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Introduction

"Who are you?  Where are you from?"  Two questions everyone is asked sooner or later in life.  They're harder to answer than you might think.  Most people answer the first question with a sentence or two about what they do.  "I'm an airline pilot.  I'm an army officer.  I'm a lawyer.  I'm a plumber."  And so on, a puppet, a pauper, a pirate, a poet, a pawn and a king, to quote a famous blue-eyed performer.  (He didn't write those lyrics, though.  He'd have probably said he was a singer.)  But who was Frank Sinatra, not "what did Mr. Sinatra do"?  

Okay, I'm going to tackle that first one.  (No, silly, not about Frank Sinatra!)  One could argue that there's a piece of paper somewhere in the attic suggesting "philosopher."  It's the document my graduate school gave me after I finished writing my dissertation "in partial fulfillment of the requirements of the degree of Doctor of Philosophy."  It was all about organic chemistry, which was an amazingly useful subject to study.  It may not have been read by more than a half dozen people, half of whom were on my thesis defense committee, two others being my late parents who through no fault of their own wouldn't have understood it at all, and the sixth being yours truly because when you write what is essentially a big book, you read it so many times you get sick of it.  But yes, it was useful because it taught me how to think and to put a story together, although that's an art form still requiring a lot of honing.  I could have said "I'm a chemist."  Or, to give it more depth, "I'm a medicinal chemist who worked on developing drugs for serious diseases."  Both are true, but that's what I do, or at least did for several decades.  It's not who I am.  The advanced degree doesn't say "Doctor of Chemistry" or even "Doctor of Science."  Those accolades belong to honorary recipients who may have achieved certain notable accomplishments in their lives, and more power to them.  No, it says "Doctor of Philosophy" which implies qualification as a philosopher.  Take that, Plato, there are lots of us out there.  Let's chat if we ever meet in the afterlife.

On to the second question.  Where are you from?  All I can say is it's been one long adventure for this nomad.  When I was much younger, I really struggled with the concept of "from."  Was it where I was born?  Was it where I lived, or where my family lived?  I conducted an exercise recently to help me record all the places I hung my hat in the last six and half decades, and there turned out to be more hat stands than you'll find in your average pop-up millinery.  My birthplace was in the only city in Great Britain that's on an island - not counting the whole joint of course (trivia gem).  That's Portsmouth, on the south coast of England.  I lived there for a grand total of seven months in one stint, five more in another, so a year in total.  Is that enough to say where one is from?  I don't think so.  Then again, for the next seven years, we moved another eight times, different towns, a couple of different countries, less than two years in any of them.  More countries and locations followed over the next decade until the family settled in the USA.  I stayed there a while too, living on either coast and in the middle as well.  A half dozen more "home towns" if one tallies up all the different zip codes.  And finally, a peregrination across the International Date Line and the Equator.  On the north side of the Southern Ocean, this rolling stone came to a blessed halt and gathered moss.  Home at last.  Melbourne, Australia.  It's not where I was born.  It's not where I spent the other scattered two thirds of my life but it's where I belong.  It's my answer to the question. 

But let's come full circle, shall we?  Back to "That's Life" by Dean Kay and Kelly Gordon.  Sung by Ol' Blue Eyes, but he wasn't the first, and I'm going to plump for David Lee Roth as the surprising best.  Personal opinion: at the end, "Dave" declares not that he's going to roll himself into a big ball and die.  Instead he sings that he will roll himself into a big ball and FLY!  That's much better!  For me, I haven't been a puppet etc. but many years in the pharmaceutical industry, one way or another, have yielded many valuable lessons.  Some of which I'll no doubt allude to in this blog.  This occupation has also given fancy to a number of insights and ideas for fiction.  No, not highbrow literature or the type of prose that critics would regard with frenzied enthusiasm.  Many critics feel honor-bound to live up to the word itself and do nothing but criticize anyway.  Perhaps rolling themselves into big balls and dying when there's nothing left for them to find fault with.  No worries.  If readers pick up a paperback in a used bookshop, an airport display, fish it out of an online shipment, or download it onto an e-book reader, and enjoy the stories, that's good enough for this old hack.  It's fun writing them, and if you say "don't give up your day job" I won't be offended.  Because the same has probably been said to any number of us.  That's life, and being positive is to fly.

Hall of Fame

That's an odd title, but like many ideas, it came to me while waking up a wee bit earlier than intended.  The first baseball player I ever heard of, about 60 years ago, shares the same name.  He pitched for the Baltimore Orioles, won more games than any other in the 1970s, never gave up a grand slam, and made it into the Hall of Fame in his first year of eligibility.  It got me thinking.  To be considered for the Hall of Fame as a pitcher, you often have to have won at least 300 games in the major leagues (Or, like my namesake, win multiple Cy Young and Golden Glove awards).  As a batter, it helps if you amass 3,000 career base hits, or, for instance, have a long career with an overall batting average of 0.300 or more.  See a pattern?  A lot of threes.  When you think about it, though, "hitting 300" for a career means you manage to get on base (outside of being walked either intentionally or due to the pitcher's inaccuracy) thirty percent of the time.  And that's really, really good.  Tough gig, pro baseball.  Seventy percent of your attempts result in the umpire giving you the thumb and sending you back to the dugout.  Try again next time, batter.  The guy on the mound has it a bit easier.  Even if he starts spraying it all over the shop there'll be a specialist in the bullpen who can come in and save the day.  Sometimes.

