I just finished reading The Body - A Guide For Occupants by Bill Bryson. Bryson is a genius and a delightful writer who makes reading a real pleasure. If you’re interested in the human body — and you are an owner of one, so yes, you are — this book is worth reading. There you go, that’s all the review you need.

But this post has a deeper purpose. I spent about 15 years working in the top levels of biomedical research. I had an extraordinary ringside seat to watch the show of how medical progress is produced. If you’re young enough to not be dead from old age and if you’ve ever visited a doctor in the USA, the overwhelming odds are that you were told to eat some magic beans. I was able to see where those magic beans come from — not physically, but rather the idea forge of the conceptual chemistry behind it all, pharmacology.

I had a special place in pharmacology — I was not an expert but I provided technical engineering support to some of the world’s most competent and knowledgeable molecular biochemistry experts. I did not have to compete with them by writing papers or begging for their grant money. I believe this gave me a more realistic view of this work.

I worked with some incredible and brilliant super geniuses. I was always impressed with their ability to attack absurdly complex problems as if they were going to succeed. However, the entire time I was involved in the life sciences, everything I saw and experienced led to a coherent and strong impression which was this: humans know nothing about biology.

When I say that, think of filling your pockets with sand — you may think that with bulging pockets you’ve got a lot of sand. But if you’re standing on a beach, well, no, that’s probably a poor way to describe it. To say you have any sand when looking out over the vast sand-lined ocean would seem slightly pathetic. So it is for saying we humans know anything about anything related to molecular biophysics, biochemistry, genetics, molecular biology, cell biology, physiology, neurology, zoology, oceanography, and so on. It is probably more hubris than truth to not accept our profound ignorance.

Rather than me opine about it, I’ve excerpted quotes from this book which (incidentally!) make the case pretty clear.

…where the human body is concerned, the details are often surprisingly uncertain.

— p4

How this [genetics] works in detail is still largely a mystery to us.

— p7

…only 2 percent [of DNA] does anything demonstrably and unequivocally practical. Quite what the rest is doing isn’t known.

— p8

…techniques for analyzing ancient DNA means that we are learning more all the time and much of it is surprising — and some is confusing and some disputed.

— p18

The answer is that nobody knows. Your body is a universe of mystery. A very large part of what happens on and within it happens for reasons that we don’t know — very often, no doubt, because there are no reasons.

— p21

As early as 1945, in his Nobel acceptance speech, Fleming warned that microbes could easily evolve resistance to antibiotics if they were carelessly used. Seldom has a Nobel speech been more prescient.

— p43

Thinking is our most vital and miraculous talent, yet in a profound physiological sense we don’t really know what thinking is.

— p54

But what scientists learned from [a notable brain injury patient] was not so much how memory works as how difficult it is to understand how it works.

— p61

…there is a great deal that we still don’t know about smell, including exactly how it works.

— p88

As with every other part of your head, the mouth is a realm of complexity and mystery.

— p94

Take the tonsils. We are all familiar with them, but how many of us know quite what they do? In fact, nobody knows quite what they do.

— p94

Also mentioned: One notable study has shown that people who have their tonsils removed while young had a 44% greater chance of suffering a heart attack later in life. Who knew? The point is, apparently no one.

Discussing an opiorphin found in the mouth:

Because it is so dilute, no one is sure why it is there at all. It is so unassertive that its existence wasn’t even noticed until 2006.

— p99

For years, even textbooks spoke of a tongue map, with the elemental tastes each occupying a well-defined zone: sweet on the tip of the tongue, sour at the sides, bitter at the back. In fact, that is a myth…

— p101

Taste buds are actually present in the roof of the mouth, in the throat, in the stomach, heart, lungs, and even testicles. Why? No one knows.

That was the problem with bleeding [as a therapeutic medical treatment]. If you could tell yourself that those who survived did so because of your efforts while those who died were beyond salvation by the time you reached them, bleeding would always seem a prudent option.

