Auf wiedersehen, Lindau!

Yesterday was my last day in Lindau, I’m sorry to say — it was also the day of the closing ceremonies on the island of Mainau, in case you were wondering why it was so quiet on the blog. I decided to leave all my electronical gear behind at the hotel and venture out for the last session with a stark naked brain.

The day began with a walk down to the harbor to board the Sonnenkönigin, a very impressive ship that can only be inadequately be called a ferry. We were welcomed aboard with a glass of wine or a glass of juice if you felt 8 am was a little early to begin, and tables heaped with food. One thing I’m going to miss a great deal when I get back to Minnesota is good bread — the stuff that is chewy and substantial and has all this flavor. Bread back home is a kind of glorified aerogel, a pale and puffy spongy substance.

We also got some musical entertainment, and a lot of hard sell for the German province of Baden-Württemburg. They can do everything, except speak proper German (really, it’s their motto: “Wir können alles. Außer Hoch-Deutsch.”) They put on a good show with lots of exhibits touting their support for basic research and industry — if nothing else, I’m convinced they value the practical benefits of science enough to heavily recruit mobs of graduate students.


Mainau is a lovely island in Lake Constance, topped with an old baroque Schloss and filled with gardens and walking paths. We were there for a final panel on sustainability. The panel consisted of four nobelists, Pachauri, Molina, Schrock, and Stocker, one government minister, whose name I’ve probably misspelled since her tag was turned away from me — Quellen-Thielen, I believe — and one annoying crackpot, Bjorn Lomborg, who really didn’t belong up on the stage. Even as insubstantial as he was, though, Lomborg did agree, along with every one else, that climate change and global warming are real phenomena. Here’s a short summary of what they said.

Pachauri: Our big problem is unsustainable growth. It’s inevitable and desirable that third-world economies expand, but the old strategies of exploiting fossil fuels aren’t going to work.

Lomborg: While global warming is real, it’s not a crucial problem, since it will only cost 0.5% of world GDP to cope with it. He’s pro-development, and thinks, for example, that while global warming may increase the incidence of malaria by 3% more, we ought to be focusing on the 100% of malaria cases occurring now rather than trying to reduce the 3%. We need to invest in better technology, but imposing limitations on CO2 emissions now is fruitless.

Molina: We aren’t taking the right path in growing economies — we need to convince the world that building sustainable energy supplies and limiting environmental damage now is the best viable long-term strategy. He had to take a poke at Lomborg, too: putting a dollar value on irreversible changes is inappropriate and misleading. Focusing on one aspect of the problem and calling the cost increases and human losses manageable hides the risks of passing a tipping point. He favors, as an important early step, incorporating the costs of externalities such as CO2 emission into the economy.

Quellen-Thielen (sp?): Germany takes climate change seriously, and the government sets policies and targets for emissions. They also materially support new technologies, like photovoltaics. These actions have not harmed the economy but instead have created new jobs and positioned Germany as a global leader.

This prompted one of the more obnoxious jabs from Lomborg, who literally sneered at German environmental efforts, pointing out that all the photocells Germany has built are already obsolete, and that it was just money thrown down the drain. Throughout, Lomborg took the attitude that direct action now is inefficient, and that we’re better off waiting for new technologies to emerge, at which time the magic of the market will kick in and our problems will go away. Quellen-Thielen reasonably pointed out that their development now means they’ve got a leg up, that they’re obtaining a reasonable fraction of their energy directly from the sun right now, and they are also building the industrial infrastructure to build on new ideas quickly.

Schrock: He was a bit out of place here; I think the presence of Lomborg effectively derailed the whole panel away from a discussion of a diversity of solutions to the global warming and into a wasted defense of the rightness of taking any policy action at all. Schrock clearly wanted to talk about catalysis and the importance of chemistry in generating technical solutions, and advocated more investment in basic as well as applied research — he fears that we could lose the potential for long-term improvements in a frantic search for solutions we can implement right now.