When I first arrived at graduate school to study synthetic organic chemistry, one or two of the more experienced sloggers (yes, graduate school is a slog) would say something like "If you can get ten percent of your experiments to work, you're doing well."  Wow.  That suggested ninety percent of them go south.  That percentage is a lot worse than a good professional baseball player's bad trips to the plate.  Natural product synthesis, which was always considered the most useful discipline in organic chemistry serving to educate those seeking a career in the pharmaceutical industry, is very challenging.  You're presented with a target, complex molecule that you have to build from scratch, otherwise known as starting materials available for purchase via a chemical supply house.  You have to design a way to make it through dozens of sequential steps.  Each of these can fail at any time, requiring a return of sorts to the drawing board, literally.  To make a long story short, making one of these natural products might be enough to earn a graduate student a PhD.  Often, even getting part way is enough.  Whole teams of students are occasionally assigned to build a single molecule, so complex might the target be.

Hall of Famers in the natural product synthesis world include famous academics, for example Elias J. Corey, Nobel Laureate, 1990.  (Same year as the bloke in the first paragraph entered Cooperstown in a different discipline.)  They can count many dozens of former students who have gone on to be well-deserving of recognition in their own right, one way or another.  All, however, will testify as to how challenging their tasks would have been.  Using a ten percent success rate, that would mean one would need to perform a thousand experiments to complete a ten-step sequential synthesis route.  Three experiments a day would mean about three years of work to get the job done.  Gee whiz, there's the three factor again.  Funny, that.

Yes, the arithmetic is simplistic but it's one of those curious little parallels.  More on the intricacies and challenges of making natural and unnatural products later, but there's another way to look at this entirely, and it's this.  No experiment fails if it is performed.  That means the senior, jaded students battling the elements to complete their advanced degree programs could have been viewing their success rates pessimistically.  Why?  Because when you conduct an experiment, you learn something new.  You may not get the result you were hoping for, but you still get a result.  That revelation will provide guidance in one of three ways.  (1) Hooray, everything turned out the way you hoped, and you can move on to the next step.  (2) Oh, crap.  This was not the right thing to do.  You've destroyed the goodies.  You have learned not to do this again, and that's very useful information.  (3) Hmm.  Looks promising but needs a tweak here and there.  You're on the right track though.  The common thread here is that you've asked a question, and you've received an answer.  You ran an experiment and discovered something new.  That is not a failure.  It is a success.  And the Hall of Fame, whether Cooperstown for baseball, Canton for American football,  Cleveland for rock and roll, or Stockholm for chemistry, physics, physiology and medicine, and literature, is full of success.  (I won't mention economics or peace because no one seems to have gotten them right or the world wouldn't be loaded with debt or conflict, but that's a topic for another rant.)  That's life, and thinking in terms of success is to fly.

He's in the drug business

About 25 years ago I had occasion to fly from San Francisco to Montreal in order to meet with corporate collaborators.  We had these face-to-face meetings about three times a year, rotating between the aforementioned sites and one in West Point, Pennsylvania.  (Readers might be able to figure out which companies were involved).  In between these summits, we conducted three-way teleconferences in boardrooms at our respective facilities.  These events were fraught with technological hurdles.  At first, we thought it would be nice to have everyone piped in by the video technology of the day.  Note: it wasn't anywhere as good as Teams or Zoom even, and while Skype wasn't yet in its infancy, it probably worked better.  Routinely, we would spend anywhere between 30 and 60 minutes overcoming the inability to see each other or project slides so remote viewers could see our presentations on screen.  During these fiddly manipulations, sound and/or vision would invariably cut out when the bandwidth choked.  After several iterations of this aggravating recurring phenomenon (which never coughed up the same problem we'd fixed before, therefore thrusting all of us and our IT experts into fresh paroxysms of frustration) one of us had a bright idea.  Instead of attempting to display our presentations on screen, let's completely dispense with the video and instead restrict ourselves to a three-way conference call.  Prior to the meeting, all slides and materials would be circulated at least a day in advance so that everyone had a chance not only to peruse the data, but formulate questions without having to fight a losing battle against the Internet.  Lo and behold, it worked well.  Everyone had a copy of the slides to make notes on, and all presenters needed to say to orient the audience was say "Slide X" or "Next slide."  Soon that too became unnecessary because everyone was in sync with the flow.  It may not have had a major effect on the project's progress as a whole, but it sure simplified the communication.  The take home message is that sometimes the best solution isn't the most technologically advanced.  I'll come back to that some other time, because it has all sorts of implications in healthcare. 

