This cannot get any better. There's everything here; the opportunity to interact with dozens of Nobel prizewinners in a very informal setting, spectacular views of the alps bordered by three countries (Germany, Switzerland and Austria), nice bicycle rides, a charming hotel to stay in, polonaises to dance to, great banquets with varied food and drink and a festive atmosphere, really nice people to interact with (my co-bloggers are super-friendly and helpful) and dinner with small groups of students and Nobel laureates. I could not have asked for anything more. Here's me with my wunderbar fellow bloggers. I also ran into Bora and PZ Myers and had a nice walk with them around town. Both of them are attending and vigorously blogging as usual and Bora was also part of a panel discussion on open science access.
This year India is a partner country and has sent the third-largest delegation of students, about 43. Guests included the minister for human resources Kapil Sibal and the minister for science and technology S. E. Chavan. As a partner country India hosted a wonderful banquet yesterday with lots of Indian food, followed by an Indian dance performance. This was followed by a Lindau tradition; a polonaise in which the ladies and the gentlemen form lines and ascend the stage from both sides. The gentlemen pick up a flower and present it to whichever lady happens to be in front of them in the center of the stage. The polonaise then breaks into a waltz, and the dancing continues late into the night. There is purportedly ghastly photographic evidence of a certain individual trying to waltz.
Most importantly, you cannot help but be taken in by the picture of hundreds of students from every possible country interacting so enthusiastically with each other, underscoring the global nature and brotherhood of science. Indians interact with Belorussians, Americans interact with Poles, Chinese interact with Russians, Zambians interact with Germans. And Nobel Prize winners participate in the dances and interact with everyone else. The atmosphere is truly international and sparkles with verve.
Today I had the opportunity to conduct an informal interview with Prof. Peter Agre whom I had also met last year. But this year it was one-on-one for 40 mins and was truly enjoyable since Prof. Agre is an exceptionally witty and nice person. You can read about the interview here.You can find the rest at the official Lindau blog, including all my posts (my name is right below each). Updating will continue all week long. Keep watching that spot for more!
- Home
- Angry by Choice
- Catalogue of Organisms
- Chinleana
- Doc Madhattan
- Games with Words
- Genomics, Medicine, and Pseudoscience
- History of Geology
- Moss Plants and More
- Pleiotropy
- Plektix
- RRResearch
- Skeptic Wonder
- The Culture of Chemistry
- The Curious Wavefunction
- The Phytophactor
- The View from a Microbiologist
- Variety of Life
Field of Science
-
-
-
The Hayflick Limit: why humans can't live forever1 month ago in Genomics, Medicine, and Pseudoscience
-
-
Course Corrections4 months ago in Angry by Choice
-
-
The Site is Dead, Long Live the Site2 years ago in Catalogue of Organisms
-
The Site is Dead, Long Live the Site2 years ago in Variety of Life
-
Does mathematics carry human biases?3 years ago in PLEKTIX
-
-
-
-
A New Placodont from the Late Triassic of China5 years ago in Chinleana
-
Posted: July 22, 2018 at 03:03PM6 years ago in Field Notes
-
Bryophyte Herbarium Survey6 years ago in Moss Plants and More
-
Harnessing innate immunity to cure HIV8 years ago in Rule of 6ix
-
WE MOVED!8 years ago in Games with Words
-
-
-
-
post doc job opportunity on ribosome biochemistry!9 years ago in Protein Evolution and Other Musings
-
Growing the kidney: re-blogged from Science Bitez9 years ago in The View from a Microbiologist
-
Blogging Microbes- Communicating Microbiology to Netizens10 years ago in Memoirs of a Defective Brain
-
-
-
The Lure of the Obscure? Guest Post by Frank Stahl12 years ago in Sex, Genes & Evolution
-
-
Lab Rat Moving House13 years ago in Life of a Lab Rat
-
Goodbye FoS, thanks for all the laughs13 years ago in Disease Prone
-
-
Slideshow of NASA's Stardust-NExT Mission Comet Tempel 1 Flyby13 years ago in The Large Picture Blog
-
in The Biology Files
Blogging from ground zero: day zero
I have finally arrived in Lindau, Bavaria to offer my thoughts on the meeting of minds between 500 students, 23 Nobel Prize winners in chemistry and the handful of acting scientific journalists such as myself. The journey itself was uneventful but very long. It took me almost the same time to get from Frankfurt to this little island as it took me to get from New York City to Frankfurt. I had to change trains twice, first at Mannheim and then at Stuttgart. Plus I think I am still to savor the punctuality of German transport since my train was delayed by more than half an hour at Stuttgart and then twice more at miscellaneous stops. However I have to admit that this still beats driving or any form of personal transport.