Stocker: he also spoke against the bean-counter on the panel, pointing out that the 2003 heat wave killed thousands, and within 30 years, that kind of event will likely have a frequency of every other year. He thinks global warming is a misnomer: it’s more than just a temperature shift, but it’s going to lead to a sea level rise, changes in the availability of water resources in some of the most heavily populated areas of the world, and is going to trigger resource wars that will be devastating. He pointed out that this really is an anomalous event in our history, that CO2 is 29% higher than at any time in the last 850,000 years. He believes we need a globally binding emissions target set right away.

So it was a mildly interesting discussion, but it could have been so much better — I suspect someone noticed it was hard to find a strong contrarian among Nobel prize winners, and decided to bring in a last-minute alternative view. Unfortunately, Lomborg’s basically an advocate for do-nothingness and did nothing but distract the others from wrestling with more substantial ideas.

After sitting in the sun for this outdoor panel, I got a sunburn and a strong desire to escape, so I spent the time afterwards wandering about in the gardens. Then the best part, getting back on the Sonnenkönigin and being handed a big mug of cold beer as I boarded. I’m beginning to get the impression that all bier in Deutschland ist frei. That can’t be true, but empirically it seems to be the case. Or maybe it’s just Baden-Württemburg’s cunning plan to persuade us that southwestern Germany is paradise.

We had more entertainment on the trip back — Stuart Pivar was aboard, doing tricks with balloons! No, actually it was some other guy who made balloon molecules, as well as strange hats. I guess the guy just looked at me and decided I needed more tentacles.

Do you want this to be the dominant image of atheism?

He also made a buckyball out of balloons, and guess who ended up wearing that on his head?

Sir Harold Kroto

And that’s all there was. A great meeting overall, lots of fun, and lots of networking. The majority of the attendees are graduate students who are brought over to hob-nob with the biggest of the big-wigs of science, and most importantly, make international connections with their peers. Any graduate student readers of this post: ask around in your department if anyone knows about nominations for the Lindau meetings. They are definitely worth attending for young people wanting to get involved in this global enterprise called science.

One evening after the talks, when we were hanging about in a gasthof enjoying some good food and beer, the Countess Bettina Bernadotte stopped by our table (Yes! You also get to meet European nobility!), and we all talked a bit about the meetings. She’s the president of the council for the meetings, and puts a tremendous amount of effort and fund-raising to get them off the ground. When asked why she was doing it, the answer was simple: that while she gets no direct personal or material gain from the meetings, as a citizen of the world she feels an obligation to make a contribution to bettering the world’s knowledge, and this is an opportunity to foster a positive benefit to science. The whole meeting is built around giving young investigators connections.

Now I’m on my long, slow way home. It was worth it, and hope I can go again.

Tonight I’m in the city of Friedrichshafen, home of the zeppelin (I asked if there were any connecting flights by zeppelin, but I’m out of luck and will have to take an Airbus tomorrow, instead.) Then I’m off to Frankfurt, Philadelphia, and finally, Minneapolis. All should be smooth this time — I don’t have any too-short layovers on this trip.

Now I’m going to stroll about and use the Fourth of July to celebrate the 90th anniversary of the first transatlantic zeppelin flight — I noticed that there was a big brass band down by the harbor, with fellows in bright green uniforms and tall hats with tassels. It should be fun!

Werner Arber: Molecular Darwinism

This talk has me a little concerned: it’s proposing something rather radical, for which Arber is going to have to show me some unambiguous evidence to convince me, and I’m coming into it with a very skeptical mindset. Here’s the relevant portion of his abstract:

The theory of molecular evolution that we also call “Molecular Darwinism” is based on the acquired knowledge on genetic variation. In genetic variation, products of evolution genes are involved as variation generators and/or as modulators of the rates of genetic variation. These evolution gene products act together with several non-genetic elements that can be assigned to intrinsic properties of matter, to environmental mutagens and to random encounter. We conclude that natural reality takes actively care of biological evolution. The evolution genes must have been fine-tuned for their functions by second-order selection, so that spontaneous genetic variation with different evolutionary qualities occurs at quite low rates. This ensures a relatively high genetic stability to individuals, as well as an evolutionary progress at the level of populations.

