A certain Nobel prize

Chemists will be green with envy to find out that a Nobel prize (possibly in Chemistry) is almost certain to be won by someone using using nothing fancier than formaldehyde, acrylamide and an ionic detergent (Sodium Dodecyl Sulfate — the SDS of electrophoresis fans everywhere)_. For details see Nature vol. 497 pp. 332 – 337 ’13 (16 May Issue). It’s by the same man (Karl Deisseroth) who already has a Nobel coming for the invention of optogenetics.

First — a bit of history. The tissue of the brain is so tightly packed that it is impossible to see the cells that make it up with the usual stains used by light microscopists. People saw nuclei all right but they thought the brain was a mass of tissue with nuclei embedded in it (like a slime mold). Muscle is like that — long fibers with hundreds of nuclei here and there. It wasn’t until that late 1800′s that Camillo Golgi developed a stain which would now and then outline a neuron with all its processes. Another anatomist (Ramon Santiago y Cajal) used Golgi’s technique and argued with Golgi that yes the brain was made of cells. Fascinating that Golgi, the man responsible for showing nerve cells, didn’t buy it. This was a very hot issue at the time, and the two received a joint Nobel prize in 1906 (only 5 years after the prizes began).

How tightly packed is the brain? The shortest wavelength of visible light is 4000 Angstroms. Cells in the brain are packed far more tightly. To see the space between the brain cell external membranes you need an electron microscope (EM). Just preparing a sample for EM really fries the tissue. Neurons are packed together with less than 1000 Angstroms between them. So how much of this is artifact of preparation for electron microscopy has never been clear to me. One study injected a series of quantum dots of known diameter into the cerebral spinal fluid (CSF) to see the smallest sized dot that could insinuate itself between neurons [ Proc. Natl. Acad. Sci. vol. 103 pp. 5567 - 5572 '06 ]. The upper limit was around 350 Angstroms. No wonder the issue was contentious when all they had was the light microscopy.

Your brain (and mine) is mostly fat. Light doesn’t get through fat very well at all. Deisseroth figured out a way to remove the fat leaving the other brain structures intact. The technique even works on brains fixed in formaldehyde for years. First they infused formaldehyde and acrylamide into brain tissue at 4 degrees Centigrade. The formaldehyde hardens the tissue, but it also links the acrylamide to the proteins making up the tissue. Then they raised the temperature to 37 Centigrade causing the acrylamide to polymerize. Then they infused sodium dodecyl sulfate into the tissue using electrophoresis. When the SDS was pulled out of the tissue (again by electrophoresis) pulling the fat (lipids) of the brain with it, this left what they call a hydrogel (which light could go through).

Using the technique it is possible to look through slabs of brain tissue 500 microns thick (5 million Angstroms thick) with a light microscope and see cell bodies and nerve fibers in their natural habitat (e.g. whole populations of neurons along with their projections). Even better you can stain the hydrogel with your antibody of choice and see what protein is where. Then you can wash this out and look at something else.

It is an incredible advance and certain to revolutionize our understanding of the brain. Look at the paper. The pictures are amazing and more are sure to follow from other workers. Definitely Nobel caliber work.

It is extremely amusing to me that this work could have been done 50 years ago. It just took someone smarter than you and I to think of it.

