redefining it in and stripping it of moral and social connotations. The translation in strictly Darwinian terms sounds circular and almost silly: “survival of the survivors,” or “survival of the reproducers.” In other words, current species are the descendants of animals that managed to reproduce more than others. If you couldn’t pass along your genes, a lot of your hereditary material would disappear in favor of those that could. And if you didn’t reproduce as much as your neighbors, and nor did your descendants, and this happened over vast periods of time, then eventually your genomic contribution to the future of your species would dwindle and perhaps even disappear.

Darwin had noticed that many factors could give an animal a reproductive edge over other members of its species: differences in fertility, an organism’s ability to survive long enough to reproduce, preference for certain mates, etc. Events that struck a population equally, like random accidents, wouldn’t have much effect: The diversity of a species would undergo slow, random changes in a process called genetic drift. That itself can produce different species. If two subpopulations are isolated from each other long enough, drift may eventually change their genomes to an extent that they can no longer mate to produce fertile offspring.

So selection begins with any trait that gives an organism a reproductive edge, increasing its frequency, compared to other variants, in the next generation. If offspring with the trait also produce more children, and the bias continues over many generations, the result may be natural selection. It always occurs as a function of a dialogue between the features of an organism and its environment; identical animals don’t always do equally well in different environments. If you could measure the frequency of particular variants of genes in a species before selection happened and then again afterwards, most would exhibit random drift. But variants in an animal that had undergone “positive” selection would show a statistical increase, while forms that lower an organism’s reproduction would become rare or even disappear.

Today the signature of these events can only be detected by studying the frequency of particular DNA sequences over time. And here is also the signature of a trope by which the process is usually oversimplified in our imagination: “fitness”, or selection, isn’t something that happens to a single individual, or even a single couple, or a single generation. Instead, it is a population effect that may require thousands of generations, or however long it takes to create a new species. The change usually takes place in multiple family lines. What happens to an individual organism plays a role, but the impact on evolution is a statistical one, spread out over vast periods of time. One can observe individual advantages in reproduction, then postulate their extension into the past and future as an “upward” style of thinking. But one can’t reason back “downward” to make predictions for specific individuals, which might die in accidents or suffer from other random events. It’s also important to note that a reproductive advantage passes along an organism’s entire genome, including factors that may support the “edge”, but also all of the other characteristics it passes down.

An organism’s reproductive ability can be influenced at every level – from single letters of the genetic code, the behavior of molecules within its cells, the function of its organs, its thinking, and its overall interactions with the environment. It comes into play at every phase of a lifetime – from its origins as a single cell, through its development in an egg or the womb, its infancy, childhood, or adulthood, up to the end of its fertile phase. Usually selection stops there, but it might continue in cases where organisms contribute substantially to the survival of their “grandchildren”. Any difference that affects an organism’s phenotype can influence selection, given a permissive environment.

Variation, heredity, and reproductive differences are directly observable and – along with the more general assumptions of science – form the basis of evolutionary theory. The first two factors are rarely called into question; selection is more contentious, but mostly because the debaters are using different tropes.

* * * *

The power of evolutionary theory lies in the way it has spawned millions of hypotheses that continue to be tested in countless ways. Even this hasn’t been convincing to “Young Earth” fundamentalists, who have discarded the basic scientific premise of a continuity of natural forces in favor of a miraculous act of Creation that took place about 6,000 years ago. Their rationale is based on a faith in what they call a “literal” reading of the book of Genesis, but each fundamentalist decides what should be read literally and what not, in response to other cultural influences, making today’s fundamentalism is much different than forms practiced in the past. The written record of languages – easy to discover through a trip to any library – makes it easy to discard the Bible’s story of language creation (the “Tower of Babel”) as a fable. But the creation of species, recorded in fossils, and recounted in the same book, is regarded differently – why?