The presence of evolution genes points to a duality of the genome: while many genes act to the benefit of the individuals for the fulfillment of their lives, the evolution genes act to the benefit of an evolutionary development, for a slow, but steady expansion of life and biodiversity.

You see the problem, I hope. These hypothetical genes that do not necessarily directly affect the fitness of the individual are assumed to be promoted in lineages by a higher level of selection. This is not easily supported by evolutionary theory: there isn’t a mechanism given for individuals to maintain a gene that will only help its many-times-great-grandchildren. It is inferring a kind of foresight to evolution that is doesn’t have a mechanism…unless, perhaps, Arber is going to give use one. We’ll see. This talk will start in about 15 minutes, and I’ll update this post as he fills us in.

A simple history lesson: modern evolutionary biology is the convergence of work that began with Miescher (1874: nucleic acids) which led to molecular biology, Mendel (1876) which led to genetics, and Darwin (1859) that approached the problem at the level of organisms and species. The neo-Darwinian synthesis fused the genetic and Darwinian line, molecular genetics brought together genetics and biochemistry/molecular biology, and molecular evolution brings all three together—he seems to claim some kind of intellectual ownership of the last concept, which is what he calls molecular darwinism.

How do bacteria generate new variants? By transformation, conjugation, or transduction. All are mechanisms that transfer genes from an external source to the bacterium. Work in the 1940s demonstrated that DNA was the carrier of genetic information.

Arber gave a little summary of E. coli gene structure, which I suppose would be helpful to all the chemists here. He defines mutation as an alteration of the nucleotide sequence; in classical genetics, it’s defined differently, as an altered phenotype that is transmitted to progeny.

Mutations are rarely favorable; often unfavorable, and very often silent or neutral. There is no good evidence for directedness of spontaneous mutations. Mutations do not appear in response to a need.

He argues that there are three elements to evolution: evolution is driven by genetic variation (mutation), directed by natural selection, and modulated by isolation as a mechanism for speciation. There are multiple mechanisms generating genetic variation: spontaneous DNA sequence alteration, DNA rearrangement or recombination, and DNA acquisition (horizontal gene transfer).

So far, this is all very unchallenging and basic, at least for someone with any background in genetics and cell biology. After sitting through one talk that completely lost me with a failure to explain the basic terms of the work, I can’t complain, but I confess, I’m having trouble staying alert through all this.

Some genes can affect the rate of occurence of mutations — these are modulators of the frequency of genetic variation. He calls these evolution genes. He says neatral reality actively takes care of biological evolution, and that this is an expansion of the biological theory of evolution. This leads to an expansion of biological diversity, and, he argues, higher complexity.

I’m not very impressed. This is a combination of the commonplace and some odd interpretations. Of course there is variation in fidelity of replication that is influenced by genetic variation. Some of it is simply thermodynamically necessary: perfect fidelity is impossible to achieve, and greater fidelity has a metabolic cost, so some of that variation is utterly unsurprising. Some is; when we have organisms that have specializations to directly generate greater genetic variation — and sex is the first to come to my mind — we have a problem to explain. I don’t see that Arber has proposed anything to explain the real problems.

At the same time, what Arber said here does not make him a friend to intelligent design creationism, or creationism of any kind, despite the claims of some unreliable creationist sources, a claim that Arber has directly rejected.

I’d have to say it was a nice enough overview, but didn’t really propose anything novel, and definitely didn’t demonstrate anything that can’t be explained in the context of modern evolutionary theory.

Richard Royce Schrock: Recent Advances in Olefin Metathesis Catalyzed by Molybdenum and Tungsten Alkylidene Complexes

Uh-oh. I’m trying to follow this talk, but it’s one for the chemistry purists: I don’t understand the words he’s saying, starting with “olefin” and continuing with “metathesis”. You’ll have to look to one of the other Lindau bloggers with more chemistry to explain it, because Schrock seems to be assuming I understand all the basics already, and I don’t.