I cannot yet offer my thoughts on the environment Lindau provides, but one thing stuck out as I passed over a bridge; a spectacular view of the Alps on the other side of the Bodensee. Again, I have yet to see around, but an island at the base of the alps which is located in Germany, Austria and Switzerland cannot exactly be dull and ugly, can it?
I have already started blogging on the Lindau blog website and I would prefer not to cross-post that material in other places. Here is the link to the website and to my first three posts:
Lindau blogs website
Exemplifying apprenticeship; The Lindau meetings
Diversity of talks; diversity of science
Surfaces, ammonia, ozone and scientific destiny
Live-blogging starts tomorrow! Here is the program for tomorrow:
I cannot yet offer my thoughts on the environment Lindau provides, but one thing stuck out as I passed over a bridge; a spectacular view of the Alps on the other side of the Bodensee. Again, I have yet to see around, but an island at the base of the alps which is located in Germany, Austria and Switzerland cannot exactly be dull and ugly, can it?
I have already started blogging on the Lindau blog website and I would prefer not to cross-post that material in other places. Here is the link to the website and to my first three posts:
Lindau blogs website
Exemplifying apprenticeship; The Lindau meetings
Diversity of talks; diversity of science
Surfaces, ammonia, ozone and scientific destiny
Live-blogging starts tomorrow! Here is the program for tomorrow:
"The partisans have ampicillin". Really?
The Russian covert antibiotic program must have been hugely successful
In an effort to stave off the boredom that inevitably accompanies adjustment to a new environment, I was watching the WW2-era movie "Defiance" yesterday. The movie is based on an astounding true story about two Jewish brothers (played by Daniel Craig and Liev Schreiber) who hide and lead a band of Jewish refugees through the forests of Belorussia for two years and thwart the Nazis' plans for their extermination. Surviving on food killed and obtained in the jungle, defending themselves with stolen small firearms and occasionally seeking the help of partisans from the Red Army, the Bielski brothers and their group provide one of the most exemplary stories of resistance against the Nazis during the war.
So far so good, and the movie is not bad at all. But during one scene my ears suddenly perked up. There is a winter epidemic of typhus threatening to wipe out the population. A nurse tells Craig that the disease is spread by lice and without medical attention the patients will certainly die. To prevent this, she says, Craig and his group must borrow ampicillin from the Red Army. "The partisans have ampicillin", she says with hope and concern.
Which is all fine, except that ampicillin was not even known in 1942. It was introduced only in 1961. Even penicillin was a closely guarded secret in 1942. Plus I am not even sure if typhus is properly treated with beta-lactam antibiotics.
I was further chagrined when in order to confirm this I visited the Wikipedia page on penicillin. While it otherwise looked ok, it also said that the first total synthesis of penicillin was achieved by Woodward. Again, not true. Woodward synthesized cephalosporin. It was John Sheehan from MIT, a mentor of E J Corey, who synthesized penicillin after a mammoth effort of 15 years. The error is now rectified.
Seems the directors of Defiance and the editors of the Wikipedia penicillin page have the same problem of fact-checking.
In an effort to stave off the boredom that inevitably accompanies adjustment to a new environment, I was watching the WW2-era movie "Defiance" yesterday. The movie is based on an astounding true story about two Jewish brothers (played by Daniel Craig and Liev Schreiber) who hide and lead a band of Jewish refugees through the forests of Belorussia for two years and thwart the Nazis' plans for their extermination. Surviving on food killed and obtained in the jungle, defending themselves with stolen small firearms and occasionally seeking the help of partisans from the Red Army, the Bielski brothers and their group provide one of the most exemplary stories of resistance against the Nazis during the war.
So far so good, and the movie is not bad at all. But during one scene my ears suddenly perked up. There is a winter epidemic of typhus threatening to wipe out the population. A nurse tells Craig that the disease is spread by lice and without medical attention the patients will certainly die. To prevent this, she says, Craig and his group must borrow ampicillin from the Red Army. "The partisans have ampicillin", she says with hope and concern.
