Why models fail us in childhood, on TV and in drug discovery

July 10, 2014 by Created by RCW

I know you’re used to me babbling in these pages, but I am sure two of you have wondered, so how does he pay his bills? I know my landlord wonders that.

Below, I have reprinted my latest commentary from DDNews, a magazine for which I write regularly and for which, to my great surprise, the Publishers pay me. Thought it might make a nice change of pace for those tired of the current pace.

For those of you who read the article, there is a bonus at the bottom (worst fruit-in-yogurt tagline, EVAR!)

Modestly Modeled

For a brief period of my childhood, I dabbled in model airplanes and model ships. And by “dabbled,” I mean I spent an inordinate amount of time with my fingers glued together. But aside from the medical agonies of modern chemistry, what struck me most about the exercise was how pale an approximation these models were of the real thing—about the only thing my miniature Spitfire had in common with the WWII fighter was the sheer carnage of the plane as it went from airborne to groundborne in its flight across the room.

More recently, my fascinations have turned to models of a more human variety, such as those found on the catwalks of America’s Top Model. (Let’s face it, after DDNews, I am all about the latest issue of Vogue.) And like the plastic variety described above, these models seem to be at best a glittery approximation of the actual thing.

It’s often hard to believe that I share about 100 percent DNA sequence identity with these mystical creatures. Now, 98 percent coherence with bonobo chimps, I have no problem believing.

All this to say that we are constantly surrounded with models that are poor facsimiles of the real deal upon closer inspection. So, it should probably should come as no surprise that the same is true in medicine and drug discovery.

Last week, I read a story in the newspaper that touted the life-prolonging properties of the diabetes drug metformin; a regular fountain of youth, the headlines implied. And yet, after coursing through the article, I eventually discovered that the rejuvenation experiments were performed on the worm C. elegans, which was shocking for two reasons.

One, I did not realize that there were largely untapped market opportunities in annelid diabetes. And two, the life-extending implications were being made based on a species that wasn’t even a chordate, let alone a mammal.

Now, I appreciate that this is an extreme example, probably overhyped by an eager press officer, but the literature is rife with examples of models that completely failed to live up to expectations when researchers tried to match success in model systems with success in actual humans.

As oncology god Judah Folkman once mused, we have become really good at curing cancer in mice.

Part of the challenge, I think, is that because we cannot experiment directly on humans, or at least not within the editorial reach of DDNews, researchers are often forced to study new compounds or therapeutic modalities on approximations of approximations of approximations of human disease.

We don’t study the impact of irinotecan on human colorectal cancer but rather extrapolate from its effects on an induced form (approximation 1) of murine colon cancer (approximation 2) in mice (approximation 3). Or we study new biologics against a chemically induced inflammation in dogs that bears a passing resemblance to rheumatoid arthritis in humans.

Within the realm of in-vitro models, the advent of technologies like 3D cell culture and microtissues is adding some biological context back into the completely artificial realm of 2D cultures of immortalized cell lines. (For more on this, see the special report “Life moves on” in this issue, on page 21). But in the absence of factors such as tissue vascularization and the like, even these advances result in weak approximations.

The goal of a better, more representative model may be getting a step or two closer, however, with the help of stem cells.

As we’ve reported previously in these pages, and as I am presently hearing at the ISSCR conference in Vancouver, stem cells are giving us enhanced opportunities to study human disease generated from the source material—human cells—potentially down to the scale of the individual patient.

The standard technical limitations of in-vitro analysis hold for stem cells—a lump of microtissue in a microwell dish does not a micro-human make—but we do have the opportunity to limit one or two approximations.

At ISSCR, for example, Daniela Cornacchia and colleagues at Sloan-Kettering and Weill Cornell Medical College describe their efforts to understand the inadvertent de-aging of cells transformed into iPSCs. Even when taken from older patients, the reversion process makes it difficult to use the cells to study late-onset diseases. The group is trying to identify factors that will allow them to induce natural aging into these cultures to improve models of such diseases as dementia.