Roger Y. Tsien: Building and Breeding Molecules to Spy on Cells, Tumors, and Organisms

The difference between biology and chemistry: biologists ask how natural systems and molecules work, while chemistry wants to know how to artificially re-synthesize natural biomolecules. Tsien favors a synthetic approach, asking hwo to build new molecules that will perform amusing and useful functions in biology. He compares it to architecture on a molecular scale that is also a rigorous test of one’s understanding of molecular function.

He thinks biology has the most interesting grand questions in all of science (hooray!). He also likes pretty colors. However, he thinks that interdisciplinary barriers prevent most biologists from knowing how to manipulate molecules other than nucleotides and proteins. Anyone who knows how to make non-linear molecules has an advantage.

His first target was intracellular Ca++, which we all know is central to cellular signaling. He gave a quick overview of Ca++ properties and functions, as a rationale for why he began looking at Ca++ indicators like aequorin. He started looking for something new, started with something selective for calcium, the calcium chelator EGTA, which lacks any chromophore. One way would be to add benzene rings (chromophores) to EGTA, which led to BAPTA, basically EGTA with two benzene rings. It has high calcium sensitivity and did exhibit a color shift, but a poor one. This work led to Fura-2 synthesis, in which you can still see the EGTA ancestor, but has a much more complex set of rings attached to it. Fura-2 requires microinjection, which Tsien wasn’t good at, so he synthesized a protected form of the molecule with a methyl ester protecting group that would be stripped by enzymes in the cell.

He showed a gorgeous image of the Ca++ wave in sea urchin fertilization, visualized with pseudo-colored images of calcium concentration visualized with Fura-2.

Next step: Tsien wanted to visualize cAMP, an important second messenger in cell processes. They needed a non-destructive way to assay the dynamics of cAMP, which is present at very low concentration in the presence of many other nucleotides. The idea again was to find a specific binding agent and coupling it to a chromophore. He chose to use a specific PKA subunit that binds to cAMP, and use fluorescence resonance with a pair of adjacent chromophores. It worked, and they built proteins with rhodamine and fluorescein that did the job.

They wanted a general means to fluorescently label designated proteins. This led to the discovery of Douglas Prasher’s work on cloning GFP.

What was wrong with wild-type GFP? It’s main excitation was at 395nm (UV), and only minor excitation peak at 475 (blue). We don’t like to zap cells with UV. He puzzled out which components of the molecule were responsible for particular peaks in the spectrum (which he got wrong), but by empirically juggling in different amino acids, he came up with a variant that emphasized suitable peaks in the spectrum. This work was done without the aid of knowing the 3D structure.

They worked out the crystal structure, and then with rational design, made more variants with different colors. The work was rejected by Science for amusing reasons: reviewers didn’t understand the significance. They got it published by sending a brief note to Science that announced the imminent publication of the crystal structure of wild-type GFP in Nature.

Tsien wanted to make a red version. A Russion group found a red GFP variant in a coral, which they then analyzed and found the structure. This work has led to lots of fluroescent proteins with colors from blue to red.

Problems: Sometimes FPs are too big, the excitation wavelengths are hard to get through mammalian tissues, and a few others I was too slow to get down. Darn.

They are now developing an infrared fluorescent protein based on biliverdin, and are also studying the role of proteases in cancer. They are using polycationic proteins sequences as tools to transport payload proteins into cells, with some clever tricks to regulate accessibility and make it chemically triggerable by enzymes present in tumors. They have a probe that selectively labels tumor cells, which can be a very useful guide for surgical removal of tumors. He also combines it with in vivo labeling of nerves, which surgeons don’t want to cut, making it a way to color-code living tissue for tumor resection, a technique called molecular fluorescence imaging guidance, MFIG.

This was another excellent talk — Tsien has an entertaining sense of humor.