Other challenges to evolutionary theory are grouped under the popular label “intelligent design.” This is indistinguishable from a religious philosophy known as Natural Theology,[8] which dominated thinking about life until the development of evolutionary theory. Its major argument holds that living systems appear so complex and well-structured – usually by analogy to a machine such as a clock – that they must have been created by some sort of supernatural intelligence.[9]

Darwin grew up in this tradition, but several major conceptual flaws convinced him to reject it in favor of evolution. It “cherry-picks” from empirical observations of life: Anything that can’t yet be explained is assigned to the domain of miracles, including biochemical processes discovered through strictly scientific methods. Once scientists provide a reasonable account of the origins of these processes, or demonstrate that some fossil species didn’t arise spontaneously, the intelligent design community shifts its focus to the next unsolved problem. Michael Behe, a biochemist who has become an advocate for the philosophy of intelligent design, has consistently taken this strategy.[10]

Another flaw is the difficulty of distinguishing between “designs” and the structures or patterns that arise due to physical and chemical laws. The spiral forms of snail shells and the tornado-like pattern of water as it moves into a drain might look like supreme achievements of an intelligent architect, but both can be explained by applying models of biological or physical components and the forces acting on them. The body of every human child is an amazing structure that arises from a single cell. Usually this process is explained by reference to biological events, rather than constant, supernatural interventions – so why not the origins of species?

Finally, even if scientists were to stumble upon some unmistakable “signatures of a designer,” how many such designers are there? Each molecule, cellular structure, organism, or species might have its own. Claiming to see the hand of a single designer in different natural phenomena is the clear sign of a particular religious agenda, and today it is usually the attempt to thrust a Judeo-Christian deity into the science classroom.

* * * *

Evolutionary theory is not yet complete because some aspects of living systems have been impossible to explore. Some of these problems represent a lack of technology; others, I think, are inevitable when human minds construct a model and try to apply it almost universally to the world.

The first area of incompleteness has to do with evolution’s portrayal of the environment. Darwin was the first ecologist: He demonstrated that the fates and forms of species were thoroughly intertwined with each other and external factors; that each species exerts an influence on others, and that overpopulation and a competition for resources play a role in natural selection. Organisms don’t change due to purely internal factors; they arise and are shaped through a complex, fluid dialogue with everything around them. This includes every other species they interact with and other aspects of the environment such as temperature, the amount of precipitation, sunlight, seasonal changes, etc. It also includes interactions at the microscopic scale. Recently, for example, scientists have caught the first glimpse of the microbiome:[11] the extraordinarily complex, dynamic populations of bacteria and viruses that inhabit our bodies and the environment. This opens the door, for the first time, on understanding their influence on our evolution (and vice versa) and human health.

Single molecules can promote or hinder an organism’s survival and reproductive capacity, so they, too, contribute to natural selection as they carry out functions in cells. Here they will serve as an example of a gap that remains in our understanding of the interplay between organisms and their environments.

Nearly every biological process involves a process whereby cells detect and respond to change. One mechanism involves signaling cascades that typically start when a molecule binds to a receptor protein on the surface of the cell. The receptor undergoes a structural and chemical change that causes it to bind to other proteins, subsequently changing their structure and behavior. This effect is transferred from one type of molecule to the next, often ending with the transport of a protein to the cell nucleus. There it helps change the overall pattern of active and silent genes in the cell, altering the population of molecules it contains, its biochemistry, and its responsiveness to other signals.

A particular signaling cascade requires certain molecules to be present or quickly produced in response to a stimulus. They need to be located in the right regions of the cell: microenvironments that must also be properly configured to respond to the signal. Signal molecules have to be present in sufficient quantities, and they are usually bound to complexes (sometimes consisting of dozens of other molecules), whose components also need to be present in sufficient quantities. Some protein complexes are “prefabricated” and localized in particular microenvironments, where they can be “switched on” through the addition of a single component.

Passing a signal requires that a protein’s atoms have a particular physical architecture. This requires the help of still more molecules that help it fold, or “decorate” it with complex sugars, or bind it to a membrane with a particular composition of fats and other molecules, etc. This takes place against the background of multiple signals that may carry conflicting “instructions” and compete to push the cell in different directions. By adopting different conformations, or docking on to different complexes, a single molecule can act as a “switching station” to route different signals in various directions.

The quantities and states of all the other molecules in a microenvironment influence whether a protein receives a signal and how the “information” is passed along. Those populations determine whether the protein will bind to its proper partner; too many copies of another protein may change its preferences (affinities) for other molecules. If everything works and the protein does transmit the signal, the contingencies must also be met by the next molecule, in a neighboring microenvironment, so that it can be passed farther.

