Tuesday, July 17, 2018

The little things that keep us going

kw: book reviews, nonfiction, medicine, cellular biology, mitochondria

Did you ever hear of a buccal smear? If you take a teaspoon and gently scrape the inside of your cheek, and put some of the stuff on a microscope slide, that's a buccal smear. The four cells in this photo are cheek epithelial cells, stained with Methylene Blue, from just such a smear.

From the scale bar you can see that the cells are around 50 microns across. They are a little compressed. A typical cell of this sort is a roundish thing about 40 microns in diameter. Methylene Blue stains DNA very well, so each cell's nucleus is seen as an oval blob about 10 microns long.

Today we are interested in something that doesn't show in this photo, the mitochondria, the powerhouses of the cell. Each of the cells above contains around 1,000 mitochondria. Mitochondria vary in size, but here they would be about the size of E. coli bacteria, a micron in diameter and 2-4 microns in length. As it happens, there are a few small bacteria in this photo, the little dots such as the one near the arrowhead labeled "Cytoplasm". Imagine about a thousand of these in each of these cells.

Let's scale this up to a size we can better imagine, and magnify one of these cells by 100,000. Some museums have made models of cells on this scale. Then the cell would appear as a lumpish thing about 4x4x4 meters in size, the size of a big bedroom with a high (12-13 ft) ceiling. The cell's nucleus would be a meter across, not quite spherical. Consider it like a bean bag chair floating somewhere near the middle. The cell isn't just a bag of fluid. "Cytoplasm" is a very complex mix of fluids and organelles. About half of the cell volume is the fluid, called cytosol; "sol" indicates it is a semifluid colloid, not just watery stuff. Just under half of the "solid" material is the mitochondria, and a similar amount of space, or a little less, is taken up by the endoplasmic reticulum (ER to its friends), a highly folded array of membranes that handle protein synthesis. There are other organelles that we won't go into here. Some can be seen in the electron microscope view on the left in the image below.


(This image is © Pearson Education.) The mitochondria scale up to be about the size of a fat sausage, such as a salami, around 10cm in diameter and under half a meter long (say, 4" diameter and a foot long or so). So now you have a bedroom with a bean bag chair suspended in the middle surrounded by salamis, and we'll have to forego describing the "shape" of the ER, except to say that it is a lot like masses of folded blankets. Mitochondria vary in shape also, from nearly spherical to long and even branched. But the sausage shape is common.

So what is this all about? Earlier this year I noticed a rather dramatic shift in my energy level. It wasn't a one-day thing, but I could think back over a few months to "how things were." My usual temperature has been 97.8-98.0°F for many years. It went to 97.6 or less, where it still is. I thought it might be one of several side effects of a diuretic blood pressure pill I had been taking for a few months. If it was, it has been a permanent side effect! I've changed to three different blood pressure medications since then, and the current one seems to have no troubling side effects. But back to energy.

Mitochondria are the powerhouses of the Eukaryotic cell. That's the kind of biological cell that makes up all multicellular life, plus protozoans and fungi, including yeast. "Eukaryotic" is Greek for "Good kernel", referring to the distinct nucleus that contains the DNA. Bacterial cells don't have a nucleus; their DNA is a long, tangled loop attached to one point on the inner cell membrane.

Knowing this, I specifically looked for a book on the subject of mitochondria and their disorders. There was really only one choice in the popular press: Mitochondria and the Future of Medicine: The Key to Understanding Disease, Chronic Illness, Aging, and Life Itself, by Lee Know, ND. Doctor Know is a naturopath, so I was a little leery, but I was cheered by the even tone and lack of hysteria in his writing. He did a great deal of research to prepare the book, which he admits is little more than an outline of many subjects related to mitochondria.

From time to time in the book the author uses a metaphor from popular culture, the Midi-Chlorians of Star Wars. They are actually modeled on mitochondria, but have the added function (in that galaxy far, far away) of tuning certain people in to The Force, so that the Jedi and the Sith have rather magical powers.

The little mitochondria in our cells have almost magical powers themselves. The first part of the book discusses their structure, activities and origins. They almost certainly began as small bacteria that were incorporated into a larger bacterium as a symbiont, on the way to the development of the first Eukaryotic cell. It may be that all cell organelles began as bacterial symbionts, including the nucleus!

Now most of the genes that produce the components of the mitochondria are held in the cell's nucleus, and turned into appropriate proteins in the cell's ER. But a small number of critical bits of DNA are kept within each mitochondrion (5-10 copies per organelle), so that crucial operations can be performed as fast as possible, in seconds or minutes rather than hours or days.

