About this Author
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
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July 1, 2008
Posted by Derek
Well, since last week around here we were talking about how (and how not to) fund research, I should mention that Bill Gates is currently having some of the same discussions. He’s doing it with real money, though, and plenty of it.
The Bill and Melinda Gates Foundation definitely has that – the question has been how best to spend it. They started out by handing out money to the top academic research organizations in the field, just to prime the pump. Then a few years ago, the focus turned to a set of “Grand Challenges”, fourteen of the biggest public health problems, and the foundation began distributing grant money to fight them. But according to this article, from a fellow who’s writing a book on the topic, Gates hasn’t necessarily been pleased with the results so far:
”. . .Gates expected breakthroughs as he handed out 43 such grants in 2005. He had practically engineered a new stage in the evolution of scientific progress, assembling the best minds in science, equipped with technology of unprecedented power, and working toward starkly-defined objectives on a schedule.
But the breakthroughs are stubbornly failing to appear. More recently, a worried Gates has hedged his bets, not only against his own Grand Challenge projects but against how science has been conducted in health research for much of the last century.”
My first impulse on hearing this news is not, unfortunately, an honorable one. To illustrate: I remember a research program I worked on at the Wonder Drug Factory, one that started with a series of odd little five-membered-ring molecules. Everyone who looked them over had lots of ideas about what should be done with them, and lots of ideas about how to make them. The problem was, the latter set of ideas almost invariably failed to work.
This was a terribly frustrating situation for the chemists on the project, because we kept presenting our progress to various roomfuls of people, and the same questions kept coming up, albeit in increasingly irritated tones. “Why don’t you just. . .” We tried that. “Well, it seems like you could just. . .” It seemed like that to us, too, six months ago. “Haven’t you been able to. . .” No, that doesn’t work, either. I know it looks like it should. But it doesn’t. Progress was slow, and new people kept joining the effort to try to get things moving. They’d come in, rolling up their sleeves and heading for the fume hood, muttering “Geez, do I have to do everything myself?”, and a few weeks later you’d find them frowning at ugly NMR spectra next to flasks of brown gunk, shaking their heads and talking to themselves.
I’d gone through the same stage myself, earlier, so my feelings about the troubles of the later entrants to our wonderful project devolved to schadenfreude which, as mentioned, is not the most honorable of emotions. I have to resist the same tendency when reading about the Gates Foundation – sitting back and saying “Hah! Told you this stuff was hard! Didn’t believe it, did you?” isn’t much help to anyone, satisfying though it might be on one level. I’m cutting Bill Gates more slack than I did Andy Grove of Intel, though, since Gates seems to have taken a longer look at the medical research field before deciding that there’s something wrong with it. I note, though, that we now have well-financed representatives of both the hardware and software industries wondering why their well-honed techniques don’t seem to produce breakthroughs when applied to health care.
Now the Gates people are trying a new tactic. The “Explorations” program, announced a few months ago, is deliberately trying to fund people outside the main track of research in its main areas of focus (infectious disease) in an effort to bring in some new thinking. I’ll let Tadataka Yamata of the Gates Foundation sum it up, from the NEJM earlier this year:
”New ideas should not have to battle so hard for oxygen. Unfortunately, they must often do so. Even if we recognize the need to embrace new thinking — because one never knows when a totally radical idea can help us tackle a problem from a completely different angle — it takes humility to let go of old concepts and familiar methods. We have seemed to lack such humility in the field of global health, where the projects related to diseases, such as HIV, malaria, and tuberculosis, that get the most funding tend to reflect consensus views, avoid controversy, and have a high probability of success, if "success" is defined as the production of a meaningful but limited increase in knowledge. As a result, we gamble that a relatively small number of ideas will solve the world's greatest global health challenges. That's not a bet we can afford to continue making for much longer.”
What’s interesting about this is that the old-fashioned funding that Yamata is talking about is well exemplified by the previous Gates Foundation grants. After last week’s discussion here about “deliverables” in grant awards, it’s interesting to look back at the reaction to the 2003-2005 round of “Grand Challenges” funding:
”Researchers applying for grants had to spell out specific milestones, and they will not receive full funding unless they meet them. "We had lots of pushback from the scientific community, saying you can't have milestones," says Klausner. "We kept saying try it, try it, try it." Applicants also had to develop a "global access plan" that explained how poor countries could afford whatever they developed.
Nobel laureate David Baltimore, who won a $13.9 million award to engineer adult stem cells that produce HIV antibodies not found naturally, was one of the scientists who pushed back. "At first, I thought it was overly bureaucratic and unnecessary," said Baltimore, president of the California Institute of Technology in Pasadena. "But as a discipline, to make sure we knew what we were talking about, it turned out to be interesting. In no other grant do you so precisely lay out what you expect to happen."
I have to think, then, that in no other grant are the chances of any breakthrough result so slim. It would be interesting to know what the Gates people think, behind closed doors, of the return they’ve gotten on the first round of grant money, but perhaps the advent of the Explorations program is already comment enough. (One round of Explorations funding has already taken place, but a second round is coming up this fall. You can start your application process here).
The next question is, naturally, how well the Explorations program might work – but that’s a big enough topic for a post of its own. . .
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May 29, 2008
Posted by Derek
Since I was talking the other day about the analytical habit of mind, this is a good time to link to an article by someone who has it like few other people alive: Freeman Dyson, who is thankfully still with us and still thinking hard. At the moment, he seems to be thinking about something that involves chemistry, physics, economics, and plenty of politics.
He has an article in the latest New York Review of Books that is one of the most sensible things I have ever seen on the issue of global warming. I strongly urge people to read it, because it’s a perspective that you don’t often see. (It ends, in fact, with a small note of despair at how seldom that particular viewpoint comes up). I found it particularly interesting, as you might guess, because I agreed with it a great deal.
Dyson stipulates at the beginning that carbon dioxide levels are, in fact, rising, and that they have been for some time. And he also is willing to stipulate that this will lead, other factors being equal, to a rise in global temperatures. He doesn’t get into the details, although there are endless details to get into, but goes on to make some larger points.
One of them is economic. One of the books he’s reviewing, by economist William Nordhaus, is an attempt to work out the best course of action. Nordhaus is not denying a problem, to put it mildly: his estimate comes out to about 23 trillion dollars of harm in the next hundred years (in constant dollars, yet) if nothing is done at all. The question is, how much will the various proposed solutions cost in comparison?
His numbers come out this way: the best current policy he can come up with, a carefully tuned carbon tax that increases year by year, comes out to only 20 trillion of damage, as opposed to 23 – that is, plus three trillion constant dollars. The Kyoto Protocol, turned down by the US Senate during the Clinton years, comes out to 22 trillion dollars of harm (one trillion to the good) if the US were to participate, and completely even (no good whatsoever) without the US. The Stern Review plan, endorsed by the British government, comes out to 37 trillion dollars of total harm, and Al Gore’s proposed policies come out down 44 trillion dollars: that is, twenty-one trillion dollars worse than doing nothing at all.
As Dyson correctly points out, these latter two proposals appear to be “disastrously expensive”. And the problem with such courses of action are that this money could be used for something better: Nordhaus also calculates the effect of finding some reasonably low-cost method to cut back on carbon dioxide emissions, such as a more efficient means of generating solar or geothermal power, the advent of genetically engineered plants with a high carbon-sequestering ability, etc. That general route comes out to roughly 6 trillion dollars of total harm, which is seventeen trillion better than doing nothing (and thirty-eight trillion better than the Full Albert). That’s by far the most attractive solution, if it can be realized. But doing an extra ten or twenty trillion dollars of damage to the global economy will make that rather unlikely, if we choose to do that.
