Category Archives: Medicine in general

Vaping — don’t do it until we know more

If you have kids, I’d advise them to stop vaping entirely until we know more. Here’s why — granted that there have been ‘only’ several hundred cases of ‘lung injury’ and a few deaths  in a 300+ million population, but in any new illness (AIDs, SARs, Legionnaire’s diseases) only the most severe cases are seen first.  

This is exactly the way it was with AIDs, the first few cases seroconverting (showing they’d been infected with the virus) had their immune system collapse almost immediately after infection.  As time wore on, we’d see seroconverters who remained healthy for 1 year, 2 years, 5 years, because (for reasons we still don’t understand) they were resistant to the virus or had a stronger immune system.  But eventually they got sick and died as well.

So it is with vaping related lung illness.  How many more cases we’ll see in  more resistant individuals in the coming years isn’t known. Will we have a nation of 30 year olds crippled with chronic lung disease?  Unlike AIDS, SARS or Legionnaire’s disease where there is a single organism, there are thousands of vaping products, and what people are putting into the machines is completely unknown.  Perhaps it’s just one drug.  Perhaps it’s a contaminated drug.  Perhaps its the particular machine.  At this point we don’t know.  It’s just like the early days of the AIDs epidemic — plausible theories abound and reliable data is scarce.  I was practicing medicine when AIDs came out in the late 70s and it was scary as hell, not knowing what was causing it.  At least with this we’re pretty sure it’s the vaping, given the age distribution and the positive histories in all.

We have one excellent example of a genetic condition predisposing to lung disease — alpha1 antitrypsin deficiency predisposes to emphysema and chronic obstructive pulmonary disease  — https://en.wikipedia.org/wiki/Alpha1_antitrypsin.  It would be useful  to see how many of the vaping cases have this deficiency.

This just in – according to the Wall Street Journal 2 hours ago 31 October ’19 ago the CDC says there have been 1,888 cases with 37 deaths.  Hopefully this is NOT the tip of the iceberg  — but probably it is.

Addendum 1 Nov ’19 I wrote this to a niece who has an 18 year old daughter entering college.  She is a teacher in a standard American high school (not in the ghetto, not filthy rich).  If any one has boots on the ground she does. Her response:  “Yes it’s very common in high school” — scary.

Addendum 8 Nov ’19  — The following comment by Peter Shenkin is so important that it belongs in the body of the blog proper —

It’s pretty impressive, but these are early times in the investigation.

If you have kids, I’d advise them to stop vaping entirely until we know more. Here’s why — granted that there have been ‘only’ …

You wrote: “Vaping — don’t do it until we know more”

We now know more; source of the following quote is at the end.

“CDC Announces “Major Breakthrough” that I Recognized and Reported Two Months Ago; Outbreak is Almost Certainly Not Associated with Legal Nicotine Vapes
Minutes ago, the Centers for Disease Control and Prevention (CDC) announced what they called a “major breakthrough” in its investigation of the vaping-associated respiratory illness outbreak. They tested lung tissue samples from 29 case patients and all 29 (100%) were found to contain vitamin E acetate oil.

This finding does represent a major breakthrough for four reasons:

1. The vitamin E acetate oil was detected in the actual lung tissue of the case patients.

2. The vitamin E acetate oil was detected in every single one of the lung tissue samples from these 29 case patients.

3. The samples came from 10 different states, confirming that the outbreak seems to have a common cause, rather than geographic variation.

4. Three of the patients whose lung samples revealed vitamin E acetate had reported using only nicotine-containing products, thus confirming that there is significant under-reporting which may explain why about 11% of the patients do not report vaping THC.”

The above quote is from: https://tobaccoanalysis.blogspot.com/2019/11/cdc-announces-major-breakthrough-that-i.html.

Full disclosure: Michael Siegel, a Public Health and Epidemiology doc who writes this blog, is my first cousin once removed. In another blog entry, he lambasts the FDA for disallowing mint vaping liquids while giving cigarette companies a pass on mint-flavored cigarettes.