Two American (social) tragedies

When the team members entered the clinic, they were appalled, describing it to the Grand Jury as ‘filthy,’ ‘deplorable,’ ‘disgusting,’ ‘very unsanitary, very outdated, horrendous,’ and ‘by far, the worst’ that these experienced investigators had ever encountered. There was blood on the floor. A stench of urine filled the air. A flea-infested cat was wandering through the facility, and there were cat feces on the stairs. Semi-conscious women scheduled for abortions were moaning in the waiting room or the recovery room, where they sat on dirty recliners covered with blood-stained blankets. All the women had been sedated by unlicensed staff – long before Gosnell arrived at the clinic – and staff members could not accurately state what medications or dosages they had administered to the waiting patients. Many of the medications in inventory were past their expiration dates… surgical procedure rooms were filthy and unsanitary… resembling ‘a bad gas station restroom.’ Instruments were not sterile. Equipment was rusty and outdated. Oxygen equipment was covered with dust, and had not been inspected. The same corroded suction tubing used for abortions was the only tubing available for oral airways if assistance for breathing was needed…”[29]
[F]etal remains [were] haphazardly stored throughout the clinic– in bags, milk jugs, orange juice cartons, and even in cat-food containers… Gosnell admitted to Detective Wood that at least 10 to 20 percent… were probably older than 24 weeks [the legal limit]… In some instances, surgical incisions had been made at the base of the fetal skulls. The investigators found a row of jars containing just the severed feet of fetuses. In the basement, they discovered medical waste piled high. The intact 19-week fetus delivered by Mrs. Mongar three months earlier was in a freezer. In all, the remains of 45 fetuses were recovered … at least two of them, and probably three, had been viable.”

A classic back alley abortion mill, except that it was all quite legal.

This wasn’t supposed to happen after Roe vs. Wade. It is so uncanny that the doc (Kermit Gosnell) convicted yesterday of these 3 infanticides graduated from a med school in Philly (Jefferson) the same year (1966) that I graduated from another (Penn). At the time Philly had 3 more (Hahnemahn, Women’s and Temple).

What is so socially tragic about Gosnell, is that he was one of very few blacks in medical school back then. Our class of 125 at Penn had one, but he was a Nigerian Prince. Whether Gosnell liked it or not he was a standard bearer for what we hoped (at the time) was the wave of the future (it was). For just how very few Blacks were being educated at elite institutions back then please see

http://luysii.wordpress.com/2012/05/22/warren-harvard-and-penn-sanctimony-hypocrisy-and-fraud/

The second tragedy is a black woman M. D twenty or so years younger (Harvard undergrad, Penn Med followed by an MBA from Wharton) who lost her license to practice in NY State after she went off the deep end and became a holistic practioner (or whatever). She treated a new onset juvenile diabetic with diet and juice after which he came to the ER in diabetic ketoacidosis with a sugar over 300.

My father was an attorney as was my uncle, later a judge. They took it very personally when an attorney was disbarred for some malfeasance or another. I feel the same way when this happens to an M. D. Imagine how the black docs must feel about Gosnell, or the idiot, Conrad Murray, who basically killed Michael Jackson with Diprivan.

If you didn’t follow the link, I’ll close with a more uplifting ending from it.

My wife has a cardiac problem, and the cardiologists want her to be on coumadin forever, to prevent stroke. As a neurologist, having seen the disasters that coumadin and heparin could cause when given for the flimsiest of indications (TIAs etc. etc.), I was extremely resistant to the idea, and started reading the literature references her cardiologist gave me, along with where the references led. The definitive study on her condition had been done by a black cardiologist from Kentucky. We had a long and very helpful talk about what to do.

Diversity is not an end in itself, although some would like it to be. I’ve certainly benefitted from knowing people from all over. That’s not the point. Like it or not, intelligence is hereditary to some extent (people argue about just how much, but few think that intelligence is entirely environmental). The parents and grandparents of today’s black MDs, Attorneys, teachers etc. etc. were likely just as intelligent as their offspring of today. This country certainly pissed away an awful lot of brains of their generations.

The DSM again

The Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-V) is in the news. The press has not been favorable, nor have two new books concerning it. Here are some links

l. A review of a book on it from today’s Nature (2 May ’13)–http://www.nature.com/nature/journal/v497/n7447/full/497036a.html
2. An article in the New York Times today concerning the Nature book and one other — neither favorable –http://www.nytimes.com/2013/05/02/books/greenbergs-book-of-woe-and-francess-saving-normal.html?ref=todayspaper&_r=0

Added 8 May ’13 The US National Institute of Mental Health (NIMH) will no longer use the Diagnostic and Statistical Manual of Mental Disorders (DSM) to guide psychiatric research, NIMH director Thomas Insel announced on 30 April. The manual has long been used as a gold standard for defining mental disorders. Insel described the DSM as ill-suited to scientific studies, and said the NIMH will now support studies that cut across DSM-defined disease categories.