— p132

This classic lack of a falsifiable hypothesis is what makes most of health care unscientific. Generally, only epidemiological studies, as opposed to explicit individual patient interactions, can even plausibly qualify as topics of proper scientific investigations. I believe senseless pharmacology is today’s therapeutic bleeding. The new field of pharmacovigilance could change that, but the fact is that pharmacology clearly quacks like quackery precisely because that field finally exists and is so new.

Our understanding of [hormones] is far from complete, and much of what we do know is surprisingly recent.

— p141

The immune system…There is a lot of chemistry involved. If you want to understand the immune system, you need to understand antibodies, lymphocytes, cytokines, chemokines, histamine, neutrophils, B cells, T cells, NK cells, macrophages, phagocytes, granulocytes, basophils, interferons, prostaglandins, pluripotent hematopoietic stem cells, and a great deal more — and I mean a great deal more.

— p199

On top of all that, every person’s immune system is unique, making immune systems harder to generalize, harder to understand, and harder to treat when they go wrong.

— p200

Much of what happens in the immune system at the cellular level is still very imperfectly understood. Quite a lot is not understood at all.

— p204

Sinuses are strange. … [They are] riddled with a complex network of bones, which are thought to help with breathing efficiency, though no one can say quite how. … Thirty-five million Americans suffer sinusitis every year, and about 20 percent of all antibiotic prescriptions are for people with sinus conditions (even though sinus conditions are overwhelmingly viral and thus immune to antibiotics).

— p213

What is perhaps surprising is how little we sometimes understand the causes of [respiratory] problems, and of no condition is that more true than asthma.

— p216

[At the beginning of the 20th century] asthma was a rare disease and not well understood. Today it is common and still not understood. The second half of the twentieth century saw a rapid increase in asthma rates in most Western nations, and no one knows why. … Indeed, where asthma is concerned, no one knows much of anything.

— p217

"You probably think asthma is caused by dust mites or cats or chemicals or cigarette smoke or air pollution", says Neil Pearce, professor of epidemiology and biostatistics at the London School of Hygiene and Tropical Medicine. "I have spent thirty years studying asthma, and the main thing I have achieved is to show that almost none of the things people think cause asthma actually do. They can provoke attacks if you have asthma already, but they don’t cause it. We have very little idea what the primary causes are. We can do nothing to prevent it."

— p218

Vitamin D, one of the most vital of all vitamins, can both be made in the body (where it really is a hormone) or be ingested (which makes it a vitamin again). … In the case of many micronutrients, scientists don’t know quite how much you need or even what they do for you when you get them. … Chromium levels fall steadily as we age, but no one knows why they fall or what this indicates. … For nearly all vitamins and minerals, the risk of taking in too much is as great as the risk of getting too little.

— p232

For all their importance, proteins are surprisingly ill-defined. Although all proteins are made from amino acids, there is no accepted definition as to how many amino acids you need in a chain to qualify as a protein.

— p234

Eight of the twenty amino acids cannot be made in the body and must be consumed in the diet.

— p235

Does this make them vitamins? No. Is the concept of a vitamin stupid? Yes.

Trans fats are essentially a form of slow-acting poison. … [in the mid-1950s] a biochemist … reported clear evidence of a link between high intake of trans fats and clogged coronary arteries, but his findings were widely dismissed, particularly with the influence of lobbying by the food processing industry.

— p236

It’s possible for doctors to go through medical school without being taught nutrition. … Perhaps nothing is more emblematic of the unsettled state of knowledge on the modern diet than the long and unresolved controversy over salt.

— p244

A possible contributing factor to this salt controversy: A 2016 study in the International Journal of Epidemiology found that researchers on both sides of the argument overwhelmingly cite papers that support their own views and ignore or dismiss those that do not.

— p245

That’s why you are told to eat more fiber: because it keeps your gut microbes happy and at the same time, for reasons not well understood, reduces the risk of heart disease, diabetes, bowel cancer, and indeed death of all types.

— p249

He addresses an ontological problem I’ve always found confusing: why is some E.coli bad and yet…

…most strains do us no harm and some are positively beneficial…

— p250

But is the problem now resolved and I have some kind of sensible answer? No. There are good strains and bad strains — the difference between them seems to be, tautologically, that one is good and one is bad. Later (p258) he points out that, "Two strains of E.coli have more genetic variability than all the mammals on Earth put together." Not helping!

