How To Drug An Oncogene.

OfIbsAndAbs

AndDownstreamEffectorsVille

In the last post I mentioned that I worked with the powerful K-Ras oncogene to make experimental tumours a long, long time ago, back in the days when our then Canadian prime minister (i.e. the guy with the really big chin) was making the very, very best of all possible non-dodgy, pasta consultant-assisted deals to buy a whole bunch of jet planes from Europa.

Hey! 

How's that for a lede!

Anyway, to recap....

When I was mucking about with K-Ras in the lab way back in the late 1980's and early 1990's, it was already becoming abundantly clear that its oncoprotein it codes for drives the formation of a whole bunch of real tumours in actual people one example of which is the hard to treat, and often deadly, pancreatic ductal adenocarcinoma (PDAC).

Which brings us to the big breakthrough that was announced recently - a novel drug treatment that significantly lengthens the lifespan of folks with PDAC in a mid-stage clinical trial.

So, how does this breakthrough drug work?

Well, as you might have guessed given the set up, it blocks the activity of the K-Ras oncoprotein.

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People were trying to block the activity of K-Ras, which lurks inside tumor cells and does its dastardly deed by jacking up cell division and survival, way before I started working on it.

So why has it taken forty years, plus, to get there?

Well...

Back in the day, one of the ways to do this was to use something called 'scrape loading' wherein cells in a culture dish are scraped to poke holes in their membranes so that you can load them up with big, honking neutralizing antibodies that bind to the K-ras protein. However, this approach doesn't work in people because poking holes in the membranes of cells inside your body is not a good thing (i.e. it's super toxic).

But people kept trying.

The thing is, K-Ras is really hard to drug. First of all, to turn K-Ras 'off' you actually have to activate an enzymatic activity that is built-into the oncoprotein. This is tough, because designing a drug that messes up an enzyme is way easier than designing a drug that revs up (i.e. activates) said enzyme. Luckily, in the case of oncoproteins that have enzymic activity, inhibiting that activity turns the majority of them off. Thus, a whole bunch of the new class of 'rational' chemotherapeutic drugs work by inhibiting the enzymatic activity of the oncoprotein. Thus, these inhibitor drugs and usually have names that end in 'ib'. A good example of this is Imatinib a drug that inhibits the activity of an oncoprotein called Bcr-Abl that drives cell division in a sub-type of leukaemia cells. 

You can also use antibodies as drugs that bind to oncoproteins to mess them up and ultimately turn them off, but these work best when they first bind to the oncoproteins that have bits that stick out of the tumor cell. These antibody-based drugs often end  'ab'. A good example of this is Trastuzumab, an inhibitory antibody that first binds to an oncoprotein called Her2 on the cell surface of one of the now treatable sub-types of breast cancer. 

The other difficulty with trying to drug K-Ras is that molecule itself is slippery and smooth which makes it difficult to find, or build, a small molecule that can bind and stick to it.

So, given all these issues, people kept trying to make K-Ras inhibitors and they kept failing. This was such a problem that by the 2000's many smart folks started saying that K-Ras was 'undruggable'. Lucky for us, some even smarter people didn't quit and started thinking that, instead of trying to turn K-Ras itself 'off' that they would instead try to block the its ability to interact with and turn on the 'downstream effectors' of the oncoprotein that actually drive uncontrolled cell division.

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By now your eyes are probably starting to glaze over with all the weird nomenclature and terminology that keeps creeping into this post no matter how hard I try to keep it out.

So. 

Let's take a little break and I'll deal with all of that next time when I get down to explaining precisely how and why the new K-Ras drug is such a blockbuster.

Talk to you all then!

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Speaking of weird nomenclature, you may have been wondering where the name 'K-Ras' comes from...Well, remember that virus I was telling you about that we used way back in the olden days (i.e. the 1980's) to get the oncoprotein expressed in cells to make experimental tumours?....Well it was first isolated by a pathologist named Werner Kirsten way back in the year of Canada's centennial based on its ability, as a cell-free extract, to cause Rats to form soft tissue tumours called sarcomas...Thus the name K-Ras...Which just goes to so that, unlike, say, fruit fly geneticists who come up with crazy gene names like Sonic Hedgehog, Armadillo and Big-Brain, cancer biologists tend to come up with pretty boring derivative gene monikers.