Microenvironments both constitute the cell and are shaped by it. They are dynamic, constantly requiring the production, refinement, and delivery of new molecules. Events within them move beyond to activate new genes, silence others, and cause changes across the entire system in intricate feedback loops. Molecules, microenvironments, and entire cells continually undergo fluid transitions – rather than adopting a clearly definable state – in which adjustments are constantly being carried out. At any given time, some proteins have achieved the form necessary to receive and pass along a signal; others are being processed; still others are being translated from RNA molecules; RNAs are being transcribed from genes at a particular frequency, etc. Every protein in a signaling cascade is undergoing similar transitions in terms of its chemistry, form, and quantities. So the success of a signal depends on the attainment of tipping points: changes from various conditions under which a microenvironment is not yet ready to receive a signal, to conditions which permit it.

Until very recently it has been impossible to capture a remotely adequate census of microenvironments or the dynamic nature of their components. As a result, proteins have generally been described as metaphorical actors – like telling the history of a war only from the perspective of generals. Some do have powerful roles, as clarified through experiments that change or remove them, but such experiments usually involve hundreds, thousands, or millions of copies of a particular molecule in highly standardized microenvironments. What is really being described is collective behavior, averaged out in a statistical way to make a model that is then applied to single molecules, in microenvironments where the major contingencies have been met.

Such descriptions aren’t perfect; they rarely describe the behavior of any single molecule, and they don’t have to. This inexactitude isn’t just a by-product of gaps in technology. Evolution predicts that it must be an inherent feature of cells. Life is constantly subject to variation and unpredictable events, so cells and their microenvironments have to have a certain tolerance for them. Most of these systems exhibit a robustness by which one molecule can step in for another, or some other “backup” system comes into play – evolution has favored them. At the same time, cells can’t tolerate everything. So far it has been impossible to define precise boundaries of permissiveness and intolerance in their microenvironments.

The same principles that govern proteins and their surroundings apply to all scales of biological organization. Simply by living – using resources and producing waste products – a cell changes the environment for itself and everything around it. In a complex organism, cells build higher levels of structure and tissue to create a body that is likewise in a fluid state of change, constantly adjusting to internal and external changes. There is an upward-moving causal chain whose restrictions are most evident in diseases where events triggered by specific molecules – in the context of their microenvironments – disrupt the body as a whole. Such upward causality participates in every aspect of growth, activity, and physiological processes such as digestion.

This is dramatically different than the common concept of environments as large external spaces in which organisms interact with each other, and where causal forces work mainly downward. That concept is also appropriate: temperature and other external factors (such as the availability of specific types of food) reorganize biological structures down to the level of molecules. But a better definition of the evolutionary environment is a to imagine a succession of fields of all scales in which biological activity has causal, fluid effects in both directions, upward and downward.

One fascinating “downward” causal chain can be found in the process of thinking, which may create a new biological environment that can affect all lower levels of biological structure. Suppose I interpret a phrase of music on a bowed instrument. That interpretation is a personal construct developed from years of experience, learning, and aesthetic tastes that constantly move back and forth between mental and physical domains. My conception of it somehow triggers specific types of motor activity across the body: muscles in the hand holding the bow do something very different than my fingerings on the string, while remaining highly coordinated. Playing music produces new cellular signals and the activation of new genes. At the same time I remain highly responsive to external feedback: feeling an irregularity in the surface of the string, noticing the expression on a listener’s face, or hearing the behavior of my fellow musicians. Thoughts, intentions, and social interactions create and constantly reshape environments for biological activity at every scale.

* * * *

This much more fluid, multi-scalar view of biology shakes up some central metaphors by which we have described living systems and the models we use to understand them: a fusion of materialism and mechanism. Their breakdown will significantly alter the way we think about issues like genetic determinism, states of health and disease, and large models such as evolution.

Materialism is probably easiest to understand in contrast to another philosophical tradition called vitalism. Until the 19th century and even later, many scientists (and all theologians) postulated a qualitative difference between living things and inorganic substances. Evolution might be fine to describe everything that had happened since the appearance of the first cell, but how did that organism arise? Vitalists believed that some “spark”, energy, or force must have been necessary to create life from the inorganic world. Theologians ascribed this to a supernatural being, but it didn’t have to be; it might simply be a type of measurable energy that simply hadn’t yet been detected in physical or chemical experiments. The idea attracted droves of physicists to the life sciences.

What they discovered ultimately led to the abandonment of vitalism in the life sciences. In 1828, Friedrich Wöhler demonstrated that a biological molecule (urea) could be synthesized using purely inorganic substances. In the 1950s, Watson and Crick drew on physics experiments to propose a model of DNA whereby a molecule could reproduce itself by purely biochemical means. Experiments at about the same time carried out by Stanley Miller showed that complex organic molecules such as amino acids could spontaneously arise in sterile conditions, even in outer space.[12] Miller never managed to build something as complex as RNA or DNA in the lab, but he didn’t have the time or virtually infinite resources of the early Earth. Every single molecule on the planet could be considered a chemical workbench, carrying out experiments over a billion years.