In such a complex arrangement, a lot of things can go wrong. It is amazing that most of the world's people, and plants and animals, live out their lives with little to trouble them except predation. The main reason a wild wolf seldom lives more than seven years, while a pet dog frequently lives twice that long, is that once a wolf reaches middle age, something is going to come along and kill it, frequently a rival wolf. We usually prevent our dogs from killing one another.

But why should a middle-aged wolf slow down? And…why do we slow down? On my Dad's sixtieth birthday, I asked him, "What is it like?" He said, "It is a lot like being 25, except everything takes longer." Now that I am over 70, I agree. Particularly since the beginning of this year. So the second part of the book (of three parts) describes a whole host of things that can go bad as the mitochondria wear out. The section has the cute title, "The Dark Side of The Force".

Section three, equal in size to the other two, around 60pp, describes what we can do about it. The two biggest factors for mitochondrial health? More exercise and less eating, particularly for Americans! The author really believes in Severe Caloric Restriction (though his photos show little sign that he practices it himself). Most things that go wrong with mitochondria trace back to imbalances that lead to excess oxidative free radicals such as superoxide. While there are many products that promote "antioxidants" to mop up such stray molecules, both exercise and a sparse diet (rich in nutrients, but with minimum calories to deliver them) prevent most of the free radicals from forming in the first place. They keep the "electron chain" that mitochondria use to turn ADP into ATP tuned up and running in balance.

One item that is not exactly an antioxidant, but that operates that way among several other things, and that I've heard a lot about recently, is Coenzyme Q10, or CoQ10. It is made in our bodies. But production drops off as we age, after age 30. Some medications, such as statins for cholesterol reduction, hinder its formation, further reducing it, and slowing down our mitochondria. Also, its lack possibly permits them to suffer more rapid decay. The author admits that it is hard to make this stuff into a pill that will work. It is a medium-sized molecule, and is hard to get into solution. So that's something I'll look into. It is only one of a dozen or more nutritive materials he discusses, and among them one more stands out. Magnesium. I am very thankful that this essential mineral (not known to be so essential just a decade or so ago) is added to many supplements including the calcium supplement I use. As usual with a complex machine like the mitochondrion, magnesium does several good things. Without it, several bad things can happen. For example, we think of ATP (Adenosine trophosphate) as a "thing", but this "thing" needs a magnesium ion to shepherd it around. Less magnesium, less energy.

Fortunately, magnesium is easy to get and being a "salty" element it is easily absorbed. A magnesium atom sits at the center of the heme complex in chlorophyll the same way an iron atom sits in the heme complex of hemoglobin, which makes our blood red. The magnesium makes the heme green in plants. The greener the plant, the more magnesium. So eat yer darn greens! (By the way, hemocyanin, the heme complex with a copper atom inside, makes the blood of crabs blue. The "cyanin" part of the word refers to the blue color, not to cyanide).

There you have it. I'll keep a lookout for newer books on the subject. At present, this book stands out, and while it contains a lot of technical language, it is well explained, so the book is easy to read.

Tuesday, July 10, 2018

Even kidneys are political

kw: book reviews, nonfiction, medicine, kidneys, organ transplants, race

A good friend of mine was already on hemodialysis when I first got to know him. We are church friends. His life was quite restricted, not only by the need to visit the dialysis center 3-4 times weekly, but by the severe fatigue that is a side effect of the treatment. When your kidneys are not producing any urine, fluid accumulates. After a couple of days, you've gained a few extra pounds. Those pounds are extracted by the dialysis machine, along with urea and other toxins. But the best of the machines is a poor substitute for a real kidney. It will keep someone alive, but not very healthy. Just the rapid removal of fluid causes severe cramping and headaches.

Fortunately, my friend was able to receive a transplanted kidney a few years later. It made a huge difference in his life! He told me right after the transplant operation that the typical "cadaver kidney" lasts between 10 and 20 years, and then the body begins to reject it, in spite of the best anti-rejection medicines. He was a bit luckier than average; it lasted 19 years. Then he was back on dialysis.

This time, one of his daughters insisted that she be tested to see if she was a "good match", histologically speaking. And she was, a very good match indeed. She donated one of her kidneys, and he is back in comparative good health. Because the match is even better than before, and because of further advances in medical treatment, this kidney is more likely to last him the rest of a good life (he isn't as old as I, but old enough to make plans no more than a few years into the future).

