Sunday, June 24, 2018

Contamination Everywhere

Petri dish

I have had a fascinating career as a technical writer and internal communicator. One of my most interesting jobs was editing procedures and batch records1 at a pharmaceutical company that used recombinant DNA to make its most advanced products. Later I wrote operating procedures at a company that made genetic analysis equipment and reagents and was hoping to bring its documentation up to the standards required by U.S. Food and Drug Administration regulations. This was the only way they could transition their products from research use only, good for serving academic and industrial laboratories, to diagnostic use with actual patients in clinical settings.

In working under FDA regulations, one of the things you learn is to believe in things you cannot see. The filters protecting the ductwork that condition the atmosphere in a clean room are either high efficiency particulate air (HEPA) or ultra-low particulate (or penetration) air (ULPA, see the specifications at IEEE Engineering 360). One removes 99.97% of particles 0.3 μm (micrometers, or millionths of the meter) in diameter from the airstream; the other removes 99.999% of particles 0.12 μm, or about a third the size of the HEPA filtration. This is dust you cannot see. These filters will catch pollen, water vapor, bacteria and their spores, most kinds of smoke, and sometimes even an odor in the air. Everything but small virus particles, which generally fall below 0.1 μm.2

For those virus particles, and for anything that happens to drift in through the airlock—although clean room suites are kept under positive pressure, so that any dirt inside will move outward, to the unqualified parts of the building—or that rides on the operator’s clothing after meticulous gowning, the regulations require rigorous cleaning. Since most forms of contamination in the pharmaceutical world involve active microorganisms, like those viruses, the specific cleaning agent is sodium hypochlorite (NaOCl), familiar to every householder as chlorine bleach. It not only removes stains, but its chemical action specifically destroys the long-chain polymers of DNA and RNA, effectively killing bacteria and neutralizing viruses.3 Sodium hypochlorite is highly alkaline—the chemical opposite of acidic—and so it also chemically attacks most surfaces like plastics and metals.4

Alternatively, surfaces and instruments might be washed with 70% ethyl alcohol, which kills bacteria by evaporating so quickly that it dries out the cell membrane before the microorganism can sporulate to protect itself. But not too quickly, though. Some people thought that if 70% alcohol was effective, 90% would be even better. But the more concentrated alcohol evaporates even before it can do its job, leaving the bacteria unaffected. Yeah, and perhaps even mildly drunk.

When working with these disinfectants, the clean room operator uses a wiping material—something like a paper towel, but denser and less prone to linting—under a procedure called “work and turn.” The operator saturates the towel, folds it a certain way, and makes one stroke across the surface to be cleaned. He or she then refolds the towel to expose a new, untouched side, and makes another stroke. The process continues until no unexposed parts of the towel remain, and then the operator discards it and starts with another. The motions for cleaning the surface are prescribed, too. The operator doesn’t just rub the saturated towel around in a circle, like a bartender wiping down the bar. Instead, he or she makes defined, overlapping strokes and never backtracks to cover an already cleaned part of the surface with a section of towel that has already been used. Cleaning a work surface requires diligence and concentration.

If you think this attention to detail is a trifle excessive, neurotic, or obsessive-compulsive, know that the pharmaceuticals this site was making were parenterals—that is, drugs that would eventually be injected into patient’s veins or muscles. Everyone on site repeated the mantra, almost daily, “We make drugs that go into people’s arms, so we have to be clean.”

In the FDA-regulated world, the word “contamination” doesn’t just apply to particles, bacteria, and viruses—dirt you cannot see—but also to the condition of the product’s being exposed, even potentially exposed, to dirt or some other kind of danger. So a batch of product, or an intermediate step in its production, that has inadequate documentation or has acquired some other defect at some point in the operation is labeled “contaminated.” If you don’t know and can’t prove whether the product is pure or not, then it’s not, and it must be discarded or “dispositioned.”5

What conclusions do I draw from all this experience with the finicky, precise, and sometimes whacky obsession with contamination in the pharmaceutical world?