And there are other effects. To quote Dyson:
” The practical consequence of the Stern policy would be to slow down the economic growth of China now in order to reduce damage from climate change a hundred years later. Several generations of Chinese citizens would be impoverished to make their descendants only slightly richer. According to Nordhaus, the slowing-down of growth would in the end be far more costly to China than the climatic damage.”
But there’s a factor that neither of the books he reviews mentions: that atmospheric carbon dioxide exchanges, on a relatively fast time scale, with the Earth’s vegetation. About eight per cent of it a year cycles back and forth, and that hold out hope for a biotech solution. Engineered organisms could fix this carbon into useful forms, or (failing that) just take out out of circulation completely. But we need to go full speed ahead on research to realize that.
The last part of his review addresses a larger question. Environmentalism, he states, is now more of a religious question than anything else. (Other people have realized that, and many who do bemoan the fact, but Dyson has no problem with it, saying that the ethics of environmentalism are “fundamentally sound”.) But here’s his problem:
”Unfortunately, some members of the environmental movement have also adopted as an article of faith the belief that global warming is the greatest threat to the ecology of our planet. That is one reason why the arguments about global warming have become bitter and passionate. Much of the public has come to believe that anyone who is skeptical about the dangers of global warming is an enemy of the environment. The skeptics now have the difficult task of convincing the public that the opposite is true. Many of the skeptics are passionate environmentalists. They are horrified to see the obsession with global warming distracting public attention from what they see as more serious and more immediate dangers to the planet. . .”
The distressing thing, as he mentions, is that many organizations (including, I'm sorry to say, the Royal Society among other groups of scientists), have decided that the issue is settled and that anyone dissenting from this view is to be slapped down. As for me, I’m not completely convinced by the current climate data, so I probably am to the right even of Dyson on this issue. Here he is, though, willing to stipulate that most of the basic assumptions are true, but finding no place for someone who can do that and still not see global warming as the Single Biggest Issue Of Our Time.
I know how he feels: I consider myself an advocate of the environment, but I think the best way to preserve it is to do more genetic engineering rather than less. Better crops will mean that we don’t have to plow up more land to feed everyone, and we won’t have to dump as many insecticides and herbicides on that land we’re using. That means that I also think the best way to preserve unspoiled spaces is to do less organic farming, and not more: organic farming, particularly the hard-core varieties, uses too much land to generate too little food, and it does so mainly to give people in wealthy countries a chance to feel good about themselves.
And I think the best way to preserve wild areas and biodiversity is to have more free trade and economic development, not to slow it down. Richer countries have lower birth rates, for one thing. (I actually think that the planet would be better off with fewer people on it, but I’m not willing to achieve that goal by killing off a few billion of us).
And finally, economic growth is what’s giving us the chance to find technologies to get us out of our problems. I know that there’s another way to look at it – that the technology we have got us into this problem, and that we should reverse course. But I don’t think that’s even possible, or desirable. I’d rather have engineered plants cleaning out the atmosphere, and I’d rather have electricity from fusion or orbiting solar arrays. I’d rather find cheaper ways to get some of our fouler industries off the planet entirely, and mine the asteroids and comets. I’d rather people get richer and smarter, with more time and resources to do what they enjoy. How we’re going to do any good by putting on hair shirts and confessing our sins escapes me.
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+ TrackBacks (0) | Category: Business and Markets | Current Events | General Scientific News
May 27, 2008
Posted by Derek
My wife and I were talking over dinner the other night – she’d seen some interview with the owner of a personal data protection service, and he made the pitch for his company by saying something about how out of (say) a million customers, only one hundred had ever reported any attempts on their credit information or the like. And my wife, who spent many years in the lab, waiting for what seemed to her to be the obvious follow-up question: How many people out of a million that didn’t subscribe to this guy’s service report such problems?
But (to her frustration) that question was never asked. We speculated about the reasons for that, partly out of interest and partly as a learning experience for our two children, who were at the table with us. We first explained to them that both of us, since we’d done a lot of scientific experiments, always wanted to see some control-group data before we made up our minds about anything – and in fact, in many cases it was impossible to make up one’s mind without it.
After a brief excursion to talk about the likely backgrounds and competencies of news readers on TV, we then went on to say that looking for a control set isn’t what you could call a universal habit of mind, although it's a useful one to have. You don’t have to have scientific training to think that way (although it sure helps), but anyone with a good eye for business and finance asks similar questions. And as we told the kids, both of us had also seen (on the flip side) particularly lousy scientists who kept charging ahead without good controls. Still, the overlap with a science and engineering background is pretty good.
What I’ve wondered, since that night is how many people, watching that same show, had the same question. That would be a reasonable way to determine how many of them have the first qualification for analyzing the data that come their way. And I’m just not sure what the percentage would be, for several reasons. For one thing, I’ve been working in the lab for years now, so such thinking is second nature to me. And for another, I’ve been surrounded for an equal number of years, by colleagues and friends who tend to have science backgrounds themselves, so it’s not like my data set is representative of the population at large.
So I’d be interested in what the readership thinks, not that the readership around here is any representative slice of the general population, either. But in your experience, how prevalent do you think that analytical frame of mind is? The attitude I’m talking about is the one that when confronted with some odd item in the news, says “Hmm, I wonder if that's true? Have I got enough information to decide?" It's an essential part of being a scientist, but if you're not. . .?
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+ TrackBacks (0) | Category: General Scientific News | Who Discovers and Why
May 7, 2008
Posted by Derek
Update: here's the map that I was imagining, thanks to Andy in the comments section. It's on the Worldmapper site linked to below, but I missed it while putting the post together. Most of my speculations turned out to be reasonable, although Venezuela (for one) looks a bit better than I thought it would, and Iran looks a bit worse. Africa and the Islamic world are, as hypothesized, almost invisible.
I’d like to see a map of the world with country size dependent on the number of scientific publications and patents – perhaps you’d want to use publications per capita, or per educated capita. That's a cartogram, and although there are plenty of interesting ones on the web, I haven't found that one yet. The US would loom large, that’s for sure. Japan might be the most oversized compared to its geography, although Singapore would also be a lot easier to pick out. Western Europe would expand to fill up a lot of space, with Germany, England, and France (among others) taking up proportionally more room inside the region and (perhaps) Spain and Portugal taking up somewhat less. Switzerland would swell dramatically.
South America would be dominated, I think, by Brazil, even more than it is on the map. You’d be able to find Argentina and Chile, but I think some other countries (like Venezuela) would dwindle in comparison. Africa, as it does so often in maps of this kind, would appear to have been terribly shrunk in all directions, with a few countries – Egypt, South Africa – partially resisting the effects. Moving on to Asia, India would appear even larger than it is, unless you went for the per-capita measurement to cut it back down a bit, and China would be a lot more noticeable than it was ten (or especially twenty) years ago.
Another region that would basically disappear would be the Middle East and most of the rest of the Islamic world. Iran would hang in there, smaller but recognizable, and you’d be able to find Pakistan, too. But the Arab countries (with the minor exception of Egypt) would nearly vanish. The figures from the Organization of the Islamic Conference (the multinational group involved) show that from 1995-2005, the Islamic countries contributed 2.5% of all the peer-reviewed scientific papers. That’s all the more interesting when you consider the amount of potential funding that washes around that part of the world.
This disconnect has been noticed by the region’s scientists, as well it might. The OIC has designated a committee of science ministers to help with a multiyear plan for modernizing things, but no one’s sure if any real money will be forthcoming. According to this Nature article (headlined "Broken Promises"), the OIC countries allocate less than 0.5% of their GDP to research and development. Most of the money promised just to fund that science committee never showed up. Lip service is, of course, a feature of politics (and politicians) everywhere, but I don't think I'm out of line if I suggest that it's very close to an art form in that part of the world.