Image at the top of the post?....These are cells isolated from the outermost part of the adrenal cortex that are being grown in a culture dish...They have been infected with the Kirsten sarcoma virus and thus the viral genome has started to make the K-Ras oncoprotein inside them...The bright white bits you can see inside the elongated cultured cells actually represent those K-Ras oncoproteins which have been fluorescently tagged by that antibody I wrote about in the post, above...As for the big donut holes in the middle of each elongated cell that have very little of the white stuff...Those are nuclei...K-Ras oncoproteins hate to be in the nucleus and instead they hangout out in the cell's cytoplasm where they bind to membranes to become functional such that they can interact with upstream signals and downstream effectors...But more about all that next time.

As for those jet planes that were first foisted upon us by the big chinned guy way back when...As much as I hate to admit it, I far prefer flying in a relatively roomy Airbus rather than the overly cramped cigar tubes that the super-fine folks down in Seattle are building these days.

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Of Oncogenes And Target Cells...

Bipotency
UberAllesVille


I started gradual school 40 years ago.

Luckily for me, a very smart woman agreed to let me come and work in her lab to try and figure out if subtle differences in a target cell would affect the type of cancer you would produce after you introduce a powerful 'oncogene' into those cells.

We chose cells from the outer part adrenal gland as the targets because, as they develop down a 'lineage', they exhibit subtly different characteristics that based on the type of steroids they synthesize and secrete.

When I started this work I had know idea that I would actually spend the first few years first isolating, then separating, and, finally, characterizing those different steroid-secreting target cells.

Then, in the end, I had to figure out how to keep the different cell types alive in a culture dish so that I could whack them with a nasty little bug called the Kirsten Murine Sarcoma Virus.

Why?

Because the genome of that virus codes for a very strong oncogene called K-Ras.

And the product of the K-Ras oncogene is an oncoprotein that turns all kinds of target cells into tumor cells when you ram it into them experimentally.

And why does it do that?

Because the oncoprotein interacts with and 'turns on' a series of signaling proteins located inside the cell that drive the uncontrolled division of that cell.

And it turns out that the K-Ras oncogene is also present in a large number of real (i.e. not just experimental) tumours in actual people, including the most aggressive, hard-to-treat, and very often deadly, pancreatic cancers.

You may have read or heard about a recent 'breakthrough' treatment for aggressive pancreatic cancer that involves the use of a revolutionary new drug.

As you might imagine given the set-up here, that drug blocks the activity of the K-Ras oncoprotein.

We'll discuss how that works next time. It's really quite ingenious and, to foreshadow things a little, the drug acts by preventing the interaction of the oncoprotein with almost all of those signaling proteins that drive cell division in the ontogenically-transformed tumor cell.

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Image at the top of the post?...Individual rat adrenal cells that can either become steroid secreting or goopy matrix producing cells sticking to the bottom of the culture dish. Because they can produce two cell types we described these cells bipotent and stem-like...The little bright, black-rimmed spots that are packed into most of the cells are actually tiny droplets of lipid that hold the cholesterol that forms the chemical backbone of steroid hormones.

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Back In Bow River, Again.

WakeUpBluey
You'llMissBrizzy


I've been doing a lot of old mannish stuff recently.

This includes helping my brother, who is doing all the heavy lifting, take care of our ailing Dad.

As such, I've been going to and from the Republic of SouthVanIsle most weekends.

Which means a whole lot of commuting by boat.

Which further means that I've been listening to a lot of musical playlists on the evil streaming service, particularly when I'm riding in to our fine province's capital city from the Swartz Bay ferry terminal.

****

Now.