Which is all fine, except that ampicillin was not even known in 1942. It was introduced only in 1961. Even penicillin was a closely guarded secret in 1942. Plus I am not even sure if typhus is properly treated with beta-lactam antibiotics.
I was further chagrined when in order to confirm this I visited the Wikipedia page on penicillin. While it otherwise looked ok, it also said that the first total synthesis of penicillin was achieved by Woodward. Again, not true. Woodward synthesized cephalosporin. It was John Sheehan from MIT, a mentor of E J Corey, who synthesized penicillin after a mammoth effort of 15 years. The error is now rectified.
Seems the directors of Defiance and the editors of the Wikipedia penicillin page have the same problem of fact-checking.
So what exactly are force fields good for?
Sue Storm tries hard to use her favorite force field to counter the 1 kcal/mol barrier
Every once in a while there is a study asking what method X (X = docking, free energy calculations, molecular dynamics, force fields etc.) is good for. Such studies can be useful to take stock of a particular paradigm. So the question that Jonathan Goodman and his group ask in this paper is "Are force fields good for reproducing non-bonded interactions, especially hydrogen bonding, pi-stacking and dispersion?". He and his group compare very high-level quantum chemical ab initio data with data obtained from the most commonly used force fields, namely MM2*, MM3*, MMFFs, OPLS-2005 etc. The ab initio data used is from Pavel Hobza who has almost consummately published on these methods. The question is; how well do the force fields do compared to the gold standard? The answer is necessarily incomplete and complex and again raises many interesting questions about the enigmatic role of hydrogen bonding in chemical and biological systems.
The complexes studied include purely pi-stacked complexes, purely hydrogen bonded complexes and mixed complexes where both interactions play roles. Typical examples include alcohol-amide complexes, water oligomers and of course, the classic stacked and hydrogen bonded DNA nucleoside bases. The parameters that the authors looked at were geometries and energies, both of optimized complexes as well as crystal structures.
The results are perhaps not too surprising; the more recent OPLS-2005 and MMFFs are probably the best in reproducing known geometries and energies while MM2* and MM3* don't perform that well in general. As noted in some other studies, at least some of the results for MMFFs and OPLS compare with those obtained with high-level ab initio calculations, thus indicating the value of these cost-effective methods for geometry optimization and energy determination (let's ignore for a moment that solvation models in ab initio methods make even these less than perfect).
What is more important though is that all the force fields are generally not good for reproducing hydrogen bonded systems compared to systems where dispersion, stacking etc. are the key players. This is partly an indication of the tricky events including long-range solvation which play an important role in h-bond formation. But what is interesting is that the methods underestimate the energetics of hydrogen bonds. While I am a little puzzled by this, one of the explanations that comes to my mind regarding this curious fact is that in real systems, h-bonding is a cooperative interaction. An h-bond can pay for loss of entropy, thus making the overall free energy of the next h-bond more favourable. Of course force fields don't calculate free energy, but to a first approximation we can probably assume that the enthalpy and free energy are similar for these simple systems. To be honest, because of the complex nature of long-range dispersion interactions I would have assumed that the force fields would be worse in modeling these. I frankly don't understand why they work better for such interactions but it's an interesting observation.
But now for some general thoughts; it's always worth remembering that for molecules like proteins which are stabilized by h-bonds, the h-bonds when formed are simply swapped for similar bonds with water, thus making a relatively insubstantial contribution to protein stability. It is the large number of such interactions that can tip the balance for a protein, but the real driving force is now universally recognized as the hydrophobic effect and the burial of non-polar groups. Calculations such as those above indicate that because of the fine-tuning of h-bonds that proteins often use to achieve stability, force fields have some way to go in predicting tiny energy differences. It is still a great challenge to model the sub-angstrom geometry optimization of h-bonds that biopolymers achieve. But force fields are hardly unique in not being able to do this; so are other methods which are still trying to break the 1 kcal/mol barrier. Ironically in this study, the mean unsigned error when the hydrogen-bonded complexes are included is about 1 kcal/mol.