But, as Ernst Mayr once said — nothing in biology makes sense except in the light of evolution. Keeping that thought in mind, what I wrote a few years ago is relevant today. Here’s the post. Although it starts off in Mathematics, it gives some history which helps explain why the DSM is the way it is.

Even so, psychiatric wisdom should be taken with a good deal of salt. A psychiatrist in my medical school class (1966) knew people who were thrown out of their psychiatric residencies because they were gay, and back then homosexuality was a psychiatric disease.

Here’s the post of 3 years ago

Reification in mathematics and medicine

Can you bring an object into existence just by naming and describing it? Well, no one has created a unicorn yet, but mathematicians and docs do it all the time. Let’s start with mathematicians, most of whom are Platonists. They don’t think they’re inventing anything, they’re just describing an external reality that is ‘out there’ but isn’t physical. So is any language an external reality, but when the last person who knows that language dies, so does the language. It will never reappear as people invent new languages, and invent them they do as the experience with deaf Nicaraguan children has shown [ Science vol. 293 pp. 1758 - 1759 '01 ]. Mathematics has been developed independently multiple times all over the world, and it’s always the same. The subject matter is out there, and not just a social construct as some say.

A fascinating book, “Naming Infinity” describes a Russian school of mathematicians who extended set theory beyond the work of the French and Germans. They literally believed that describing a mathematical object and its properties implied that the object existed (assuming the properties were consistent). The mathematicians involved were also very devout mystical Christians, who were called “Name Worshippers”. They thought that repeatedly invoking the name of Jesus would allow them to reach an ecstatic state. The rather contentious theory of the book is that their religious stance allowed them to imbue all names with powerful properties which could bring what they named into existence and this led to their extensions of set theory. Naturally the Communists hated them, and exterminated many (see p. 126). People possessed of all absolute truths dislike those possessed of a different set.

Docs bring diseases into existence all the time simply by naming them. This is why the new DSM-V (Diagnostic and Statistical Manual of Mental Disorders) of the American Psychiatric Association (APA) is so important. Is homosexuality a disease? Years ago the APA thought it was. If your teenager won’t do what you want, is this “Adolescent Defiant Disorder”? Is it a disease? It will be if the DSM-V says it is.

There are a lot of things wrong with what the DSM has become (297 disorders in 886 pages in DSM-IV), but the original impetus for the major shift that occurred with DSM-III in the 70s was excellent. So it’s time for a bit of history. Prior to that time, it was quite possible for the same individual to go to 3 psychiatric teaching hospitals in New York City and get 3 different diagnoses. Why? Because diagnosis was based on the reconstruction of the psychodynamics of the case. Just as there is no single way to interpret “Stopping by Woods on a Snowy Evening” (see the previous post), there isn’t one for a case history. Freud’s case studies are great literature, but someone else would write up the case differently.

The authors of the DSM-III decided to be more like medical docs than shrinks. In our usual state of ignorance, we docs define diseases by how they act — the symptoms, the physical signs, the clinical course. So the DSM-III abandoned the literary approach of psychodynamics and started asking what psychiatric patients looked like — were they hallucinating, did they take no pleasure in things, was there sleep disturbance, were they delusional etc. etc. As you can imagine, there was a huge uproar from the psychoanalysts.

Now no individual fits any disease exactly. There are always parts missing, and there are always additional symptoms and signs present to confuse matters. The net result was that psychiatric diagnosis became like choosing from a menu in a Chinese restaurant, so many symptoms and findings from column A, so many from column B. (Update 2013 — Having been to China for 3 weeks this year, restaurant menus over there aren’t like that).