And that's a very short-sighted approach. Many of these countries are sitting on huge amounts of money at the moment, which should be invested against the day that their oil runs out (or against the day that the world decides that it's not as desperate for oil as it once was). That latter day will, presumably, be hastened along by the countries who spend more on research. . .
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April 17, 2008
Posted by Derek
There have been several articles in Nature recently about performance-enhancing drugs. But these aren’t steroids or blood-cell therapies: they’re performance enhancers for scientists and engineers. Chief among them are Ritalin (methylphenidate), Provigil (modafinil), and various beta-blockers, to enhance concentration and wakefulness. The whole topic came to the fore last December, in an article suggestively titled "Professor's Little Helper". Here are the results of their informal readership poll. It's not a huge trend, at least not yet. The fraction of their self-selected sample who had never taken any such compound was in the solid 70% range, and you'd expect people with some experience to be disproportionately represented in such a poll. But usage is out there, nonetheless.
The first question to ask in these situations is, do such drugs work? As you’d guess, there’s no controlled data set to work with. There is, under current regulations, absolutely no way that any company with such a compound would run a trial for cognition enhancement in otherwise healthy people. The FDA has made it clear over the years that they are in the business of regulating drugs that help sick people, not ones for people who have no disease at all. In fact, I don’t think that the current regulatory framework even accommodates the idea of making people “better than well”, and if someone proposed such a study, it’s a solid bet that the FDA would turn it down.
So, in the absence of anything rigorous, we have a flood of anecdotal data, which is what the Nature pieces are full of. Take that along with the many reports of students using these drugs, and you have something significant going on, which has been coming on for a while now. Back when I used to work on Alzheimer’s, we used to speculate about what would happen if we ever did come across something that usefully enhanced human memory. I was sure that a large off-label market would develop among college students. I have to admit, I never considered their professors.
But do they work? Well, I’m willing to stipulate that they do, but I’m not sure to what extent. One confounding variable, which will be very hard to address outside of a controlled trial, is the placebo effect. I have to think that there’s a strong one in this area, that if you think you’ve taken something that helps your concentration and memory, that those functions will measurably improve. How much this counts for is impossible to say – but again, I’m willing to stipulate that there are pharmacological effects above and beyond placebo. In other words, I believe that a controlled trial of healthy individuals would, in fact, show improvement in cognition while taking such compounds. How much, and in what particular tasks, and for how long, and across what subgroups of people, and across what particular dosing regimens, and in what proportion to objectionable side effects, I have no idea. But I think that there’s something there.
And there will be more. I feel sure that other compounds will be developed that affect normal cognition in what are (at least under some circumstances) are beneficial ways. They will not, however, be approved for that purpose. That’s a long, long way off. They’ll be approved for Alzheimer’s, or sleep disorders, or some category of attention deficit disorder, which is how we have the compounds we have now.
This situation is similar to various possible anti-aging therapies. There, too, I think that compounds will come eventually that should be able to show benefits, according to what we understand about aging in other species. But they won’t be approved for that. They’ll be approved for diabetes, most likely, considering the strong links between insulin action and lifespan, or possibly for other slow-developing degenerative disorders. But if aging itself is a slowly developing degenerative disorder, what then?
I’ve been meaning to write something about this story for a while, but one of the problems has been that I’m still quite divided about what I think about it. (Normally my opinions come to me more quickly, for better or worse). Some background: people who’ve known me personally for a while generally know that I’m personally very much opposed to chemically altering the way that I think or feel. I never drank in high school, for example, which I can tell you made me stick out a bit in late-1970s Arkansas. Nor did I in college or afterwards; I still don’t drink now. And that personal prohibition goes even more for other recreational drugs, as you’d imagine.
My reason for that has long been that I enjoy my brain the way it is, and have seen no reason to mess up its function for fun. But the advent of cognition enhancing drugs is a scalpel to dissect that line of thought. What if the ingested chemicals add to some of the parts of my brain that I value the most? That “mess up its function” clause has been taken out and flipped upside down. And what if it’s for work, and not for recreation? Is that more allowable, because it’s somehow less frivolous? (All right then, what if I were to enjoy having a better memory, which I likely would?) That gets to a less creditable reason for my objection to alcohol and other such drugs – perhaps I’m not just objecting to them on practical grounds. Perhaps I’m objecting because I don’t want other people to have a good time, at least not like that.
Food for, well, thought. I’m still working this one out, I have to say. The issue of caffeine will come up as I do – I don’t drink tea or coffee, actually, having never wanted to end up in the position of having to drink either to function. But I don’t object to caffeinated soft drinks, although I don’t generally seek them out. But I have, when I’ve needed to stay awake – so how high a horse can I get on, anyway? Caffeine is a good proving ground for positions on the newer compounds.
Comments are, as always, welcome. I suspect that this is one of those issues that everyone has an opinion on. . .
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February 12, 2008
Posted by Derek
Manipulating nanoscale objects is a very hot research area these days, but no one’s quite sure whether it should be called physics or chemistry. The single-atom stuff (like the famous 1989 spelling of I-B-M using an early scanning tunneling microscope tip) would probably be the former, while moving whole molecules around would probably be the latter.
Now we’re to the point where you might consider it biology, since several recent papers describe ingenious uses of DNA as nanoscale pliers and Velcro. A report in Science from a group in Munich, demonstrates a nanoscale depot on a chip, formed by short DNA strands bound to its surface. Various molecules are tagged with complementary single strands of DNA. When you bring the two close enough, they hybridize, winding together spontaneously into a small double helix, which Velcros each molecule down to a defined position.
The second key to the work is that each of the molecules has a second, different DNA strand bonded to its other side. This one is complementary to a single strand attached to the tip of an atomic force microscope, so when that moves in close enough, those two hybridize as well. For the moment, the target is bound front and back.
But here's the trick: the two DNA helices are engineered so that the double helix on the bottom opens base-by-base, like a zipper, while the one on the AFM tip shears off all at once. That gives them different strengths, so when you pull up on the AFM tip, you can see the force profile of the "zipper" strand giving way as the attached molecule pulls free. Now it's dangling from the tip of the AFM, its newly freed DNA strand waving in the, uh, nano-breeze, I guess.
This was now moved to another portion of the chip, where more DNA strands awaited. These, like the tip strands, where also in the stonger "shear" geometry, but these were even longer, with more residues to wrap up with that free DNA strand on the molecule of interest. Lowering the two into proximity caused them to hybridize, and now pulling up on the tip caused the tip strand to unwind instead, leaving the molecule stuck on the new location on the chip. The AFM tip could then be sent back to the depot to pick up another molecule, and so on. (The illustration, courtesy of Science for nonprofit use, will give you the idea). The fluorescent molecules they used could then be imaged on the chip, confirming that they'd been arranged as expected.
The whole process took care, as you can imagine. The team kept the number of DNA strands on the tip quite low, in order to have a better idea of what was going on. Under their conditions, about one-third of the time, they picked up just one unit from the “warehouse”, and another twenty per cent of the time they got two at once. In the dropoff step at the new location, they sometimes noticed that no extra force was needed to pull the tip up, which indicated that they hadn't make a connection. In those cases, a shift of the tip assembly a few nanometers one way or another generally brought things within range for a successful transfer. It's not like you can see what's going on - light itself doesn't come small enough to let you do that in the normal sense - so you just have to feel your way along.
This is an early proof of concept, so it's not like we're going to be assembling nanomachines next week through this technique. (The DNA tags, for one thing, are rather large compared to the molecules that they're attached to). But the idea is there, and the idea works. We're starting to move single molecules around to where we want them to go, and making them stay put once they've been delivered.