So are force fields good for anything at all? The short answer is yes, exemplified by the massive number of publications that regularly use force fields as well as the substantial number of people in academia and industry studying them. Obviously people think they are important, otherwise so many common programs doing everything from protein folding to drug-protein interactions would not have relied on them. I have had reasonable experience with force fields and have always kept in mind a couple of things about them that are worth reiterating:
1. Force fields are usually good at reproducing geometries, and best for reproducing sterics.
2. Force fields are usually not so good at reproducing energies since energy estimation is a function of the special parameterization and convergence criteria unique to every force field (As the Zen master says, "What the answer is depends on what question you ask"). However, relative conformational energies using a single force field for instance may be useful.
3. As a corollary, force fields can be pretty poor for dealing with molecules having a large number of polar functional groups. While this means that peptides are hard to model, modeling of peptides has also been mitigated by the fact that unlike small molecules, the chemistry to be parameterized is limited.
3. Many times the real problem is not with force fields per se but with the accompanying implicit solvation models. Admirable effort has been expended in developing these models but to be honest we still don't understand enough about that enigmatic solvent named water to do a satisfactory job. We are just scratching the surface when it comes to modeling things like solvent entropy for instance.
If you are following the field's developments, you also see an engaging and ongoing debate that pits the "science first" camp against the "parameterization first" camp. The science first camp disapproves of the other camp's efforts to improve their force fields simply by adding more parameters and optimizing against experiment; to them it is much more important to meticulously improve the methodology by incorporating as much real science as possible. The parameterization first camp argues that statistical methods have their honored place in the annals of science and that getting results fast and efficiently is important for application-oriented scientists like drug discovery people. I believe that as in other matters, both sides are right. It is an uncomfortable feeling when you don't truly understand the science behind a method and yet the method works, but at the same time it is important to have a well-parameterized and tested model that could help you in a practical sense, even if incompletely understood.
As with everything else, finally it is an astute application of force fields that takes into account their strengths and limitations which will lead to productive results. One of the most interesting things about doing science involves weighing the pros and cons of methods, techniques and algorithms and deciding what judicious combination would provide the best answer and why. It may not always work, but it could keep us from getting seduced by the dark side of the force (field)
Paton, R., & Goodman, J. (2009). Hydrogen Bonding and π-Stacking: How Reliable are Force Fields? A Critical Evaluation of Force Field Descriptions of Nonbonded Interactions Journal of Chemical Information and Modeling, 49 (4), 944-955 DOI: 10.1021/ci900009f
The anti-question, or when bias can be a good thing
A recent publication indicates that more bias in the form of natural product scaffolds not yet synthesized could improve hit rates in screening
Most drug discovery projects are inaugurated with some kind of screening campaign where millions of molecules are screened against a biological target. Even though the hit rate from High-Throughout Screening (HTS) can be quite low, HTS still provides one of the best starting points to discover interesting new structures that display biological activity. In spite of this, there is frequent disappointment at the low rates from HTS which could be as low as 0.05%.
But instead of focusing on the low hit rate from HTS, what if we express surprise that this hit rate is actually high? This thought takes me into a slight digression. In his remarkable book The Black Swan, the author Nassim Nicholas Taleb talks about an "anti-library", the set of all books you have not read. The anti-library is in some ways more important than your library because it really tells you what you are ignorant about.
Similarly we can define an "anti-question". The anti-question is a question opposite to one which we might usually ask. So instead of asking; "Why is this drug specific for this protein?", we could ask "Why is this drug not hitting other proteins?". The value of the anti-question is that it forces us to analyze and evaluate things that we otherwise may not and enables us to think outside the box. As the wise doctor constantly exhorts detective Sponer in "I Robot" to get to the all-important right question, so it could be important to get to the right anti-question.
In the context of HTS, the anti-question actually turns out to be logical. Instead of asking, "Why is the hit rate from HTS so low"?, one should ask "Given the number of small molecules in small-molecule space (~10*60) compared to the extremely low number typically screened in HTS campaigns (10*6), why should we get any hits from HTS at all?". Even narrowing down the unimaginably large small-molecule universe to more drug-like or lead-like entities, we still run into a numbers paradox since even this number is orders of magnitude greater than what is usually screened.
In their most recent paper, Brian Shoichet and his team ask this important anti-question, and it leads them down an interesting road. Most campaigns that screen libraries focus on readily available commercial compounds and fragments that can be synthesized by organic chemists. This bias in turn reflects what has been more or less synthetically accessible through more than a hundred years of synthesis. Compared to this, the Kyoto Encyclopedia of Genes and Genomes (KEGG) contains metabolites whose structures are untainted by the minds of organic chemists. These are scaffolds among secondary metabolites and natural products that have simply been found.