But at the risk of digressing (oh, dear.  Too late...).  This very same project was one I was leading on the smaller partner's side, so I was responsible for pulling together the lion's share of our sub-team's slides to present at one of the actual face-to-face meetings, where we all got to see each other's body language and get a sense of individuals' tastes in assorted meals and beverages throughout the two-day event.  The program was reaching an intriguing stage of its development, and we were all excited about where it could lead.  (Side note, we wanted it to lead to successful clinical trials and ultimately to a marketed drug, if that wasn't obvious).  The San Francisco team had to change planes in Edmonton, Alberta, before boarding an internal connecting flight to Quebec.  And that's where I made a mistake for the first (and stupidly not the last) time.  It's an oddity, perhaps, that customs and immigration services between the US and Canada are in the latter country.  When flying from the northern nation to the southern one (can't speak for Alaska, never been there) you actually pass through border control when you're still in the Canadian airport.  It's as if the post-security section of the terminal is technically on US soil.  Saves a bit of time, admittedly, because when you land back in the States, it's as if you've flown in from Chicago, or Boston, or LA etc.  Straight into a domestic terminal.  But going the other way?  Yes, you're in Canada too when that happens, and if you're not careful, you could get a whole slew of questions you hadn't anticipated.

Edmonton was where I made the silly mistake of telling the truth.  "What's the reason for your visit to Canada?" said the border control officer.  "I'm here for a conference."  Not a lie.  A conference is where one confers.  I've used it many times when being asked to enter countries all over the world, often when giving talks or presentations at conferences.  But it can also mean discussions among interested parties, and you only need two people to make a conference.  This officer wasn't buying it.  "What's the conference about?" he asked.  "A project collaboration with our partners," I said.  "Where do you work?"  I told him the company name and its location.  "What do you do?"  he followed up with.  "I'm a chemist."  BOOM!  (No, that sound didn't go off.  It was an airport.  Not a good place to say "Hi" to your pal named Jack.)  Up went the red flag.  Chemists are bad.  Organic chemists are really bad.  They made a show about one a few years back called Breaking Bad.  "What kind of chemist?"  He was looking through my passport and his screen, and glancing sideways at his colleague, who looked to be about to give one of my co-travelers and colleagues the hairy eyeball himself.  "I'm a medicinal chemist."  A bit of clarity.  Next question please?  "What are you working on?"  For crying out loud, I can't tell you!  It's proprietary.  Not in the public domain!  For the joint project team's eyes only!  Shoot, what am I going to say, I wondered.  "We're developing a treatment for osteoporosis."  Good thing I didn't say joint and bone disease.  They might have taken the "joint" part out of context and given me a full cavity search next.  I was beginning to wonder if I was going to be asked to whip out my presentation and give it to them.  Instead the guy smirked at his buddy.  "This guy's in the drug business."  He handed my passport back.  I thanked him and remarked "If I'd said that to you, you wouldn't be laughing."

The next couple of times I traveled to Montreal, irrespective of route, I always got singled out and grilled, coming or going.  The assorted forms you need to fill out when entering or leaving certain countries require you to state your occupation.  That's when I learned my lesson.  I stopped putting "chemist" on the form and replaced it with "Biotech Research."  It was like night and day.  A couple of times I'd get a question flying into LAX or London, like "what do you do back home?" and I'd say "cancer research" (again, perfectly true, collaboratively).  No longer was I the evil meth lab suspect.  More like "Cool.  What kind of cancers?  We need help with such and such."  "Working on it," invariably brought a nod of appreciation.  That's life, and doing something to help people is to fly.

The Equation of Doom

Wrestling with troubling equations was made tremendously easier with the advent of the pocket calculator in the early 1970s.  Until that point we had to rely on log tables, algebraic transformations by hand, and of course slide rules to help crunch the numbers.  Significant figures be damned: more than three was a luxury.  How the astronauts of the 1960s coped with traveling to the Moon has always been a monumental triumph of computation.  That achievement was personified by the extraordinary skills of Katherine Johnson, the closest thing to a human computer there was in those days.  It's said that John Glenn himself wouldn't trust the actual computers' projections of his first orbital trajectories until Mrs. Johnson checked them by hand.  Roll on a few years and the very first electronic four-bangers came on the market.  These delighted many who were fed up with sliding cursors back and forth over ever-stiffening 12-inch and 6-inch slide rules whose scales required a magnifying glass to read otherwise.  The added advantages of scientific funcions like trig, logs, roots, and (gasp) exponential notation and memory followed.  Programmability and statistical capabilities were the next leap.  Unless one is a specialist, though, most of the functions are superfluous, such as anything involving hyperbolic trigonometry.  Esoteric delights like Poisson and Weibull distributions were of no interest.  Occasionally one stumbles across a Student's t test, but beyond that, most of them have no application in medicinal chemistry.  Still, it's one thing to need a capability, entirely another to know you have it should the need ever arise.  Then there's the quirky system used by Hewlett-Packard machines, known as Reverse Polish Notation.  As in 3 enter, 4 plus, gives you 7.  Easier than 3 + 4 equals, gives you the same.  It's like Marmite for Brits.  You either love it or hate it.  And if you're in the former category it becomes a struggle to use calculators that don't use RPN, as it's called.  I started collecting HP calculators, some for use of course, others simply because I liked them.  Scientific, graphic, financial, you name it.  I still have several, despite having sold many on eBay (yes, there's a market for vintage models).  Probably the most famous example is the gold standard HP12C, first marketed in 1981, and still going strong 45 years later.  Has all the useful financial functions but sadly lacked the scientific ones, or at least sines and cosines and stuff.  What a silly oversight, but there it is.  And that's what brought me to realize what's at the root of the world's economic problems.  It's the equation of doom, and it's the same one that's built into every HP12C, HP17BII+, and even the newer models other manufacturers push out to high school and college kids.  It's called the TVM equation, or time-value-of-money.