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+ TrackBacks (0) | Category: Chemical News | General Scientific News
February 5, 2008
Posted by Derek
Commenting appears to still be hosed around here, which is a shame, because I have some ask-the-readership posts stacked up. Writing posts under these conditions feels like shouting into a void! I hope things will be fixed soon, but it's quite a tangle behind the scenes.
Time is short today, at any rate, so here's a link to an image that I found simultaneously exciting and unnerving. There's a large project going on to make the world's best electron microscope, through several simultaneous improvements in the electron beam's shape and brightness, refinement of the detectors, damping vibrations in the sample stage, and so on.
So here's the latest. Those are two gold crystalline domains meeting each other at the corner - and those ping-pong balls are the gold atoms. You can clearly see them arranging to meet each other's packing structure at the interface, and if you look to the edges you can see some depth data as well. Those resolutions (well below one angstrom) are real, by the way, and the damn instrument is only about half done.
The group reports that when they scan sample multiple times, they can see individual gold atoms moving around between images. The next steps will include moving to lower-energy electrons for use in biological samples, and I can't even guess what we'll see then. More on the project here.
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November 15, 2007
Posted by Derek
After extolling the joys of finding things out in the post directly below, I couldn't resist linking to this story for those who haven't seen it. Now, this guy is really out there on the edge, and I wish him well with his theory (available here on Arxiv for the mathematically inclined). What I especially like is that he's ready to make some testable predictions.
You know, when Feynman met Dirac, the first thing he mentioned to him was how wonderful it must have been to discover the equation that bears his name. If Garrett Lisi's theory can predict particles out of thin air the way Dirac called the positron, he'll be remembered the same way. Good luck to him, and to those like him.
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+ TrackBacks (0) | Category: General Scientific News | Who Discovers and Why
November 8, 2007
Posted by Derek
I just came across this article, provacatively titled "Dumber in English". What the author, Stefan Klein, really means is "Dumber In Your Second Language", and he's almost certainly right about that.
I know that when I was doing my post-doc in Germany, I was significantly less nimble in German. I didn't have much practice in the language, and that meant a lot of mental overhead while using it. I never became truly comfortable with it, although I did get better. The throbbing headaches stopped after a few weeks, for example, which was certainly a visible and welcome sign of improvement. After a I started to dream in the language (and once in a great while I still do, with progressively less impressive fluency). I knew that I was really learning the stuff when I dropped a piece of apfelkuchen into a mud puddle, and reflexively swore in German. (Not to fear, the cake was in a paper bag, and was recoverable with quick action).
Scientifically, I was working under a handicap, and I knew it. My secret weapon, though, was the way the chemical literature was (and is) largely written in English. But this is a particularly painful thing for Germans, since their language was once on top of the heap in chemistry, physics, and several other sciences as well. Reading Klein's description of a recent conference in his native country, you can feel it:
". . .All the speakers – six Germans, plus three from the United States and one from Great Britain – were outstanding. And they all spoke either English or, in the case of a German speaker, now and then something similar. Unusual word-choices and serpentine sentences can make a speech seem more brilliant than it actually is.
But who in the audience spoke English? No one. And even the four foreign guest speakers could easily have understood a lecture in German, because simultaneous translation was available over headsets that were readily on hand. As someone from the sponsoring foundation told me, of course it would be better if the local guests would simply speak German. This would increase the public resonance. But the professors had another idea. Their argument: People only take a conference seriously when English is the official language. . ."
He brings up the historical practice of scholarly Latin, and how this dissolved in the 16th and 17th centuries as thinkers began to write in the vernacular. (This, though, actually hindered the flow of information, as far as I can see - a lingua franca isn't such a bad thing). He also worries that science will come to be even more separated from the general run of the population in non-English speaking countries, but I'm not so sure. Most native English speakers don't have much of a connection with the subject, despite every linguistic advantage. There's also the problem of whether some languages will cease to develop their scientific vocabularies, preferring the English terms out of convenience. As far as I can tell, this is already happening - mind you, English borrows terms from the other languages as well, although not to the same extent.
Klein also brings out some examples of concepts that he feels come across better in their original German than in translation. but here I'm not so convinced. Einstein's complaint about "spukhafte Fernwirkung", to pick one, is generally rendered into English as "spooky action at a distance", which seems to me to get the concept across very well, as opposed to Klein's clunky "long distance ghostly effect". There are definitely things that don't translate well from German to English (and across any other language pair you can name), but this isn't one of them.
I don't see anything stopping the rise and dominance of English in the sciences (and to be sure, neither does Klein). I realize that I write from the perspective of a native English speaker, and having had to live in another tongue, I can sympathize with those who have to come to grips with the language. (Especially our ridiculous spelling, although I'll vote for that over German grammar any day of the week). To my mind, the advantages of being able to speak the same language, however roughly, outweigh the problems of a scientific tower of Babel.
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October 15, 2007
Posted by Derek
There was a fascinating comment added to the recent discussion here on ammonia synthesis. It was pointed out that the amount of man-made Haber Process available nitrogen is outclassed by the amount fixed biologically. The legumes do their share, but a lot more is handled by free-living single-celled organisms. What's really startling is the estimate for the total amount of nitrogenase enzyme, by weight, that is responsible for the production of at least 100 million metric tons a year of reduced nitrogen: about twelve kilos.
It's important for us, as chemists, to contemplate figures like that lest we forget how unimpressive our own techniques are in comparison. Not all enzymes are that impressive, but many of them are extremely impressive indeed. One of Clarke's laws gets quoted a lot, the one about any sufficiently advanced technology being indistinguishable from magic. But there's no magic involved - these are things that we could do, if we just knew enough about how to do them.
Enzymes use a variety of effects to work these wonders, but a lot of it comes down to holding the reacting species in one place and lining everything up perfectly. It isn't as important to hold on to the starting materials or products, as it is to interact with and stabilize the highest-energy species in the whole process, the fleeting transition state. Various chemical groups can be brought to bear that activate or deactivate specific bonds, and everything works, at its best, with near-perfect timing. If you want molecular level-nanotechnology, this is it, and there's absolutely no reason why it has to be done inside a peptide backbone. If we understood enough, all sorts of other polymers, with all sorts of new functionality built into them, could presumably do things that Nature has never needed to do, under conditions that we could select for.
But we're unfortunately a long way from that. There's still a tremendous amount of argument about how even model enzymes actually work, with some rather exotic mechanisms being proposed. And if we don't understand what's going on, we sure can't design our own imitations. Making enzymes from scratch brings together a whole list of Very Hard Problems, from protein folding to femtosecond reaction dynamics, and making enzymes out of something other than proteins will be even harder. We're going to need to be a lot smarter, as a species, to figure out how to do it.
But learning more about such stuff is one of the things we do best. At least for the last few centuries it has been, and if we keep it up, there seems to reason why we shouldn't be able to figure out this one, too. Then, at long last, human ingenuity will have pulled even with blue-green algae, the fungi that live in rotting logs, and various sorts of pond scum. The little guys have had a big head start, but we're gaining fast.
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October 12, 2007
Posted by Derek
The Haber-Bosch ammonia synthesis doesn’t intrude itself into the public consciousness much, but this year’s Nobel gave it a bit of a push. One thing I’ve noticed, though, is that whenever the topic of artificial fertilization comes up, it always kicks up a small dust storm of comment around it.