This led to a rather atheoretical approach, but psychiatric diagnoses became far more consistent. Docs have always been doing this sort of thing and still do (look at the multiple confusing initial manifestations of what turned out to AIDS back in the 80s). Different infections were classified by how they acted, long before Pasteur proved that they were caused by micro-organisms. Back when I was running a muscular dystrophy clinic, we saw something called limb girdle muscular dystrophy , in which the patients were weak primarily in muscles about the shoulders and hips. Now we know that there are at least 13 different genetic causes of the disorder. So there are many distinct causes of the same clinical picture. This is similar to the many different genetic causes of Parkinson’s disease I talked about 2 and 3 posts earlier. At least with limb girdle muscular dystrophy it is much easier to see how the genetic defects cause muscle weakness — all of the known genetic causes involve proteins found in muscle.

Where DSM-IV (and probably DSM-V — it’s coming out later this month) went off the rails, IMHO, is the multiplicity of diagnoses they have reified. Do you really think there are 297 psychiatric disorders? Not only that, many of them are treated the same way — with an SSRI (Selective Serotonin Reuptake Inhibitor). You don’t treat all infections with the same antibiotic. This makes me wonder just how ‘real’ these diagnoses are. However in defense of them, you do treat classic Parkinsonism pretty much the same way regardless of the genetic defect causing it (and at this point we know of genetic causes of less than 10% of cases).

There is a fascinating series of articles in Science starting 12 Feb ’10 about the new DSM-V. The first is on pp. 770 – 771. One of the most interesting points is that 40% of academic inpatients receive a diagnosis of NOS (Not Otherwise Specified — e.g. not in the DSM-IV — clearly even 297 diagnoses are missing quite a bit).

But insurance companies and the government treat this stuff as holy writ. Would you really like your frisky adolescent labeled with “prepsychotic risk syndrome” which is proposed for DSM-V. Also, casting doubt on the whole enterprise, are the radical changes the DSM has undergone since it’s inception nearly 60 years ago. We’ve learned a lot about all sorts of medical diseases since then, but strokes and heart attacks back then are still strokes and heart attacks today and TB is still TB. Do these guys really know what they’re talking about, and should we allow them to reify things?

That being said, cut psychiatry some slack. Regardless of theory, there are plenty of mentally ill people out there who need help. They aren’t going to go away (or get better) any time soon. Psychiatrists (like all docs) are doing the best they can with what they know.

That’s why it’s nice to be retired and reading stuff that it is at least possible to understand — like math, physics, organic chemistry and molecular biology. But never forget that it is trivial compared to human suffering. That’s why the carnage in the drug discovery industry is so sad — there goes our only hope making things better (written in 2010, but still true in 2013).

The New York Times does it again

http://www.nytimes.com/2001/09/11/books/no-regrets-for-love-explosives-memoir-sorts-war-protester-talks-life-with.html?pagewanted=all

This is a link to an interview with Bill Ayers, former weatherman and terrorist which appeared 11 September 2001. In it he says He says he ”I don’t regret setting bombs. I feel we didn’t do enough.” I think the interview was on the bottom left corner of the front page (at least the edition available in Syracuse that day).

Today (15 April ’13) they have an article by a prisoner in Guantanamo on the opinion page saying it’s killing him.

Tomorrow, expect stories about Muslims cowering in fear. Next week — Islam is a religion of peace.

Res ispa loquitur

Denaturation equals loss of protein function doesn’t it? Not !

In the old days when protein pretty much meant enzyme, heating them caused loss of their catalytic activity (e.g. denatured them). A more familiar example is what happens when you boil an egg — the albumin in the egg white turns into a solid (delicious) mass.

Now that we know a bit more about protein structure, it was clear what was going on when an enzyme was denatured. Consider a typical serine protease with its catalytic triad of 3 amino acids (aspartic acid, histidine, serene) which have to be correctly juxtaposed in 3 dimensional space for the enzyme to work. However, in a typical enzyme, aspartic acid is 45 amino acids away from histidine on the linear protein chain. Serine is even farther away 92 amino acids and in the other direction to boot. Heating the protein causes the chains to contain more kinetic energy, the protein chain (polypeptide backbone if you’re fancy) flops around, and the 3 amino acids separate from each other, and in the case of albumin, they never find their way back.