The best of these playlists arrive by way of my youngest kid, who, as I've mentioned here before, keeps me up to snuff on all things new and happening.

Which is why we're going to see another young kid named Julia Jacklin, live and in-person, in the fall.

But, as an old guy, sometimes I can't help but build my own mixtapes, errrr, playlists.

And, as you might imagine, these lists are often larded with personal aural nostalgia.

And one group I've been overdosing on quite a bit these days is called 'Cold Chisel'.

Like Ms. Jacklin, the Chiselers are from Australia. 

Unlike Ms. Jacklin, the Chiselers hit their peak in the early 1980's before they imploded spectacularly, pretty much for good.

At least creatively because, as you might have guessed, their filthily lucred reunion tours are never ending.

****

I've never been to the Bow River that is located in northern most West Australia.

But I did spend a few months vagabonding around the 'Struth Island, mostly in a used Holden HD, with my friend S. in the second half of 1981 and the first bit of 1982.

And while we spent the first few few days of the latter year trying to learn how to surf on a beach not far from Australia's southernmost tip that is festooned with the so-called 12 Apostles, we rang in the New Year at a concert in Melbourne watching, you guessed it...

Cold Chisel.

They were a powerhouse of blues-infused rollicking and rolling pub rock with a hulking, stage-stalking Jimmy Barnes on vocals, masterful Ian Moss on guitar, a wicked rhythm section, and the maestro, and chief songwriter, Don Walker way at the back, stage right, on keyboards.

Anyway...

Whenever, I listen to to their song titled 'Bow River' I am immediately transported right back to that time and place when I discovered the group while simultaneously doing and thinking all sorts of young man not-so bluesy, because-everything's-rosey-not-grey-and-out-in-front-of-you-type things.

Gosh.

It really is incredible how music can do that to you.

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In a weird way Chisel is Australia's version of the Tragically Hip, massively popular at home but no matter how hard they tried they both failed miserably in their attempts to crack the American market.
SubHeader?...At the start of our sojourn we landed in Sydney and immediately took a bus out to the end of the line going north (which is another Chisel lyrical trope) because we'd been told that was a good place to start hitch hiking...And it was...Our final ride got us to Brisbane, which is where we plunked a few hundred dollars down on our super reliable Holden HD, which looked kind of like a late 60's Rambler sedan...Anyway, during that last hitch trip one of the other passengers was a young red haired kid that the car's driver kept calling Bluey, which is apparently the Australian version of the Irish 'Ginger' designation for folks of that fiery follicular hue...Brizzy is, of course, slang for Brisbane...They shorten pretty much everything down there  and stick a 'y' or and 'ie' on the end of it.
Thanks so much to reader EG for prodding me into doing the editing and publish button pushing on this one...It had been sitting in the queue for a few weeks now. 

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My Evening Ride's Ultimate Destination

Something'sHappeningRoundThere
AshevilleVille


Weirdly, it is not the real musician in the family who keeps me informed about what the kids are up to these days.

Which means that it is littler e. who gets me to go to shows to make sure I occasionally see/hear stuff by musicians that are new to me.

And, so, Friday night we rode the seawall, starting from the big sphere at the east end of False Creek, downtown to take in the group 'Wednesday' at the Vogue on Granville.

To be honest, I couldn't imagine riding downtown on a Friday night without those divided bike lanes.

Which is not to say that being cut-off by a Tesla or seven is any more dangerous than the most energetic and surf-obsessed mosh-pit we witnessed from our perch at the front of the balcony.

The music itself was most interesting, although somewhat screamified  in the live version by both the opener, 'Gouge Away' and Karly Hartzman and compatriots.


And then there was the fact that half-way through the show I was struck dumb by the realization that one of my favourite Wednesday tunes, 'Phish Pepsi', resembles that first hit tune from days of yore by Sheryl Crow - both musically and thematically.

As we exited the theatre, ears ringing, and me with a small dollop of 1992-era young man's blood pumping through my veins, I briefly locked eyes with a fellow departing reveller which left us both thinking that maybe, just maybe, one of us was not the oldest person in the building.