The incidence of acute appendicitis in the rich world is about half today what it was in the 1970s, and no one is quite sure why. It remains more common in wealthy countries… though the rates in developing countries have been rising rapidly… but again no one knows why.

— p255

On the topic of the composition of poop:

We are a long way from understanding it all.

— p257

Sleeping is the most mysterious thing we do. We know that it is vital; we just don’t know exactly why. We can’t say with any certainty what sleep is for, what is the right amount for maximum health and happiness, or why some people fall into it with ease while other struggle perpetually to attain it.

— p260

Why the eyes move during REM sleep is uncertain.

— p263

How exactly melatonin relates to sleep is still not understood.

— p267

A seventy-year-old produces only a quarter as much melatonin as a twenty-year-old. Why this should be, and what effect it has on us, remain to be determined.

— p268

We are really at the beginning of our understanding of the importance of circadian rhythms for all living things…

— p269

No one understands why we yawn.

— p273

…until recently drug trials very often excluded women, largely because it was feared their menstrual cycles could skew results…. People had been assuming that women are just 20 percent smaller then men, but otherwise are much the same. We now know that there is much more to it than that… Such findings are seriously consequential because women and men can respond to drugs in very different ways — ways often overlooked by clinical trials.

— p283

Examples: phenylpropanolamine, Hismanal, Pondimin, and Ambien.

…Vaginal secretions were the only bodily fluid about which virtually nothing was known despite their importance to conception and a woman’s general sense of well-being.

— p284

This is quoting Mary Roach’s book Bonk and doesn’t say if anything more is known today.

Even now, there is a huge amount concerning female anatomy about which we are uncertain.

— p285

Discussing two large surveys that showed from 1950 to 1997 the length of an erect penis went from 6 inches to nearly 1 inch shorter:

Why is this? The bottom line is that we don’t know.

— p288

Why are sperm counts in Western countries lower than they formerly were? Among the suggested causes have been diet, lifestyle, environmental factors, frequency of ejaculation, and even (seriously) wearing tight underpants, but no one knows.

— p290

Also on sperm production:

…why such an extravagance of production, even at the lower end when only one sperm is required for conception, are questions that science has yet to answer.

— p291

For a decade or so [around 1900], [oophorectomy, removal of the ovaries] was the operation of choice for well-off women with menstrual cramps, back pain, vomiting, headaches, even chronic coughing. In 1906, an estimated 150,000 American women underwent oophorectomies. It more or less goes without saying that it was an entirely pointless procedure.

— p295

If you think that was fun times in the history of medical care, check out Walter Freeman jamming icepicks in the eyes of 2500 people to give them lobotomies.

Despite its lavish spending, the United States has one of the highest rates of both infant and maternal death among industrialized nations… The average cost of childbirth in the United States is about $30,000 for a conventional birth and $50,000 for a Cesarean, about three times the cost for either in the Netherlands. Yet American women are 70 percent more likely to die in childbirth than women in Europe…

— p298

I like to point out that the cost of childbirth as "health care" is absurd when you consider that a human being can not be more healthy than to have just given birth.

We are only beginning to understand the importance and nature of a woman’s vaginal microbiome. Various studies have found that people born by C-section have substantially increased risks for type 1 diabetes, asthma, celiac disease, and even obesity…

— p300

On top of all that [thwarting of microbiome functions], about four women in every ten are given antibiotics during delivery, which means that doctors are declaring war on babies' microbes just as they are acquiring them. We have no idea what the consequences this has for their long-term health, but it’s unlikely to be good.

— p301

Why can phantom pain in a lost limb last a lifetime? No one can yet explain why.

— p305

Exactly how pain works is, as you will gather, still largely a mystery.

— p305

We still don’t know exactly how the brain constructs the experience of pain…

— p307

Spinal cord injuries are dismayingly common. More than one million people in the United States are paralyzed from them.

— p311

Holy shit. Can that be true? More of the devastation of our horrific transportation mess.

Migraines are almost wholly a mystery.

— p313

Almost! I’ll return to that topic.