These vary widely in the reasonableness. Pointing out that artificially fixed nitrogen moved agriculture from (ultimately) a solar-powered base to (largely) a fossil-fuel base is both accurate and a good starting point for further discussion. See the comments to the Nobel post for an example – a person can argue that the Haber process didn’t require fossil fuels per se, or that we use more of them cooking the food than we do growing it (which may be true), or that we use more of them moving the food around (which I think is almost certainly true, and which opens up another set of questions) and so on.
Other good topics for discussion are how close various parts of the world were to a Malthusian food crisis when the ammonia synthesis came along, the other industrial effects of relatively cheap ammonia, the tradeoff of intensive fertilized farming in smaller areas versus more traditional routes in larger ones, etc. But if you’d like an example of an unreasonable comment, I’ll let this one over at Megan McArdle’s Atlantic Monthly blog stand in for a lot of similar fuzzy-mindedness:
"Higher yields due to the petroleum rich Haber-Bosch method also mean faster soil erosion and increased need of rotation etc. Combined with applying this method for inefficient livestock agriculture - it has destroyed NOT saved the rainforest and other ecosystems. Chemical fertilizer in ecology are like statism for the economy. You can force short-term results but nothing more!
At least 800 million people still go hungry.. their way forward into a sustainable future is less livestock agriculture and (more) organic natural farming.
Haber-Bosch is on the same environmental level as coal, oil! Not good, not sustainable, ideologically toxic for survival. We have to get rid of it pronto if we want our children to have "a nice life".
. . .All the social sciences, all the non-biological sciences like chemistry and physics should drop immediately what they are doing and learn more about their mother (and forget as much as possible about their "father" - you know who I mean?)!"
It’s hard to know where to start with this sort of thing. But I think I’ll do what Richard Dawkins did for Prince Charles a few years ago. Dawkins’s “You’re an idiot” style of debate isn’t always productive (for example, I think he does more harm than good to his cause as an atheist), but in this case I think the board across the nose was a good idea. He pointed out that if we’re going to use “naturalness” as a criterion, then agriculture isn’t going to make the cut, either. And that doesn’t mean factory farming and Roundup-Ready seeds; that means agriculture of any kind beyond remembering where the good patch of wild blueberries is and getting there before the bears do:
I think you may have an exaggerated idea of the natural ness of "traditional" or "organic" agriculture. Agriculture has always been unnatural. Our species began to depart from our natural hunter-gatherer lifestyle as recently as 10,000 years ago - too short to measure on the evolutionary timescale.
Wheat, be it ever so wholemeal and stoneground, is not a natural food for Homo sapiens. Nor is milk, except for children. Almost every morsel of our food is genetically modified - admittedly by artificial selection not artificial mutation, but the end result is the same. A wheat grain is a genetically modified grass seed, just as a pekinese is a genetically modified wolf. Playing God? We've been playing God for centuries!
The large, anonymous crowds in which we now teem began with the agricultural revolution, and without agriculture we could survive in only a tiny fraction of our current numbers. Our high population is an agricultural (and technological and medical) artifact. It is far more unnatural than the population-limiting methods condemned as unnatural by the Pope. Like it or not, we are stuck with agriculture, and agriculture - all agriculture - is unnatural. We sold that pass 10,000 years ago.
Dawkins is correct. We live in an unnatural world, and that goes for a lot of prehistory, too. Our world has been unnatural ever since we started applying our intelligence to it. When humans first started building shelters to get out of the cold and rain, I suppose you could say that this is no more than what an animal does when it digs a den. Killing a mammoth partly in order to use its bones for a house is a step beyond that, but in the same league as what beavers do to birch trees. But clearing land, planting seeds in it, tending and harvesting a crop, and saving some of its seeds to plant again is another order of living. Just because it all happened a long time ago (and because no one yet knew how to write it down) doesn’t make it any more in tune with ancient natural harmonies or whatever. (Try this PDF on for size).
We've been trying to fertilize the soil for thousands of years with whatever was on hand - manure, dead fish, the ashes of the plants that were burnt to make the field. And we've been modifying the genetic profile of our food crops over that same time with awe-inspiring persistence and dedication. (Good thing, too). No, when we move from that to artificial fertilizers and genetically engineered seeds, we’re talking about differences in degree rather than differences in kind. Large differences in degree, true, and worth discussing they are, but not on the basis of either their antiquity or their "naturalness".
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August 14, 2007
Posted by Derek
A co-worker put me on to an interesting paper earlier this year by Harvard's George Whitesides (with a co-author credit going to a well-known chem-blogger). Whitesides, a perennial favorite in Nobel betting, does a lot of absolutely first-tier physical organic chemistry, an area that I love to read about (and one that I'd probably be an awful practitioner of).
Almost all drugs bind to sites on proteins. Some proteins have only one site (that we know of) that a small molecule will fit into, while others have several. There have been a lot of attempts over the years to go after the latter group by hitting more than one site at the same time - but with only one drug. Imagine two different drug molecules, each fitting into a different site on a single (multi-sited) protein. Now imagine combining them into one compound, by attaching some sort of linking chain between them, and you've got one (larger) molecule that can reach around and fill two binding sites.
This has worked in some cases, at least on a research level (I'm not aware of any drugs that have yet made it to market by taking advantage of this effect, though). (Update: there is a marketed protein, bivalirudin, that binds to two sites on thrombin, but I'm still not aware of any small molecule drugs in this category). You can pick up huge amounts of affinity by this trick, though, to the point that neither of the original "business ends" of the molecule need to be particularly good binders on their own. And since we in the industry are distressingly good at producing molecules that don't bind to things very well, the idea of combining some of these into multivalent wonders is appealing.
But there are a lot of unknowns. Figuring out how to modify the original structures in order to tie them together is, as they say, non-trivial. (If you hang around scientists and engineers much, you know to head for cover when you hear that expression). And what kind of chain should you use, anyway? How long does it have to be, and what happens if it's too long or too short? And what's the linking chain doing, anyway - sticking to the surface of the protein, waving around by itself, or what?
Whitesides and his people have used carbonic anhydrase as a model system, which is an enzyme whose structure and behavior is as well known as these things get. They find, not unreasonably, that when the linking chain is too short the activity of your wonder molecule just gets killed: you're stuck with one end bound to the protein, and a big tail flopping around uselessly, unable to reach the next binding site. The "just-right" chain length is the best, naturally. But (interestingly) you don't pay much of a penalty for being longer than necessary, even several times longer. Apparently the chain will coil around and find something to do with itself as long as the two ends are bound.
And while it's doing this, it doesn't appear to be contacting the protein in any meaningful way. This took a lot of careful experimental thermodynamics to check, but there's no extra binding energy involved with any of the common chains. So if you're going to try this trick, Whitesides's advice is not to worry about what chain to use. Stick with a plain-vanilla linker, as flexible as possible, make it a bit longer (at least at first) than you think you'll need, and you've improved your chances right there. And he has the numbers to back this up, which is what physical organic chemistry is all about: opinions made solid by data. It's good stuff.
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July 19, 2007
Posted by Derek
This week's award for the most straight-faced research whopper goes to. . .the government of Brasil, of all the possible candidates. In their attempts to bounce back from a disastrous explosion at their launch site a few years ago, the Brasilians have successfully fired a sounding rocket with an experimental payload.
I'm not quite sure what exactly was in these experiments - from press reports, it looks like some enzyme kinetics and some DNA repair studies. Both of these were to be looked at under microgravity (aka free fall), which I have to say does not sound like a very fruitful area of research to me - of all the forces that affect enzyme behavior, gravity seems like one of the least likely to show any effects.
And there's the problem that (since this was far from an orbital flight) the payload experienced only about seven minutes of free fall. With a faster enzymatic reaction, you might be able to run something similar on a "Vomit Comet" airplane flight, frankly. And as for the DNA repair work, that was to be after exposure to ambient radiation, which no doubt can be simulated quite well on the ground. But that wouldn't be so good for publicity and national pride, would it?