Eat meat without worry (but you can feel guilty if you want)

From an article in the New York Times 1 October 2019  “In a statement, scientists at Harvard warned that the conclusions “harm the credibility of nutrition science and erode public trust in scientific research” “.

Strong stuff indeed.  Are they talking about Trump and the post-truth era?

Not at all. They are talking about a study in the Annals of Internal Medicine saying that the evidence that meat is bad for you is lousy, and not to be relied on.

To which I say, Amen.

— Here’s a link to the actual article — https://annals.org/aim/fullarticle/2752326/effect-lower-versus-higher-red-meat-intake-cardiometabolic-cancer-outcomes  — which the journal claims is freely available.

The authors looked at large numbers articles on the health effects of meat consumption to see if the conclusions that meat was harmful were warranted by a statistical analysis of the study.  In most cases they weren’t, or if they were, the evidence was weak.

Naturally there has been a counterattack, saying that one of the authors accepted money from the meat industry.  So what.  The studies are out there in print.  Statistical analysis is statistical analysis, and critics are welcome to perform their own statistical analyses of the papers.

This is far from the only example of dietary advice based more on hope and ideology than anything else.  A copy of two old posts (11/18 and 3/15) on the subject appears after the **

“erode public trust in scientific research”

This is exactly what I used to worry about when hysteria about common things causing cancer was at its height.  Joe sixpack’s logical conclusion to such things was — what the Hell, if everything causes cancer I might as well smoke.

Here are four things which medicine knows which are very likely to be true 50 years from now

l. Don’t smoke
2. Don’t drink too much (over 2 drinks a day), or too little (no drinks). Study after study has shown that mortality is lowest with 1 – 2 drinks/day
3. Don’t get fat — by this I mean fat (Body Mass Index over 30) not overweight (Body Mass Index over 25). The mortality curve for BMI in this range is pretty flat. So eat whatever you want, it’s the quantities you must control.
4. Get some exercise — walking a few miles a week is incredibly much better than no exercise at all — it’s probably half as good as intense workouts — compared to doing nothing.

Not very sexy but likely to still be true in 50 years.

There is tremendous resistance of researchers to having their conclusions disputed.  Another brouhaha concerns how much you should weigh.  Over 50 the lowest mortality rates occur with body mass indices (BMIs) between 25 and 30 (which currently is called overweight). A post on the subject appears after the ****BMI

**

Published 11/18

Eat what you want, no one really knows what a healthy diet is.

All dietary recommendations are based on sand so eat what you want and enjoy your Thanksgiving meal.  How can I say this? Just in time for Thanksgiving, the  august pages of Science contain the following article entitled “Dietary Fat:  From Foe to Friend ?” [ Science vol. 362 pp.  764 – 770 ’18 ].  Think I’m kidding?  Here is a verbatim  list of NINE current controversies (translation — not settled science) from the article.

1. Do diets with various carbohydrate-to-fat proportions affect body composition (ratio of fat to lean tissue) independently of energy intake? Do they affect energy expenditure independently of body weight?

2. Do ketogenic diets provide metabolic benefits beyond those of moderate carbohydrate restriction? Can they help with prevention or treatment of cardiometabolic disease?

3. What are the optimal amounts of specific fatty acids (saturated, monounsaturated, polyunsaturated) in the context of a very-low-carbohydrate diet?

4. What is the relative importance for cardiovascular disease of the amounts of LDL cholesterol, HDL cholesterol, and triglycerides in the blood, or of lipoprotein particle size, for persons on diets with distinct fat-to-carbohydrate ratios? Are other biomarkers of equivalent or greater importance?

5. What are the effects of dietary fat amount and quality across the lifespan on risk of neurodegenerative, pulmonary, and other diseases that have not been well studied?

6. What are the long-term efficacies of diets with different carbohydrate-to-fat proportions in chronic disease prevention and treatment under optimal intervention conditions (designed to maximize dietary compliance)?

7. What behavioral and environmental interventions can maximize long-term dietary compliance?

8. What individual genetic and phenotypic factors predict long-term beneficial outcomes on diets with various fat-to-carbohydrate compositions? Can this knowledge inform personalized nutrition, with translation to prevention and treatment?