Medical science offered very little in the way of safe, lasting relief [from pain] back then [100 years ago]. We are not much further along now… …some 75 percent to 85 percent of people get no benefit at all from even the best pain drugs, and those who do get benefit don’t usually get much. … Pharmaceutical companies have poured billions and billions into drug development but have not come up with a drug that controls pain effectively and doesn’t cause addictions.

— p314

Opioid use has become such big business that we have now reached the surreal situation that pharmaceutical companies are producing drugs to alleviate the side effects of opioid overuse. Having helped to create millions of addicts, the industry is now profiting from medications designed to make their addiction a little more comfortable.

— p315

Nobody knows quite why placebos work, but they do… Placebos don’t shrink tumors or banish plaque from narrowed arteries. But then, come to that, neither do more aggressive painkillers, and placebos at least have never sent anyone to an early grave.

— p316

A report in The Journal of the American Medical Association concluded that the victims had been suffering from a "subtle but nevertheless primarily organic illness whose effects may include exacerbation of underlying psychogenic illness." Which is another way of saying, "We have no idea."

— p320

Though Paget’s findings [about breast cancer treatment] were correct and incontestable, no one paid any attention to them for about a hundred years, during which time tens of thousands of women were disfigured to a far greater degree than was necessary.

— p345

Quite early on, it was realized that radium accumulated in the bones of people exposed to it, but this was thought to be a good thing because it was believed that radiation was wholly beneficial. Radioactive products were liberally added to many medications, with sometimes devastating consequences.

— p345

E.g. Radithor.

During WW1 it was realized that mustard gas slows the creation of white blood cells. Thus was born chemotherapy. "What is quite remarkable," one cancer specialist told me, "is that we are basically still using mustard gases [as a foundation for chemotherapy]."

— p348

The unfortunate bottom line is that breast cancer screening doesn’t save a lot of lives. For every thousand women screened, four will die of breast cancer anyway (either because the cancer was missed or because it was too aggressive to be treated successfully). For every thousand women who are not screened, five will die of breast cancer. So screening saves one life in every thousand.

— p362

But at least it is a lot of fun for women and costs society nothing! Not!

We have reached the decidedly bizarre point in health care in which pharmaceutical companies are producing drugs that do exactly what they are designed to do but without necessarily doing any good. A case in point is the drug atenolol, a beta-blocker designed to lower blood pressure, which has been widely prescribed since 1976. A study in 2004, involving a total of 24,000 patients, found that atenolol did indeed reduce blood pressure but did not reduce heart attacks or fatalities compared with giving no treatment at all.

— p364

We rarely know, for instance, what happens when various medications are taken in combination.

— p366

See the relatively new field of polypharmacy for the full mess.

We don’t have any idea why we age, or actually we have lots of ideas; we just don’t know if any of them are correct. … It may be that [multiple] factors work together… Or it may be something else altogether. No one knows.

— p370

In sum, it’s clear that telomeres are important not just for understanding aging but also for understanding cancer, but unfortunately we are still a long way from fully understanding either.

— p371

Reviewing the animals that experience menopause: sheep, humans, narwhals, and humans:

Why any animals get it is a question yet to be answered.

— p373

Nobody is quite sure what amyloids do for us when they are working properly… How tau proteins relate to amyloids and how both relate to Alzheimer’s are also uncertain…

— p378

We can’t even definitively diagnose Alzheimer’s. The only certain way to identify the condition is postmortem…

— p379

[Alzheimer’s] is the third most common cause of death among older people… and we have no effective treatment for it at all.

— p380

That’s a lot of stumbling in the dark!

I would like to dig into one area of obnoxious ignorance a little more carefully because it is something I am forced to take personally: antioxidants. Have a look at this depressing situation.

Antioxidants are molecules that neutralize free radicals, so the thinking is that if you take a lot of them in the form of supplements, you can counter the effects of aging. Unfortunately, there is no scientific evidence to support that.