First, our drugs are well made. This care in manufacturing—along with review and oversight of the initial development process, and double-blind testing for safety and efficacy before releasing a new drug to the public—means there’s not a medication made in this country that I would not willingly take on my doctor’s advice. Similar enforcement regimes are practiced in the rest of the developed world. I don’t know that I can say the same for medications made in less cautious countries.

Second, and despite the theme and message hammered home to audiences through now three generations of science fiction and horror movies, products made with recombinant DNA and other advanced biological techniques are not going to get out into the environment, mutate beyond all imagining, and take over the world.

Recombinant DNA is simply the technique of taking a gene that exists in nature, perhaps even in the human genome; isolating it from its chromosome and the embedded system of promoter regions that allow it to function inside the cell’s nucleus; looping it into a plasmid, or circle of double-stranded DNA; and inserting it into the cell body—not the nucleus—of a compatible host cell. There, the host cell’s mechanisms for transcribing DNA into RNA and then translating RNA into proteins proceeds to work on the foreign plasmid just as if it was just a part of the cell’s normal genome. Host cells can be yeasts, bacteria like E. coli, or certain mammalian cells that have long lives and can replicate freely.

The recombinant cells are put into a closed vessel called a “fermenter” or bioreactor, fed a growth medium plus oxygen and other supplements, and allowed to grow. If the protein produced from the plasmid is supposed to be secreted from the cell—such as the human clotting factor produced at our site—then it enters the liquid in the reactor and can be periodically siphoned off and purified as a biological agent. If the protein is normally held within the cell, then the reaction campaign is stopped after a specified period, the cells are extracted and split open, or “lysed,” and the protein is purified from the organic debris.

Fermenter campaigns are a delicate thing. Get the mixture wrong in the growth medium, add too much oxygen, fail to draw off enough of the resulting carbon dioxide, let the temperature vary by a couple of degrees—any number of maladjustments can cause the cells in the bioreactor to die. Oh, and allowing an outside bacteria or other cell type to invade the mixture will contaminate the process, too. Other cells are not only a danger to the identity, safety, quality, and purity of the final product, but they also compete with the host cells for the fermenter’s calibrated resources. Since the host cells are carrying that extra DNA and the burden of making all those copies of a foreign protein, they don’t compete very well.

If recombinant DNA host cells need to be pampered that much inside a bioreactor, which is the safest of all possible environments for them, imagine how vulnerable they must be out in the real world. A bit of used media that carries a few live host cells would pose no real threat if it ever got dumped down a drain—although no pharmaceutical company would be so careless. In an environment crawling with every kind of bacteria, fungi, and other microorganisms, a cruelly burdened strain of E. coli or a baby mouse kidney cell would stand no chance of survival, let alone of attaining wild and uncontrolled growth.

And my third conclusion is that the environment outside the laboratory is a really rough place. I was working at the genetic analysis company after the bioterrorism scare with weaponized anthrax bacilli in the Senate building, and we were tasked with developing a genetic method for detecting the spores in the U.S. Postal Service’s bulk mail centers. As part of that program, we convened a meeting with a number of influential microbiologists to explore what other biological vectors might be weaponized by terrorists and so would need screening.

Most of these experts had just come off a congressional hearing about the recent outbreaks of bird flu, and when we put this question to them, they just laughed. “Mother Nature is the greatest terrorist of them all,” one of the experts said. What he meant was, for every human attempt to culture, refine, and package an infectious agent, the environment itself is inventing a thousand different ways to kill us, like avian influenza viruses, bacteria, molds, and fungi spores. Evolution is at work all the time and, in the aggregate, is a lot more powerful than any human ingenuity. What can get into the lab and ruin your experiment or your production run is far more dangerous than anything that can get out of the lab and into the water supply.