Martin Chalfie: GFP and After

Chalfie is interested in sensory mechanotransduction—how are mechanical deformations of cells converted into chemical and electrical signals. Examples are touch, hearing, balance, and proprioception, and (hooray!) he references development: sidedness in mammals is defined by mechanical forces in early development. He studies this problem in C. elegans, in which 6 of 302 nerve cells detect touch. It’s easy to screen for mutants in touch pathways just by tickling animals and seeing if they move away. They’ve identified various genes, in particular a protein that’s involved in transducing touch into a cellular signal.

They’ve localized where this gene is expressed. Most of these techniques involved killing, fixing, and staining the animals. He was inspired by work of Shimomura, as described by Paul Brehm that showed that Aequorin + Ca++ + GFP produces light, and got in touch with Douglas Prasher, who was cloning GFP, and got to work making a probe that would allow him to visualize the expression of interesting genes. It was a gamble — no one knew if there were additional proteins required to turn the sequence into a glowing final product…but they discovered that they could get functional product in bacteria within a month.

They published a paper describing GFP as a new marker for gene expression, which Science disliked because of the simple title, and so they had to give it a cumbersome title for the reviewers, which got changed back for publication. They had a beautiful cover photo of a glowing neuron in the living animal.

Advantages of GFP: heritable, relatively non-invasive, small and monomeric, and visible in living tissues. Roger Tsien worked to improve the protein and produce variants that fluroesced at different wavelengths. There are currently at least 30,000 papers published that use fluroescent proteins, in all kinds of organisms, from bunnies to tobacco plants.

He showed some spectacular movies from Silverman-Gavrila of dividing cells with tubulin/GFP, and another of GFP/nuclear localization signal in which nuclei glowed as they condensed after division, and then disappeared during mitosis. Sanes and Lichtman’s brainbow work was shown. Also cute: he showed the opening sequence of the Hulk movie, which is illustrated with jellyfish fluorescence (he does not think the Hulk is a legitimate example of a human transgenic.)

Finally, he returned to his mechanoreceptor work and showed the transducing cells in the worm. One of the possibilities this opened up was visual screening for new mutants: either looking for missing or morphologically aberrant cells, or even more subtle things, like tagging expression of synaptic proteins so you can visually scan for changes in synaptic function or organization.

He had a number of questions he could address: how are mechanotransducers generated, how is touch transduced, what is the role of membrane lipids, can they identify other genes important in touch, and what turns off these genes?

They traced the genes involved in turning on the mec-3 gene; the pathway, it turned out, was also expressed in other cells, but they thought they identified other genes involved in selectively regulating touch sensitivity. One curious thing: the mec genes are transcribed in other cells that aren’t sensitive, but somehow are not translated.

They are searching for other touch genes. The touch screen misses some relevant genes because they have redundant alternatives, or are pleiotropic so other phenotypes (like lethality) obscure the effect. One technique is RNAi, and they made an interesting observation. Trying about 17000 RNAis, they discovered that 600 had interesting and specific effects, 1100 were lethal, and about 15,000 had no effect at all. The majority of genes are complete mysteries to us. They’ve developed some techniques to get selective incorporation of RNAis into just neurons of C. elegans, so they’re hoping to uncover more specific neural effects. One focus is on the integrin signaling pathway in the nervous system, which they’ve knocked out and found that it demolishes touch sensitivity — a new target!

They are now using a short-lived form of GFP that shuts down quickly, so they’ve got a sharper picture of temporal patterns of gene activity.

Chalfie’s summary:

  • Scientific progress is cumulative.

  • Students and post-docs are the lab innovators.

  • Basic research is essential. Who would have thought working on jellyfish would lead to such powerful tools?

  • All life should be studied; not just model organisms.

Chalfie is an excellent speaker and combined a lot of data with an engaging presentation.

Warming up for the big meeting

It’s another exciting day of exciting lectures, I hope. I know that this morning was the most anticipated one on my dance card; here’s what we’re looking forward to.