So denaturation came to be associated with the idea of an unstructured protein (meaning really a protein with multiple structures changing into each other all the time). For more details on this see http://luysii.wordpress.com/2010/08/04/why-should-a-protein-have-just-one-shape-or-any-shape-for-that-matter/ and http://luysii.wordpress.com/2010/10/24/the-essential-strangeness-of-the-proteins-that-make-us-up/. I find it nothing short of miraculous that the proteins making us up have just a few 3 dimensional shapes (conformations of the protein backbone), e.g. that any protein is structured at all. The two links will tell you why I think this way.

However some bacteria have a protein which functions in this disordered state. It’s called HdeA and it is found between the two layers of the cell membrane in Gram negative bacteria such as E. Coli and Shigella. The region between the two layers of the membrane is called the periplasm. The outer membrane is quite leaky, so when an animal ingests the bacterium, it is exposed to the acid conditions in the stomach (which can be as concentrated as 1 MOLAR HCl (e.g. pH = 1). This causes most normal proteins to ‘denature’ — e.g. lose their 3 dimensional shape and become unstructured.

Enter HdeA, which has a nice shape and forms a dimer at physiologic pH (e.g. around 7). When exposed to acid, the dimer splits apart and the protein becomes ‘unstructured’ — but certainly not denatured in the old sense, because it is the unstructured form of HdeA which is functional. It serves as a molecular chaperone, using its floppy protein backbone, to bind and protect other proteins which have become unstructured due to the acid pH. Amusing no? Anything not expressly forbidden, must occur (Gell-Mann on particle physics on the way to discovering the 8fold way)

Here are a few references and some gory details for the aficionado.

[ Proc. Natl. Acad. Sci. vol. 106 pp. 5557 - 5562 '09 ] HdeA is a bacterial chaperone protein found in the periplasm which is activated by pH’s under 3 (which the ingested bacteria find themselves in as soon as they hit the stomach, because the outer membrane of gram negatives is permeable to molecules smaller than 600 Daltons). It is one of the smallest chaperones known (mass 9.7 kiloDaltons). HdeA undergoes an acid-induced dimer to monomer transition. It functions as a disordered monomer without the need for ATP. Activation exposes the hydrophobic dimer interface which is critical for substrate binding). The partially unfolded character of active HdeA allows the chaperone to adopt different conformations as required for recognition and high affinity binding of different substrate proteins. So the disordered state is crucial to function and one can’t equate disordered with denatured.

[ Proc. Natl. Acad. Sci. vol. 107 pp. 1071 - 1076 '10 ] Most molecular chaperones are either ATP dependent or rely heavily on their ATP dependent chaperone counterparts (??) to promote protein folding. There is no ATP in the bacterial periplasm which is permeable to the outside. However, there is a chaperone there in E. Coli and Shigella called HdeA. It binds to substrates at low pH (preventing aggregation). When pH is neutralized, the proteins are released. Unfolding and dissociation of HdeA into monomers caused by low pH, actually activates is chaperone function by inducing the exposure of structurally plastic, high affinity binding sites for unfolding proteins on HedA, allowing it to prevent protein aggregation. Partially unfolded HdeA monomers are quite flexible, allowing it to bind to a variety of substrates, some of which are much larger than the 9.7 kiloDalton HdeA itself. Inactivation of HdeA is triggered by pH neutralization, which induces its refolding and dimerization.

Next up, two background posts and then a longer post on the most interesting paper I’ve read in the past 5 years.

How to spread the new H7N9 flu

People are naturally nervous about the new strain of influenza virus (H7N9) which, as of 5 April had killed 6 people. Eerily the new flu emerged in Asia almost exactly 1 decade after the SARS epidemic. The causative agent of SARS is a Coronavirus, a completely different virus from influenza. To add to the confusion, in the past 9 months a new strain of Coronavirus has emerged in the Middle East, with a high initial case fatality rate (11/16).