9. How does variation in the carbohydrate-to-fat ratio and in sources of dietary fat affect the affordability andenvironmental sustainability of diets?

Then totally ignoring the above controversies — they say they agree on such bromides as

l. With a focus on nutrient quality, good health and low chronic disease risk can be achieved for many people on diets with a broad range of carbohydrate-to-fat ratios.

2. Replacement of saturated fat with naturally occurring unsaturated fats provides health benefits for the general population. Industrially produced trans fats are harmful and should be eliminated. The metabolism of saturated fat may differ on carbohydrate-restricted diets, an issue that requires study.

Basically I think you can eat what you want. Perhaps some day the research needed to base dietary recommendations on solid data will have been done, but that day is not here.

Here is an older post (March 2015) written when the dietary guidelines were changed yet again.

The dietary guidelines have been changed — what are the faithful to believe now ?

While we were in China dietary guidelines shifted. Cholesterol is no longer bad. Shades of Woody Allen and “Sleeper”. It’s life imitating art.

Sleeper is one of the great Woody Allen movies from the 70s. Woody plays Miles Monroe, the owner of (what else?) a health food store who through some medical mishap is frozen in nitrogen and is awakened 200 years later. He finds that scientific research has shown that cigarettes and fats are good for you. A McDonald’s restaurant is shown with a sign “Over 795 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 000 Served”

Seriously then, should you believe any dietary guidelines? In my opinion you shouldn’t. In particular I’d forget the guidelines for salt intake (unless you actually have high blood pressure in which case you should definitely limit your salt). People have been fighting over salt guidelines for decades, studies have been done and the results have been claimed to support both sides.

So what’s a body to do? Well here are 4 things which are pretty solid (which few docs would disagree with, myself included)

l. Don’t smoke
2. Don’t drink too much (over 2 drinks a day), or too little (no drinks). Study after study has shown that mortality is lowest with 1 – 2 drinks/day
3. Don’t get fat — by this I mean fat (Body Mass Index over 30) not overweight (Body Mass Index over 25 and under 30). The mortality curve for BMI in this range is pretty flat. So eat whatever you want, it’s the quantities you must control.
4. Get some exercise — walking a few miles a week is incredibly much better than no exercise at all — it’s probably half as good as intense workouts — compared to doing nothing.

Not very sexy, but you’re very unlikely to find anyone telling you the opposite 50years from now.

Typical of the crap foisted on the public (vitamin D and fish oil prevents cancer, heart disease and all sorts of horrible things) is it’s refutation once a decent study has been done

A large-scale trial has found no evidence that two popular supplements reduce the risk of cancer or the combined risk for a trio of cardiovascular problems.

JoAnn Manson at Brigham and Women’s Hospital in Boston, Massachusetts, and her colleagues recruited more than 25,000 healthy men and women in their fifties or older for a trial examining the effects of fish oil and vitamin D supplements. Some participants took both, others took only one type and the remaining participants took two placebos.

After an average of 5.3 years in the trial, participants who had taken fish oil had essentially the same likelihood of cancer as people who hadn’t. Compared with the placebo group, the fish-oil group had a lower rate of heart attack but the same rate of total cardiovascular events, a category that included heart attacks, strokes and death from cardiovascular disease.

Vitamin D supplements conferred no clear health benefits against cardiovascular disease or cancer, compared with a placebo.

Neurons synapsing with tumor cells, unbelievable but true

As a neurologist, I’ve seen more than enough breast cancer metastatic to the brain.  I never, in a million years, would have though that brain neurons would be forming synapses with them, helping them grow in the process.  But that’s exactly what two papers in the current Nature prove [ Nature vol. 573 pp. 499 – 501, 526 – 531 ’19 ]

The evidence is pretty good.  There are electron micrographs of brain metastases showing breast cancer cells acting like glia, surrounding a synapse between two neurons.  There are synaptic vesicles right next to the presynaptic membrane of the neuron which is apposed to the postsynaptic neuron (that’s what a synapse is after all). They are also present in the same neuron, whose membrane is tightly apposed  to a tumor cell, which stains positive for a type of glutamic acid receptor (the NMDAR).