Most of us would almost certainly never have heard of either free radicals or antioxidants if a research chemist in California named Denham Harmon had not, in 1945, read an article about aging in his wife’s Ladies' Home Journal and developed a theory that free radicals and antioxidants are at the heart of human aging. Harman’s idea was never anything more than a hunch, and subsequent research proved it to be wrong, but nonetheless the idea has taken hold and will not go away. The sale of antioxidant supplements alone is now worth well over $2 billion a year.

"It is a massive racket," David Gems of University College London told Nature in 2015. "The reason the notion of oxidation and ageing hangs around is because it is perpetuated by people making money out of it."

"Some studies have even suggested that antioxidant supplements can be harmful", The New York Times has noted. The principal learned journal of the field, Antioxidants and Redox Signaling, noted in 2013 that "antioxidant supplementation did not lower the incidence of many age-associated diseases but, in some cases, increased the risk of death."

— p372

Ok, fine, some suckers waste their money on useless supplements — what’s the big problem? The problem for me is that people believe antioxidants are categorically beneficial for health and I know for a fact that is not correct. I know this because antioxidant preservatives will reliably trigger devastating migraines in my head.

What is very insidious is that "vitamin" E is one such molecule. The so-called vitamin E is something almost no humans ever have a deficiency of. Ingesting huge quantities can not make any sense at all when promoting health. However, at a high enough concentration, this kind of molecule (tocopherols) has the property of killing microbes. This is why it is liberally added to many processed foods.

I always read the ingredients of everything I eat and if I ever see vitamin E or any kind of tocopherols I will not eat it. While the quote from the book says that migraines are almost wholly a mystery, I have at least figured out exactly what cause mine and it’s garbage not-food like tocopherols. One of the things you often see next to the tocopherol item in an ingredients list is in parentheses: "(for freshness)".

I strongly advise anyone to avoid eating anything which has on its ingredient list "for freshness". (Especially TBHQ, BHT, BHA, and vitamin E aka d-tocopherols). Sure, unlike me, you may be able to not have your next 20 hours destroyed by pain far worse than any other you’ve ever imagined. But consider when a packaged food company has to add that crap, the product is definitely not fresh. Or wholesome in any way. It really is quite suspect. By avoiding such garbage, you will find that you’re eating real food that is simply higher in quality and better for you in all ways.

Some people believe that you can ignore those weird mystery ingredients in processed food. I however believe that you can have only one of the following two beliefs about small molecule chemistry.

  • Small molecule chemistry doesn’t do much and is safe to apply arbitrarily in food products.

Or!

  • Small molecule chemistry does something and pharmacological products are not completely inert.

Common sense and I lean heavily toward the latter. The complication is that even when a small molecule ligand binds correctly with its targeted receptor perfectly, it is inevitable that it will also bind with other unintended receptors. Which ones? As with almost everything that could be known about biochemistry and biology in general: we just do not know.

UPDATE 2020-02-20

Although this website has a bit of the character of a crazy homeless person on the bus, this description of the essential function of what antioxidants (endogenous and otherwise) decompose make it clear that simplistically getting rid of all reactive oxygen species (free radicals) may not be such a brilliant plan.

Even though the presentation of this material on this website is bizarre it seems reasonably well grounded and as factual as it can be. If nothing else this website is interesting and shows clearly that things are more complex than a simple "unlimited antioxidants are always good" narrative.

UPDATE 2020-03-11

You don’t have to read the article or the paper it’s writing about. Just check out the title and subtitle.

Bacteria in our guts break down dozens of popular drugs - Study suggests drugmakers should consider bacterial metabolism when designing and testing new drugs

The point there is that no matter what drugs you ingest, the metabolites that slosh around your system after your microbiome finishes randomly modifying them are going to be individual-specific and very hard to usefully predict. Let’s not even think about the implications to the endeavor I spent a lot of my career working on, rational drug design.

And…

My blog post here may answer a question posed in the title of another article I found today: Why Doctors Still Offer Treatments That May Not Help.

Regarding medical treatments initiated by doctors, the article says…

According to the analysis, there is evidence of some benefit for just over 40 percent of them. Only 3 percent are ineffective or harmful; a further 6 percent are unlikely to be helpful. But a whopping 50 percent are of unknown effectiveness.

Note that this says "some" benefit, not a cure!