My wife and I were in Hong Kong for the past few weeks for a happy family event, and the horror of the SARS epidemic was widely reported on TV and newspaper (interviews with survivors etc. etc.). I’d estimate that, on any given street in Hong Kong, Beijing, Kyoto, Osaka between 1 – 5% of people are wearing masks covering their nose and mouth. This was not a reaction to the news of the new flu (which came out only 6 days ago), but an attempt by those ill with any febrile illness to avoid spreading it.

First, a bit of reassurance. The most severe cases of any epidemic are always the ones by which it announces its presence. So the high case fatality rate (6/16) reported so far almost certainly won’t hold up. Later on, after the causative organism has been identified, and the immune response to it worked out (involving proteins attacking the bug — e.g. the antibodies), we always find that there were hordes of people who had only a mild illness or who weren’t sick at all (except for AIDS, but even there the most severe cases came to light first). However you don’t need a high fatality rate for an epidemic to be lethal — the 1918 flu had a case fatality rate of 10 – 20% yet it killed between 50 and 100 million people.

You couldn’t come up with a better way to spread a respiratory virus that what happened at JFK airport at two midnights ago (it’s the morning of the 6th here in the USA). Two large flights arrived at about the same time — the Cathay Pacific flight we took from Hong Kong had around 200 people. The other flight seemed equally large. Everyone had to go through immigration, showing passports etc. So upwards of several hundred people came off the planes and into a corridor perhaps 15 – 20 feet wide 10 feet high and several hundred feet long. There was one immigration official for US citizens and perhaps 2 more for the non citizens. So there we were, for well over an hour packed cheek by jowl in this space as people were processed through.

If you can think of a better way to spread an infectious virus between a group of unrelated people who will disperse all over New York City, and probably all over America, I’d like to hear it.

Off to China in the Morning

Not much blogging in the past few months, not that there hasn’t been fascinating stuff to write about. Fortunately happy family events have kept me away.

The 40s seem to be the new 20s, as 3 family members are getting married in the next few months at ages 42, 45 and 46. We’re off to a Chinese Wedding Banquet for our oldest and his wife, followed by a wedding of our niece, followed by a wedding of our youngest son — all in the next 3 months. So stay well and keep thinking.

I am sweating the health of any progeny to emerge. For why, see the following post http://luysii.wordpress.com/2012/08/30/how-fast-is-your-biological-clock-ticking-ii-latest-results/

Q. E. D

The following are from two posts in August 2011, two months after Chavez first let the world know he was being treated for cancer.

My opinion of docs who diagnose over the phone, or who render opinions on people they’ve never seen is not high, although we all indulge in this from time to time. The worst example is that of the

1,189 PSYCHIATRISTS SAY GOLDWATER IS PSYCHOLOGICALLY UNFIT TO BE PRESIDENT! That determinedly flamboyant headline dressed the cover of Fact magazine one month before the presidential election of 1964. The entire issue was an examination of the “unconscious of a conservative,” based largely on answers to a questionnaire sent to the 12,356 psychiatrists listed by the American Medical Association. Of the 2,417 who replied, 657 said Barry Goldwater was fit for the presidency, 571 declined to take a position, and 1,189 called him unfit—the latter in no uncertain terms. Some of their opinions: “emotionally unstable,” “immature,” “cowardly,” “grossly psychotic,” “paranoid,” “mass murderer,” “amoral and immoral,” “chronic schizophrenic” and “dangerous lunatic.” One psychiatrist even felt that a proposed Goldwater visit to Hitler’s Berchtesgaden “is enough to convince me of his strong identification with the authoritarianism of Hitler, if not identification with Hitler himself.”

The unprofessional—not to say unbalanced—nature of such remarks brought immediate condemnation from the A.M.A. and the American Psychiatric Association. It said more about the state of American Psychiatry at the time than it did about Goldwater.For more details see: http://www.time.com/time/magazine/article/0,9171,838361,00.html#ixzz1WemleKVu

But here I am, about to indulge in the same thing concerning a very public figure. Why? Because what I’m about to say has received absolutely no attention in the press that I can find. First, look at these 3 pictures of Hugo Chavez.

http://www.guardian.co.uk/commentisfree/2011/jul/24/hugo-chavez-cancer-popular 24 July

http://www.guardian.co.uk/world/2011/aug/01/hugo-chavez-hair-cut-venezuela 1 August

http://www.guardian.co.uk/world/hugo-chavez 31 August

What’s the point? The rather remarkable change in his facial appearance over this short period of time. In just 6 weeks or so he has developed the classic face of someone receiving very high doses of corticosteroids (Cushingoid facies). The loss of hair due to his chemotherapy is irrelevant — it happens to most and is reversible when the chemo stops.