Selah.


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Pedalling Towards Bedlam.

WhatWouldJoanDidion
WriteVille


I don't know about you, but...

I yearn for the brake of natural consequences to slow the spinning of a world that has been pushed to the brink by the reckless (and feckless and deadly) pushing and shoving of a coterie of very bad actors.

And so, as I pedal across Lotusland each morning, I find myself cheering on the ever rising petrol prices that are visible on the big boards at the bright and shiny cluster of gas pumps at Oak and 25th.

Yesterday the big boards blinked out $2.13 a litre.

Which gave me a little thrill of consequence realized.

Until.

I also realized that I, too, was starting to spin.


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Where the heckfire have I been?...Started a new administrative job at the beginning of the year and thought I'd take January off from the bloggodome...That stretched out a little....What changed?...Well, as I pedalled home last night the open skies and a brisk westerly at my back felt like...Springtime.
Butchered header and subheader?...This!


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The Silliest Thing Ever Written?

TheWeeklyStandard?

NeverHeardOfItVille

From America's number one conservative public intellectual...

Or some such NYT/PBS/AtlanticMonthly-type thing:

..(P)erhaps the most important belief that the neoconservatives can impart to us is that the American dream is real. The original neocons, the sons and daughters of immigrants, aspired to make it in America and contribute to their adopted home. If libertarians oriented their politics around freedom, and progressives oriented their politics around equality, the neocons tended to orient theirs around social mobility. They wanted to create a world in which poor boys and girls like themselves could rise and succeed. They understood that this ascent required not just economic opportunity, but also the right values...

David Brooks, December 9, 2025

Now, regardless the veracity of the claim regarding the most important imparted 'belief' of the Neocons, it is not clearly stated anywhere in the fine piece quoted above how, exactly, our Mr. Brooks thinks replacing the concept of making America great again with the concept of an America once again dreaming will be an antidote to Trumpism.

Then again, perhaps we should not expect any kind of real, actual thinking from the very same super-fine public conservative intellectual who once did his best, way back in to 2016, to calm the qualms of Republican and Democratic US'ians alike by telling them that rather than Mr. Trump it was for sure  'gonna be Rubio'.

Sheesh.


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Subheader?...In case you missed it (or, more likely, have forgotten), the always money losing den of neanderconnish intellectualism called the Weekly Standard was once our Mr. Brooks employer.



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Wither Gene Editing Blockbusters To Come?

SometimesASequenceIsJustASequence

WhoseCorrectionMayBeTooSmallToProfitFromVille

On Monday we talked a little bit about a new gene editing technology that has the potential to efficiently treat a devastating inherited immunodeficiency disorder.

The work was funded by a biotech spin-off company called Prime Medicine that has already signaled that it will have a hard time funding the further development of the technology as a viable therapeutic. This was reported by Hedi Ledford writing in Nature back in May when the initial results of the work were first announced (sorry 'bout the paywall):

"...Despite these early signs of success, Prime Medicine also announced that it will not develop the therapy, called PM359, any further on its own. “Prime Medicine is exploring options for the continued clinical development of PM359 external to the company,” it said in a statement.

That decision reflects the harsh realities of developing gene-editing therapies for very rare diseases, says David Liu, a chemical biologist at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, and a co-founder of Prime Medicine. “The science has moved far enough that many patients would benefit from these gene-editing treatments,” he says. “But it boils down to an issue not just of science and technology, but of economics.”...

Of course, some of this is little more than biotech posturing and, to be clear, the company has raised significant amounts of money despite the fact that its stock price has fallen significantly since its IPO three years ago.

The thing is, the disease concerned is very rare which, as an editorial in the Guardian noted recently, makes developing the technology any further really difficult given the costs involved and the commercial incentives that drive our current system of drug development:

"...Novel gene-editing breakthroughs are making headlines. But therapies are expensive and complex to develop. The cost of bringing any new drug to patients is now around $2bn, in part because, as Brian David Smith notes in New Drugs, Fair Prices, the “success rate, from discovery to market, is tiny” and there are approved treatments for “less than 10% of the 8,000 diseases that affect humans”. Commercial incentives, he argues, skew innovation towards lucrative cancer drugs and long-term treatments for large populations. Complex gene therapies for very rare conditions are seen as too costly to develop and too small to profit from..."