So biology chose materialism, at a time of rapid industrialization, which made it easy to choose machines as the guiding metaphor for understanding cells and organisms. The components of machines interact based on their physical composition and structures. Obviously organisms were very complex machines, but technology was becoming more complex as well. New machines provided a richer source of metaphors. With the advent of computers, people began discussing biology in terms of systems, as intricate networks of feedback loops and self-regulatory mechanisms somehow analogous to electronic circuitry.

Even with such fabulous machines on hand, the metaphor has reached its limits and, strictly speaking, can no longer be applied. One limitation should have been clear from the outset: Machines couldn’t reproduce themselves. And not even the most complex machines come close to possessing the complex, interlinked, fluid microenvironments described above. We usually design machines with rigid parts that have single, repetitive functions; if they break down, they can be fixed by changing a single part. Their components aren’t continually, fluidly, rebuilt at every level; they haven’t been tested and redesigned to adapt to any contingency. Human machines are rigid and designed to operate as stably as possible under specific conditions foreseen by engineers, rather than in continually changing enviroments whose variations know few bounds. Applying the machine metaphor to life leads to concepts of genetic diseases, for example, in which solutions are sometimes seen as machine-like exchanges of new parts for defective ones. Sometimes that might work, but it may not – the metaphor doesn’t really apply.

Another blow to the metaphor is the fact that by nature, no two organisms are alike; variation is an inherent quality of every species, and a tolerance for unpredictability is essential to its long-term survival. That is much less true of machines, particularly in the age of mass production, where variation in a particular model is usually regarded as an accident. This will be explored in more detail in the next section.

By abandoning the metaphor of the machine, we also abandon a naïve style of hard deterministic thinking that has arisen around notions of genes and organisms. (“My genes made me do it; my genome dictates my life.”) Determinism might be appropriate in a system that works completely from the bottom up, where rigid components dictate the behavior of a system, then the next higher scale of structure and so on. But what if the causal chain flows both upward and down, in which every component is responsive to unpredictable environmental events, contains immeasurable amounts of variation, and where human behavior creates new environments that shape biological activity? Causality itself is a model, usually based on the idea that one state naturally transforms to another after the application of some (model) force. It can only strictly be applied if it’s possible to define states – will it work in the context of ultimately fluid causal systems?

How could it be achieved, for example, in the case of music? To start you would have to fully describe both the material and mechanical basis by which aesthetic experience is physiologically “recorded” in the brain and nervous system. You would have to assume that internal physical structures not only underpin but cause particular thoughts. The system would have to be responsive to unpredictable effects, like an expression of pleasure or distaste on the face of someone in the audience. It’s safer to postulate a system in which unpredictable external stimuli from the environment exert a shaping influence on physical structure that works downward as well. Thoughts themselves – and their content – change the physiological substrate that permits them. Experiments in neurobiology have demonstrated that this is the case.[13]

* * * *

To survive, organisms can’t have some of the features we normally associate with machines. Every existing life form encodes at least a billion years of compromise that creates various degree of tolerance for variation at every scale of biological organization. There are boundaries, of course: Some variants are so disruptive that they are fatal. But just as deadly is any failure of the mechanisms that tolerate variation and change.

The field of biology has had a hard time fully grasping the extent – possibly even the concept – of this variation, and this is the last “gap” in evolutionary science I will discuss. It causes a fundamental problem in defining biological objects – whether single molecules or species. I think it can be dealt with, but this will probably require a new type of model-building. That may be difficult because the problem is closely linked to more general issues of human cognition.

The link is probably easiest to grasp through a metaphor, something much simpler than a molecule or a species – let’s take the concept of a “chair”. As a child I perceive individual chairs in various contexts, do various things with them, and hear people talk about them. There is no real consensus among cognitive psychologists about what happens next, but at some point a child creates conceptual models of “things called chairs” and begins using the models to name things she hasn’t seen before. At that point other people may correct her. She has to understand that different objects can have the same name while remaining distinct from objects with another name. In doing so she integrates features such as shapes, colors, textures, functions, parts, and different materials. Other features include a lifetime trajectory that involves being built, undergoing changes, and falling apart or being destroyed.