There is another set of structures; the Generated Database (GDB), a theoretical set which contains all possible molecules containing less than 11 heavy atoms consisting of first-row elements (C, O, N, F). This number is not as large as may be imagined and amounts to about 26 million. In the study the authors essentially compare the set of purchasable or commercial KEBB compounds found in their own annotated library called ZINC with the GDB. They use a similarity measure called a Tanimoto coefficient derived from 2D fingerprint comparison to accomplish this. 2D fingerprints use different kinds of protocols for breaking up a molecule into bit strings and then compare bit strings by distances and atom types.
The comparison indicates something interesting; the compounds in the purchasable set are much more similar to the KEBB compounds than are the compounds from the rest of the GDB. In other words, purchasable compounds contain scaffolds that are biased towards those in the KEBB. This is a good thing, since metabolites are usually primed by nature to show at least some biological activity. Another noteworthy finding was that the bias also increased with molecular size, as compounds became more drug-like or lead-like in terms of size.
However, the more surprising and useful observation was that there are hundreds of scaffolds in the KEBB that are notpresent in the commercial library. The authors also do this comparison for other popular commercial libraries designed specifically for screening and find a similar result. The bottom line; while synthesized commercial libraries of molecules show a bias toward natural products and metabolites, there are also several natural product scaffolds that are not found in these libraries.
So what is the prescription? Introduce further bias! The compounds in the KEGG are more or less optimized for biological activity. If their scaffolds are not yet present in the commercial libraries, organic chemists should go ahead and focus on synthesizing these scaffolds and adding them to screening libraries. More such scaffolds could increase the hit rate in HTS by enriching libraries in biologically relevant scaffolds. Of course the usual caveats of false positives and promiscuous compounds should be kept in mind, and it's also not clear that proteins like kinases which are optimized to bind certain core scaffold structures would greatly benefit from these diverse scaffolds. But in terms of unmined drug space, introducing such further bias would be beneficial.
This study again goes to show the possibilities for finding new stars in the constellations and galaxies of the drug universe. Hopefully the universe will keep on expanding.
Hert, J., Irwin, J., Laggner, C., Keiser, M., & Shoichet, B. (2009). Quantifying biogenic bias in screening libraries Nature Chemical Biology DOI: 10.1038/nchembio.180
Most drug discovery projects are inaugurated with some kind of screening campaign where millions of molecules are screened against a biological target. Even though the hit rate from High-Throughout Screening (HTS) can be quite low, HTS still provides one of the best starting points to discover interesting new structures that display biological activity. In spite of this, there is frequent disappointment at the low rates from HTS which could be as low as 0.05%.
But instead of focusing on the low hit rate from HTS, what if we express surprise that this hit rate is actually high? This thought takes me into a slight digression. In his remarkable book The Black Swan, the author Nassim Nicholas Taleb talks about an "anti-library", the set of all books you have not read. The anti-library is in some ways more important than your library because it really tells you what you are ignorant about.
Similarly we can define an "anti-question". The anti-question is a question opposite to one which we might usually ask. So instead of asking; "Why is this drug specific for this protein?", we could ask "Why is this drug not hitting other proteins?". The value of the anti-question is that it forces us to analyze and evaluate things that we otherwise may not and enables us to think outside the box. As the wise doctor constantly exhorts detective Sponer in "I Robot" to get to the all-important right question, so it could be important to get to the right anti-question.
In the context of HTS, the anti-question actually turns out to be logical. Instead of asking, "Why is the hit rate from HTS so low"?, one should ask "Given the number of small molecules in small-molecule space (~10*60) compared to the extremely low number typically screened in HTS campaigns (10*6), why should we get any hits from HTS at all?". Even narrowing down the unimaginably large small-molecule universe to more drug-like or lead-like entities, we still run into a numbers paradox since even this number is orders of magnitude greater than what is usually screened.
In their most recent paper, Brian Shoichet and his team ask this important anti-question, and it leads them down an interesting road. Most campaigns that screen libraries focus on readily available commercial compounds and fragments that can be synthesized by organic chemists. This bias in turn reflects what has been more or less synthetically accessible through more than a hundred years of synthesis. Compared to this, the Kyoto Encyclopedia of Genes and Genomes (KEGG) contains metabolites whose structures are untainted by the minds of organic chemists. These are scaffolds among secondary metabolites and natural products that have simply been found.