Breast cancer types have been subdivided by the proteins they contain and don’t contain.  A particularly nasty one, is called triple negative — lacking the estrogen receptor the progesterone receptor and the herceptin receptor. Triple negative breast cancers account for 15 – 20% of all breast cancers, and some 40% of this group will die of brain metastases.  This paper may explain why.

The paper did some work using immunodeficient mice, transplanting human triple negative breast cancer cells into the brain.  Synapses formed between the mouse neurons and the breast cancer cells.

It is known that NMDAR signaling promotes growth tumor growth in other cancer types, and that increased NMDAR expression in breast cancer cells is associated with poor prognosis.

It is incredible to think that the brain is forming synapses with metastatic tumor cells to help them grow, but that’s what must be faced.

The excellent study confined itself to breast cancer metastatic to brain, but the study of other tumors (particularly lung) is sure to follow.

Good luck, RBG

Once again the press seems to dancing around a serious health problem of major public figure without saying just what it is.  Just about everyone admires RBG, but saying “The tumor was treated definitively and there is no evidence of disease elsewhere in the body” as the Supreme Court announced yesterday sounds wonderful doesn’t it?  Except that it isn’t.  8 months ago she had two metastatic tumors removed from her lung.  Sometimes it is possible to tell the tissue of origin from slides made from the tumors, but, as far as I can tell, this information was never released.  Now they say there is no sign of tumor elsewhere in her body (just as they said 8 months ago).

One hopes for the best for her.  Agree or disagree with her political philosophy, she is an admirable, brilliant and likable individual who has overcome a lot over the years.

Unfortunately Justice Ginsburg has metastatic cancer.  Her prognosis is not good.  As President Trump said “I’m hoping she’s going to be fine. She’s pulled through a lot. She’s strong, very tough.”

She had better be.

Addendum 28 August ’19

We’ll see how the right responds when RBG passes.  Here’s leftist folk hero Bill Maher on the death of one of the Koch brothers.  There are other similar responses.

What can dogs tell us about cancer, and (wait for it) sexually transmitted disease

What can 546 dogs tell us about cancer, and STDs (sexually transmitted diseases)?  An enormous amount ! [ Science vol 365 pp. 440 – 441, 464 3aau9923 1 –> 7 ’19 ].  You may have heard about the transmissible tumor that has reduced the Tasmanian Devil population from its appearance in ’96 by 80%.  The animals bite each other transmitting the tumor.  Only 10 – 100 cells are transferred, but death occurs within a year.  The cells survive because Tasmanian devels have low genetic diversity.

The work concerns a much older transmissible tumor (Canine Transmissible Venereal Tumor — aka CTVT) which appeared in Asia an estimated 6,000 year ago, and began dispersing worldwide 2,000 years ago.   Unlike the Tasmanian devil tumor, the tumor is usually cleared by the immune system.

The Science paper has 80+ authors from all over the world, who sequenced the protein coding part of the dog genome (the exome) to a > 100fold depth.   The exome contains 43.6 megabases.   The tumor is transmitted by sex, and the authors note that this mode of transmission nearly requires a rather indolent clinical course, as the animal must survive long enough to transmit the organism again.  This fits with syphilis, AIDs, gonorrhea.  Contrast this with anthrax, cholera, plague which spread differently and kill much faster.

So what does CTVT tell us about cancer?   Quite a bit.  First some background.  The Cancer Genome Atlas (CGA) was criticized as being a boondoggle, but it at least gave us an idea of how many mutations are present in various cancers– around 100 in colon and breast cancers.

Viewed across all dogs, the CTVT genome is riddled with somatic mutations (as compared to the genome of the dog carrying the tumor) –148,030 single nucleotide variants (3.4/1000 !) 12,177 insertion/deletions.  Of the 20,000 dog genes only 2,000 didn’t contain a mutation.   This implies that most genes in the mammalian genome aren’t needed by the cancer cells.  The CTVTs also show no signs of the high rates of chromosomal instability seen in human tumors.