In other words, life science geeks who are trying to develop new therapeutics are constantly pushed to work on indications that exclusively serve large numbers of patients because they are told that they will never be able to garner funding to move their discoveries from the lab bench to anywhere near the bedside if they don't.

So.

Are there other models out there that might give us a better chance of moving all this exciting universe-denting research forward towards the clinic?

Stay tuned...

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Image at the top of the post is from a prime editing explainer from the good folks at MIT.



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The Casinofication Of Everything, Reloaded.

It'sNotJustTheWideWorldOfSports

AnymoreVille


From Judd Legum writing at his Substack:

Two major news networks, CNN and CNBC, recently announced partnerships with Kalshi, an online predictions market. Kalshi allows the public to place bets on a dizzying variety of news events. There are currently Kalshi markets for the winner of the 2028 presidential election, next month’s unemployment rate, next week’s top TV show on Netflix, whether the announcers will say “Cheesehead” during Sunday’s Green Bay Packers football game, and thousands of other future events...

{snip}

...“Kalshi is replacing debate, subjectivity, and talk with markets, accuracy, and truth,” Kalshi CEO Tarek Mansour said in a December 2 press release...

Hmmmm...

Markets, Accuracy and Truth.

Which one of those is not like the other?

Or, put another way, which of the three can be goosed, by either money or algorithms, when required?

Sheesh.


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A Truly Impressive Bit Of 'Prime' That Has Nothing Whatsoever To Do With Free Home Delivery.

WillTheWondersNever

CeaseVille


Chronic granulomatous disease (CGD), one form of which is called p47GCD, is a condition wherein the affected people can't generate and pump electrons into tiny membranous sacs within immune cells. Normally, the pumped-in electrons generate reactive oxygen species in those little sacs that rip up invading bacteria and fungi. Thus, people with p47GCD, which is inherited, can't fight off common infections.

The gene affected in p47GCD is called p47phox, the product of which is a protein that plays a key role in the formation of an electron generator called NADPH oxidase. The inherited mutation in p47phox that messes up the electron generator has been known for some time. The trouble has been that fixing messed up 'loss of function' mutations has been very, very hard, indeed. 

Now, an amazing technology called 'prime' editing, which is CRISPR-based, has been used to fix the inherited p47CGD mutation in patient stem cells that were then coaxed into becoming into immune cells with the newly corrected p47phox gene.

Two patients have received the treatment so far and it appears to be working in the short term. The work has been peer-reviewed and it has just been published in the New England Journal of Medicine. The following is the final sentence from that paper's abstract:

"...NADPH oxidase activity was observed in neutrophils (i.e. a key subpopulation of immune cells with the little electron-pumped sacs that whack bacteria and fungi) within 1 month and was maintained for 6 months and 4 months as of the last follow-up visit in Participants 1 and 2, respectively. These results support further investigation of prime editing of CD34+ (stem) cells to treat p47-CGD..."

Note: the stuff in the brackets, above, is mine and is meant only to be explanatory

This is a truly impressive early stage potential therapy whose development required the melding of fundamental, translational and clinical life science research. Ultimately, its further development could produce an efficient, longterm treatment for this rare but devastating disease.

However, will the development of this potential therapy continue?

Stay tuned...


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Neither Velvet Nor Foggy.

MayYourEarsBeMerry
AndBrightVille


If you need a little listening enjoyment for the next few days...

Hear Mel Torme tell a super young Terry Gross how he and Bob Wells wrote the 'The Christmas Song' (Chestnuts Roasting) in just 25 minutes on a sweltering summer day in Los Angeles in 1945...As an added bonus, Hugh Martin explains how he and Ralph Blaine wrote and then modified 'Have Yourself a Merry Little Christmas', first for Judy Garland and later for Frank Sinatra....Here.