Contamination is everywhere. Your immune system and that of every other human being on the planet is working hard just to keep up. And eternal vigilance is the price of safe drugs and a healthy food supply.

1. In the pharmaceutical business, a “batch record” is the procedure for making, storing, and packaging a product at every step. Unlike, say, a “standard operating procedure,” which simply tells you how to operate a piece of equipment or perform a task in abstract, the batch record includes checks and signoffs at each step in the manufacturing process. It provides written proof that the steps were performed correctly and in the proper order; that the results of every measurement were noted; that critical steps and measurements were also observed and confirmed by a second operator; and that the entire document was reviewed by the department supervisor at the time of production and by a representative from quality assurance before product release.
       Batch records apply not just to the product itself but also to any part of the plant and its operation that might affect the product’s identity, safety, quality, and purity. So the operators will complete a batch record for cleaning tanks, sterilizing hoses and utensils, calibrating equipment, and even mopping the floor in the production suite.

2. Of course, if a virus gets airborne at all, it will probably be riding on a water droplet from a sneeze or a dust particle derived from a flake of skin.

3. Because a virus is not technically alive, outside a host cell, you can’t “kill” it. But you can stop it from doing whatever it’s going to do, which is the same thing.

4. But that’s not the worst hazard in the manufacturing suite. At the pharmaceutical company, we used to clean mixing tanks with heated sprays that alternated hydrochloric acid (HCl) with sodium hydroxide (NaOH)—an acid followed by a base. This would scour out any protein residue left over from the manufacturing process. And then the procedure followed it all with pressurized steam at 122°C. You might worry about putting these acidic and caustic flushes down the sewer drain, but first they were sent to a holding tank, where the two chemicals neutralized each other, producing salt water.

5. And don’t believe that means just thrown away. A dispositioned batch has a documentation process all its own, so there is no possibility that it might get back into the product stream.

Sunday, June 17, 2018

Everyday Miracles

Yeast cells

My mother wanted her sons to be strong and self-reliant. That was why she started us early doing household chores like vacuuming, dusting, cleaning bathrooms, doing laundry, and washing dishes—or in our time, loading the dishwasher. She also taught us the rudiments of cooking: how to measure and pour, boil an egg, and fry bacon without splattering ourselves or setting the kitchen on fire, all so that we could at least survive without the contemporary equivalent of McDonald’s or Taco Bell.

Because her own mother had been an excellent baker, and she was a fair hand at it herself, she taught me how to make bread and scones. Sure, you can buy these things in the store readymade, but she believed in knowing how to rustle up a meal from the basics you have on hand. And with kneading dough and watching it rise, I discovered the miracle of yeast.

Yeast—Saccharomyces cerevisiae, for the most common species, used in baking and brewing—is one of the most complex of all single-celled microorganisms. Yeast is actually part of the fungus kingdom. Unlike bacteria, yeast cells hold their genetic complement inside a nucleus, as do most plants and animals, rather than letting it float freely inside the cell body where it can transcribe and translate willy-nilly. Thus yeasts are eukaryotes, just as we are, because secluding the genome inside a nucleus is the first step toward developing a multicellular organism, capable of differentiated and specialized tissue types. In fact, yeasts are believed to have evolved from multicellular organisms. But now yeasts reproduce asexually, by budding new cells off existing parent cells.

The yeast genome (see the Saccharomyces Genome Database) has 6,275 genes—of which about 5,800 are thought to be functional—in more than 12 million base pairs. These genes are packed on 16 chromosomes, which doesn’t compare badly with the human’s three billion base pairs on 23 chromosomes. In fact, about a third of yeast genes are shared with the human genome. For comparison, most bacteria have just one or two chromosomes, looped in a circular shape called a plasmid for easy transcription, and containing about 1,500 genes.

Because of the antiquity of bread and beer making, anthropologists believe yeast was humankind’s first domesticated species, predating wheat or rice, cows or sheep, and perhaps even the dog. It certainly came into our lives after the hunter-gatherer stage, when we settled down in one place long enough to brew up a pot of beer. It also must have come sometime after the discovery and taming of fire, because you can’t bake bread on a flat, sun-heated rock.

