The peculiar blindness of the highly intelligent

This is not a scientific post. While at Graduate Alumni day last April at Harvard, I listened to the main speaker go on and on about how irrational (translation: stupid) people were when it came to risk, particularly that of flying after 9/11. In terms of miles traversed, flying is far safer than driving. The speaker was Louise Richardson
PhD ’89, government, presently Principal and Vice-Chancellor of the University of St Andrews. Her topic was “Terrorism: what have we learned?”

Here’s who she is and what she’s done. In the years after 9/11, in addition to her teaching and management roles, Professor Richardson gave over 300 talks and lectures on terrorism and counter-terrorism to educational and private groups as well as policy makers, the military, intelligence, and business communities. She has testified before the United States Senate and has appeared on CNN, NBC, the BBC, PBS, NPR, Fox and a host of other broadcast outlets. Her work has been featured in numerous international periodicals.

Clearly, she’s listened to. As I sat there I wondered how her advice for society could be any good, given her contempt for the way most of its members think. I’m sure in the several hundred of so listeners there were some adamantly opposed nuclear power. Two years previously we heard professor Daniel Schrag talk on a geologist’s perspective on global warming, saying there was no such thing as ‘clean coal’ and how slowly carbon dioxide is cleared from the atmosphere. Clearly, nuclear power is cleanest mode of energy production, with the lowest risk etc. etc. Why are some highly educated (and presumably intelligent) people against it?

Which brings us to the mind set of Professor Gruber. Amazingly, Howard Dean (a man of the left) had the following to say about Professor Gruber and Obamacare on MSNBC

First Gruber: “The problem is not that Gruber said it– the problem is that he thinks it”

Then ObamaCare “The core problem under the damn law is that it was put together by a bunch of elitists who don’t fundamentally understand the American people. That’s what the problem is”

How could free health care be so unpopular.

The common delusion of the highly intelligent is that since they think so well, everyone should think like them, and if they don’t their behavior and institutions should be directed by their intellectual betters. Nothing much has changed in Cambridge in 54 years. This mindset was just as common then as it is now. You can see how well it’s working.

Well, probably most readers of this blog are highly educated (technically at least), and years away from dealing with the mass of humanity. Most doctors in practice see the full spectrum of the populace, because everyone gets sick.

Here’s what’s out there. Part of the neurologic examination is the mental status examination. One assesses a variety of things — orientation, speech, affect, calculation, memory etc. etc. One part often used to assess higher cognitive function is the ability to abstract. People are asked things like, what’s similar about an apple and an orange, a table and a chair. What’s different about a river and a lake. They can be asked for the meaning of familial proverbs “a stitch in time saves nine, people who live in glass houses shouldn’t throw stones. The point of the mental status is to separate the normal from the abnormal.

I pretty much had to abandon similarities and differences because so many normally functioning people thought extremely concretely. For the apple/orange similarity I’d get back they’re both round, or (worse) one is red the other is orange (not a similarity), or the proverb would be repeated back verbatim. I’d guess that 1/3 of people think this concretely.That table and chair were both furniture or that apples and oranges were both fruit was only the response about 60% of the time. You can either call the 1/3 abnormal (which means you need to redefine normal) or decide that the test is useless for picking up pathology. I chose the latter.

This is why I’ll only interview high school students for my Ivy league alma mater (Princeton). Princeton needs them as much as they need Princeton. They bring a dose of reality to a very cloistered environment.

It’s why I don’t read novels

You can’t make up stuff like this. A nephrologist whom I consulted about our daughter-in-law’s bout with pre-eclampsia, asked me about her brother-in-law when she found out I’d been a neurologist. Long out of practice, I called someone in my call group still practicing, only to find out that his son (who was just a little guy when we practiced) is finishing up his PhD in Chemistry from Princeton. Put this in a novel and no one would believe it.

The reason for the post, is that Princeton’s new Chemistry building, built to the tune of .25 gigaDollars, isn’t working very well. According to his son not all the hoods are functional. There are other dysfunctionalities as well, lack of appropriate space etc. etc. All is not lost however, the building is so beautiful (if non-functional) that it is used as a movie set from time to time. Any comments from present or past inhabitants of the new building?

Here’s the old post.