It also implies either that his docs are grossly overtreating him or that he is a very sick man. Doses of corticosteroids high enough to produce such massive facial change should never be used lightly. Back in the day, this was all I had for the flareups of multiple sclerosis, and it was never easy on patients.

We do not know what sort of cancer he has, if it has spread, and if so, how far. If his cancer was curable don’t you think it would have been trumpeted in one of his nearly daily press releases?

More worrisome for Chavez, is the fact that high doses of corticosteroids, invariably produce side effects. One you are seeing — the change in facial appearance. Two others are the invariable worsening of diabetes (should he have it) and the much increased possibility of stomach ulcers and bleeding. Both are fairly easily managed, particularly ulcers — none of my MS patients ever got ulcers because I began treating them as if they already had one (e.g. milk and maalox) when I started the corticosteroids. This was long before we know about Helicobacter and ulcers

High doses of corticosteroids usually produce a sense of euphoria. Cognitive processes aren’t as good, and they are one of the few known causes of reversible cerebral atrophy.

Far more worrisome for Venezuela and the rest of us, is the psychosis occasionally seen with high doses of corticosteroids. He is a man of enormous power, and hopefully no one has given him nuclear weapons.

So like my Cuban friend’s mother who prays for Castro’s health because her mother (who played cards with him when they were both young) is determined to outlive him, we must hope for a peaceful conclusion to Hugo’s illness.

From another post in August 2011

Also if he had a curable form of cancer, don’t you think he’d have told us exactly what it is? More likely, he’s putting on a front so his regime doesn’t collapse. Years and years ago I was a member of the Council on Foreign Relations in a western town. Various speakers were brought in — General Maxwell Taylor, etc. etc. The most interesting was the current Egyptian ambassador (or an attache). He said that the governments in the mideast were all ‘one bullet governments’ — which was all it would take to change their direction radically –all were run by one man at the top — this before the assassination of Anwar Sadat.

At least we see Chavez. Recall the last hospitalization of Yasser Arafat in France. We were told that everything was going well. What we were not told until very late, was that all this information was from the family and not from the people taking care of him. The investigative press was nowhere to be found.

This is unlikely to change. The powerful will always be able to warp the medical system to their desires. Think Michael Jackson, or even president Woodrow Wilson (incapacitated by a variety of strokes in his last years in office).

Now on to the present.
We are told by Chavez or someone permitted to speak for him, that he has a 2 centimeter lesion, either at the site of the old surgery or near it. Assume, for better or worse, that this is true. What does it mean? Well, one of three things:

1. Stop calling this a lesion. Only tumors act like this. No one gives chemotherapy enough to make your hair fall out for ‘lesions’ that aren’t tumors.

2. They couldn’t get the whole tumor out (meaning it’s incurable), and despite the high doses of steroids he’s on (recent pictures of him show his face even more Cushingoid than the 3 cited above) the tumor has grown further and needs to be removed (for any of several reasons, none of which is good).

3. At the time of the initial surgery, they thought they had removed the tumor, and the present 2 centimeter lesion has grown from something they didn’t see, because it was too small. Assume that what they missed was 1 milliMeter in diameter. Anything larger wouldn’t have been missed (assuming the people operating on him were competent — but ask Fidel about that — he’s still recovering years later from whatever they did). Since the lesion now 2 centimeters, this means that its volume in milliMeters is 4188 cubic milliMeters (4/3 pi r cubed, with r = 10). This is roughly 12 doublings of the tumor, or around 1 doubling every 17 days. The chances of a benign tumor growing this fast are remote (although my late mother had exactly that in her pelvis and lived another 40 years).

