THE NIGHT BEFORE DEFENSE (or A Visit From Citrate)

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Twas the night before Defense, when all through the lab

Not a gel box was shaking, with stain or with MAb;

The columns were hung in the cold room with care,

In hopes that my protein, I soon could prepare;

 

The post-docs were nestled all smug in their beds,

While extracts of barlied hops muddled their heads;

With the tech in the suburbs and PI the same,

I had just settled down to another video game.

 

When out of the fridge there arose such a clatter

I sprang from the terminal to see what was the matter.

Away to the cold box, I flew like a flash

But the stench was o’erpowering and I threw up beef hash.

 

The mould on the dampest of walls which were cold

Had the softness of kittens only seven weeks old;

When what to my view, a thing I despise

But a half-eaten sandwich and four tiny mice;

 

With a little old scientist, so lively and galling,

I knew at a glance, it was Linus Pauling.

More vapid than undergrads, his charges they came,

And he whistled, and shouted, and called them rude names.

 

“Now, Watson! Now Francis! You strange little modellers!

On Luria! On Bertani! You stupid old broth’lers!

To the top of the bench, to the top of the wall!

Purify! Purify! Purify all!”

 

As dry heaves before the committee meeting, bend

A young student’s body and his colon distend,

So up to their earlobes, acytes they grew,

With a sack full of antibodies, their skin turning blue.

 

And then, for a second, I heard from the ‘fuge,

An unbalanced rotor spinning something too huge.

Where I put down my hand, to better hear the sound,

Came the snapping of sparks from a wire sans ground.

 

Pauling’s hair was all wavy, and I thought I must be sick

`Cause the curl in his hair looked just like a helix.

On an arm load of oranges, he started to snack

Recalling his fetish with ascorbate, the quack.

 

His eyes were all wrinkled, but the cheeks were yet red;

Not too shabby for a man who was several years dead;

The leer of his smile was just a tad scary

And the snow on his rooftop made his head yet quite hairy;

 

The end of a pipette, he held in his teeth

And a pile of kimwipes lay around his big feet.

He held a small vial of something quite gel-ly,

A mercaptan no doubt, for it make him quite smelly.

 

He changed `round the columns, adding to the confusion

And I laughed to spite my own paranoid delusion.

A wink of his eye and a rotation of his head,

Told me whatever I drank would soon leave me dead.

 

He spoke not a word, just buggered up my work,

And dried all my resins, that silly old jerk.

And separating his middle finger from first, fourth and third,

That crazy, old bugger, just flipped me the bird.

 

He grabbed up his cohorts and ran down the hall,

And away they all flew, letting me take the fall.

That is why, dear Committee, I am sorry to say,

I need a five year extension, starting today.

Inferno(t) – a review

inferno-2016-film-movie

In a follow-up to The Da Vinci Code and Angels & Demons, Tom Hanks returns as famed symbologist Robert Langdon, the only man capable of solving the great riddles of today with clues left by our medieval artists and thinkers. In this case, it is the location of bioengineered microbes designed by mad billionaire Bertrand Zobrist (Ben Foster)—think Elon Musk with microscopes instead of rocket ships—to eradicate 95% of the world’s population.

And as the adventure starts, it appears that Langdon may be involved more directly in this mystery than even he thought possible. Along the way, he battles officials from the World Health Organization (WHO), zealous followers of the billionaire and the crafty dealings of a security firm.

As a fan of the previous two movies and puzzle-focused stories in general, I was looking forward to this latest installment. Hanks was back. Ron Howard was back as director. And Dan Brown, the novelist on whose books the movies are based, never tells a boring story.

Unfortunately, this latest venture simply does not live up to the mysteries developed in its predecessors. Simply put, the puzzle is missing and the action is merely serviceable.

To watch the trailer for this movie is to assume that the riddle of this story is wrapped up in Dante’s Divine Comedy, source of our Western vision of Hell. And, for about two minutes, it is.

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Dante couldn’t have predicted this new level of Hell

But unlike the earlier movies where clue was found buried in clue, each one linking together in an almost mystical way and tapping into the deep-seated paranoia of conspiracy freaks like me, here it was merely a token gesture. Dante’s masterpiece and the elements that followed it felt completely contrived, mere window decoration for the modern mystery that wasn’t much of a mystery.

And even the characters surrounding Langdon were largely throw-away, none showing the intricate twists and turns that kept you guessing throughout the earlier movies. In almost all cases, the functions of the characters were obvious from the outset (to explain more would be to serve spoilers).

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Tom Hanks and Felicity Jones spend a lot of time sight-seeing

And I think screenwriter David Koepp (Jurassic Park, Mission:Impossible, War of the Worlds, Angels & Demons) suspected as much as he littered the screen with small red herrings that suggested insights to the characters but never amounted to anything afterward.