Princeton Chemistry Department — the new Oberlin

When I got to grad school in the fall of ’60, most of the other grad students were from East and West coast schools (Princeton, Bryn Mawr, Smith, Barnard, Wheaton, Cal Tech etc. etc.), but there were two guys from Oberlin (Dave Sigman, Rolf Sternglanz) which seemed strange until I looked into it. Oberlin, of course, is a great school for music but neither of them was a musician. They told me of Charles Martin Hall, Oberlin alum and inventor of the Hall process for Aluminum — still used today. He profited greatly from his invention, founding what is today Alcoa, running and owning a lot of it. He gave tons of money to the Oberlin Chemistry department, which is why it was so good back than (and probably still is).

What does this have to do with Princeton? Princeton’s Charles Hall is emeritus prof Ted Taylor, whose royalties on Alimta (Pemetrexed), an interesting molecule with what looks like guanine, glutamic acid, benzoic acid and ethane all nicely stitched together to form an antifolate, to the tune of over 1/4 of a billion dollars built the new Princeton Chemistry building. Praise be, the money didn’t go into any of the current academic fads (you know what they are), but good old chemistry.

An article in the 11 May “Princeton Alumni Weekly” (yes weekly) about the new building contains several other interesting assertions. The old chemistry building is blamed for a number of sins e.g., “no longer conducive to the pursuit of cutting-edge science in the 21st century”, “hard to recruit world-class faculty and grad students to what was essentially rabbit warren” etc. etc. Funny, but we thought the place was pretty good back then.

When the University president (Shirley Tilghman, a world-class molecular biologist prior to assuming the presidency — just Google imprinting) describes Princeton Chemistry as ‘one of Princeton’s “least-strong departments” you know there are problems. Is this really true? Maybe the readership knows.

Grad school applications are now coming from the ‘very top applicants’ — is it that easy to rate them? This is said not to be true 10 years ago — wonder how those now with PhD’s entering the department back then feel about this.

Then there is a picture of a young faculty member “Abby Doyle” who joined the department 6 years after graduating Harvard in 2002. As I recall there was a lot of comment on this in the earlier incarnation of ChemBark a few years ago.

The new building is supposed to inspire collaboration because of its open space, and 75 foot atrium, ‘few walls between the labs and glass is everywhere’. Probably the article was written by an architect. The implication being is that all you need for good science is a good building, and that bad buildings can inhibit good science. Anyone out there whose science has blossomed once they were put in a glass cage?

It’s interesting to note that the undergraduate catalog for ’57 – ’58 has Dr. Taylor basically in academic slobbovia — he’s only teaching Chem 304a, a one semester course “Elementary Organic Chemistry for Basic Engineers” (not even advanced engineers)

Comments anyone?

No longer looking under the lamppost

Time flies. It’s been over 5 years since I wrote http://luysii.wordpress.com/2009/09/25/are-biochemists-looking-under-the-lamppost/, essentially a long complaint that biochemists (and by implication drug chemistry and drug discovery) were looking at the molecules they knew and loved rather than searching for hidden players in the biochemistry and physiology of the cell.

Things are much better now. Here are 3 discoveries from the recent past, some of which should lead to drugable targets.

#1 FAFHA — a possible new way to treat Diabetes. Interested? Take a long chain saturated fatty acid such as stearic acid (C18:0). Now put a hydroxyl group somewhere on the chain (the body has found ways put them at different sites — this gives you a hydroxy fatty acid (HFA). Next esterify this hydroxyl group with another fatty acid and you have a Fatty Acid ester of a Hydroxy Fatty acid (an FAHFA if you will). So what?

Well fat makes them and releases them into the blood, making them yet another adipokine and further cementing fat as an endocrine organ. Once released FAHFAs stimulate insulin release, and increase glucose uptake in the fat cell when they activate GPR120 (the long chain fatty acid receptor).

A variety of fatty acids can form the ester, one of which is palmitic acid (C16:0) forming Palmitic Hydroxy Stearic Acid (PAHSA) which binds to GPR120. if that weren’t enough PAHSAs are anti-inflammatory — interested read more [ Cell vol. 159 pp. 238 239, 318 - 332 '14 ]. I don’t think the enzymes forming HFA’s are known, and I’m willing to bet that are other HFAs out there.