Are molecular oncologists looking under the lamppost?

There’s an old joke about a drunk who lost his keys coming home from the bar one night. Daybreak found him still crawling around searching under a lamppost. A passerby asked him why he didn’t look elsewhere. Drunk’s answer: “That’s where the light is”

The molecular biology you need to understand the following can be found in the 5 posts in the “Molecular Biology Survival Guide”. Here’s the link http://luysii.wordpress.com/category/molecular-biology-survival-guide/

The parts of the genome we understand the best are the parts that code for protein. The Cancer Genome Atlas spent a lot of money (1.5 Billion $) looking at genes coding for protein. They started with the most highly curated (translation: hopefully valid) set of genes. There have been tons of papers coming out of the project. Unfortunately, all we know is that every cancer studied so far has lots of mutations in the protein coding genes (the average breast or colon tumor has 90+ such mutations). Many of the mutations found were in previously known cancer causing genes (oncogenes). It would be great if, say, the same few genes were mutated in a given type of cancer. Unfortunately this isn’t the case. There is very little overlap in the mutations between two tumors of the same type. Of course this bears out the well recognized clinical fact not all tumors from organ X (say breast) act the same, even when they are sub classified by the way they look under the microscope (histological type).

This brings us to [ Science vol. 339 pp. 957 - 959 - 961 '13 ]. Once you venture away from the parts of of the genome coding for the amino acids of a protein, the next best understood parts, are those immediately in front (5′ to) the gene itself. The closest element is called the promoter, and is usually within 100 base pairs of the site at which transcription of DNA into RNA begins. Then farther out (sometimes thousands of base pairs out) come the enhancers, which help transcription factors do their work.

TERT is a protein which helps to keep the ends of chromosomes (telomeres) intact. This work looked at the promoter rather than the protein itself, and found two mutations. Together they were found in an astounding 50/70 melanomas, and 24/150 of a variety of cancer cell lines. I think this is much, much higher than any particular oncogene was found mutated in the Cancer Genome Atlas. The net effect of the two mutations was to make binding of a type of transcription factor (ETS) easier, resulting in more TERT being made.

So it’s time to start looking at the 98% of the genome NOT coding for protein. The problem with looking here, is that we really don’t know what it’s doing. The days when it was called junk are mercifully behind us. The second problem, is that we’re going to find changes from the ‘standard’ genome (which really doesn’t exist — the average infant contains 30 mutations not present in either parent) and we have no clue as to how to interpret them.

Everett Koop M. D. RIP

Not many outside medicine know just what he did before becoming surgeon general and famous. He essentially invented the subspecialty of pediatric surgery. Sure, surgeons had been operating on kids from time immemorial, but that’s all Koop did. One of his triumphs was esophageal atresia, meaning that in a newborn part of the esophagus was either absent or too small to pass even fluids, meaning death. The size of the organ in the newborn is a pencil or smaller, and Koop figured out a way to replace or hook up (anastomose) the parts of normal size.

As a med student in Philly, I was lucky enough to make rounds with him at CHOP (Children’s Hospital Of Philadelphia) in the 60′s. He was a typical Pennsylvania Dutchman, very solid, no nonsense, serious, not pompous, rather reserved.

Probably the most accomplished Surgeon General we’ve ever had. I was particularly appalled when Senator Ted Kennedy mau-mau’ed him. Koop was devout and against abortion, and the attacks on his character by the hero of Chappaquiddick were disgusting to those of us who knew him.

Even though Reagan didn’t want him to do it, he was very outspoken about AIDs, and didn’t try to sweep it under the rug as a punishment from God etc. etc. This prominent and early focus probably saved millions of lives, as ignoring it, would have just helped it spread even faster and farther. This is basically the physician’s focus — to deal with the world as it is, not as we wish it to be, and do what we can even for those whose behavior brought misfortune on them. Koop was just being a doc.

To Kennedy’s credit, he later apologized to Koop.