The work provides evidence that cancer isn’t inherently progressive.  This gives hope that some relatively indolent human cancers (say cancer of the prostate) can be controlled.  This calls for ‘adaptive therapy’  — something that limits tumor  growth rather than trying to kill every cancer cell with curative therapy which, if it fails, essentially selects for more aggressive cancer cells.

Some 14,412 genes have 1 mutation changing the amino acid sequence (nonSynonymous) and 5,704 have protein truncating mutations.  The ratio of synonymous to non synonymous mutations is about 3 implying that the mutations which have arisen haven’t been selected for (after all the triplet code for 20 amino acids and 1 stop codon has 64 possibilities), so the average amino acid has 3 codons for it.  This is called neutral genetic drift.

They also found 5 mutated genes present in all 541 tumors — these are the driver mutations, 3 are well known, MYC, PTEN, and retinoblastoma1.

Tons to think about here.  I’ll be away for a few weeks traveling and playing music, but this work should keep you busy thinking about its implications.

 

 

Antioxidants — the dark side

There was (and probably still is) quite a vogue for antioxidants.  They were supposed to counteract aging, vascular disease, and prevent cancer.  So much so that 25 years ago, they were given in a trial to prevent lung cancer.  It didn’t work.  Here are the gory details

[ New England J. Med. vol. 330 pp. 1029 – 1035 ’94 ] The Alpha-Tocopherol, Beta-Carotene Trial (ATBC trial)  randomized double blind placebo controlled of daily supplementation with alpha-tocopherol (a form of vitamin E), beta carotene or both to see if it reduced the incidence of lung cancer was done in 29000 Finnish male smokers ages 50 – 69 (when most of the damage had been done).  They received either alpha tocopherol 50 mg/day, beta carotene 20 mg/day or both.   There was a high incidence of lung cancer (876/29000) during the 5 – 8 year period of followup.  Alpha tocopherol didn’t decrease the incidence of lung cancer, and there was a higher incidence among the men receiving beta carotene (by 18%).    Alpha tocopherol had no benefit on mortality (although there were more deaths from hemorrhagic stroke among the men receiving the supplement).   Total mortality was 8% higher among the participants on beta carotene (more deaths from lung cancer and ischemic heart disease).  It is unlikely that the dose was too low, since it was much higher than the estimated intake thought to be protective in the uncontrolled dietaryt studies.   The trial organizers were so baffled by the results that they even wondered whether the beta-carotene pills used in the study had become contaminated with some known carcinogen during the manufacturing process.  However, tests have ruled out that possibility.

Needless to say investigators in other beta carotene clinical trials (the Women’s Health Study, the Carotene and Retinoid Efficacy Trial) are upset.  [ Science vol. 264 pp. 501 – 502 ’94 ]  “In our heart of hearts, we don’t believe [ beta carotene is ] toxic”  says one researcher.

This is not science.

On to the present [ Cell vol. 178 pp. 265 – 267, 316 – 329, 330 – 345 ’19 ] in which the following appears “Recent evidence ‘suggests’ that antioxidants can also promote tumor formation”

The work concerns an animal model of nonsmallcell lung cancer (NSCLC).  I’m always wary of animal models, as they have been so useless in pointing to a useful therapy for stroke.  But the model is worth studying as it provides a mechanism by which antioxidants promote metastases of the primary tumor.  It is also worth studying because it shows the fiendish complexity of cellular biochemistry and physiology.

The only way you can appreciate complexity is by being buried in details. So let’s begin.  The actual details aren’t that important, just the number and the intricacy of them.

30% of humans with NSCLC have mutations in two genes (NFEL2L2, KEAP1).  The mutation in NFEL2L2 produces mutated NRF2 (a transcriptional activator of the antioxidant response gene set). The mutation doesn’t inactivate NRF2, but leaves it in a hyperactivated state.  KEAP1 normally inactivates NRF2, but not the mutated forms found in NSCLC.