Yeast is not hard to get. In the second novel of my time-travel series, The House at the Crossroads, a young woman from the far future learns the basic skills of a medieval housewife: “Dame Agnes also taught her how to isolate and nurture the yeast cultures she would need—both for fermenting and to make her dough rise—by putting fruit skins and vegetable peels in a jar with water and leaving them in a warm, dark place overnight.”

The basic function of yeast—that is, for human purposes—is to eat up sugars and starches, known as carbohydrates, and excrete ethyl alcohol and carbon dioxide. For making beer and wine, we capture the alcohol and let the carbon dioxide waft away. For making bread rise, we let the carbon dioxide pump up the dough—which is why bread has tiny holes throughout the loaf, while a cracker does not—and let the alcohol evaporate in the baking.

Anyone who has seen a lump of dough, kept for an hour under a tea towel on the back of the stove, rise into a glorious dome twice the size of the original lump will know what I mean by a miracle.1 It’s a form of magic to see this grainy, yellowish powder—store-bought yeast—which becomes a gray muck when mixed with warm water, turn out anything as sweet and pleasant smelling as good bread. And yeah, that smell is the alcohol. The same miracle occurs when a bushel of crushed up grapes, or spouted and dried barley, or even mashed up potatoes plus water turns into wine, beer, or vodka.

Christ’s miracle of turning water into wine at the wedding in Cana just speeded up the process. He might as easily, although less dramatically, have made the balls of dough for the feast’s bread pop up before being put into the oven. These are miracles of time, not necessarily of substance, nor of reversing the normal course of events—such as the raising of Lazarus.

Cooking has other small miracles, too. There is the moment when you are mixing the dough in the first place, and the flour, water, and other ingredients go from a soggy mass to a plastic lump. Or when you’re making gravy, and the isolated streams of beef drippings, water or wine, and those little clumps of flour come together into a smooth paste and then a glistening liquid. Or the moment when an egg beaten with milk and seasonings and poured into a hot pan simmering with olive oil or melted butter turns from a runny yellow liquid into light and fluffy solids—or into a foamy custard, if you have more patience and you’re trying to make an omelet.

A young man who thinks food comes from the kitchen, or prefers to spend his money at McDonald’s or Taco Bell, never gets to see these things. And that’s a pity.

1. For certain applications, such as biscuits and scones, you can also use baking powder. This is a mixture of the alkaline sodium bicarbonate and a weak acid like potassium bitartrate, or cream of tartar. It releases carbon dioxide through an acid-base reaction once you get it wet. You can also use sodium bicarbonate to make soda bread. These chemicals are easier to handle than yeast, which can be killed with too much heat during the rising process or an unsatisfactory ingredient in the bread making—such as the time I tried to make Jim Beam bread, don’t ask. Dead yeast leaves you with a flat loaf like a paving stone.

Sunday, June 10, 2018

Fear Itself

Steelcraft cabin cruiser

Over the years, I’ve found something strange about myself. I may sometimes become nervous or fretful about future events, such as the ordering of steps to complete a project under deadline, or the progress of negotiations on a contract whose terms might eventually end up in court. A lot of this agitation has to do with the clock that’s continually running inside my head and my attempts to keep things functioning smoothly. Sometimes, also, I succumb to existential fears: the things unseen in the darkness but felt in the imagination that can spook anybody.