Children don’t come pre-programmed with a concept of a “chair”; each of us builds our own in an individual, constructive process based on encounters with specific chairs. The process is highly flexible, permitting us to recognize things that don’t fit any “classical definition” of a chair – such as something with a leg broken off, or a chair in a dollhouse, or a two-dimensional stick-drawing of a chair. All of these acts are based on tropes.

Building a model for a biological entity – such as a protein, or a species – requires a similar process. After specific objects are studied, an abstraction is made to define a “class model” that is as inclusive as possible of everything that belongs and everything that does not. From the beginning the model is intended for refinement: We haven’t yet encountered every object that can potentially belong to the class, so it is difficult to describe the boundary conditions. And since this process is based on experience, it is inherently statistical and subjective, while proposing a model that can be expanded or restricted as it is applied to new objects.

Experimentation allows science to escape the corsets of an inappropriate model. For a long time it might have been fine to think of atoms as tiny planetary systems, made of small, solid objects. But experiments forced the development of quantum mechanics, which suddenly said that objects on the human scale aren’t good metaphors for the subcomponents of atoms. Photons or electrons can’t be snagged like footballs and held onto; they may seem to disappear as they move from place to another, temporarily converted to energy; they are always in transition.

* * * *

Let’s see where this type of thinking gets us in biology by considering one of the most fundamental components of organic life: a protein. The usual biological account of the features of proteins goes something like this: Proteins are strings of amino acids (a metaphor: they share some features of human-scale “strings” but not others). They have sequences: the list of amino acids in their order in the string (a complex metaphor with a time, spatial, and behavioral component:  you imagine traveling down a text in a certain direction and reading letters as they appear). Proteins have a complex, three-dimensional structure or architecture (which don’t behave like most objects on our scale, unless you’re thinking of something like jello, because they are constantly in motion and often reshape themselves).

They have life histories that play a crucial role in their current behavior: Sequences in genes are transcribed into an RNA molecule, which is used as a template for proteins. This simple account skips many steps of processing, each of which may change the molecule’s final form, so the history becomes encoded in its final location, structure, and functions. Proteins have functions that are usually metaphorical (receptors, signal transducers, inhibitors, promoters, etc.). Originally such names convey an impression of their activities, but the terms are ultimately based on specific chemical reactions. In describing features and functions we use letters, texts, mathematical symbols, sequences, and other tropes.

Every feature of a protein naturally appears in extensive variations that can’t be fully measured or catalogued. For example, proteins never have a static, completely immovable structure, although we depict them in two or three-dimensional pictures that give this impression. These are symbols for a type of archetype that probably never exists, at least for any length of time.

Once the features of a specific protein have been defined, it is given a “class” name that can be applied species-wide (“human beta-catenin”) This class is further extended to other species in a process called homology. There is a compelling evolutionary reason to do so: human and mouse versions of beta-catenin evolved from the same gene in an ancestral species. This is established by noticing extensive overlap in their sequences, and it usually allows researchers to draw parallels between a protein’s structure and function in different species.

The central problem in this type of model is that it does not (in fact, cannot) capture a full view of variation along any parameter. It’s impossible within one species, often within one organism, and sometimes even within a single cell. There are two reasons: The technological problem stems from the fact that until very recently, we didn’t have instruments that could identify a single aberrant molecule against the background noise of alternative forms, either in terms of sequence, structure, or function. A single copy may have experienced some sort of accident in which a bit is cut off. Or it might have been improperly folded, or undergone some other processing error.

The second problem lies with the impossibility of defining a consensus sequence within a species. Random mutations continually occur and produce new versions of the molecule; there is no way to predict all possible variations that may occur and yet remain functional. It is possible to predict that specific changes will eliminate the production of a molecule, but not other parameters of variation. This problem is magnified when trying to cross species boundaries.

If we can’t define the sequence of a single gene, how can we define a species? Once again, naming species is a convention – an example of reasoning from specific examples up to a general model, then down again to new examples. This doesn’t create an objectively applicable definition because there is no “consensus genome” (or any other single feature) that can be definitively attributed to a species. Even if you could carry out some sort of census of every living individual, each birth produces a unique genome with variations that might break the rules.