So, what will these experiments lead to, you ask? I'll let the experimental coordinator field that one, although you may well have guessed the answer already: "Eventually, the results could help us develop new processes and pharmaceutical products to treat cancer." Well, sure - with a sufficiently open-minded definition of the word "eventually". And the word "treat". And probably the word "new", and while we're at it, the word "results" as well.
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June 7, 2007
Posted by Derek
There are plenty of headlines today about the large Wellcome Trust-funded genomic study of common diseases. Unfortunately, most of those headlines are misleading. The ones that say "Genes Identified For Common Diseases" are the most common wrong ones, but any that include secrets, keys, new dawns, locks being opened, or mysteries being solved are also full of it. (You'll need to go to people who know what they're talking about for less sensational coverage - try the RSC, for one).
Not that this isn't a fine study, and a very interesting piece of work - far from it. This is just the kind of rigor and effort (14,000 patients, 3,000 controls) that's needed to trace out these sorts of connections. Contrary to popular belief, most genomic effects on disease are subtle and shifty, and tangled up throughly with both environment and with dozens (hundreds? thousands?) of other genetic markers. These folks are doing the right thing in the right way.
But the press, at least some of it, isn't. The genes identified in this study are not enough to tell you if you're going to get a particular disease or not, not by themselves. And they're not going to lead to therapies any time soon, either, because in many cases we have no idea how or why they're connected to the diseases in question. Nor do we have drug candidates that target the proteins that the genes code for, and it wouldn't surprise me a bit if most of them turn out to be un-druggable from the start with our current technology. I speak from sad experience on that issue, like many other folks in the drug industry.
That's not to say that we won't figure out how these things are involved in disease, or how to attack them therapeutically. But we didn't just open a locked chest full of the secret keys to health here - we found fragments of a map that'll tell us where to look for the clues to the pieces of an even bigger puzzle. It's the state of things, though, that this really is an advance, and it wouldn't hurt the public to know.
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April 19, 2007
Posted by Derek
Well, we're exactly on the opposite side of the year for Nobel season, but Paul over at Chembark has the latest odds on the next Chemistry prize. There are a couple of ringers in the list, but it's an excellent reference for big achievements by living chemists. It's also a useful thing for people who are immersed in synthetic organic chemistry to look over, because we sometimes have an exaggerated view of our place in the chemical world. I'll post more on this sort of thing in a few months, but clip and save Paul's post until then. . .
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March 23, 2007
Posted by Derek
There's an unusual article in Nature that several folks have e-mailed me about. It's unusual for several reasons. For one thing, it's synthetic organic chemistry, and there's not much of that in Nature at all - it's an interesting choice of journal on the part of the authors, Phil Baran of Scripps and two of his students, Thomas Maimone and Jeremy Richter. The title also gives away the other odd feature (as a title should): "Total Synthesis of Marine Natural Products Without Using Protecting Groups".
I was talking about protecting groups here just a couple of months ago. In synthesizing complex molecules, they're often necessary, because there will often be several similarly reactive groups exposed at the same time, and you need to be able to distinguish them. Or you'll need to do something severe to another end of the molecule-in-progress, which an amine or alcohol somewhere either won't let you do or won't survive if you try.
The trouble, as any synthetic chemist can tell you, is that protecting groups introduce their own complexities. Ideally, you want to be able to put them on and remove them with no loss of material, but that's impossible. Ideally, you'd want each one to be removable under conditions that won't disturb any of the others, or anything else in your molecule, but that can be a tall order too as they start to add up. And ideally, you'd want all of them to be able to stand up to anything else you'd like to do, until it's time for them to leave, but that's not available in the real world, either. Sometimes a big part of the work (mental and physical) that goes into a total synthesis is figuring out how to manage all the protecting groups.
Baran makes the case that this has gone too far. He's made several complex molecules without protecting anything at all. There's a price to be paid, of course - some of the steps along the way have not-so-impressive yields because of the bareback conditions. But the counterargument is that the overall yield of the synthesis is often higher in spite of this, because there are so fewer steps, and the cost and complexity are cut similarly.
Of course, you can't do this by just plowing ahead with the same reactions that a protecting-group-laden synthesis would use. They're on there for a reason, and that method would send you right into the ditch. Baran tries instead to mimic the biochemical synthesis of these molecules as much as possible, since after all, cells don't use protecting group chemistry, either.
This is an idea with a long and honorable history in organic chemistry, starting with Sir Robert Robinson's startling one-pot synthesis of tropinone back in the 1917. That one is usually taken as the father of all biomimetic syntheses, although it's been pointed out (by no less an authority than Arthur Birch) that this is partly a legend. But it's a legend that has performed function of its reality, leading to a whole series of biologically-inspired syntheses. This latest paper is a call to make biomimetic synthesis the centerpiece of the field again.
I'm sympathetic to that view, but it's not going to be easy. Read closely, the paper shows that this kind of work can be very difficult indeed, even when the biogenic pathways to your target molecules have been studied (which isn't always the case). There are a lot of steps here that required careful coaxing to work in reasonable yields, or at all - no one should confuse the lack of protecting groups with a savings in time. And these difficulties also undermine the claim of reduced cost and complexity a bit, since they represent plenty of time and effort - and if they aren't synonymous with cost and complexity, I don't know what is. Academia may obscure this a bit, since we're only talking graduate student labor here, but it's a real issue.
Where I see this making an impact industrially is in process chemistry. Many times companies work out several parallel routes to an important drug substance, looking for the lowest overall cost. That's where attention to no-protecting-group methods could pay off. Process groups already try to avoid these steps anyway, for the same reasons.
But for the most part, drug substances aren't so complex that they need lots of protecting group manipulation. We could always try to get into more complicated structures through these routes, but this leads to a chicken-and-egg problem. The medicinal chemists generally don't have the time to investigate the picky conditions needed to make no-protection chemistry work, so they're not going to have access to the shorter, higher-yielding syntheses needed to do analoging work. (And there's the real problem that these analogs might need complete re-optimization of the trickier steps each time, which would be a real nightmare). The process chemists would have the time and mandate to work out the no-protection stuff, on the other hand, but if med-chem can't deliver a good drug candidate, then they have nothing to optimize.
The Nature link above is subscriber-only, but you can read the supporting information with all its synthetic details here if you like. It's a pretty big PDF file, though, so be warned. I'd be interested to hear what readers, both academic and industrial, think about this one.
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February 22, 2007
Posted by Derek
An undergraduate reader sends along this request:
I was wondering if you had some recommended readings for a second year student, eg books that you have read and made a palpable impression on you when you were my age.
That's a good question, despite the beard-lengthening qualification of "when you were my age". The books that I would recommend aren't the sort that would require course material that a sophomore hasn't had yet, but rather take a wider view. I would recommend Francis Crick's What Mad Pursuit , for one. It's both a memoir of getting into research, and a set of recommendations on how to do it. Crick came from a not-very-promising background, and it's interesting to see how he ended up where he did.
Another author I'd recommend is Freeman Dyson. His essay collections such as Disturbing the Universe and Infinite in All Directions are well-stocked with good writing and good reading on the subject of science and how it's conducted. Dyson is a rare combination: a sensible, grounded visionary.
Another author to seek out is the late Peter Medawar, whose Advice to a Young Scientist is just the sort of thing. Pluto's Republic is also very good. He was a fine writer, whose style occasionally comes close to being too elegant for its own good, but it's nice to read a scientific Nobel prize winner who suffers from such problems.