But from years of riding a motorcycle, I’ve noticed that my fear of actual and immediately present dangers seems to be muted—if not entirely absent. Looking back, I attribute this to an event that happened in 1954, when I was just six years old. I’ve told this story before, but it bears repeating in terms of personal fear.1

My father loved boats and boating. From the early 1950s, he was a member of the Power Squadron, which was an organization of small boat owners to teach seamanship and good boat handling practices. We lived on Long Island, just northeast of New York City, and he bought a twenty-six-foot cabin cruiser. It was built by Steelcraft and thus was unusual for having a steel hull instead of marine plywood or, more recently, fiberglass. The design was originally for a boatyard launch, because the hull was so small, but various entrepreneurs had fitted them out with cabins in the same way that the people these days convert delivery vans into rolling living rooms. Because of the hull material, my father named the boat Rusty. And that was apt because, although the steel was painted, it still bubbled up with blisters of rust in the salt water of the Sound. Every spring he and my mother would spend a couple of weekends chipping the hull and bilges and repainting them while my brother, who was just eight years old, and I played in the sand nearby and occasionally tried to help out.

My family kept the boat at an anchorage on Manhasset Bay, and every weekend during the summer when the weather was clear we would take it up the Sound. We only went an hour or two, east to Lloyd’s Neck or Eaton’s Neck along the north shore of Long Island. There we would anchor in the cove, picnic on the beach, dig for clams at low tide, and sleep over Saturday night. It was our version of having a cabin on the lake.

In the summer of 1954, my father planned an extended trip to coincide with his two-week vacation. He would take our family in the boat around New York City to the Hudson River, up to Albany, through the Champlain Canal and the Federal Locks, and into Lake Champlain itself on the New York–Vermont border. He figured he could make it as far as Burlington, Vermont, at the center of the long lake, in the first week and return in the second week.

It was an idyllic trip. I remember long days on the river and canal, seeing West Point and Storm King Mountain, the paper mills around Albany and the pulpwood barges coming down from the plantations in Quebec to feed them, and Schuylerville—which I only learned later was the site of the Battle of Saratoga in the American Revolution. My father, who had grown up in the Hudson Valley, played tour guide during the day, and my brother and I scrambled around the marinas where we tied up in the evening.

The turning point, both literally and figuratively, came in Burlington. On the morning we were supposed to begin the return trip to New York City, the people at the dock warned my father that a storm was coming and this was no day to be out on the lake. My father was a good sailor, and he listened to the weather reports, too. But he also had a schedule to keep. And the sun was shining that morning when we cast off and headed south.

By late morning, the clouds had rolled in and the waves started to build up. What we didn’t understand but discovered later was that hurricane Carol, which was churning up the East Coast and aiming for Boston,2 had calved a secondary storm, not quite a hurricane but with high winds, that had gone up the Hudson Valley. We got caught in that storm.

Lake Champlain is not very deep, averaging sixty-four feet—although some spots go down four hundred feet. A relatively shallow lake can kick up some real waves in high winds. And, of course, we had the winds themselves to deal with and the sheets of rain that came with them. Champlain is also a relatively narrow lake, averaging about fourteen miles across, so my father didn’t have a lot of leeway—which is a nautical term for how much you can let yourself drift downwind before running aground—in which to maneuver.

I was standing in the main cabin with my butt and shoulders pressed against the door that led out to the back deck. My father was at the lower helm—he also had a steering position on a flying bridge mounted on the cabintop, but that was no place to be right then. My mother was helping him by turning the hand-operated windshield wiper—a relic from early automotive days—and wiping condensation from the inside of the glass. Both of them were too busy to bother about me.

The wind was coming from astern, and the door at my back was banging and rattling until it seemed about to blow in. I imagined a furious imp stood outside, pounding on it. When I looked through the window, though, I couldn’t see anything except the bare deck, with a little toy sailboat of ours that had been pushed into the scupper, and the waves piling up on either side of the boat. If the Rusty had a freeboard of about three feet, waterline to rail, then those waves must have been ten or twelve feet tall, and maybe more. They certainly towered above the boat to my inexperienced eye.