Why is this equation so heinous?  Here's my answer, and I'm sticking to it.  Put in simple terms, it can be written as PMT x 100 x (1 - (1 + I / 100) ^ -N) / I + FV x (1 + I / 100) ^ -N + PV where PMT is the payment amount, FV = future value, PV = present value, I is the interest rate, and N is the number of compounding periods.  Financial calculators all have these buttons that allow you to solve for any one of the variables given the other four, and it's an amazingly useful feature if you want to know how much you can afford like a mortgage or a car loan, or, for example, how much interest you'll make when saving.  There are derivatives of this equation and other terms like net present value, internal rate of return and the like, involving uneven cash flows etc., not to mention subtleties regarding whether the mortgage calculation is performed in Canada, but I won't go into that here.  What I will point out is the notion of amortization, i.e. what happens when you take out a large loan and need a long time to pay it back.  Imagine, for instance, that you buy a house for a million dollars.  (Yes, that's getting quite realistic these days, if not a painful thought.)  Forget the down payment and finance the whole buck.  Over a standard 30 year mortgage, paid monthly, with an annual interest rate of 6%, your payments are: (thanks to my trusty HP Prime!) $5995.51.  Per month.  Over 360 months, that adds up to $2,158,383.60.  More than twice the amount you've borrowed.  The interest payments alone are more than the principal.  Even with a 4% interest rate, your total interest payments add up to $610,694.00.  And with an 8% interest rate (the horror...) you'd pay $1,641,554.00 in interest alone.  Money literally thrown away, the only beneficiary being the lender.  But what's worse is the staging of the payments.  They are front-loaded in the interest portion, such that in the first year of our 6% interest rate example, you only knock off $12,280.17 of the principal.  $59,665.95 goes towards the interest.  Sixty grand a year, tossed aside.  Think about it.  If 6% were charged on top of a million bucks, that would be an extra sixty grand you'd pay.  Total.  Wouldn't that be nice?  But that's not the way things are done.  In the amortization schedule, you have to keep paying for 21 years out of the 30 to see the principal on the loan drop below $500,000.  You've already paid a shedload of interest by this point.  $978,960.72 to be precise.  Almost a million bucks and you still have another half a million left on the principal over the next nine years, although it will diminish more quickly now.  See the problem?

Aha.  That's why everyone is in debt.  I'm not talking banks, but many individuals and especially nations.  If it takes the average household 30 years to pay off the biggest debt it's likely to incur, how can one expect a country to solve its own debt burden within a single election cycle?  Answer:  It can't.  And this is why virtually every large economic powerhouse, and a whole bunch of the smaller ones, are deep in the red.  One hears words like trillion-dollar national debt, interest in the hundreds of millions, or billions.  (That raises the question no one ever seems to answer: to whom is all this interest owed, who determines the interest rates in the first place, and who's actually making money off it?)  Frankly it doesn't matter, because all they ever seem to do about it is agree to spend more money they don't have in the first place, or print more, throwing terms around like quantitative easing, and so on.  They try to claw some of it back by the only means they can think of, such as taxes, but does that help?  The short answer is no.  It never works.  No country has ever taxed itself into prosperity, and the reason behind it all is the blasted TVM equation.  It's destined to cause the imbalance.  (Irony.  Equations are supposed to balance....)  

There was a pretty famous tax collector, a bloke called Matthew.  Oddly enough, a book he once wrote, at least in the King James translation, chapter 6, verse 12, he reports: "Forgive us our debts, as we forgive our debtors."  Various denominations of the Christian faith use words like trespass(es) to replace "debt(or)s" in the Lord's Prayer, but perhaps Matt's account (or was it his reformed accounting practice?) was on to something.  We'll never solve the debt problem when the TVM equation of doom is at work, because of the imbalance it creates.  However, that's life, even if we can't always fly. 

Seven Miles Up, Everybody is a Hippopotamus

Speaking of flight, one of the recurring peripheral themes in my stories is aviation.  The very first short story I managed to get published in an obscure magazine, well over 30 years ago, involved air travel, and there are always a few journeys or references to assorted aircraft somewhere along the line.  It's been an ongoing fascination of sorts for sixty years.  My first experience that I actually remember was unusual, in that three of the plane's engines failed half way across the English Channel, necessitating a return to London Heathrow.  Good thing the de Havilland Comet had four.  As passengers we were told that one engine had conked out, but I suppose the quietness of the cabin provided more direct evidence as to the aircraft's difficulties.  It took many years for my old man, who was waiting for my mother and me at the planned destination, to admit what he'd been told in confidence by a very nice man who'd looked after us on the day.  Side note: this fellow was the former head of the Israeli Air Force, seemed to know the captain, and got the skinny on what had happened.  I reckon my mother would have freaked out if she'd known!  Oddly enough the replacement aircraft, a Hawker Siddeley Trident, had three engines.  Good job all the mechanical failures that day happened in the order they did.  Over the years I loved "collecting" commercial aircraft, checking off every model from Vickers, Fokker, Handley Page, Boeing, Airbus, and other assorted manufacturers I could, including four-seater twin-props, regional airplanes, wide-bodies, a private jet, and even a chopper or two.  It was a sad day when I realized Concorde was never going to happen, but you can't win them all.