I've often mentioned Robert Root-Bernstein's Discovering, an odd book about where scientific creativity comes from and whether it can be learned. I think the decision to write the book as a series of conversations between several unconvincing fictional characters comes close to making it unreadable in the normal sense, but the last chapter, summarizing various laws and recommendations for breakthrough discovery, is a wonderful resource.
Those are some of the ones that cover broad scientific topics. There are others that are more narrowly focused, which should be the topic of another post. And I'd also like to do a follow-up on books with no real scientific connection, but which are good additions to one's mental furniture. I have several in mind, but in all of these categories I'd like to throw the question open to the readership as well. I'll try to collect things into some reference posts when the dust eventually clears.
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+ TrackBacks (0) | Category: General Scientific News | Who Discovers and Why
October 9, 2006
Posted by Derek
A recent issue of Nature (443, 382, 28 September 2006, subscriber link) carried an intruiging article about Japan's five-year "Protein 3000" project, which is now winding down. Carried out under the auspices of RIKEN, the project was designed to use a large-scale NMR facility to solve the structures of at least 3000 proteins, and along the way advance the understanding of protein folding in solution.
Whether or not it succeeded depends on who you ask, because the answer isn't obvious. The project does seem to be on track to make its numerical goals, but according to the article, many protein-structure people think that a large number of the structures that have been solved are, well, junk - easy, closely-related ones that were put on the list to run up the numbers. While the organizers dispute that, as they certainly would, another problem is that understanding protein folding has turned out to be (you know what's coming) harder than expected. The project was supposed to cover a large swath of a hypothetical 10,000 different folds, but now the real number is thought to be two or three times that. So the best case was that Protein 3000 would have worked out about a third of all possible protein folds, but now they're looking at perhaps 5 to 10% of them.
The Japanese government has a real weakness for big programs like this. I think that Protein 3000 has been one of their biggest forays into that area, but in the past they've announced all sorts of gaudy projects in computation and the like, most of which haven't worked out quite as planned. The "Fifth Generation" project is perhaps the most abject failure of the lot, but at least that one seems to have produced a number of researchers who could do something else. But the Protein 3000 business has some folks worried:
Several researchers have also expressed concern that the factory approach at the NMR facility has deprived young researchers there of the skills necessary to solve more complicated and important scientific riddles. It might have "destroyed the next generation", says one.
(Kurt) Wüthrich, who helped plan the NMR centre in 1998 and was a science adviser in 2000-04, agrees that the facility is a wasted opportunity. "A centre of that size should contribute to methodology, but there has been nothing," he says. "It became a one-man show with 40 NMR machines - there is no knowledge."
Not a good review, considering it comes from a man who knows a bit about the use of NMR to attack protein structure. What I find instructive about such things is that these projects are often just the sort that large government-level granting agencies take it into their heads to fund. Sometimes they work out, but the majority of the time they don't.
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October 4, 2006
Posted by Derek
The Kornberg Nobel seems to have set off some "whither chemistry" noises over here (see the comments to this post). I wanted to highlight an especially provocative one:
Derek, I hope I don't offend my chemist colleagues (I'm myself a former chemist), but as a chemist you have to realize that Chemistry is a science of a lesser public impact. Done at the edges of important matters, it's physics, done at the edges of interesting issues, it becomes biology. You ask for the final explanation of matter and energy and you are a physicist, you are interested in the beauty and complexity of life, you are a biologist. Sorry, chemistry is a practical science, but today its mostly a set of tools.
Hey, I did say it was provocative. As you'd guess, I don't agree, but that doesn't mean that I don't understand this point of view. There seem to be a fair number of chemists with similar sinking feelings, to judge from the letters that show up from time to time in Chemical and Engineering News. The problem is, the same argument by exclusion slice-and-dice can be applied to any other scientific discipline, so long as you define its edges by labeling the things around it as "important" and "interesting".
I could turn things the other way by wondering if, then, some of the important parts of physics are the parts that overlap with chemistry, and some of the most interesting parts of biology are the ones that do likewise. But I don't want to get into a shouting contest about whose work is most useful or exciting, because I don't think it gets us anywhere to talk in those terms.
For me, chemistry is the science that deals with behavior of systems on a molecular level. As you go down to the atomic level, you get into physics (and by the time you're in the subatomic range, you're in physics up to your eyebrows). As you go up from single molecules to larger and larger molecular systems, you start to shade into biology, because the largest and most complicated of those we know about are living organisms.
So rather than bemoan these other disciplines poaching on chemistry's territory, or decide that all the good stuff belongs to them and that chemistry is left with nothing, I'd prefer to think that the field is in an excellent position. We're just at where both those other fields start to get really tough. Look at physics - you can do quantum mechanics on single isolated particles, but once you start bringing in more of them, things get very sticky very quickly. That's why there are all those molecular modeling programs, each full of its own assumptions and approximations, because that's the only way you can approach the calculations at all. Moving up from single particles to atoms and on to molecules is a huge leap in complexity.
And as for biology, the complexity has become more apparent by movement in the other direction. If you thought classical zoology or botany were pretty tangled up, take a look at them on the molecular level! Biology has made tremendous advances through the treatment of its smallest mechanical parts as real molecules behaving chemically. Look at the med-chem concept of a receptor - it was a revelation when people finally realized that this wasn't just a convenient bit of mental shorthand, but a concept that reflected an actual physical entity. And of course, the question of when a collection of molecular machines can be considered a living organism has set off arguments for decades.
No, being in the middle of the range has its advantages. These folks are in our territory because there's so much here to attract them. As chemists, we have to realize this and make the most of it, not sit around moaning about how other people are hogging the spotlight.
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Posted by Derek
As everyone will have heard, Roger Kornberg has been awarded the chemistry Nobel for his work on RNA polymerase. This is certainly deserved, since his lab has been working on this important area for years, gradually zooming in on the enzyme's structure and function through biological and X-ray methods.
But he wasn't on anyone's short list to win the Chemistry prize, and I doubt if Kornberg considers himself a chemist. For some time now, the Nobel people have been using the prize as an overflow from the Medicine/Physiology area, which this morning led Paul Bracher over at the Endless Frontier blog to call for chemistry to colonize the Physics prize. Kornberg wasn't on his long list of candidates with odds, because most everyone on his list was, well, a chemist.
But it is nice to have another enzyme-studying Kornberg from Stanford with a Nobel. Arthur Kornberg is still alive, and still publishing papers as of a few years ago. I hope he's in good enough health to enjoy his son's achievement.
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October 2, 2006
Posted by Derek
Every time a Nobel Prize is announced, reporters try to put in some sort of "news you can use" context. That's usually pretty easy to do with the Medicine/Physiology prize, and usually impossible with Physics. Chemistry falls into a middle ground - as opposed to some of the pure-knowledge physics awards, the chemistry discoveries are being used to do something in the physical world, but explaining what that is can be tough.
How did the popular press handle today's award? I invite readers to share any particularly clueless news stories, but most of the the reports I've heard have stressed the potential therapeutic value of RNA interference. There's often been a list of diseases that might be treated, with no particular timeline given, which is a good thing. NPR at least had some disclaimers in there, mentioning near the end that researchers still needed to find a way to dose the compounds, get them to the tissues of interest, make sure that they weren't toxic, and prove that they do affect the diseases they're targeted for.
Minor details, all of 'em. Right? That's just about 85% of drug development right there, actually, and the fact that these can be lumped together at the end of a news segment might be why (among other things) the "government research discovers all the drugs" idea has such staying power. I think that people see all those hard steps without realizing that they're hard . All that stuff about dosing, toxicity, selectivity, it's all what you do in the last few months before you hit the pharmacy shelves, I guess, along with picking a color for the package.