There is another set of structures; the Generated Database (GDB), a theoretical set which contains all possible molecules containing less than 11 heavy atoms consisting of first-row elements (C, O, N, F). This number is not as large as may be imagined and amounts to about 26 million. In the study the authors essentially compare the set of purchasable or commercial KEBB compounds found in their own annotated library called ZINC with the GDB. They use a similarity measure called a Tanimoto coefficient derived from 2D fingerprint comparison to accomplish this. 2D fingerprints use different kinds of protocols for breaking up a molecule into bit strings and then compare bit strings by distances and atom types.
The comparison indicates something interesting; the compounds in the purchasable set are much more similar to the KEBB compounds than are the compounds from the rest of the GDB. In other words, purchasable compounds contain scaffolds that are biased towards those in the KEBB. This is a good thing, since metabolites are usually primed by nature to show at least some biological activity. Another noteworthy finding was that the bias also increased with molecular size, as compounds became more drug-like or lead-like in terms of size.
However, the more surprising and useful observation was that there are hundreds of scaffolds in the KEBB that are notpresent in the commercial library. The authors also do this comparison for other popular commercial libraries designed specifically for screening and find a similar result. The bottom line; while synthesized commercial libraries of molecules show a bias toward natural products and metabolites, there are also several natural product scaffolds that are not found in these libraries.
So what is the prescription? Introduce further bias! The compounds in the KEGG are more or less optimized for biological activity. If their scaffolds are not yet present in the commercial libraries, organic chemists should go ahead and focus on synthesizing these scaffolds and adding them to screening libraries. More such scaffolds could increase the hit rate in HTS by enriching libraries in biologically relevant scaffolds. Of course the usual caveats of false positives and promiscuous compounds should be kept in mind, and it's also not clear that proteins like kinases which are optimized to bind certain core scaffold structures would greatly benefit from these diverse scaffolds. But in terms of unmined drug space, introducing such further bias would be beneficial.
This study again goes to show the possibilities for finding new stars in the constellations and galaxies of the drug universe. Hopefully the universe will keep on expanding.
Hert, J., Irwin, J., Laggner, C., Keiser, M., & Shoichet, B. (2009). Quantifying biogenic bias in screening libraries Nature Chemical Biology DOI: 10.1038/nchembio.180
Overmedicated overachievers
Since we were on the subject of messing with brain chemistry in the last post, it's worth pointing out an interesting and a more than a little disturbing and provocative article by Margaret Talbot in the New Yorker that deals with the controversial use of stimulant drugs like Adderall and Ritalin.
Talbot especially focuses on Ivy League students who seem to be on a veritable diet of cocktails of these drugs. They not only turn them into supermen and women when it comes to writing papers and doing assignments, but "enhance" their social, romantic and personal lives. Websites on which anonymous users share their experiences with these compounds abound, and these users often are not bashful about sharing not just experiences but samples of such drugs. Nor do doctors seem to hesitate in rather liberally prescribing these medications. Talbot chronicles the experiences of several users who report on an overall enhanced sense of perception and understanding. The phenomenon is of course not limited to Ivy League students, but professors at top schools as well as their students seem to be ideal test cases, considering the pressures of academic life and the myriad ways to cope that they come up with.
So the question naturally is; is this a good thing? The bigger question I want to ask is; in twenty years, when I meet a person, do I want the sum total of his or her personality to be essentially defined by 5 magic pills that are popped into the mouth every morning, like recharging a battery? Are we going to enhance our lives with drugs so much that our intrinsic persona is only vaguely visible, if at all, under a thick blanket of smiles, appropriate social manners, and exuberant behavior that is artificially induced by medication? And of course, do we understand enough about brain chemistry to use these neuroenhancers on a regular basis? (This one's easy; the answer is a terse 'no')
Proponents of the drugs say that these molecules tickle similar receptors in the brain as caffeine. If copious quantities of stimulant black coffee are still kosher, what's wrong with minute quantities of Ritalin taken essentially for the same purpose? It's hard to make an argument against this, but from a long-term perspective I would be much more skeptical about the effects of...I don't know, amphetamines on the brain compared to coffee?. The long-term effects of both Ritalin and Adderall are not known. A related matter is that the temporary stimulation and enhancement induced by these drugs may mask the loss of deeper and important functions that may not be apparent in the short-term. Indeed, perhaps the most troubling side-effect that Talbot documents is a loss of truly creative thinking. As she says, this is not surprising. Truly creative thinking often happens when the mind is wandering, when one is not too focused on a particular task. Ritalin-like compounds that may bring about intense spells of concentration may deprive us of those strokes of insights that actually result from a scatter-brained loss of focus.