A sadder day still, for those of us who've made enough trips around the sun to remember exactly where we were almost 25 years ago, was 9/11.  (Local Starbucks buying my commute coffee.  What came over the airwaves that day eliminated the need for caffeine while driving across the Golden Gate Bridge.)  Not many of us got any work done that day, as we were glued to radios and portable TVs broadcasting updates, and by early afternoon we were all told to take the rest of the day off regardless.  An eerie collateral effect was the silence of the skies above us for the next several days as all air travel stopped.  Our company was directly in the flight path north of San Francisco International.  For avid plane watchers used to seeing the steady flow of takeoffs when taking routine walks around the nearby marina, knowing all was right with the world, it was doubly strange.  Only when flights resumed did it feel as though we might slowly head to a new normal, albeit one that has existed ever since with security checks to which nobody really objects. 

Where's the real science connection (as opposed to silly fictional tales)?  I once made a chemical compound that still shows up in the literature from time to time, called K11777.  It's an enzyme inhibitor that made it into the clinic, the idea being to cure Chagas's disease, a parasitic scourge endemic mostly to South America.  It even appeared on a BBC World documentary some years ago.  It got its name in 1995 when I encountered one of the very first Boeing 777s, before it had entered service, parked at Washington Dulles in United Airlines livery.  What a fantastic aircraft, I thought: the next compound I make will contain the number 777.  And so it happened.  Side note: the compound works as advertised.  It'll probably never make the market because it's off patent and nobody will make any money off it, but it cures the disease in animals infected with a lethal dose of the Chagas parasite.  And thanks for the plane, Boeing, I've been half way around the world in those babies many times.

Decades ago, air travel was  more fun.  There was enough space in the cabin to relax and not worry about being crammed in.  The difference was seat pitch.  In economy class this used to be 34-36 inches.  You could recline your seat and not stuff the tray behind you into the solar plexus of the unfortunate occupant in the corresponding seat.  Now it's 30-32 inches.  Aircraft seat widths also have shrunk.  In the aforementioned triple-7s, what used to be 9 abreast has now grown to 10 abreast, squeezing an extra column of passengers into the same place.  Fuselage design hasn't responded in kind, and even if it did, airlines would undoubtedly expand the occupancy to fill the available space.  18 inch wide seats have shrunk to 17 inches, or even 16.5.  Now it would be judgmental to cast too many aspersions on the number of oversized passengers stacked into chairs in which they struggle to fit.  But let's face it, most of us can help our girth.  The one thing we can't help is our height.  A tall person sitting in an economy seat at 30 inch pitch is impractical at best.  Especially if everyone on all sides is a hippopotamus.

Ever notice how Hollywood and TV shows consistently muck up one particular continuity aspect of their products?  The scene is this.  Passengers in a wide body aircraft, say a 747.  Seat configuration of 3-4-3 is a giveaway.  It takes off.  Then there's a shot indicating the plane is airborne.  Suddenly it has transformed into a DC-9, with a T tail, two engines aft, and an interior seating configuration of 3-2 in coach.  Shift back to the interior and somehow it's a Tardis, much bigger on the inside.  At the end of the journey, stock footage of a 737 landing at LAX appears (even though the destination is anywhere but Los Angeles).  Two engines on the wing, narrow body, 3-3 configuration.  Who checks this stuff?  There's supposed to be someone in charge of continuity, but the fact that they invariably get it completely wrong is mind-boggling. You'd think sometimes they'd stumble across the right aircraft types for their scenes by sheer random choice, but no.  It's almost as if the production staff is told, "Whatever you do, don't get this part right."  It gives me the screaming ab-dabs every time I see this, to the point where I might receive a certain look or phrase that I can only interpret as "there you go again." 

But let's toss the peeves aside and end on a positive.  One day, if possible, I'd love to take a flight in what many would consider one of the greatest aircraft ever designed.  There are a few of them still around, offering the opportunity.  To save anyone the bother of guessing, it's the Spitfire, the fighter that helped save Britain.  If I ever get the chance, that'd be a genuine bucket list activity, and it would beat every commercial aircraft I've ticked off the list.  That's life, and to fly... shoot, that's the tag line.  You probably know it by now.  Go ahead and finish it yourself.

Addicted to Lab

No, this had nothing to do with dog breeds, although we did have a mixed yellow one once.  About 40 years ago cousin Robert put out a worldwide hit with which most of us are familiar.  Okay, he almost certainly wasn't really my cousin, but as I know little about the Cornish paternal side of my family past a couple of generations back, I have no idea if there was a Yorkshire branch in there somewhere.  Either way, if you replace the word "love" from the song, that described a certain work style I was unable to abandon for the next thirty years.