One character, in fact, who appears vital from the story perspective effectively disappears from the story completely, factoring in no way into the ending of the story despite being involved in the precipitating events.

In the absence of medieval puzzles and ambiguously motivated characters, we are left with a barely passable action film that trots its merry way across the Mediterranean to the pretty unspectacular climax. Even the summary denouement is uninteresting and a bit saccharine.

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Entire screenplay written on back of Dante’s head

This is not a terrible movie, but I’m not sure I would even recommend it as an entry point to the Dan Brown pantheon, instead recommending you stick solely to the other two.

For me, Inferno never really got beyond a cold ember.

See also:

Tom Hanks returns as Robert Langdon in Inferno (Associated Press)

Say hello to the 10th circle of Hell (The Guardian)

A devil of a time making sense (Wall Street Journal)

NeoHuman podcast, starring me

Willis NeoHuman

My friend Agah Bahari is interested in everything, which is one of the things that I love about him.

Not that long ago, he decided to indulge his interests by starting something he calls the NeoHuman podcast (which matches nicely with his NeoHuman blog), inviting many of the interesting people he knows to discuss pretty much anything that comes up.

Well, seems he ran out of interesting people and so he invited me to participate…and we talked about anything: biotechnology, pharma, global healthcare, designer babies, creativity, writing, screenwriting, 9/11, marketing, and the novel he and I are writing about his life.

But my favourite part is the question he asks all his guest, which is roughly:

If you met an intelligent alien life-form, what would you describe as the greatest human accomplishment and as the worst human accomplishment?

Never boring, my friend Agah.

Agah-me

(Photo stolen with love from Kelly Brienz Showker)

Substance over volume

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When you meet someone who does not speak your language, there is a cliché response of talking louder to make yourself understood. There is something within many of us that says if we simply pump up the volume, we can overcome the disconnect.

A couple of months ago, Tufts University released their latest estimates for the average cost of developing a new drug: $2.6 billion (I’ve seen estimates up to $5 billion). Eleven years ago, the same group calculated the costs at $0.8 billion.

Now, every time these estimates arise, the hand-wringing begins over how the costs were calculated, which factors make sense and which are over-reaching. What no one seems to argue, however, is that drugs are less expensive to develop today than they were a decade ago.

So what has this to do with speaking louder?

The same period has seen amazing technological achievements designed to facilitate and accelerate drug discovery and development.

Combinatorial chemistry was heralded as a way to expand compound libraries from hundreds to hundreds of thousands. High-throughput and high-content screening, as well as miniaturization and automation, were lauded as ways to screen all of these compounds faster under the paradigm of “fail early, fail often”. And given the masses of data these technologies would churn out, the informatics revolution was supposed to convert data into knowledge and knowledge into healthcare.

And yet, for all of these improvements in throughput, I question whether we have seen much improvement in the number or quality of drugs being produced. We certainly haven’t made them less expensive.

Please understand, I don’t place any fault in the technologies. These are truly marvels of engineering. Rather, I question the applications and expectations of the technologies.

Almost two years ago, GSK CEO Andrew Witty told a London healthcare conference: “It’s entirely achievable that we can improve the efficiency of the industry and pass that forward in terms of reduced prices.”

The pivotal question here, I believe, is how one defines efficiency.

I wonder how many people simply felt economies-of-scale would improve discovery, much as mass production made Henry Ford a rich man. But drugs are not cars, and where throughput and scale make sense when you have a fully characterized end product, they have their limitations during exploration.

When I was a protein biochemist in an NMR structural biology lab, I spent some time trying to wrap my head around two concepts: precision and accuracy. A 3-Å protein structure is very precise but if the structure isn’t truly reflective of what happens in nature, it is meaningless. A 30-Å protein structure is much less precise, but if it is more accurate, more in tune with nature, then it is likely more useful.

By comparison, I wonder if our zeal to equate efficiency with throughput hasn’t improved our precision at the cost of our accuracy. If you ask the wrong question, all of the throughput in the world won’t get you closer to the right answer.

In researching the DDNews Special Reports over the last couple of years, I have spoken at length to several pharma and biotech specialists about this topic, and many feel that the industrialization of drug discovery and development has underwhelmed if not outright failed. Several have suggested it is time to step back and learn to ask better questions of our technologies.

But getting back to the costs issue.

I know many will rightly point out that the largest expense comes from clinical trials. To address this challenge, new technologies and methodologies are being developed to get the most useful information out of the smallest patient populations.

Here again, however, no one segment of the drug development process stands in isolation, and I think back to the compounds reaching the clinic and question the expense of incremental improvements.