Another practical issue that these medicines pose is that of unduly ramping up competitiveness. Consider that your co-worker is on these medicines and it's apparently enhancing his or her productivity. Would you feel pressured to aid your normal faculties with a boost of these babies? Wouldn't you like to stay competitive by asking your doctor for Ritalin so that you are sure that it's you and not your co-worker who bags that lucrative contract or job position? In an era where competitiveness has becoming so mind-numbing that's it's hardly noticed, do we need more incentives for competing even harder? It's a question that is going to constantly rear its head.
In the end though, I have a problem with these enhancers for the same reason that I have a problem with antidepressants. We are in an era where ordinary problems like shyness are being presented as "disorders" that may benefit from a pill. Attention Deficit Hyperactive Disorder is of course a real, clinical manifestation. But aren't all of us attention deprived to varying extents during the day. Simply as a scientific fact, wouldn't it generally help us if all of us take Ritalin? Who wants to be a member of Ritalin nation?
But that's just my opinion. Our parents' and grandparents' generations exemplified the maxim "Where there is a will, there's a way". Maybe for us it's going to be, "Where there's no will, there is a pill". I cannot wait for the singularity.
Talbot especially focuses on Ivy League students who seem to be on a veritable diet of cocktails of these drugs. They not only turn them into supermen and women when it comes to writing papers and doing assignments, but "enhance" their social, romantic and personal lives. Websites on which anonymous users share their experiences with these compounds abound, and these users often are not bashful about sharing not just experiences but samples of such drugs. Nor do doctors seem to hesitate in rather liberally prescribing these medications. Talbot chronicles the experiences of several users who report on an overall enhanced sense of perception and understanding. The phenomenon is of course not limited to Ivy League students, but professors at top schools as well as their students seem to be ideal test cases, considering the pressures of academic life and the myriad ways to cope that they come up with.
So the question naturally is; is this a good thing? The bigger question I want to ask is; in twenty years, when I meet a person, do I want the sum total of his or her personality to be essentially defined by 5 magic pills that are popped into the mouth every morning, like recharging a battery? Are we going to enhance our lives with drugs so much that our intrinsic persona is only vaguely visible, if at all, under a thick blanket of smiles, appropriate social manners, and exuberant behavior that is artificially induced by medication? And of course, do we understand enough about brain chemistry to use these neuroenhancers on a regular basis? (This one's easy; the answer is a terse 'no')
Proponents of the drugs say that these molecules tickle similar receptors in the brain as caffeine. If copious quantities of stimulant black coffee are still kosher, what's wrong with minute quantities of Ritalin taken essentially for the same purpose? It's hard to make an argument against this, but from a long-term perspective I would be much more skeptical about the effects of...I don't know, amphetamines on the brain compared to coffee?. The long-term effects of both Ritalin and Adderall are not known. A related matter is that the temporary stimulation and enhancement induced by these drugs may mask the loss of deeper and important functions that may not be apparent in the short-term. Indeed, perhaps the most troubling side-effect that Talbot documents is a loss of truly creative thinking. As she says, this is not surprising. Truly creative thinking often happens when the mind is wandering, when one is not too focused on a particular task. Ritalin-like compounds that may bring about intense spells of concentration may deprive us of those strokes of insights that actually result from a scatter-brained loss of focus.
Another practical issue that these medicines pose is that of unduly ramping up competitiveness. Consider that your co-worker is on these medicines and it's apparently enhancing his or her productivity. Would you feel pressured to aid your normal faculties with a boost of these babies? Wouldn't you like to stay competitive by asking your doctor for Ritalin so that you are sure that it's you and not your co-worker who bags that lucrative contract or job position? In an era where competitiveness has becoming so mind-numbing that's it's hardly noticed, do we need more incentives for competing even harder? It's a question that is going to constantly rear its head.