Similarly, Rohan Nadkarni and Carlos Pilquil of McMaster University are endeavoring to produce 3D lung tissue from iPSCs that contain both conducting and gas-exchange zones mimicking normal lung function. If the model bears out, it may provide an even more realistic platform to study respiratory diseases in vitro.

Until we are in a position where we can do high-throughput human screening—in a 96-well cube farm, perhaps—the search for better model systems must be a priority. And given the challenges of translating preclinical success into clinical success, perhaps it should be a higher priority than the development of new therapeutics.

Look for more on this topic in a special feature on disease modeling in the November issue of DDNews.

Added bonus for blog readers:

#1 on the left photo and #2 on the right photo

Much Review About Nothing

July 7, 2014 by Created by RCW

http://prettycleverfilms.com/movie-reviews/modern-times/review-much-ado-about-nothing-2013

There is a certain degree of irony in this review of Joss Whedon’s Much Ado About Nothing which is just that; the reviewer complains at length about the bare-bones nature of the production and the lack of interpretation over mere presentation (i.e., modern dress without modern sensibilities).

I seriously doubt the reviewer would have had quite the same issues with the setting simplicity if this had been a staged production rather than a filmed production, and it is important to remember that Shakespeare’s plays were written for the stage, not the screen.

As to modern interpretation and sensibilities, I largely think this is impossible without a complete rewrite of the play into another project all-together and most particularly in the case of the comedies. Take, for example, the movie 10 Things I Hate About You as a modern interpretation of The Taming of the Shrew.

The tragedies so better lend themselves to simple modern reinvention by simply changing the uniforms of the many and varied soldiery or political figures. As an example, I give you House of Cards, which to me is a retelling of Richard III with a soupcon of Othello for flavour.

And let’s face it, Much Ado About Nothing is one of the more frivolous and playful of Shakespeare’s comedies…it is play for the sake of play. It offers no deep meaning but instead centres on the silliness of love; a topic that will remain universal for all time.

Which brings me to the biggest challenge I have with this review.

The reviewer seems to assume that Whedon meant for this to be anything more than a lark…but Whedon being Whedon, a lark that he filmed with very good friends who happen to be very good actors.

I know as little as the reviewer, but I have every reason to believe the choice of modern dress was simply the reality of not having racks of Renaissance costumes lying around the house. The choice of black & white cinematography was perhaps an homage to the screwball comedies of yesteryear, of which this play is truly one and possibly the most yester of yesteryears.

As you can probably tell, I liked the movie…I had few expectations other than laughter and those were met. I also liked Kenneth Branagh’s version, which really only differed in multiple sets, colour film and period costume.

Canada – a musical tribute

July 6, 2014 by Created by RCW

It took me a few days, but I finally saw the musical tribute to my home and native land, written and performed by Canada’s Ambassador to the Stars (the actual stars, not the vainglorious ones) astronaut Chris Hadfield and his brother Dave.

It’s a beautiful little song, although I have to admit, parts of it feel really kind of hokey and it completely plays to many of the (don’t care if they’re true) stereotypes of my people.

Regardless, I hope everyone enjoys it (and comes to visit, if you don’t already live here…plenty of poutine to go around).

How I Met Your Series Finale

July 5, 2014 by Created by RCW

Earlier today, my friend Marsha Mason posted her weekly blog on Why The Face. This week, Marsha chose to focus on series finales of television programs, picking up on the How I Met Your Mother phenomenon now that the teeth-gnashing and hair-pulling have died down.

Marsha considered this outpouring from the perspective of the magnanimous response of the show’s creators. An excerpt of her blog post:

And while they did what they felt they needed to do to bring their story to its completion, there was no way they were going to tell their audience that any of their feelings were wrong.

A beautiful way to look at the uproar.

But of course, Marsha’s post also made me think about the challenges of writing a series finale (damn you, Marsha, you made me think again).

I truly feel for showrunners who are faced with this task. It is a daunting task made that much more difficult by a dedicated audience, who for the most part can only be disappointed.