Many people have an addictive personality.  In some it manifests as substance abuse they can't stop, in others it shows up in other risky or socially unacceptable behaviors.  A milder form of the disorder is having a sweet tooth.  I'm very lucky I didn't acquire any of these traits, except one (okay, maybe a couple of foodstuffs like broccoli and oats.  Must have been a horse in a previous life).  It started when I was eight.  I received one of those old-fashioned chemistry sets for Christmas.  My very first exposure to chemicals was in the mixing of blue copper sulfate solution with a separate test tube containing a solution of lead nitrate.  Lo and behold, when the two were combined, magic happened!  A brilliant white precipitate of lead sulfate fell out of solution, leaving the remaining liquid not as copper sulfate any more, but copper nitrate.  I'd synthesized my first chemical substance!  Roll on another few years, to teenage high school chemistry labs, where we exposed solutions of sugar to yeast, resulting in ethanol, which we distilled into small flasks.  (Yes, the teacher said it was okay to taste it if we wanted, but don't overdo it!)  It took until I was in graduate school, however, to realize that I was about to do something no human on earth had ever done before.  And that was to make a brand new molecule that had never been synthesized by anyone, or anything natural.  Wow!  That was amazingly cool.  Sure, I'd made other organic compounds when getting my bachelor's degree, either in classes or in a summer research program, but those had been made before.  This was the first one of its kind.  (Anyone who's reading this as an experienced medicinal chemist will probably say something like "yeah, yeah, yeah, so what, big deal, we've all done it, don't go blowing it all out of proportion.)  But as the years went on, that sense of excitement never completely disappeared, even after I'd synthesized, designed, or contributed to the concept and preparation of literally thousands of never-before-seen compounds.  Some of which are in use today.  Most of them aren't.

Most chemists in the pharma or biotech industry, when they reach a certain level of management, leadership, or organizational complexity, find themselves no longer participating in practical or laboratory activities.  They wind up running project teams, groups, attending interminable meetings, preparing slides for presentation to colleagues, supervisors, and collaborators, acting as mentors to younger scientists and so on.  Academics are no different, in large part.  Instead of doing the practical stuff they're occupied with teaching and going through the endless cycle of grant applications, hoping someone will give them money to continue churning out discoveries and graduates.  And they all have one thing in common.  They wind up spending a lot of time on their backsides.  

I hate sitting down to work.  (I have a standing desk at home.)  It's one reason why I never could stop working in the lab, even when I had a large group to supervise or projects to lead.  It probably cost me some career advancement, but I did it because it was fun, I could work standing up rather than driving a desk all day, and I loved making new compounds that might one day cure or at least treat an illness.  There was also the satisfaction of doing the actual experiment itself: mixing chemicals, designing or following a procedure to do it right, monitoring what was happening in a reaction, and mastering the art of cleaning up what I'd made so it could be tested.  Along the way I probably engaged in some unorthodox methods, but you'll never see those written up in a publication.  These little technical skills emerge from handiwork and practice, and no small amount of instinct.  You can't teach it, but you can live it.  That was what being a practical organic chemist was all about.

They say "do what you love, and you'll never work a day in your life."  It's true.  One of those hackneyed but aggravatingly inaccurate phrases is "work-life balance."  Draw a Venn diagram as follows.  (We all know what they are, we learned it as kids.)  Draw three circles: one large, the other two inside.  Overlap the interior ones if you like.  Write "life" somewhere in the big circle, outside the perimeters of the other two.  Because everything we do is life.  Now write "work" in one of the smaller circles.  There's clearly no such thing as a balance between work and life.  Work is part of life.  A subset, in Vennspeak.  The other circle can be called play, leisure, non-work activities, something like that.  "Fun" would be a good word.  But it's those two that have to balance, or intersect.  Not work and life.  For those of us lucky enough to have been able to draw the two inner circles almost on top of each other, it's because we love what we do.  And we might be addicted to it, as long as we're still afforded the opportunity to do so, or to have the luxury of stopping it at our own pace.  That's life, and being addicted to doing what we love is to fly.

So long, Phil, and thank you.

TIme for something a little more technical here.  If you're an organic chemist you'll get it.  Maybe if you're a drug developer or patent attorney.  Professional athletes and journalists probably won't read any further.  In March of 2026 I received the sad news that my post-doctoral adviser, Professor Philip L. Fuchs, had died at the age of 80.  Chemistry professor, lover of all things vulpine thanks to the English translation of his surname, and huge sports fan always happy to have a bet with some of us on everything from every team sport to the Indy 500.  His own post-doctoral adviser was none other than Nobel laureate E.J. Corey, Hall of Famer as he could be considered.  I first met Phil in early 1980 when scouting out graduate schools, and discovered, like so many who eventually passed through his fiefdom, that he was a larger-than-life character in more ways than one.  Having been told that his graduate course on advanced synthetic chemistry would be not only the hardest course I'd ever take, but also the best, the experience itself lived up to every expectation and then some.  He was a splendid teacher who not only brought the subject to life, but one could tell he lived it himself.  He also wanted those who attended his course to absorb the principles and apply them rigorously.  However, there was one aspect to his work that presented a conflicting opinion to another I'd gladly absorbed in the course of graduate study.  "Work with the molecule, don't fight it," was the mantra.  Not so PLF.  He'd do battle with it and beat the living daylights out of it until it submitted, when necessary.  And he usually won.  Although there were one or two occasions when he didn't.  That Mellencamp tune "The Authority Song" has the chorus "I fight authority, authority always wins."  Replace the word authority with "entropy" and that's why you can't win them all.  It's thermodynamics, and the laws of physics trump the laws of mankind every time.