Inside the cabin, everything was chaos. My mother and father were fully occupied keeping the boat on course and hitting the waves at the right angles. So they had no time for anything or anyone else. The coffee pot with some of the cold morning coffee slid across the high dinette table and crashed into the chart bin next to me. Some of those charts carried brown spots and streaks for years afterward. The portable radio, which was our main source of news and weather, flew after it and shattered on the steel bulkhead. I watched all this and could do nothing, because I was fighting that imp.

We were kept in the storm—but off the shore, and didn’t sink—until late afternoon. Then my father could round the point of Fort Ticonderoga, which sheltered us from the winds. My mother went out through the bow hatch—which meant she was standing on the closed lid of the head, or toilet—to unclip the anchor, let it go, and pay out line while my father handled the engine throttle to put the boat in reverse and drag the anchor along the bottom until it could catch.

When we were safely anchored, my mother came back into the lower cabin. Even though she was wearing hooded rain gear, the wind had driven the rain into her face and hair and down her collar. At the same time, my father brought me forward and told her, “This little fellow needs some dry clothes.” My mother shrieked, “He needs dry clothes?” because the fronts of my shirt and shorts were bone dry. Then my dad turned me around, and I was as soaked as she was from rain that had blown in around the edges of the door.

And my brother? He slept through the whole experience in the lower bunk and only came awake when an onion from the galley rolled up against his nose. Or that’s what he always said. Not until forty years later did he confess that he was awake the whole time and terrified.

My parents spent the rest of the evening cleaning up the cabin, watching their bearings to see if the anchor was holding or had torn loose, and trying to nurse the shattered radio—luckily none of the tubes had broken, only the plastic case—to give them a weather report. By about seven o’clock the storm had abated enough that we could cross the narrow stretch of water to a town on the east side of the lake and get some dinner at a rustic local restaurant.

That day on Lake Champlain the entire Thomas family, parents and children, might have disappeared without leaving a bit of wreckage on the face of the water. We might have departed Burlington in the morning and never reached land, and no one would know. So it was a miracle—or good seamanship on my father’s part in dire straits—that saved us. But those five or six hours at the cabin door, fighting the imp and watching the waves roll past, high above my head, changed me forever.

At the age of six, I learned that you could think you were going to die, and you wouldn’t. You could hold out at your self-assigned station, bracing that door, fighting that imp, for longer than you thought you ever could. You could do this because it was your job, your part to play, your place in the family. And there would be no point in giving in to fear, because at the moment of crisis everyone else is busy and no one is going to turn around and take care of you.

That’s a tough thing for a child to learn, but I thank whatever gods may be that I learned it young.

1. See the third footnote to Son of a Mechanical Engineer from March 31, 2013.

2. Hurricane Carol was famous for blowing down the steeple of Old North Church in Boston. The original steeple—this one was a replacement—was the site of the lanterns signaling “one if by land, two if by sea” in the ride of Paul Revere. History is everywhere in the East—and everywhere else, I guess.

Sunday, June 3, 2018

Keeping an Even Temper

Roman mask

Maybe it’s just me. Maybe it’s the place I live, the San Francisco Bay Area. But it seems that too many of the people I meet publicly these days are innately hostile. Like a case of walking road rage. You smile at them and get a glare or a blank stare in return. You ask a question, and you get a reply that is either tinged with scorn—like “Shouldn’t you already know the answer?”—or cold indifference—like “Why don’t you just go jump off the Earth?”

Were people always this rude? I don’t remember this kind of reaction when I was growing up in the East. Sure, some people are grumpy—some of them perpetually. And some people are too busy to talk or pay attention to those around them. That’s always been true. But it seems more and more people in society today are either aggrieved or battened down. It seems as if the social glue that holds us all together has dried out.