RNA interference is probably going to have a long climb before it starts curing many diseases, because many of those problems are even tougher than usual in its case. That doesn't take away from the discovery, though, any more than the complications of off-target effects take away from it when you talk about RNAi's research uses in cell culture. The fact that RNA interference is trickier than it first looked, in vivo or in vitro, is only to be expected. What breakthrough isn't?
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Posted by Derek
I'd been predicting for years that RNA interference would be worth a Nobel, and this year the committee did what many expected them to do. But not many people expected them to do it this early - not even Craig Mello himself. And he's being modest in that quote about having an "inkling" that it "might be possible", but that's understandable. Congratulations to him and to Andrew Fire!
I notice that the committee didn't go back as far as the initial observations of the first observations in plants (or in nematodes). The explanation for all these results started with Fire and Mello, and that's where the committee started as well.
Update: Paul Bracher sets the odds for Wednesday's prize in chemistry. I might run some of the numbers a bit differently, but not terribly so, and it's a pretty comprehensive list of possibles.
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September 27, 2006
Posted by Derek
As we move into October, we enter what scientists know as Nobel Season. The Chemistry prize will be announced next Wednesday, so it's time for the annual sport of figuring out who will get it. For those keeping score at home, here's the list of previous winners.
Last year I looked around for a betting market, but the action was pretty thin. I haven't detected any great amounts of money hitting the table this year, either, but Thomson ISI does have their poll going again. But it's next to useless, as far as I can tell, because I don't see any of their listed choices as front-runners for the award this year. (Nature's Sceptical Chymist blog agrees).
For example, I have nothing against Dave Evans and Steve Ley, who are both top-rank synthetic organic chemists. But if they're on the list in that category, there are several others who should be, too - not that I think it's necessarily going to be a synthetic organic year. And it wouldn't surprise me to see Stuart Schreiber eventually win a Nobel, but I think the committee can safely wait on that one, too, since his resume is still lengthening nicely. And as for Tobin Marks, it would surprise me to see another organometallic-themed award right after last year's. No, if Thomson's site had a secure connection to put my credit card down on a bet, I'd take the field rather than their choices and feel very happy about it.
Over at the Endless Frontier, Paul Bracher has his money down on either the green fluorescent protein folks (Tsien et al) or perennial pick George Whitesides. Keep in mind, though, that he works for Whitesides, so he may not have the most objective opinion there. I wouldn't object to a win for him, though, but I'd like to see how the committee would phrase it - the traditional line on a Whitesides pick is that he's contributed to too many areas to pin down. More Nobels have gone to hedgehogs than to foxes.
The green fluorescent protein suggestion is a good one, though. And perhaps this will be the year that the committee recognizes RNA interference, which could land in the chemistry award as easily as anywhere else. My runner-up to those suggestions is nanoscale structures (Stoddart et al.), but I have that pick running substantially behind the other two. That's mainly because the other two have demonstrated some real-world utility, but hey, fullerenes. Add your own picks in the comment section, and let's see who calls it.
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September 19, 2006
Posted by Derek
There's a paper in the latest Ang. Chem. that will be of interest to everyone who's into the way that various chemicals smell. And hey, what organic chemist isn't?
It's by a flavor and fragrance chemist, who lists many tables of compounds that have very minor structural variations but completely different smells. One noteworthy example is geraniol, which is a large component of the scent of roses. Adding a methyl group next to its primary allylic alcohol coverts it to an analog with an "intense fungal odor", which I don't think I'm going to be lining to up sample any time soon. And you'd have thought that the smell of geraniol would be pretty robust - you can saturate the allylic double bond, and it's still rosy. Take that compound and substitute an aryl group for the isobutenyl on the other end - still rosy. But don't mess with that primary alcohol.
The take-home lesson is that there are no major SAR trends in odor that you can count on. A substitution that works in one series can do nothing when applied to a closely related compound, or it can take the odor off in a completely unexpected direction. That aryl-for-isobutenyl switch I mentioned, for example, isn't silent if you try it on benzylacetone (4-phenyl-2-butanone). The starting ketone smells "sweet and floral", but the corresponding methylheptenone is described as "pungent, green, herbaceous".
The reason for all this craziness is that there are hundreds of olfactory receptors, most of which appear to respond to huge numbers of compounds as agonists. (There's that induced fit again)! And it's not like the agonists all smell the same, either. There also appear to be multiple binding sites involved, and possibly other protein cofactors as well. The structural complexities are bad enough, but there are probably neural processing effects laid on top of them, which makes the author predict that "consistently accurate prediction of odors will not be possible for a very considerable time". He's quick to point out that it's not like the flavor and fragrance industry has to money to underwrite the work needed to do it, either.
Does this remind you of anything, fellow medicinal chemists? If the perception of smell is the physiological readout in this case, how different is this from all the physiological states we're trying to produce with our small drug molecules? How well do we really understand their binding, and how much can we trust our SAR models? Hey, the fragrance people have big advantages on us - they can immediately test their molecules just by sticking them under their noses, which is like a five-second clinical trial with no FDA needed. And they're still as lost as geese. A lot of the time, so are we.
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+ TrackBacks (0) | Category: General Scientific News | Life in the Drug Labs
September 10, 2006
Posted by Derek
OK, the votes in the comments to the Explain This! post came out with NMR/MRI as the clear winner, with a strong plurality wanting to make sure that Fourier transforms are part of the explanation. So that's what I'll take on, but it's not going to appear this week. I'm going to try to pitch the explanation to an intelligent lay reader who doesn't have any particular physics, chemistry, or math skills. I'm out of my mind.
In second place were various suggestions about X-ray crystallography, and perhaps that'll be topic number two. Chirality would be tied with that, except there were actually more votes against it than for it, with people finding it not all that hard to explain. (They've clearly never tried to explain to someone whose specialty is running a Morris water maze assay why all the compounds flipped from R to S just because a group changed out on the far end of the molecule). Other multiple-vote getters were Woodward-Hoffman/FMO, structure determination in general, and antibiotic resistance.
Many of the single-vote topics would be good as well, and some of them would be quite tricky. The person who suggested point group symmetry, though, brought back some memories. I'd never covered anything in that area as an undergraduate, for one reason or another. So there I am in my first year, taking an optical spectroscopy class, and on about the second day the professor launches into a discussion of symmetry operations and their relevance to infrared absorption bands (which is considerable).
And this was the first lecture I had ever heard where I understood nothing but the common verbs and the minor parts of speech. I listened to the whole thing with mounting alarm. It had taken me all the way to graduate school to come definitively to the limits of my knowledge, but the pavement ran out right there. I was so stunned I couldn't even take notes - I'd never tried to take notes on something that I wasn't comprehending at all, so I didn't know how.
That evening, I stalked over to the chemistry library and checked out, among other things, Harry Gray's book on group theory, renowned as the first one on the subject "that you could read in bed without a pencil in your hand". And I didn't go to bed myself until I understood just what I'd been listening to that morning, because I didn't enjoy the experience one bit, and wanted to make sure that it never happened again.
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August 22, 2006
Posted by Derek
Via the excellent Arts and Letters Daily, I found this piece by science writer K. C. Cole on dealing with editors in the popular press. She and others in her field have had their difficulties over the years when writing about things that even the researchers involved are confused about:
Editors, however, seem to absorb difficulty differently. If they don't understand something, they often think it can't be right - or that it's not worth writing about. Either the writers aren't being clear (which, of course, may be the case), or the scientists don't know what they're talking about (in some cases, a given).
Why the difference? My theory is that editors of newspapers and other major periodicals are not just ordinary folk. They tend to b |