Phil's favorite functional group was the vinyl sulfone, which would appear time and time again in every synthetic project, every complex molecular target, and every methodological study.  A series of dozens of papers illustrating its versatility appeared in assorted journals of chemistry over decades of work, all with the tag line "Syntheses via Vinyl Sulfones [insert Roman numeral here]."  There was no escape, the vast majority of his graduate students and post-docs over his long career discovered they were destined to tackle the R-CH=CH-SO2-Ph moiety somewhere in their journey.  (Often those H atoms were replaced by carbon substituents but there's no useful way to insert pictures in this text box, and that's not the point anyway).  This little sequence of atoms and bonds left my circle of friends for a few years but then came storming back in the middle of 1993.  It occurred to me that vinyl sulfones might make very interesting enzyme inhibitors, especially for cysteine proteases, whose active site contains a thiol group, or SH.  In fact, the active site is more like a charged thiolate, or S- group, and therefore a potent nucleophile.  However, long days in Phil's labs taught us that adding nucleophiles to vinyl sulfones wasn't a trivial exercise.  Sometimes these groups were placed in awkward locations on an elaborate intermediate, and it required a lot of brute force and nucleophilic power, like potassium carbanions, to achieve any reaction at all.  (Examples in a few of those papers).  But what if you stuck a vinyl sulfone on an amino acid and turned it into a substrate-like molecule by bunging on another amino acid or two?  Peptidyl vinyl sulfone?  Would that react with a cysteine protease?  Oh, boy, did it ever.  And yet it wouldn't react with glutathione, which is everywhere in the body, a whopping great source of thiols that surely ought to mop up any of these interloping vinyl sulfones.  The theory was that histidine, which is protonated in the enzyme's active site, acts inductively on the sulfonyl oxygen, polarizing the double bond and making it more attractive to thiolate attack.  Outside the active site the compound was mighty stable.  Did we "prove" that?  In the strictest sense of the word, no.  Circumstantial, yes, direct, no.  But the compounds were terrific cysteine protease inhibitors, and we published the results in the Journal of Medicinal Chemistry in 1995.  (After filing patent applications of course!).  And one of them was K11777, mentioned earlier in that blog about aviation.  Since then that paper has been cited quite a lot, and the inhibitor series has been used many times in generating crystal structures of cysteine proteases from humans, rodents, rabbits, and assorted parasites.   

But then, as so often is the case, certain roadblocks appeared in the form of dogma.  Could these compounds ever become drugs?  Would Phil's gift to organic synthesis be suitable for treating diseases in actual patients?  One company where I worked thought so.  And then it went off the rails.  One exec at the company with whom we merged thought otherwise.  "I will not spend a cent of [company] money on irreversible inhibitors" was the clear warning message given  (Along with "you're on shaky ground.  One more word and you're fired.")  Note: these days everyone talks about covalent inhibitors, but this shouldn't be confused with irreversible inhibitors.  You can get covalent reversible inhibitors, where the drug forms a weak bond with its target, but it can come off easily and rapidly in an equilibrium.  Irreversible inhibitors bind to the target protein permanently.  This is chemical irreversibility.  (Biological irreversibility is a separate phenomenon where the net effect on a biological system is one-directional, such as extreme tight binding but no chemical bond is formed).  Thus there are subtleties in the semantics.  Aside from that admittedly wordy distinction, the industry at the time had a "thing" about irreversible inhibitors.  They would be toxic!  They would provoke an immune response!  Oh, no!  Never mind the fact that arguably two of the greatest drugs ever invented, aspirin and penicillin, are both irreversible enzyme inhibitors, it wasn't worth challenging the powers that be/were with such nonsense.  If there's one thing I've learned in life, humans whose minds are made up cannot be persuaded of anything to the contrary, so don't waste one's energy, especially if your livelihood might depend on it.  Even when their conclusions are based on "what could go wrong" rather than "have you actually tested it and proved it would?"

Yet the hope that one day irreversible inhibitors could re-emerge and treat serious diseases came to fruition.  A very good junior scientist, now a professor in Beijing, worked on a project I was lucky enough to lead in the early part of the century.  He wanted to make an irreversible inhibitor of the target, an enzyme called Bruton's tyrosine kinase, or BTK.  We had many discussions on what groups of atoms to put together.  A vinyl sulfone even went into the series, but he made the key contribution, which was a simple acrylamide.  Roll on a decade or so, and the compound was approved by the FDA for the treatment of various cancers.  It's called ibrutinib, marketed as Imbruvica.  Multibillion dollar molecule.  Its development and clinical trial management were all made possible because some courageous people licensed it and did the bloody experiments to show it could work, rather than being worried about what could go wrong.  Since then there have been quite a few irreversible inhibitors approved for the treatment of assorted cancers.  There's even one in the clinic being tested for type II diabetes.  More power to them all.  Maybe some of this had a little bit to do with Phil Fuchs and his vinyl sulfones.  Despite some of the battles along the way, personal conflicts, and shifting of tides, it was worth fighting alongside the molecules despite the two-legged skeptics.  Thanks Phil, and RIP.  I reckon you're flying now.