Oncolytics CEO Brad Thompson discussed the challenge in Cancer in the Clinic (June 2014 DDNews).

“If you could double [overall survival], you could show that in a couple of hundred patients. If you want to do a 10-percent improvement, you’re talking thousands of patients to do it to the statistical level that everybody would prefer to see. How do you run a study like that?”

That is a huge difference in financial expenditure that begs the question is an efficacy improvement of just 10 percent of value.

From an individual patient perspective, assuredly. From a pharmacoeconomic perspective, maybe not, and particularly with the growing prevalence of high-cost targeted biologics. Maybe we need to aim for bigger improvements before moving candidates forward, which happens long before the clinic.

Again, I’m not placing blame. The history of any industry is filled with experimentation in different methodologies and technologies. Everyone involved had the best of intentions.

But after a couple of decades of middling results, perhaps it is time to question how and when many of these advancements are applied. Simply yelling at a higher volume doesn’t seem to be enough.

[This piece was originally published in the January 2015 issue of DDNews. A lot has happened in the year since, including some amazing results in the field of immuno-oncology that might just address the demand for high-performance treatments even if only for a select patient population. For more on that, see my June 2015 Special Report “Body, heal thyself”.]

When numbers fail (DDNews commentary)

Dutee Chand

Athletics bodies have questioned whether sprinter Dutee Chand has an unfair advantage.

What is normal?

The question may sound absurdly philosophical, particularly for the pages of DDNews, and yet healthcare directly or indirectly deals with this question on a daily basis. And the clinical response can be as life-altering as the societal and political responses that we see on the news every night.

An entire industry has been created to test and monitor health using various diagnostic assays, to the most recent of which DDNews dedicates an entire section. In some cases, the results of these assays are binary—the classic example is being a little bit pregnant. But in most cases, healthy (or normal) falls within a range of values—think LDL/HDL, blood glucose or body temperature.

In part, this is a recognition that results can vary within an individual throughout the day, and on the larger scale, because individuals are products of their genetics and environments. What might be a healthy level for me in Toronto may actually be limiting in Johannesburg.

But even with the recognition of variability, we must always be vigilant in questioning how the normal range was defined. Was it based on the combined results of 200 male Manitoba bush pilots (I have read such a study), or a sampling of tens of thousands of individuals from around the world? If only for economic reasons, the former is more likely to be the case.

In 2011, Boston University’s Shalinder Bhasin and colleagues examined this challenge by identifying reference ranges for testosterone in healthy men. Suggesting that these ranges “have been derived previously mostly from small convenience samples or from hospital or clinic-based patients,” they examined a much larger cohort from the Framingham Heart Study (Gen 3), publishing their results in the Journal of Clinical Endocrinology & Metabolism.

Although most values were consistent with historic values, their lower limit of total testosterone was higher than that used historically but was “closer to the thresholds associated with sexual and physical symptoms in a recent investigation of older men.” Thus, when it comes to testosterone, it seems (sample) size matters.

But what about the outliers, the norms who don’t fit the norms and the unwell who do?

As a bit of a sidestep, just over a year ago, the International Association of Athletics Federations (IAAF) banned Indian sprinter Dutee Chand from competing in sanctioned competitions because her blood testosterone levels fell into the normal range of male athletes rather than that of her female competitors. Thus, the group decided, she would have an unfair advantage over her fellow runners.

What made this ruling particularly challenging, however, was that Chand’s testosterone levels were natural; they did not come about from doping. Her levels simply fell outside of the clinically accepted norm for women.

Closer to home for me are two friends who live with symptoms of hypothyroidism and have resorted to alternative medicine because they were dissatisfied with the medical establishment. In both cases, standard thyroid function tests suggest they fall within the normal range and therefore would not benefit from standard treatment. This may be true, but neither knows because it was never tried.

Admittedly, these are anecdotes. Three women struggle because they do not fit ascribed definitions, whether of health or pathology. And for every anecdote I can list, the healthcare establishment can rightly point to hundreds if not thousands of individuals who fit the defined ranges of normalcy.

It’s a conundrum I have discussed previously: healthcare is population-based while health is personal.

In our zeal to standardize healthcare and make medicine more scientific, we have to be careful not to ignore the natural variabilities of individuals within those populations. So-called normal ranges should suggest action, not dictate it.

Even as we pursue the precision medicine mandate, spending billions (and possibly trillions) of dollars on expanding our understanding of human biology and generating technologies to value every facet of it, we have to make sure that our knowledge doesn’t blind us to the patient’s truth. If that happens, if all we accomplish is a bigger monolith, then we have failed in the mission.