Instead, scientists rely on statistical definitions of objects and parameters that loosely define boundaries of inclusion and exclusion. Suppose that someone discovers a bit of tissue in the woods and asks a lab to identify the species – “Did it come from a human? A gorilla? Or Bigfoot?” A sample is sent to the lab, which produces a DNA sequence. Most likely this exact sequence has never been seen before. It doesn’t matter: It can be attributed to an existing species if the amount of variation doesn’t exceed certain statistical parameters. If it falls substantially outside a norm for humans, gorillas, or other known species, it is deemed to be a new one. Even then, the statistical values permit it to assign it to a space on the evolutionary tree (it’s from a new species of bear or hominid).

By necessity, biological models of objects ranging from proteins to species fall into the domain of a more basic cognitive issue. We construct models individually in a complex process that involves metaphors and other tropes, a process limited by experience, unable to account for all existing and permissible variations, and yet applicable to new objects in a fluid way that is, for lack of a better word, statistical in nature. Like living systems, our mental models are simultaneously individual, robust and flexible. They arise in specific contexts (the way an organism is born into specific genomic and environmental conditions) including physical laws, human beings, and other ideas, and then venture into new territory.

* * * *

What does all of this say about the future of evolutionary debates? In a sense, it shifts the focus from specific questions about biology to more fundamental discussions of scientific practices and “everything else.” It draws a closer link between scientific thinking and everyday cases in which we construct and apply models of the world – including religious systems and the learning of language. It demonstrates that there is something fundamentally flawed about applying bottom-up/top-down reasoning to open-ended systems – at least if we expect the result to be a comprehensive definition that will always work.

Models of species themselves play a central role in popular debates on evolutionary theory. Bitter fights are waged over the question of whether evolution produced new ones, or did they all appear on Earth “as they now are” in an instant of Creation. The second perspective is just wrong – if for no other reason than the fact that the human genome has changed immensely even over the past 6,000 years, simply by adding several billion members to the population. Modern studies of organisms show that it has to be wrong. The notion of a species itself comes from science and bears no relationship to the number of names we have for animals (or organisms) in a particular language. So any time the concept of species comes up in these discussions, people are discussing wildly different things. And they rarely mention that within science, the models are being revised to encompass a more fluid notion of variation and populations that exhibit it in wide, unpredictable amounts.

I believe that what I have called “upward and downward thinking” – reasoning from specific examples to abstract models that are then applied to new examples – is a component of the acquisition of virtually every human concept, and that the act of acquiring it is individual and constructive. This process usually involves tropes that help individuals learn things in a multi-dimensional way, but whose application is not very well controlled. Individuals are usually left to decide on their own what features of a network of relations should be transferred from a known object to a new one. The development of a model is therefore inherently subjective, although it seems to become more objective after it has been shared, its predictions and boundaries have been tested by many people in a wide range of contexts, and becomes a currency for social agreement. This process entails an inherent cognitive flaw, at least in open-ended systems like cells or the attempt to design a new type of chair, that I will explore more fully in later work.

But this account can already shift some of the rhetoric of evolutionary debates because it discounts certain metaphors that are clearly inappropriate and no longer apply. Natural selection itself is an upwards-downwards concept. It can’t be considered some sort of external force – like a heat wave that scorches a population and leaves only one individual with a unique form of a gene standing. Seeing it as a statistical event that happens within a subpopulation, rather than individuals, and something that only happens over many generations is a large shift from the “survival of the fittest” mentality.

I think this view of life also rings the death-knell for the concept of a “selfish gene” (or “selfish allele”). A particular form of a molecule is only successful if it operates within a microenvironment that is permissive (and possibly encouraging) to its activity. This means that many molecules must be attuned to each other to create functional environments. When selection favors a gene, it simultaneously favors all the contingencies that allow it to succeed. These are not established in advance but arise through dialogue. At the moment, we are unable to survey all of the forms of a particular gene that are found in a population, or the variants of other genes that collaborate with it, or establish the mutual constraints on their behavior. So while we know that genes are “social” rather than selfish, at least theoretically, the extent of these mutual contingencies can’t yet be measured.

Evolutionary theory has proven tremendously valuable when it comes to assigning new facts a place in a model; its direct applications have also been incredibly powerful in manipulating organisms and biological systems. This has led to accusations that scientists are “playing God” by taking “artificial control” of “natural processes.” The metaphor only makes sense if you accept its religious premise; additionally, it is merely a way of dressing up the old debate between vitalism and materialism in new clothes. The same charge of “playing God” can be leveled at the inventor of a new type of chair, or anything else, unless you believe that there is some qualitative difference between manipulating living systems and “inorganic” objects (like wood, which is still organic, just no longer attached to a tree).