#2 Maresin1 (7S, 14S dihydroxy docosa 4Z 8E 10E, 12Z 16Z, 19Z hexaenoic acid to you) is the way you start making Specialized Proresolving Mediators (SPMs). Form an epoxide of one of the double bonds and then do an SN2 ring opening with a thiol (glutathione for one) forming what they call a sulfido-conjugate mediator. It appears to be one of the many ways that inflammation is resolved. It helps resolve E. Coli infection in mice at nanoMolar concentration. SPMs further neutrophil recruitment and promote macrophage clearance of apoptotic cells and tissue debris. Wouldn’t you like to make a drug like that? Think of the specificity of the enzyme producing the epoxidation of just one of the 6 double bonds. Also a drug target. For details please see PNAS vol. 111 pp. E4753 – E4761 ’14

#3 Up4A (Uridine Adenosine Tetraphosphate) — as you might expect it’s an agonist at some purinergic receptors (PO2X1, P2Y2, P2Y4) causing vasoconstriction, and vasodilatation at others (P2Y1). It is released into the colon when enteric neurons are stimulated. Another player whose existence we had no idea about. Certainly we have all the GI and vasodilating drugs we need. If nothing else it will be a pharmacological tool. Again the enzyme making it isn’t known — yet another drug target possibly. For details see PNAS vol. 111 pp. 15821 – 15826 ’14.

There is a lot more in these 3 papers than can be summarized here.

Who knows what else is out there, and what it is doing? Glad to see people are starting to look

Maybe it is the system after all

This is a totally NONscientific post.

My late father and his brother had the classic liberal conservative argument for the 60 years or so I was intellectually conscious enough to register it (and probably longer). His brother would say ‘it’s the system’ – all we have to do is change it and things would be better. My father would say people will corrupt any system.

Our family was full of people of the left, and my mother recalls someone arguing in all seriousness that Finland had attacked Russia in WWII. I can well recall the gloom pervading a family gathering after Eisenhower beat Stevenson, and the imprecations of disaster to follow.

Based on decades of medical practice, I tended to agree with my father. Now I’m not so sure.

But first 3 examples:

The Veteran’s Administration system: The original impetus for a system was to care for injured soldiers in peacetime. Who could possibly object to that. Yet as a resident in the 70′s our acute ward was so filled with very chronic patients (20 year paraplegics) that we had to turn away the truly acutely ill. We also had one paraplegic young man shot while robbing a convenience store (he was on active duty at the time, so this was considered service connected). I’m not even mentioning the current scandal about falsified wait times, while those in charge gave themselves performance awards.

Workman’s compensation: Who could argue with compensating an honest workman for a disabling injury suffered on the job? Read “The Jungle” by Upton Sinclair about life in the Chicago Stockyards a century ago if you don’t agree. Then there was the Rerat law firm (no kidding) specializing in suing the Burlington Northern Railway for injuries. This leads into example #3

Disability: Disabled people should be supported by the society at large. Who would disagree. I got an early taste in the service from ’68 – ’70 doing medical boards. No problem for the war injured to get disability. But then there were the general officers about to retire, whom the system somehow found barely able to function. Then look at the scandal at the Long Island Railroad, where for a time, a corrupt group of union officials and docs made sure nearly 100% of retirees were 100% disabled. See http://www.nytimes.com/2008/09/21/nyregion/21lirr.html?_r=0

The real problem is with Social Security Disability payments. Here the frauds and grafters were basically stealing from my disabled MS, muscular dystrophy, stroke patients. These are people who truly need the money. I thought the system would bankrupt from them. But apparently it hasn’t.

There are 3 excellent systemic ideas which have been significantly corrupted by the people using it.

So my dad was right and my uncle, a man of the Left was wrong.

They’re both gone now, my dad at 100, my uncle at 94. Uncle Irv wouldn’t like why I’m now coming around to his position — it is the system (at least in some cases).

What changed my mind? Venezuela. This is a country sitting on the largest proven reserves of oil, which has begun to import oil. It should be fabulously rich, now that the leader is ruling by decree for the poor and downtrodden. It is one of 3 countries in the world rationing food. There is no excuse for this — no US embargo (Cuba), no war fought on its soil in the past 100 years (North Korea).