As to Chand’s racing career, the Court of Arbitration for Sport recently overturned the IAAF’s rule, giving them two years to prove that the higher testosterone levels truly give the runner an unfair advantage.

DDNews_0915
Originally published in DDNews in September 2015, this is one of a series of commentaries I write each year. If you’re interested in recent technological and business innovations in biotech, pharma and healthcare, you should check the publication out.

Illiterate in 3 languages…all English

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“That which we call a rose, would by any other name, smell…”

William Shakespeare, Bad Line Break theatre

As many of you know (or have quickly surmised), I am Canadian, and more specifically, Anglo Canadian. Unto itself, that’s a pretty cushy thing to be in this country.

In choosing to live as a writer, however, I added an otherwise unnecessary twist to my life—I forced myself to learn English as a second language.

Wait. Didn’t you just self-identify as an English-speaking Canadian?

Yes, I did. But I’m a Canadian English-speaking Canadian.

And one of the first things you realize when you become a Canadian writer is that you will probably starve for lack of work.

Now, I’m not knocking Canadian writing, whether fiction, for film and television, journalism, what have you. It is easily some of the most beautiful writing available in the English world. But it is often written to (if not for) an incredibly small market, and opportunities to succeed are therefore often few and far between.

If feels like 8 writers encompass the entire Canadian television landscape. And name a Canadian movie. (I’ll wait.)

Nope and nope.

Nope and nope.

Okay, now name one not directed by David Cronenberg or Denys Arcand.

I was once offered a job as the Editor of a Canadian biotech magazine—yes, I used to be even more nerdy—for $30kpa. And yet, already on my resume was a job working for an American biotech mag that started around $65kpa.

Bottom line is thank goodness for my passion to write, because my passion for money has taken a beating.

(Side note: This was a choice I made and for which I take full responsibility. I don’t mean this to be a “life is so unfair” rant.)

What this has meant, therefore, is that to make it as a writer, I have had to learn English as a second language. In this case, American English.

Recently, the BBC published a short article that tried to explain Canadian English within the context of its British and American counterparts. Rightly, the author noted that the differences were more than a matter of spelling (e.g., centre v center; honor v honour). Rather, the differences also manifested in idioms, speech patterns and word choice.

As long as everyone's having fun

As long as everyone’s having fun

As with most Canadians, I had a bit of a leg up on learning American as our proximity to the border (mere kilometres and even fewer miles) means we are inundated daily by American film and television programming. But I also had the additional benefit of having been married to an American, and a Southerner to boot (more on “boots” later).

Where I would recommend taking the 401 across north Toronto, Leela would suggest taking 66 from Fairfax into Washington. Luckily, we were both practical enough to set aside arguments about whether we needed to go to hospital or the hospital.

All this to say that although the differences between Canadian English and American English can be subtle, they can easily explode before the eyes of the unsuspecting.

Writing for an American biotech magazine and working with American editors was something of an ESL boot camp. And over the intervening 15 years, I like to think I honed my American skills to the point where you suspect I am from Minnesota or Western New York (hello, North Tonawanda).

In fact, I’m going to rely heavily on my multi-Angloism as most of my writing, whether for money or in my screen- and novel writing, is aimed at American audiences. And although my primary goal remains writing the best story, my secondary goal is writing it in the most innocuous way. I don’t want my writing to “read” Canadian.

Versus

Truth be told, I don’t want my writing per se to be noticeable at all. If it is, I’ve taken the reader out of the story.

This is not to say that I want my stories to be bland, but rather that I want all of the art to be in the story itself, rather than the more mechanical aspects.

In my Canadian stories (so far a sitcom pilot and screenplay), which are set in Canada, involve Canadians and target Canadian audiences, I write Canadian. For pretty much everything else, I write American.

Should I start targeting British audiences, then I’ll spend more time learning British English, and make fewer spelling changes.

In the meantime, I’ll continue to bounce back and forth between the multiple Englishes like a character out of Monty Python.

What’s it aboot?

Anyone can make fun of how Canadians communicate (or don’t). Goodness knows Canadians do. But I have to admit that I struggle with the whole “oot and aboot” phrasing that American audiences in particular seem to see as a Canadian phrase.

It’s not that I think we pronounce these words correctly so much as we don’t say “oot”. Rather, we say “oat”.

As I mentioned, I was married to a Southerner, and one day, we had a lengthy conversation about the word “South”. Try as she might, Leela could not get me to pronounce the “ou” without it taking on a surreal emphasis akin to “owwwwwww”.

Instead, I would say “Soath”. And instead of “about”, I would say “aboat”. And as I made a point of listening closely to Anglo-Canadians speak, I never heard a single one say “aboot”. It was always “aboat”.

That being stated, I will totally cop to “eh”. It’s us. End of story.