In the end though, I have a problem with these enhancers for the same reason that I have a problem with antidepressants. We are in an era where ordinary problems like shyness are being presented as "disorders" that may benefit from a pill. Attention Deficit Hyperactive Disorder is of course a real, clinical manifestation. But aren't all of us attention deprived to varying extents during the day. Simply as a scientific fact, wouldn't it generally help us if all of us take Ritalin? Who wants to be a member of Ritalin nation?
But that's just my opinion. Our parents' and grandparents' generations exemplified the maxim "Where there is a will, there's a way". Maybe for us it's going to be, "Where there's no will, there is a pill". I cannot wait for the singularity.
Atypically typical: The single vs multiple compound hypothesis in schizophrenia
One of the most painful parts in the book "A Beautiful Mind" narrates how the brilliant mathematician John Nash was admitted to a Trenton hospital and subjected to what was then one of the most fashionable treatments for schizophrenia- insulin shock therapy. The periodic administrations of large doses of insulin to induce convulsions and coma not only was embarrassing for the future Nobel Laureate and his family but it may have possibly damaged parts of his mind- and not just brain- beyond repair. It may have scarred a beautiful mind.
But we had lobotomy, and we had insulin shock therapy. And then we evolved. The drugs chlorpromazine and reserpine revolutionized the treatment of schizophrenia in the 1950s (recall the movie "Awakenings"). Since then a variety of drugs have been used for mitigating the symptoms of this devastating disorder. However most of these drugs target what are called the "positive symptoms" of the disease, which include delusions, agitation and hallucinations. The "negative symptoms" include social withdrawal, depression and poverty of speech, symptoms not targeted by many drugs. More importantly, many of the early drugs had nasty side effects, termed "extrapyramidal symptoms" (EPS) which included involuntary twitching of facial and other muscles, part of what is termed tardive dyskinesia. A lot of focus has been put over the years on reducing these effects as well as in mitigating negative symptoms. Medicines supposed to achieve these goals have been traditionally termed "atypical antipsychotics"
Now an article co-authored by Nobel Laureate Arvid Carlsson questions this widely accepted definition of atypical antipsychotics and suggests that the definition actually hampered the development of these drugs for more than 30 years. The article contains some rather technical commentary, but what I could get from it is the following: the most widely accepted hypothesis for the etiology of schizophrenia is the so-called "dopamine hypothesis", pioneered by Carlsson himself, that contends that high levels of dopamine in the brain are associated with psychoses. Drugs like clozapine are supposed to prevent dopamine metabolism by binding especially to the D2 family of dopamine receptors. These drugs bind to other receptors too but it's their action at dopamine D2 receptors that's important in managing the symptoms of schizophrenia.
Carlsson contends that the flaw in 30 years of antipsychotic therapy lies in searching for the perfect "atypical" antipsychotic which will tackle both positive and negative symptoms of schizophrenia as well as EPS. It was believed for many years that all these effects could not be disentangled from each other and necessarily went together. This led to the search for a "magic bullet", a single compound that could hit all symptoms. Carlsson says that recent studies on the action of antipsychotics suggests different mechanisms responsible for different symptoms, including mechanisms involving novel receptors that were not implicated before. The drugs also cause different levels of occupancy for D2 receptors in different tissues and parts of the brain, and thus provide the opportunity for designing multiple compounds that hit subtypes in different places. According to Carlsson, the "atypical" compounds used to treat psychoses should actually be called "typical" since they usually do a good job of treating the positive symptoms of the disease. The bottom line is that multiple avenues for treating the symptoms of schizophrenia arising from different molecular mechanisms should be explored, instead of focusing on a single compound that would encompass all features. Different compounds should be used for targeting positive and negative symptoms.
To me this narrative reinforced what is becoming clear about CNS disorders and the accompanying therapy; that non-selective drugs targeting different mechanisms are often more beneficial than single, selective drugs targeting only one receptor, and that multiple pathways affect the development of a disease whose symptoms and side-effects may be classified into distinct categories only with deceptive convenience. The brain is the most complex structure known to man. Its manipulation and the treatment of its disorders deserves an approach that is not too less complex and nuanced.
Gründer, G., Hippius, H., & Carlsson, A. (2009). The 'atypicality' of antipsychotics: a concept re-examined and re-defined Nature Reviews Drug Discovery, 8 (3), 197-202 DOI: 10.1038/nrd2806
Subscribe to:
Posts (Atom)