My friend is Asian. I wonder what the outcome would have been if he were Black. After reading Hundreds of Interlaced Fingers: A Kidney Doctor's Search for the Perfect Match, by Vanessa Grubbs, M.D., it seems likely he'd have died by now. The book is partly memoir, partly a medical travelogue, and partly an exposure of a medical system that has not yet become free of racism.

Vanessa and her husband, Robert Phillips, are Black. As a Black woman in medical school, and as a Black, female M.D., she had trouble enough getting the residencies and fellowships she needed for her chosen specialty. Now, part of that may have been that her choices didn't solidify until she had nearly finished medical school. The "solidifier" was Robert. He was already in advanced renal disease when she met him, and being kept alive with hemodialysis.

Love is really blind, it seems. Knowing what she knew (not enough, it seems), she still fell in love with him. She offered him one of her kidneys. After a lot of discussion, and testing that showed how good the match was, he accepted. She had already found out that Blacks on dialysis typically wait an extra 2-4 years, compared to a White or Asian, for a transplant to become available. It is not just a numbers issue. Blacks are seldom put on the transplant list as early as Whites or Asians, and until recently priority on the list was according to time on the list, not time since dialysis became necessary. That has since been changed, but it is not the only inequity in the system.

You'd think, once the transplant was performed, everything would be copacetic. The transplant doctor made a minor error or two, errors of, as Dr. Grubbs puts it, "laziness." Another surgeon, a more diligent one, had to re-install the new kidney so its outlet would not clog! There is much more about issues that a White doctor would probably never notice, but that she did notice.

Along the way, there is a lot of information about kidneys and kidney disease. Dialysis patients seldom talk about their troubles outside their family; I know my friend was pretty quiet about it. But the plain fact is, a dryer-sized machine is, even as we approach the year 2020, a poor substitute for a quarter-pound organ. And it all comes down to glomeruli.

The title of the book describes an image like this one, a highly magnified portion of a glomerulus. The glomeruli (plural of glomerulus) are tiny, highly-structured tangles of blood capillaries situated each in its own capsule. The capillaries have some special features that make them efficient filters, to remove the right amount of fluid and toxins from the body. The toxin-laden fluid collects in the capsules. Tubes from all the capsules are gathered together to feed the ureters that send urine to the bladder.

A glomerulus is small. There are about four of them in each cubic millimeter (a pinhead) of inner kidney tissue; about 4,000 per cc. This comes to 2/3 of a million per kidney. And they aren't just passive filters. They contain enzymes and other active "machinery" that cooperate in blood filtration. It has been said that the kidney is second only to the brain in complexity.

Because of this complexity, it will probably be a good, long while before researchers figure out how to grow someone a new kidney from their own stem cells, making auto-transplanting a reality and eventually closing down most dialysis centers. It is one thing to grow someone a new ear or fingertip (we're nearly there right now); but even growing a liver would be easier.

I hope, long before auto-transplantation is developed, that the remaining racial disparities are dealt with. In addition to race, there is money. I'll let a quote from the book suffice:
"We get paid much more to keep someone on dialysis than to keep them off it…It's profitable to build another dialysis center, but we haven't figured out how to build comprehensive palliative care services."
The fact is, not everyone in end-stage renal disease should have dialysis. Until the kidneys totally fail, certain palliative care and other measures can afford a person a better quality of life. And even at the very end, some people have the fortitude to decide, "I've had enough of this. Uremia isn't the worst way to die; better than most. It's time to go." Very few doctors, who got into the business to "help people", usually internalized as "help people not die", are willing to offer a terminal patient every option, rather than just the options of "fighting the disease."

I am not sure how effective an activist Dr. Grubbs is, but the presence of this amazing book is a great first step to exposing some issues that have been swept under the rug.

Saturday, July 07, 2018

The ChRIstMas sEason

kw: book reviews, crime fiction, short stories, anthologies, christmas

It seems there is a book series for everything. For those who like to read a lot of crime fiction, I find the Soho Crime Series. The volume that caught my eye is titled The Usual Santas (no editor[s] named), and the title is that of a story within by Mick Herron.

The title story is perhaps the most memorable. Eight mall Santas have finished their service for the night, and gather together as is their wont for a bit of complimentary grub before going home. Also, as is their habit, they do not change out of their Santa costumes, preferring to not know who their compatriots are, though they have met this way, season after season, for many years. But they find a ninth Santa among them. They discuss how to determine who the "newcomer" might be. You didn't think I would tell you more than that, did you?