One gene turned on by activated NRF2 is HO1 (heme oxidase).  During oxidative stress heme is released from heme containing resulting elevated intracellular heme lever resulting in the creation of free radicals which are inherently oxidative.  HO1 destroys heme. So this is one mechanisms of NRF2’s antioxidative activity.

Heme isn’t all bad, as it destabilizes BACH1 (not the composer)which is a prometastatic transcription factor.  Antioxidants (N-acetyl-cysteine, tocopherol [ vitamin E to you ] reduce heme levels stabilizing BACH1 (hence promoting metastasis).  Genes activated by BACH1 include glycolytic enzymes (hexokinase2, GAPDH).  So what?  Cancer cells use a lot of glycolytic enzymes even when oxygen is available — this is called aerobic glycolysis.  This is the Warburg effect.

I’m sure there’s far more to discover, but this should be enough to convince you that things are pretty complicated inside us.

The wages of inbreeding

Saguenay Lac St. Jean is a beautiful region of Quebec. It’s fairly isolated. Once you get to the top of the lake there is no way that you can drive farther north (no road).  We spent part of our 25th anniversary there.  The population bears a heavy load of genetic disease (through no fault of their own).

The reason is historical. Only 8,000 people emigrated from France to Quebec between 1608 and 1763. After the English victory that year  only 1,000 emigrated in the next 90 years.  In 1992, the population of the Saguenay  region was around 300,000 and Quebec itself 2,000,000.

This means that once the population began expanding with relatively little outside input, recessive genes began to meet each other, as in a large population there are so many more ways to make this happen than in a small one.

To keep the the nonBiologists reading this aboard, here is what recessive means. Our genome has 46 chromosomes.  We all have two sex chromosomes (either X and Y or X and X).  The other 44 chromosomes come in pairs.  This gives you two copies of each gene.  The classic recessive gene is that for sickle cell anemia.  If just one of the pair has the Sickle trait you are OK, if both have it, you have sickle cell anemia (which you definitely don’t want to have).  Actually if you live in Africa it is better if you have one gene with the trait as it makes you more resistant to Malaria.  This is why the trait became so common in Africans.  It’s natural selection in action (and in a human population to boot).  Just one good sickle gene (not carrying the trait) is enough to mask the effects of the bad gene, so the carrier is normal.   This is why sickle cell trait is called a recessive gene.

Here is one example.  The incidence of a muscle disease (myotonic dystrophy) worldwide is 2 – 14/100,000.  In the Saguenay region it is 189/100,000.

Even 20 years ago, the carrier frequency of many genetic disorders up there was quite high [ Proc. Natl. Acad. Sci. vol. 95 pp. 15140 – 15144 ’98 ]

Spastic ataxia 1/21

Type I tyrosinemia 1/22

Sensorimotor polyneuropathy 1/23

Pseudovitamin D deficient rickets 1/26

Cytochrome C oxidase deficiency 1/26

Cystinosis 1/39

Histidase 1/32

Lipoprotein lipase 1/43

Pyruvic kinase 1/64

Then again, there are all sorts of genetic diseases found only in this region.

Similar conditions may apply to the ancestors of today’s native Americans — for details see the previous post — https://luysii.wordpress.com/2019/07/16/the-initial-native-americans-were-quite-inbred/.  Incredible as it may sound, the rape and pillage of the conquistadores may have actually been good from a genetic point of view.  Similar considerations may apply to any pair of populations meeting each other for the first time.  Hard stuff indeed, but you can’t repeal biology.

So, from a genetic point of view, it’s good if you reproduce with someone from a different group.  It’s why I’m glad to have a Chinese daughter in law, 2 grand-nephews whose father is Hindu, and a Russian woman about to marry our nephew.

 

 

How general anesthesia works

People have been theorizing how general anesthesia works since there has been general anesthesia.  The first useful one was diethyl ether (by definition what lipids dissolve in).  Since the brain has the one of the highest fat contents of any organ, the mechanism was obvious to all.  Anesthetics dissolve membranes.  Even the newer anesthetics look quite lipophilic — isoflurane CF3CHCL O CF2H screams (to the chemist) find me a lipid to swim in.  One can show effects of lipids on artificial membranes but the concentrations to do so are so high they would be lethal.