Hear 'This American Life's' very first Christmas show from 1996, wherein David Sedaris tells the tale of being a Macy's Christmas Elf way before Will Farrell ever met Zoe Deschanel while wearing green tights....As an added bonus you get to hear the late, great David Rackoff tell the tale of how he once played a store window Freud for an entire Christmas season...Here.

And, finally, this podcast has little, if anything, to do with the Christmas season...It's just that Tweedy guy from Wilco/Musical Dadland talking about just about everything under the songwriting sun...Here.

Have a great holiday everyone!


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The Rot At The Heart Of The Stream-O-Verse.

WhatWouldBurlDo

IvesVille


From deep in the bowels of Reddit, one user shouts a high wattage truism out into the void...

"(T)heir entire existence relies on being slightly more convenient than piracy."

Meanwhile.

Where the heckfire can I find an uncut, crisp and sharp version of Frosty The Snowman?



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Personally, I still kinda like Reddit. It seems to be one of the few gigantic online platforms, like Wikipedia, that hasn't totally ensh*ittified...
Tip 'O The Toque to Katherine Trendacosta writing at one of my new favourites, Techdirt.




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The Advent Jukebox, Revisited!

 

It's Bigger E!

Backed with the lost (old) boys of never lab...

You can find more of E.'s advent jukebox offerings....Here....and...Here.

Or, with fewer copyright takedowns...Here.

Happy, hippy, and hippest of holidays everyone!

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Why Would Anyone Go There?

CancellingPlaydates

BetweenFriendsVille


From Chris Michael, writing in the Guardian:

All tourists to the United States would have to reveal their social media activity from the last five years, under new Trump administration plans.

Customs and Border Protection (CBP), an agency under the Department of Homeland Security (DHS), would also require any email addresses and telephone numbers visitors have used in the same period, and the names, addresses, birthdates and birthplaces of family members, including children...

And, it would appear that many Canuckistanians have already decided not to go there:

...Statistics Canada said Canadian residents who made a return trip to the US by car dropped 36.9% in July 2025 compared with the same month in 2024, while commercial airline travel from Canada dropped by 25.8% in July compared with the previous year, as relations between the two countries plummeted...

The thing is, most of that initial drop was based on a fuzzy notion of tarrif-driven patriotism.

However...

If the new US'ian 'plans' are enacted the reasons not to go will be personal.

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Twenty-Five (Or -Six) Minutes Before Four In The Morning.

NotQuiteCohen
TimeVille


When I was a teenaged kid, and just starting to pay attention to popular music as punk started to break, the band formerly known as the Chicago Transit Authority was so prolific and ubiquitous that their music seemed like wall paper.

And sometimes, like with the infamous and very popular compilation Chicago IX, which was released in 1975, it seemed like all the walls, in every single house everywhere, were being re-papered with, well, the same paper.

Anyway...

That particular compilation is 50 years old now, which means that it is being re-worked and re-released seven ways to Sunday.

But now, somehow, that old wallpaper is kind of comforting, and even a little bit interesting when you see and hear it done in more of a jam bandish-type way (see above).

And best of all, it means that two of the original horn players, Lee Loughnane and Jimmy Pankow are out and about talking about how they all got together at DePaul university and made all that music in the first place. They even talk a bit about the magic and the math of how the original horn arrangements were composed in a way that even a music theory dunderhead like myself can understand and enjoy.

You can listen to a long form conversation with Mess'rs Lougnane and Pankow...Here.


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Tangential allusion to an ear worm in the subheader, especially given that we're not that far from the 'end of December?...This!


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William Gibson's Overdrive

NeitherAleph

NorOracleVille


Regarding the image above of 19th century writing desks or 'slopes' as they were known...

From the mind of the estimable Mr. Gibson:

"Bronte sister laptops!"

Stick that in your steampunk genre and smoke it!



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