Osamu Shimomura: Chemistry of Bioluminescence

Martin Chalfie: GFP and After

Roger Y. Tsien: Building and Breeding Molecules to Spy on Cells, Tumors, and Organisms

Richard Royce Schrock: Recent Advances in Olefin Metathesis Catalyzed by Molybdenum and Tungsten Alkylidene Complexes

Werner Arber: Molecular Darwinism

OK, I confess, Schrock’s lecture won’t be my cup of tea, and I have no idea what his title says, but the rest sound fun, and the last one sounds controversial. I’ll be back in a few hours with some short summaries.

wednesday morning at Lindau, part 2

This morning was a long session broken into two big chunks, and I’m afraid it was too much for me — my recent weird sleep patterns are catching up with me, which didn’t help at all in staying alert.

Robert Huber: Intracellular protein degradation and its control

This talk was a disaster. Not because it wasn’t good, because it was; lots of fine, detailed science on the regulation of proteases by various mechanisms, with a discussion of the structure and function of proteasomes, accompanied by beautiful mandalas of protein structure. No, the problem was that this listener’s jet lag has been causing some wild precession of my internal clocks, and a quarter of the way through this talk all systems were shutting down while announcing that it was the middle of the night, and I really couldn’t cope. I’m going to have to look up some of his papers when I get home, though.

Walter Kohn: An Earth Powered Predominantly by Solar and Wind Energy

Kohn has made a documentary to illustrate the power of solar energy. It was very basic, a bit silly — John Cleese narrates it — but might be useful in educating the pubic. He showed excerpts from it, and while it was nice, it didn’t fire me up.

Peter Agre: Canoeing in the Arctic, a Scientist´s Perspective

This was a bit strange. We’ve had all these science talks on global warming, so Agre decided to just show us what we stand to lose, and showed us photos of his vacations on canoeing trips in Canada and Alaska. They were gorgeous photos, but please don’t show me your photo album when I’m crashing hard.

I think my new and revised plan is to take a nap this afternoon and try to recharge a bit. I really must be alert for tomorrow’s session with Shimomura, Chalfie, and Tsien, which are the talks I was most anticipating. There’s also a curious talk by Werner Arber on something called Molecular Darwinism which has my skeptical genes tingling; I’ve got to see what kinds of evidence he provides for that. So brain must not melt down now.

Wednesday morning at Lindau

I’m here for another long session of talks. Unfortunately, this is Big Chemistry day, and I’m struggling to keep up with the unfamiliar. I need more biology for it all to make sense!

Rudolph Marcus: From ‘On Water’ and enzyme caalysis to single molecules and quantum dots. Theory and experiment.

I was afraid of this. This Lindau conference has a primary focus on chemistry, and I am not a chemist…and I just knew there would be a talk or two at which I would be all at sea, and that was the case in Marcus’s talk, which was all hardcore chemistry. I got the general gist — he’s making an argument that you need both a solid grounding in theory in order to carry out computational chemistry, which seemed fairly obvious to me — but I confess that his discussion of the details of on-water catalysis, single molecule enzyme catalysis, and quantum dots lost me, through no fault of his. I don’t have the background to follow the context of the discussion.

Kurt Wüthrich: Structural genomics — exploring the protein universe

This was more of that tricky chemistry stuff, but at least it was related to biology. Wüthrich studies 3D protein structures, specializing in using NMR of proteins in solution. He fave a little background, and talked especially about his particular interest in hemoglobin, an interest that continues — he currently works at catching EPO doping in athletes. The more interesting part of the work is his current contributions to analyzing the structure of proteins in the genome. He made the point that there are currently over 6 million gene sequences tucked away in databases, but we know the the 3D structure of only about 50,000 of them. He’s part of a very large research consortium that is trying to fill in the gaps with high throughput, automated techniques.

Harold Kroto: Science, society and sustainability

If you’ve ever heard a Kroto talk, you know it is pretty much indescribable.

He did present all of chemistry in 30 seconds, but much of it was about about science education, science’s role in society, and how science is going to be necessary to save the world. There was a good strong bit of promotion of atheism (he’s one of us!), and an amusing tour of the Creation “Museum”, which he visited recently. All I can recommend is that you keep an eye on the Lindau site — they will make the lectures available online at some time.