Normal isn't.  

Nerd alert.  I like certain puzzles that fool people with the obvious, especially if the audience should know better.  A few years ago, I had fun with a bunch of chemists over lunch, most of whom I worked with, many holding advanced degrees in the subject.  I asked them, "What's the molecular weight of sodium?"  (Sodium is useful, but don't toss a lump of it in a bucket of water because it'll react violently and produce hydrogen, which will catch fire and explode.)  A few of them piped up "Twenty-three."  Another looked at a periodic table and read off a number.  "Twenty-two point nine eight nine seven."  One confessed to being unable to remember but didn't need to because it was written on the container.  Most, however, quoted the most stable isotope, which is Na-23.  Trouble was, everyone got it wrong.  Except someone I asked later in the day, and was the only individual not to have missed the point, perhaps because she didn't deal with organic molecules for a living.  Sodium doesn't have a molecular weight.  It's an atom, not a molecule, so it has an atomic weight.  Okay, so I asked what was effectively a stupid question (although not in the same class as "are you asleep" which may be the dumbest of all posers).  But the exercise points out how educational bias and training can sometimes blind us to reality.

My favorite example is another simple equation.  2 + 2 ≠ 4 .  As in "the simple sum doesn't reflect reality as we know it" with two specific cases that are relatively easy to prove.  "But of course it's four!" you say.  I suppose there are some who hide behind esoteric proofs and philosophical meanderings (okay, mea culpa...!) but there's a far simpler way to put this.  And it has all to do with how you depict it, not how you say it.  Ever heard the expression "Sixty is the new forty" when thinking about how today's middle-aged folks want to feel young and in ways may even be able to fool themselves or others that they are?  In 1976 I turned 10.  A couple of years ago, in 2024, I turned 40, so I'm now 42.  How does that work?  Ah, but three years ago I wasn't 39.  I was 3F.  That's 63 in base 16.  Computer scientists know all about hexadecimals, as well as binary.  Therefore, you'd imagine that said individuals would easily know the answers to the above inequality.  Aha.  2 + 2 = 10 (base 4) and 2 + 2 = 11 (base 3).  It's high school math.  But it's still pronounced "four" aloud.  It's only written like ten or eleven.  Depicted, not said.  

Told you.  Nerd alert.  Guilty as charged.  But so what?  At least it's not harmful, merely a bit of silliness.  Where it all came from I have no idea, because throughout life, personal and professional, I've been surrounded by people who are not silly or goofy - many of whom you can tell a joke or amusing anecdote to and who'd deliver nothing more than a blank stare.  Obviously they were normal and had no truck with anything or anyone two or more standard deviations from the mean.  "You're the weirdest person I've ever met."  A former colleague declared this to me some thirty years ago.  (If you're reading this, O former colleague, you know who you are...!)  But it was said and received with tongue in cheek and in good spirit, if that's anatomically possible.  It got me thinking.  Is there any such thing as normal?  Medical tests and screens all provide guidelines which, if test subjects present outside them, either subject them to the offer of treatments or disqualify them for interventions, such as certain clinical trials.  We don't want outliers messing up the data readouts, after all, do we?  I suppose it's fair when millions of dollars have been invested in research and dozens of people-years, the product usually being one chemical compound or biological that has made it through to the heady heights of human testing.  We want to give this special molecule the best chance of success so it can help as many people as it can to become "normal" again.  Or, to slow the process of abnormality, at the very least.

Shifting diagnostic guidelines and narrowing of the windows of normality (or is it normalcy?  I never know the difference, if there is one) are a feature of the last few decades of Western medicine.  The tighter the aperture, the more potential patients exist.  Close it so that anyone whose measures deviate slightly from the guidelines, or whose risk factors (as judged by algorithms, standardized questionnaires etc.) becomes a cash cow.  Several books have been written on the topic of overdiagnosis and unnecessary intervention, but what it boils down to (aside from money, of course) is that normality is the new abnormality.  Some wiseacre once said that an expert is someone who knows more and more about less and less until he or she knows absolutely everything about nothing.  Perhaps the same can be said for normality.  Someone whose biomarkers (to use a generic term) fall outside what the latest medical guidelines consider normal and healthy is now qualified to receive a particular drug, which may or may not do anything whatsoever to increase healthspan.  Or they may simply be considered at higher risk because of their age, irrespective of what is or isn't in their blood.  Ah, Mr. Patient, I see you're getting on a little.  Plus, your skin shade suggests you may have some DNA in you that could put you in the firing line for everything between dandruff and Munchausen syndrome by proxy.  You'd better start taking this pill and you'll have to do so for the rest of your life.  But golly gee, it'll get those biomarkers into the normal range.  Whoopee!  Cha-ching....  Well, there are some biomarkers you can't measure in a lab.  If they're outside the range of what's considered average for the day, there are a few adjectives available even if there aren't any drugs.  And normal isn't one of them.  We're all odd in our own way, some more eccentric than others.  Some might even live in a household full of weirdos.  Including the cat.  And that's great.  Because that's life, and if one is too normal, one might be unable to fly.