It must be the system there. Sorry uncle Irv, it’s your system not dad’s.

Conservatives sometimes bash the left for being unpatriotic. Not uncle Irv — he was at the battle of Kasserine pass in North Africa, and the battle of the Bulge in Europe, and is at rest in a military cemetery.

The way it ought to be

A recent paper described the use of sulforaphane in treating autism [ Proc. Natl. Acad. Sci. vol. 111 pp. 15550 - 15555 '14 ] A sulforaphane trial (double blind, randomized) on 44 men age 13 – 27 with moderate to severe Autism Spectrum Disorder received sulforaphane (50 – 150 micoMoles) for 18 weeks followed by 4 weeks without treatment. There was no change in the 15 placebo patients, while there was a 33% decline in the Aberrant Behavior Checklist scores. When the sulforaphane was stopped total scores rose toward pretreatment levels.

I had posted on sulforaphane before — see the end of this post. I wrote the lead author asking if some of the therapeutic effects could be due to the anti-androgen activity of sulforaphane. He wrote back in a few days.

“Sorry, I missed your email. Absolutely possible. We did not measure androgen levels, but will do so in the future.
Thank you so much.”

Contrast this to the absent responses on whether the subjects in two functional MRI studies of the default network were asleep. See http://luysii.wordpress.com/2014/10/11/the-silence-is-deafening/

Vegetarians are wimps: Science now tells us why

Oh, it started innocently enough. Population studies had shown that men who ate lots of cruciferous vegetables (collard greens, cabbage, brussels sprouts, broccoli, cauliflower, bok choy etc. etc.) had less prostate cancer. Some folks in Oregon decided to find out why [ Proc. Natl. Acad. Sci. vol. 106 pp. 16663 - 16668 '09 ]. One of the compounds found in all these veggies is sulforaphane. There are all sorts of places to be found on the web that will sell it to you for your health. Sulforaphane is said to fight cancer, improve diabetes and kill bacteria (if you believe Wikipedia). Hosanna.

Prostate cancer is made worse by male hormones (androgens). They produce their effects in cells by binding to a protein (the androgen receptor) which then goes into the nucleus of the cell and turns on the genes which make males male. If there’s no androgen around the receptor just sits there outside the nucleus (e.g. in the cytoplasm), doing nothing. Some forms of prostate cancer have mutations in the receptor which turn it on whether androgen is present or not. This makes the cancer even worse. So one of the mainstays of prostate cancer therapy is lowering androgen levels by a variety of means, none of them pleasant — such as castration and various pills.

The Oregon work shows that sulforaphane decreases the amount of androgen receptor around resulting in less androgenic effects, and presumably less prostate cancer in the long run. How this is thought to occur is pretty interesting, highly technical and is to be found in subsequent paragraphs. It also explains why vegetarians are such wimps.

The androgen receptor sits in the cytoplasm bound to a protein called HSP90 (heat shock protein of 90 kiloDaltons). This protects the androgen receptor from being destroyed. Sulforaphane is a fairly simple molecule — a straight 4 carbon chain with a methyl sulfoxide group at one end and an isothiocyanate (-N=C=S ) group at the other. It should be pretty lipid soluble, meaning it can go everywhere in the body without much trouble. The authors showed that sulforaphane inhibits an enzyme called histone deacetylase 2 (HDAC2). This results in more acetylation of HSP90 on lysine, inhibiting the association of HSP90 with the androgen receptor, leading to increased destruction of the receptor and less androgenic effects in the cell.

The active site of one histone deacetylase that we know about is a tubular pocket containing a zinc binding site and two aspartic acid histidine charge relay systems. My guess is that the business end of sulforaphane is the isothiocyanate, which could react by nucleophilic attack of either the histidine nitrogen or the aspartic acid oxygen on the carbon of the -N=C=S group. Perhaps one of readers knows how it works.

Histone deacetylase inhibitors are presently very ‘hot’ and one of them, SAHA was approved by the FDA for the treatment of T cell cutaneous lymphoma in 2007, and many others are under active investigation. It’s important to remember that although this class of enzymes was discovered by their ability to remove acetyl groups from histones, they also remove acetyl groups from proteins which are not histones (e.g. HSP90).