Genetic engineering and other activities certainly might affect human evolution by altering the environments in which we live, and that it might do so rapidly by releasing organisms that reproduce quickly under particular environmental conditions. On the other hand, changes are inevitably happening anyway as we change the environment in other ways, deliberately or not. Our planet now hosts seven billion humans who continue to produce new babies and waste products, who continually create new technologies, and who spread both diseases and cures at a faster rate than ever before. Our own existence and behavior are integral components of the environments of the future.

The more profound issue that underlies many of these debates, I think, is fear – fear of certain types of change, especially if they seem to threaten something of value. Evolution offers no guarantee that humans will survive (nor does the notion of a “Rapture”); it also allows for changes that we personally wouldn’t care for. We can only be glad that ancient hominids didn’t regard themselves as the pinnacle of Creation and somehow nip future evolution in the bud. They could never have succeeded, nor could the eugenicists, because there is no way to prevent random biological variation and gain long-term control over the fate of our species.

The alternative to a fluid, evolving view of life is a static model that is the gateway to a mechanistic view and thus a deterministic one. If the central metaphor in understanding life is a man-made machine, it is easy to overlook all of the aspects that are non-machine-like, particularly in the interconnectedness of every level of every biological system. To think otherwise is to continue to debate evolution in an intellectual Flatland that the theory has already escaped.

I don’t think a deterministic system can survive within a much greater model that is fluid, individually constructed, open-ended, tolerant of variation, engaged in a multidimensional conversation with its environment – in other words, organic. The metaphor of a watch – or of any other machine – is far too mechanistic to describe any living system. The amazing complexity of life is not evidence of deliberate creation or intelligent design; in fact, its unpredictability is the best evidence for an ongoing process of evolution.

– Russ Hodge, April 2013


[1] Russ Hodge. Evolution: the History of Life on Earth. New York: Facts on File, 2009.

[2] Richard Rodgers and Oscar Hammerstein. “The Farmer and the Cowboy should be Friends” (song). Oklahoma (musical). 1943.

[3] For a fairly complete list of tropes, see “Figure of speech,” http://en.wikipedia.org/wiki/Figure_of_speech

[4] In 1872 Francis Galton, a cousin of Charles Darwin, studied the health of the British Royal family. So many people prayed for their health, he reasoned, that if “third-party” prayer were effective, they ought to have exceptional health. But it appeared to have no effects on their longevity.

[5] Edwin A. Abbott. Flatland: A Romance of Many Dimensions. Dover Publications, 1992.

[6] Hull’s comment from a book review is widely quoted; I have not yet found the original source.

[7] “Ockham’s razor”. Encyclopædia Britannica. Encyclopædia Britannica Online. 2010. Retrieved 1 July 2011.

[8] William Paley. Natural Theology. (Originally published in 1802). DeWard Publishing, 2010.

[9] Intelligent design in court. See, for example, “Judge rules against ‘intelligent design.’” http://www.nbcnews.com/id/10545387/ns/technology_and_science-science/t/judge-rules-against-intelligent-design/. Last accessed on April 5, 2013.

[10] Behe, Michael. Darwin’s Black Box: the Biochemical Challenge to Evolution. Tenth Anniversary Edition. New York: Free Press, 2006.

[11]See, for example, the “Human Microbiome Project.” http://commonfund.nih.gov/hmp/ Accessed April 15, 2013.

[12] Miller, SL. A production of amino acids under possible primitive earth conditions. Science. 1953 May 15;117(3046):528-9.

[13]  see, for example, Hubel, D.H.; Wiesel, T.N. (February 1, 1970). “The period of susceptibility to the physiological effects of unilateral eye closure in kittens”. The Journal of Physiology 206 (2): 419–436.

Tennis player Andy Roddick states basic principle of (science) communication

When asked about a possible return to next year’s Wimbledon tournement, ousted player Andy Roddick stated:

“If I don’t have a definitive answer in my own mind, it’s going to be tough for me to articulate a definitive answer to you,” he said.

Citation:

Serena Williams racks up Wimbledon-record 23 aces; Andy Roddick ousted – The DenverPost

http://www.denverpost.com/golf/ci_20981468/serena-williams-racks-up-wimbledon-record-23-aces#ixzz1zMjgjM00