For me, the best series finales were done by shows like The Fugitive and M*A*S*H, where luckily, the writers had a hard end point in their story, i.e., the capture of the real killer and the end of the Korean conflict, respectively. In these cases, the resolutions between characters was more obvious (not to give the sense that the episodes would have been easy to write or weren’t written well). Similarly, The West Wing had the end of Bartlett’s 8-yr term and the inauguration of the new POTUS.

For other shows, the challenge is that the lives of the characters typically continue beyond the finale, if only in their fantasy worlds. From their perspectives, this isn’t the end of their lives; it’s Tuesday.

Thus, writers are forced to pencil in a flurry of seemingly arbitrary events to explain why the characters are parting ways or moving on, and typically, this means leaving a lot of unresolved questions for the audience. Closure is impossible when nothing is truly closing.

Take, for example, the end of The Sopranos…the family sits down to dinner in a restaurant…fade to black. After years of a series filled with violence that would make Titus Andronicus blush, the pure normality of this ending was almost a let down, and yet, rang as a true moment in human lives.

The alternative is to go big, such as the ludicrous ending of my beloved series House. The final 20 minutes or so looks like it was written by a group of pubescent boys hopped up on 24 consecutive hours of Grand Theft Auto. For god’s sake, it’s Gregory House…you couldn’t have him die of something he and his team couldn’t diagnose in time, only to have a letter arrive a week later from House showing he knew the diagnosis months ago?

Of course, the biggest complication is likely that most series have run out of steam well before they are given the opportunity for a series finale. All of the really great opportunities to end the series have long passed, the characters have little left to say to each other and it is only the blood-from-a-stone networks and die-hard fans who keep applying the paddles to the moribund concept. I give you the finale of Seinfeld. For this reason, I really do not look forward to the series finale of The Big Bang Theory.

(I feel an admonition from Lee Aronsohn coming on.)

In these cases, better the mercy killing of cancellation than the sad wheeze of life-support equipment.

(Images are property of owners and are used here without permission…finale!)

You never “no”

July 5, 2014 by Created by RCW

Because my mother refuses to throw anything away, but prefers to store it in a drawer or cupboard until I come for a visit, I was reminded this past trip to BC about a phase in my writing career that kind of occurred sideways.

Several years ago, I was in desperate need of a job (wow, some things never change). So desperate, in fact, that I decided to take a flyer on and leverage my background in science writing and magazine editing for a job as editor of a manufacturing automation industry trade magazine published by CLB Media.

It should be noted, I knew and to this day know nothing about manufacturing. But I can write and I can edit and I have a good idea for design. I also have a fondness for money.

It was obvious throughout the interview with the magazine’s Publisher and Director of Sales & Marketing that I could write and knew magazines well, but that if I got the job, I would have to scramble to understand the issues and lingo of a completely alien industry. They were kind, but it was obvious the job and I were not a match.

When I finally got home, I was in the middle of discussing the interview with my wife when I received a phone call from the company VP, Publishing who said my interviewers had mentioned me and that the company had a medical humour magazine (Stitches) and companion consumer pub (Stitches for Patients) that were in need of a new editor. Would I be interested in talking to him and its Publisher the next day.

Uh, yeah!

The job didn’t last very long–the magazines had been in a steady decline for years before they found me and never recovered sufficiently to keep operating–but it was a great experience, and not only allowed me to write nerdy medical comedy but also allowed me to eventually add the title Associate Publisher to my resume.

And all because I was desperate enough to apply for a job for which I had few qualifications but showed general competence and a willingness to listen and learn.

I offer the covers of my first three issues of each magazine below (thanks mom). The insane covers are the work of the amazing illustrator Max Licht under the direction of the equally amazing Art Director Graham Jeffrey.

Meanwhile, in BC – Campbell River, Qualicum Beach

July 4, 2014 by Created by RCW

The final batch of photos from my brief vacation on Canada’s west coast…in this case, from a Canada Day trip up Vancouver Island to Campbell River and around my mom’s house above Qualicum Beach.