So veggies are a two-edged sword.

Just because a receptor is there doesn’t mean it’s doing anything

Normally when we see a receptor on the surface of a cell (such as the receptor for Vascular Endothelial Growth Factor — VEGF) we assume that when its ligand binds, something happens inside the cell. Not always so, says Cell vol. 159 pp. 473 – 474, 584 – 596 ’14. VEGF is crucial in fetal development (inactivation of just one of the two copies of the gene is lethal for the mouse embryo [ PNAS vol. 95 pp. 14389 - 14394 98 ]).

One of the problems in diabetic retinopathy is proliferation of retinal blood vessels. For those who don’t already know — light outside the eye has to pass through all 10 cellular layers of the retina before it hits the photoreceptors which can absorb it. So more vessels in the neuronal layers isn’t good.

The Cell paper shows that in the developing retina, VEGF is depleted near neurons, by neuronal engulfment of the VEGF/VEGF receptor complex and degradation. The complex doesn’t do anything metabolically to the neuron. This prevents misdirected angiogenesis into the neuronal plane.

This turns what we’ve always thought about receptors on the cell surface on its head — they must be doing something inside the cell, when a ligand binds to them. Apparently not always.

Another financial piety bites the dust

If only businesses looked past the next quarterly earnings report all would be well. Productivity and profits would increase if CEOs would think long term. Investors hunger for such thinking.

Well, a large firm with earnings that beat analysts estimate by over 5% did that exactly yesterday and the stock dropped 6% today, Revenue rose 59%, but costs rose 41%.

The head, a brash youngster spoke saying that the ‘company’s long-term goals stretch more than a decade into the future and require “investing aggressively”.

Yes, this happened to Facebook. So much for the long term view

Ebola — an update (25 Oct ’14)

The experiment of nature referred to in a previous post (https://luysii.wordpress.com/2014/10/16/an-experiment-of-nature/) when Amber Vinson, a nurse who had helped care for a fatal case of Ebola, took a commercial flight from Cleveland to Dallas the day she became symptomatic with Ebola is almost over. She was diagnosed 14 October, the day she took the flight, and so far no one on the flight has become ill (presumably the 100+ or so are under surveillance).

However, another experiment of Nature has just begun. An M. D. who’d been in Africa treating Ebola victims was diagnosed with it on the 23rd. He had returned to NYC from Africa 14 October and had been up and about in the city. According to the Times he began to feel sluggish the evening of the 21st, went all over the city on the 22nd, including a 3 mile jog on the west side, and noted a mild temperature (100.3 not 103 as initially reported) the morning of the 23rd — reported it immediately and was hospitalized the same day. New York City chastened by the disastrous response to the first case in Texas, sent 3 guys in Hazmat suits to his apartment to pick the doctor up, according to the NYT of 26 October. Some contacts, such as his fiancee are easy to trace, the people he rode with on the subway are not.

The incubation period is said to be no more than 21 days, so neither experiment of nature is truly over. From this case we now know the incubation period can be as short as 7 – 9 days.

As noted in the previous post — The genome of Ebola is RNA which mutates much more rapidly than DNA genomes. It does this so quickly that at death from AIDS (another RNA virus), there are so many viral variants present that the infecting ensemble is called a quasiSpecies. With a large population infected in Africa there is more Ebola virus extant than at any time in the past.

We have a small handle on just how fast the virus is mutating [ Science vol. 345 pp. 1369 - 1372 '14 (12 Sep '14) ]. This is a report of 98 virus genomes from 78 patients from Sierra Leone (all this year). The Ebola genome contains 18,959 to 18,961 nucleotides and codes for at least 7 proteins. Compared to all previously known Ebola genome sequences, the virus from Sierra Leone contains 341 fixed changes (e.g. the changes were present in every virus they sequenced). The changes were present in all 7 proteins.

It isn’t clear (to me) from reading the paper how much variation in the viral genome there is (1) in a given individual (2) between individuals. Note that all samples were obtained from late May to early June this year, so the work is a good baseline.

Why is this scary? Because, as is typical for a virus with a genome made of RNA, Ebola is mutating rapidly. This means that we can’t be sure that its incubation characteristics, or its ability to spread from human to human will remain constant.