If the problem is the place I live, then I have a counter example. Some years ago, we traveled to Austin, Texas, to visit friends. In our journeys around town and across the state to see various sights and attractions, I encountered a pretty good slice of average Texans. I remember seeing and noting many more smiles, friendly greetings, and cordial responses than I’d been getting in California lately. As one example, I was turning a corner in the corridor to the men’s room in one museum and almost collided with an older man, a short fellow half my size wearing a business suit and a Stetson hat. As we mutually retreated, he tilted his head back and said in the cheeriest way, “Howdy!”1

If that had been in San Francisco or Oakland, he would have pushed past me and growled, “Get the [expletive] out of my way!” When I first came to Berkeley, forty years ago, I was standing in line at the cash register in a stationery store. The woman ahead of me completed her purchase, turned quickly, was surprised to find me there, and said, “What are you doing here? You’re blocking my way. Get out!” Yes, ma’am, right away, and sorry to be breathing your air.

This was not how I and my brother—and my spiritual sisters and my cousins, whom I reckon up by dozens—were brought up. My mother was constantly telling us to put a smile on our faces, and not just so that we would be pleasanter company around the house. We were supposed to be nice to the people we meet, nod to the people we know, hold doors for the people coming behind us, pick up our own litter and sometimes that of other people and go find a trash can, and answer respectfully and cheerfully when asked a question.

Being polite is not just good manners but a survival strategy. If you meet the world with a frown or a glare, you’re going to attract the attention of psychopaths. It’s just not healthy living in a state that perpetually provokes people. Incidents of road rage—even of the walking variety—begin with the first honk, the first snarl, the first rude gesture.

I’m also surprised at how casually these people will disrespect me. I stand six foot six and broad in proportion, usually move briskly about my business, and am not apparently decrepit—or not yet anyway. I try not to be menacing in my demeanor, appearance, and body language, consciously do not invade other people’s personal space, and back off a step in any encounter just to be polite. A sensible person could see that I am a healthy male who outweighs them, has a longer reach with more leverage, and could mow them down in any physical clash.2 And yet many smaller, weaker, less equipped people mouth off to a man my size as if they were surrounded by the invisible force field of protection that once was provided by the decorous traditions of a Western civilization in which they apparently no longer believe.

As a result, I walk around with a fixed, sometimes slightly dazed, smile on my face that is only beginning to crack at the corners. And still, as I encounter people out on the street, I am prepared for the next rude look or snarling reply. I am not really happy about it.

There is an art in this world that has to do with empathy, with taking the other person’s views and feelings into account, considering their own situation, and trying not to make them feel bad. Not make them look and feel like fools. My mother taught me this as a kind of protective coloration. “If you don’t move your hand as if you were striking at the dog, you’re less likely to get nipped,” she would say. She taught the art of moving through the world without riling people and attracting the psychopaths you might encounter.

It’s also a better way to get what you want. During forty years in businesses ranging from publishing to engineering, a public utility, and various biotech companies, I saw enough people fail to accomplish their mission and goals, who got their proposals crushed and saw their days go wrong, because they met the world, and the people whose cooperation they needed, with a hard word and the presumption that they were going to be dealing with fools.

Being polite and friendly and perhaps cracking a smile and a joke—“Howdy!”—also gets you better service in restaurants and other retail encounters. I makes other people, unless they are snarling under their own dark cloud, want to do the little bit extra that makes for good, friction-free exchanges.

Perhaps these angry people feel entitled. Many in the Bay Area do, because after all we live in Nirvana, the utopia that is now, and the utopia that is yet to come. Our views are correct, our politics impeccable, and our lifestyle and livelihoods sustainable. Or perhaps these people have had their expectations crushed once too often in this best of all possible worlds. And maybe they are just perpetually grumpy and busy.

But I would share with them my mother’s secret of keeping an even temper, putting a smile on their faces, meeting the world halfway, and taking a moment to make the other person around them feel good.

1. I also remember seeing little blue signs along the Texas highways: “Drive friendly.” For whatever reason, that makes me feel good inside.

2. Well, at the age of seventy, I probably still could, being an old black belt who runs through the karate katas every other morning as a form of exercise (see Isshinryu Karate). I would take my licks in a fight against a younger man with any street experience, but I am not exactly feeble or undangerous myself.