The eighteen stories are in three sets, lighthearted, dark, and warmhearted (each in its own twisted way). They are set all over the world, in all imaginable cultures among those that have adopted, at least in a mercantile way, the Christmas season. A Hindu street urchin with a flair for drawing ponders how to depict her close friend. POW's in North Korea (set in 1953) try to cobble together some kind of seasonal cheer. Jane Austen ponders the loss of a dowager's diamond necklace. As one might imagine, one fellow's mischief is another's mayhem.

Fun stories to read. I seldom read crime, but a collection of this quality, I'll make an exception for.

Monday, July 02, 2018

A searcher's story

kw: book reviews, nonfiction, spirituality, faith, memoirs

I was tempted to title this post, "Looking for God in all the wrong places," but it seems a bit too cheeky, don't you think? Alan Lightman has been a prominent physicist, and is that rare breed, a scientist who is also a qualified professor of the Humanities. It may in part stem from an experience he had in his younger years, as related in Searching for Stars on an Island in Maine: lying back in a small boat near his favorite island, looking into the starry sky, he had a transcendent experience. You can't un-experience such an experience.

Make no mistake, Dr. Lightman is a committed scientist. He is thus most comfortable with a Materialist philosophy, which posits that the physical world is all there is. As one of many paraphrases puts it, "If you can't measure it, it doesn't exist." And we must admit that scientific materialism has gotten us pretty far. But, while he is "most comfortable" in Materialism, he isn't entirely comfortable with it or within it. There is that pesky experience—and there have been others—that is just as real to him as the shoes on his feet.

Science and Religion represent the stereotypes of Relativism versus Absolutism. Although there are certain absolutes in the scientific realm, and some relatives in the religious or spiritual realm, the dichotomy is pretty clear for most instances. As a committed Materialist who nonetheless finds in himself a yearning for something Absolute, Dr. Lightman dwells in a boundary land.

It is sometimes said that scientific evidence must include reproducibility. If I mix chemicals A and B and chemical C is always produced, I can try to publish the results of my experiments. But the journals (major ones, at least) will send the article to other scientists to review, to pass judgment, whether it is worth publishing. If the experiment can be replicated, of course, at least one reviewer is likely to do just that, to make certain that chemical C does indeed result, and not chemical D or E…or nothing at all. Of course, all the experiments that are that easy have been done and published long ago, so now a reviewer will instead determine if the experiment is at least repeatable in principle. Only in the most controversial cases will someone attempt to replicate the experiment.

I like to pose the following to my scientific friends:
Non-repeatable phenomena: Many people engage in a certain activity that is known to usually evoke certain emotional responses in other people. This activity can be carried out by one person alone, or several persons carrying it out together. A large number of standard "recipes" exist (though we are not talking about cooking here). Frequently, following a specific recipe yields a known result. But not always. Some people try, but get a different result, sometimes even a response opposite to that expected. The outcome is not at all consistent!
Can you think what this activity may be?

Singing. And before you think, "Oh, some people just don't have a good voice," I am sure you know of people with a fine, melodious voice who nonetheless cannot convey the expected emotional impact of a specific song. Even: not all expert, operatic tenors can sing "Nessun Dorma" and get the same response that Luciano Pavarotti could. And I suspect that nobody with a "good" voice can effectively convey the power of a Bob Dylan song.

But what about simple systems? One of the simplest systems of all is a single electron moving through a hole and hitting a detector that can tell you where it hit (a sensitive CCD can do that). It may not be simple to set up, but once operating, suppose that roughly one electron per second is released to zoom through that hole. You are in a room with many others, and a screen is set up to record the results of each electron's impact on the CCD. You are given the chance to place a bet on where the next electron will hit. Do you place a bet?

If you know the initial speed and trajectory of the electron, and the diameter of the hole, you can calculate with absolute certainty, using the law of diffraction, what is the probability that it will fall on any particular segment of the CCD. But nobody can predict on which segment the next electron will land. So here in one experiment you have an Absolute matter and a Relative matter.

The book's chapters do not dwell on electrons, but are instead titled things like "Hummingbird", "Truth", "Transcendence", "Monk" and "Death". The second chapter is titled, "Longing for Absolutes in a Relative World," and introduces the rest. I kept hoping to read that this seeker after faith had found faith in God. At least in this book, he has not done so. An absolute God is apparently a step too far for him, an Absolute just too, well, absolute. But when you have experienced transcendence, you can never forget that there are things our relativistic science can never account for, and perhaps, the things that it can account for are in the minority.