Producing the paper, required lots of collaboration between people in the USA and Africa, so there are 58 co-authors of the paper. Showing just how bad the disease is five of the fifty-eight co-authors died of Ebola. R. I. P. Mohamed Fullah, Mbalu Fonnie, Alex Moigboi, Alice Kovoma, S. Humarr Khan.

Who said this?

“You have to take care of all the sectors in —- as much as you can,” he said, “and if it’s entirely a numbers game and numeric representation, then obviously you would be talking to half of the people in —– who earn less than $1,800 a month.”

The present system serves to “insulate candidates from popular pressure to create a welfare state, and would allow the city government to follow more business-friendly policies.”

Clue: It is not a Republican dinosaur or the Koch brothers.

No it’s the Beijing-appointed leader of Hong Kong, Leung Chun-ying as reported 2 days ago in the New York Times — http://www.nytimes.com/2014/10/21/world/asia/leung-chun-ying-hong-kong-china-protests.html?_r=0

Amazing isn’t it? Well, perhaps not. In March 2013 my wife and I saw Bentley dealerships in Beijing. In the Causeway Bay area of Hong Kong, there appeared to be one high end jewelry store (Cartier, etc. etc.) per block.

What’s a fellow-traveller to do?

Watching electrons being pushed

Would any organic chemist like to watch electrons moving around in a molecule? Is the Pope Catholic? Attosecond laser pulses permit this [ Science vol. 346 pp. 336 - 339 '14 ]. An attosecond is 10^-18 seconds. The characteristic vibrational motion of atoms in chemical bonds occurs at the femtosecond scale (10^-15 seconds). An electron takes 150 attoseconds to orbit a hydrogen atom [ Nature vol. 449 p. 997 '07 ]. Of course this is macroscopic thinking at the quantum level, a particular type of doublethink indulged in by chemists all the time — http://luysii.wordpress.com/2009/12/10/doublethink-and-angular-momentum-why-chemists-must-be-adept-at-it/.

The technique involves something called pump probe spectroscopy. Here was the state of play 15 years ago — [ Science vol. 283 pp. 1467 - 1468 '99 ] Using lasers it is possible to blast in a short duration (picoseconds 10^-12 to femtoseconds 10^-15) pulse of energy (pump pulse ) at one frequency (usually ultraviolet so one type of bond can be excited) and then to measure absorption at another frequency (usually infrared) a short duration later (to measure vibrational energy). This allows you to monitor the formation and decay of reactive intermediates produced by the pump (as the time between pump and probe is varied systematically).

Time has marched on and we now have lasers capable of producing attosecond pulses of electromagnetic energy (e.g. light).

A single optical cycle of visible light of 6000 Angstrom wavelength lasts 2 femtoseconds. To see this just multiply the reciprocal of the speed of light (3 * 10^8 meters/second) by the wavelength (6 * 10^3 *10^-10). To get down to the attosecond range you must use light of a shorter wavelength (e.g. the ultraviolet or vacuum ultraviolet).

The paper didn’t play around with toy molecules like hydrogen. They blasted phenylalanine with UV light. Here’s what they said “Here, we present experimental evidence of ultrafast charge dynamics in the amino acid phenylalanine after prompt ionization induced by isolated attosecond pulses. A probe pulse then produced a doubly charged molecular fragment by ejection of a second electron, and charge migration manifested itself as a sub-4.5-fs oscillation in the yield of this fragment as a function of pump-probe delay. Numerical simulations of the temporal evolution of the electronic wave packet created by the attosecond pulse strongly support the interpretation of the experimental data in terms of charge migration resulting from ultrafast electron dynamics preceding nuclear rearrangement.”

OK, they didn’t actually see the electron dynamics but calculated it to explain their results. It’s the Born Oppenheimer approximation writ large.

You are unlikely to be able to try this at home. It’s more physics than I know, but here’s the experimental setup. ” In our experiments, we used a two-color, pump-probe technique. Charge dynamics were initiated by isolated XUV sub-300-as pulses, with photon energy in the spectral range between 15 and 35 eV and probed by 4-fs, waveform-controlled visible/near infrared (VIS/NIR, central photon energy of 1.77 eV) pulses (see supplementary materials).”

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