About That New Pancreatic Cancer Drug...

 

GTPaseActivatingActivity?
WeDon'tNeedNoStinkingGTPaseActivatingActivityVille

 

As we discussed in earlier posts, I spent some time many years ago working on an oncogene called 'RAS' under experimental conditions in the lab.

 

At the time, I was lucky enough to make a small scientific contribution to a massive experimental literature that accumulated late in the last century which demonstrated that the oncoproteins coded by RAS oncogenes cause cells to divide ceaselessly in certain tissue types under certain conditions. Around the same time, clinical researchers determined that RAS oncogenes drive the formation of a bunch of different tumour types in real, actual people, one of which is the aggressive, and ultimately deadly, pancreatic ductal adenocarcinoma, also known by the acronym 'PDAC'.

 

So, given all this, the great hope at the turn of the century was that we would be able to quickly develop a drug that blocks the ability of RAS oncoproteins to cause cells to divide.

 

Easy-peasy, right?

 

Wrong.

 

****

 

Why has it been so hard to develop a clinically useful RAS blocker?

 

First, a little bit of a cell biological digressive explainer (feel free to skip this section if you like)...

 

It turns out that there are normal RAS genes in every single cell of our bodies. These genes code for normal RAS proteins that respond to transient external growth signals and magically turn them into signals inside cells that turn on cell division. This is given a fancy name called 'signal transduction'.

 

Specifically, when a growth signal, say a hormone, binds to the outer surface of a normal cell RAS proteins just inside the cell grab onto a molecule called GTP, which is a funky little molecule called guanosine with three phosphates a hanging off it (this is the small grey bit shown in the image above). 

Binding GTP switches  RAS proteins into the 'ON' position (the purple blob in the image above). When they are in the 'ON' position, normal RAS proteins then bind to a bunch of  'effector' proteins in the cell's cytoplasm. This binding of effector proteins next flips a set of cytoplasmic relay switches, a subset of which moves into the nucleus where they turn DNA synthesis to double up all the cell's chromosomes. This drives cell division in a  process  called 'mitosis' that just about everybody reading this likely learned about in grade 5 or 6. 

Therefore, the growth signals that arrive at the outer cell surface are sometimes called mitogens and normal RAS proteins are often called transducers of the mitogenic signal that drives cell division. Already, I figure you are probably getting a good idea of what might happen if this mitogenic signal transducing activity were to be enhanced by, say, oncogenic mutations in the RAS gene - but first, let's finish talking about what happens with normal RAS proteins.

 

When the growth signal/homone is no longer present at the cell surface, normal RAS proteins activate their intrinsic enzymatic activity, called a GTPase, that rips one of the phosphates off the bound GTP. This gives rise to a guanosine with just two phosphates, which is also known as a 'd'iphosphate. Thus, the bound molecule is  known as GDP. The key here is that normal RAS proteins bound to GDP no longer bind the effector proteins that drive DNA synthesis and cell division stops. Put another way, normal RAS proteins bound to GDP move into the OFF position. As a result, when things are working properly normal cells only divide when they receive appropriate external mitogenic signals in healthy tissues.

 

In contrast, oncogenic mutations in RAS genes cause amino acid changes in the resulting RAS oncoproteins that destroy the protein's GTPase activity. This means that RAS oncoproteins can't rip off the third phosphate stuck to guanosine to form GDP.  Therefore, oncogenic RAS proteins are always bound to GTP and stuck in the ON position - that's what is really depicted in the diagram above.

 

The take home message here is that cells with oncogenic RAS mutations don't give a hoot-in-heckfire about whether they see appropriate mitogenic signals. Instead, because they are always have GTP stuck to them (RAS ON) they are constantly binding to effector proteins the DNA synthesis/mitosis switches that drive cell division. This is especially true in cells that make up the ducts that drain little tiny glands in the pancreas that secrete the digestive juices into the small intestine.  Thus, oncogenic RAS mutations drive the growth of these pancreatic ductal cells which results in the formation of the aggressive, hard to treat lesions known as the pancreatic ductal adenocarcinoma (PDAC) tumours mentioned above ('adeno' stands for gland and 'carcinoma' stands for the lining tissues that give rise to ducts and glands in the pancreas - thus, the tumour name).

 

OK.

 

Cell biology digression over...

 

****

 

Most of the new anti-cancer drugs that aren't antibody-based are small molecules that can slide into cells where they bind to an oncoprotein and block its action by messing up the protein's intrinsic enzymatic activity.  Thus, the name of these drugs often end in 'ib', short for 'inhibitor'.

 

One of the first of these drugs was imatinib, or Gleevac, which was developed thirty years ago to treat a chronic form of leukemia. Imatinib binds to and blocks the enzymatic activity of an oncoprotein called Bcr-Abl. In this case the  oncoprotein is an enzyme called a kinase that likes to stick phosphates on Bcr-Abl-specific effector proteins that also help drive cell division.

 

Unfortunately, taking this approach to develop a drug to inhibit RAS oncoproteins jammed in the ON position has turned out to be very, very hard for at least two reasons.

 

First, RAS oncoproteins have a really smooth outer surface that makes it hard to find small molecules that can bind and stick to them on their own. 

 

Second, in a weird twist of fate, you actually have to activate a RAS oncoprotein's enzymatic activity (i.e. the GTPase activity described in the section above) to switch it to the OFF position. Finding a small molecule that can do this kind of thing is really tough because it is way easier to find a compound that binds to and jams up/inhibits an enzyme's activity (i.e. what imatinib does to Bcr-Abl) than it is to find a compound that binds to/activates an already messed up enzymatic activity (i.e. the intrinsic GTPase activity that is abolished up by mutations in oncogenic RAS). 