Attention shifted to the GABA[A] receptor, because anesthetics are effective in potentiating responses to GABA  — all the benzodiazepines (valium, librium) which bind to it are sedating.  Further evidence that a protein is involved, is that the optical isomers of enflurane vary in anesthetic potency (but not by very much — only 60%).  Lipids (except cholesterol) just aren’t optically active.  Interestingly, alfaxolone is a steroid and a general anesthetic as well.

Well GABA[A] is an ion channel, meaning that its amino acids form alpha helices which span the membrane (and create a channel for ion flow).  It would be devilishly hard to distinguish binding to the transmembrane part from binding to the membrane near it. [ Science vol. 322 pp. 876 – 880 2008 ] Studied 4 IV anesthetics (propofol, ketamine, etomidate, barbiturate) and 4 gasses (nitrous  oxide, isoflurance, devoflurane, desflurane) and their effects on 11 ion channels — unsurprisingly all sorts of effects were found — but which ones are the relevant.

All this sort of stuff could be irrelevant, if a new paper is actually correct [ Neuron vol. 102 pp. 1053 – 1065 ’19 ].  The following general anesthetics (isoflurane, propofol, ketamine and desmedtomidine) all activate cells in the hypothalamus (before this anesthetics were thought to work by ultimately inhibiting neurons).  They authors call these cells AANs (Anesthesia Activated Neurons).

They are found in the hypothalamus and contain ADH.  Time for some anatomy.  The pituitary gland is really two glands — the adenohypophysis which secretes things like ACTH, TSH, FSH, LH etc. etc, and the neurohypophysis which secretes oxytocin and vasopressin (ADH) directly into the blood (and also into the spinal fluid where it can reach other parts of the brain.  ADH release is actually from the axons of the hypothalamic neurons.  The AANs activated by the anesthetics release ADH.

Of course the workers didn’t stop there — they stimulated the neurons optogenetically and put the animals to sleep. Inhibition of these neurons shortened the duration of general anesthesia.

Fascinating (if true).  The next question is how such chemically disparate molecules can activate the AANs.  Is there a common receptor for them, and if so what is it?

Happy fiscal new year !

A sad (but brilliant) paper about autophagy

Over the past several decades I’ve accumulated a lot of notes on autophagy (> 125,000 characters).  It’s obviously important, but in a given cell or disease (cancer, neurodegeneration) whether it helps a cell die gracefully or is an executioner is far from clear.  Ditto for whether enhancing or inhibiting it in a given situation would be helpful (or hurtful).

A major reason for the lack of clarity despite all the work that’s been done can be found in the following excellent paper [ Cell vol. 177 pp.1682 – 1699 ’19 ].  Some 41 proteins are involved in autophagy in yeast and more in man.  Many are described as ATGnn (AuTophagy Gene nn).

Autophagy is a complicated business: forming a membrane, then engulfing various things, then forming a vacuole,  then fusing with the lysosome so that the engulfees are destroyed.

The problem with previous work is that if a protein was found to be important in autophagy, it was assumed to have that function and that function only.   The paper shows that core autophagy proteins are involved in (at least) 5 other processes (endocytosis, melanocyte formation, cytokinesis, LC3 assisted phagocytosis and translocation of vesicles from the Golgi to the endoplasmic reticulum).

Experiments deleting or  increasing a given ATGnn were assumed to produce their biological effects by affecting autophagy.

The names are unimportant.  Here is a diagram of 6 autophagy proteins forming a complex producing autophagy

1 2 3

4 5 6

So 2 binds to 1, 3 and 5

But in endocytosis

1 2 3

5

form an important complex

In cytokinesis the complex formed by

2 3

5

is important.

Well you get the idea.  Knocking out 2 has cellular effects on far more than autophagy.  So a lot of work has to be re-thought and probably repeated.