 

By analogy, if you think of an oncoprotein as a spark plug that drives the cell division engine, imatinib binds to and sits in the gab between the electrodes at the top of the Bcr-Abl to  gum up and block it from firing. Conversely, in the case of RAS, you would have to develop a drug that sits in the gap and causes the busted plug to spark . Obviously, fixing busted enzymes/spark plugs with a small molecule  is way more difficult just gumming up/messing up the firing of the plug as happens with imatinib.

 

As a result, it turns out that finding a small molecule that can first bind to the slippery surface of the RAS oncoprotein and then fix its messed up spark plug firing turned out to be almost impossible.

 

Thus, starting as far back as the early 2000's, a lot of very smart people began to think that RAS oncoproteins were undruggable. 

 

Luckily, a few even smarter people kept trying, using different approaches to the one described above. One of these  was developed by an academic research scientist named Gregory Verdine at Harvard who had been working on small molecule molecular glues that cause proteins to stick together. One of these glues, which was originally isolated from bacteria, acts as a molecular chewing gum that sticks a big, honking protein called 'Cyclophilin A' to a bunch of other proteins inside mammalian cells. That kind of work, which at the beginning seems like it might not be immediately applicable to any specific clinical problem, is the type pure, fundamental discovery-based research that is almost always publicly funded.  

 

Anyway, after the original discovery work had been done, Verdine came up with the idea that his molecular glue could be chemically modified such that it could stick cyclophilin A specifically to RAS oncoproteins. To start working on this 'translational' research problem, Verdine and his colleagues raised venture capital money and formed a biotech company called Warp Drive Bio. 

 

Why move away from public funding to do this kind of translational work in attempt to develop a compound that could turn out to be clinically useful? 

 

Well.

You could argue that it is done to try and hit the financial biotech jackpot. And, there is a some of that going on. In fact, most public institutions want their researchers to form such spin-offs because they usually own the intellectual property rights.

 

However, there are also a couple of other major factors that work against researchers who try to translate their fundamental research findings into something clinically useful using public funding alone. First, this translational stuff often costs more money than most publicly funded research grants can provide. Second, it is grinding, step-by-step work that is often viewed as incremental by public research grant adjudicators who are trained to instead reward novelty. Thus, even getting public funding for this type of work can sometimes become very difficult

 

Regardless, Warp Drive Bio never quite got there translationally and a number of years after its founding the company was acquired by a second company called Revolution Medicines that soon set their team of excellent molecular modellers and synthetic chemists to work modifying Verdine's molecular glue. In doing so, the RevMed folks developed a slew of new lead compounds, a few of which did the trick and stuck the Cyclophilin A protein to RAS oncoproteins. 

 

Miraculously, these new compounds worked. One of them, which RevMed calls 'daraxonrasib', is represented as the little bit of orange chewing gum that is labelled RAS(ON) inhibitor in the image above

 

The fact that the inhibitor worked was somewhat dogma busting because it has no effect on the RAS oncoprotein's messed-up GTPase activity (i.e. it does not fix the busted enzymatic sparkplug). Instead, it turns out that the Cyclophilin A molecule  (i.e. the turquise blob in the image above) that is stuck to the purple RAS(ON) protein by the chewing gum inhibitor is so big and bulky that it prevents the effector proteins from binding to the complex.

 

And that's the key here - when the effector proteins can't bind there is no switch flipping resulting in DNA synthesis. As a result, the  RAS(ON) oncoproteins can no longer drive tumor cell division. 

All of which is great translational science but the real proof is in the clinical trial pudding.

And that pudding was cooked in a recent phase three clinical trial, the results of which were published in the New England Journal of Medicine a few weeks ago. The following is straight from the paper's abstract: 

 

... A total of 500 patients, including 91.8% with (oncogenic) RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or (standard) chemotherapy (252 patients). The median overall survival in the RASG12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy...

 

 

Now.

 

That doubling of survival in RAS oncogene-driven PDAC patients, which amounts to an improvement of over just six months, may not seem like much, but...

 

Don't forget that this improvement is for the worst-of-the-worst of all the RAS oncogene-driven tumours where no significant improvement in chemotherapeutic treatment has been seen for years.

Imagine that!

 

______

The image at the top of the post is a schematic/cartoon from the Revolution Medicines website...A paper describing the translational generation and characterization of  a number of their RAS(ON) inhibitor compounds, including daraxonrasib is here. 

 

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Kraut Rock Prop Wash A-Go-Go

IsItStillFunFunFunOnTheAutoHahn
NotKraftwerkVille


Just in case you were wondering...

Those German-built, import duty-waived ferries that were designed to drive the final nail in the coffin of our local ferry building industry back in the days of GordCo, Inc. v1.0 are still throwing hella prop wash at every single berth they dock in.

On the bright side, they still kinda/sorta work.

Some of the time.


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Image at the top of the post...One of those fine Celebrations pounding Berth 4 at Swartz Bay this morning.



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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 the oncoprotein it codes for drives the formation of a whole bunch of real tumours in actual people. One example of the latter are hard to treat, and often deadly, pancreatic ductal adenocarcinomas (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.

****

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.

****

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!

_____

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.

_________

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.

_______
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.


______
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.


______

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...

______

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?



______
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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