Notice that all 6 functions involve movement of membranes.  So just regard the 6 proteins as gears of different diameters which can form the guts of different machines as they combine with each other (and proteins specific to the other 5 processes mentioned) to move things around in the cell.

Set points, a mechanism for one at last.

Human biology is full of set points.  Despite our best efforts few can lose weight and keep it off.  Yet few count calories and try to eat so their weight is constant.  Average body temperature is pretty constant (despite daily fluctuations).  Neuroscientists are quite aware of synaptic homeostasis.

And yet until now, despite their obvious existence, all we could do is describe setpoints, not explain the mechanisms behind them.  Most ‘explanations’ of them were really descriptions.

Here is an example:

Endocrinology was pretty simple in med school back in the 60s. All the target endocrine glands (ovary, adrenal, thyroid, etc.) were controlled by the pituitary; a gland about the size of a marble sitting an inch or so directly behind the bridge of your nose. The pituitary released a variety of hormones into the blood (one or more for each target gland) telling the target glands to secrete, and secrete they did. That’s why the pituitary was called the master gland back then.  The master gland ruled.

Things became a bit more complicated when it was found that a small (4 grams or so out of 1500) part of the brain called the hypothalamus sitting just above the pituitary was really in control, telling the pituitary what and when to secrete. Subsequently it was found that the hormones secreted by the target glands (thyroid, ovary, etc.) were getting into the hypothalamus and altering its effects on the pituitary. Estrogen is one example. Any notion of simple control vanished into an ambiguous miasma of setpoints, influences and equilibria. Goodbye linearity and simple notions of causation.

As soon as feedback (or simultaneous influence) enters the picture it becomes like the three body problem in physics, where 3 objects influence each other’s motion at the same time by the gravitational force. As John Gribbin (former science writer at Nature and now prolific author) said in his book ‘Deep Simplicity’, “It’s important to appreciate, though, that the lack of solutions to the three-body problem is not caused by our human deficiencies as mathematicians; it is built into the laws of mathematics.” The physics problem is actually much easier than endocrinology, because we know the exact strength and form of the gravitational force.

A recent paper [ Neuron vol. 102 pp. 908 – 910, 1009 – 1024 ’19 ] is the first to describe a mechanism behind any setpoint and one of particular importance to the brain (and possibly to epilepsy as well).

The work was done at significant remove from the brain — hippocampal neurons grown in culture.  They synapse with each other, action potentials are fired and postsynaptic responses occur.  The firing rate is pretty constant.  Block a neurotransmitter receptor, and the firing rate increases to keep postsynaptic responses the same.  Increase the amount of neurotransmitter released by an action potential (neuronal firing) and the firing rate descreases.  This is what synaptic homeostasis is all about.  It’s back to baseline transmission across the synapse regardless of what we do, but we had no idea how this happened.

Well we still don’t but at least we know what controls the rate at which hippocampal neurons fire in culture (e.g. the setpoint).  It has to do with an enzyme (DHODH) and mitochondrial calcium levels.

DHODH stands for Di Hydro Orotate DeHydrogenase, an enzyme in mitochondria involved in electron transfer (and ultimately energy production).   Inhibit the enzyme (or decrease the amount of DHODH around) and the neurons fire less.  What is interesting about this, that all that is changed is the neuronal firing rate (e.g. the setpoint is changed).  However, there is no change in the intrinsic excitability of the neurons (to external electrical stimulation), the postsynaptic response to transmitter, the number of mitochondria, presynaptic ATP levels etc.

Even better, synaptic homeostasis is preserved.  Manipulations increasing or decreasing the firing rate are never permanent, so that changes back to the baseline rate occur.

Aside from its intrinsic intellectual interest, this work is potentially quite useful.  The firing rate of neurons in people with epilepsy is increased.  It is conceivable that drugs inhibiting DHODH would treat epilepsy.  Such drugs (teriflunomide) are available for the treatment of multiple sclerosis.

The paper has some speculation of how DHODH inhibition would lead to decreased neuronal firing (changes in mitochondrial calcium levels etc. etc) which I won’t go into here as it’s just speculation (but at least plausible spectulation).