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Need Yves Smith’s analysis of new Pfizer hostile takeover of Astra-Zeneca

Derek Lowe at In the Pipeline has a post on Pfizer’s hostile move on Astra-Zeneca:

What the hell is Ian Read thinking? Pfizer is apparently going hostile with their attempt to buy out AstraZeneca, all but ensuring that the deal, if it goes through, will take place at the highest price and in the messiest fashion that it possibly could. And for what?

If you’ve been following Pharmageddon from the beginning, you will know that Astra-Zeneca’s fall off the “patent cliff” was one of the steepest in the industry.  The patent cliff is the term used in the industry that refers to the expiration of patents for the major blockbuster drugs.

Patent Cliff by company since 2010.

 

Weirdly, most blockbuster patents have expired within the past decade because they were discovered in the 90′s, the golden age of drug research.  If you’re wondering why your blood pressure meds are suddenly so affordable, that’s why.  They’re generic now.  Pharma can’t make as much money off them anymore.  Great!, you say.  And it probably is great, to some extent.  The problem is there is not a lot in the pipeline to replace them, that is, if you’re interested in more effective drugs with fewer side effects.  There are several reasons for this that I’ve discussed in previous posts but the primary cause is NOT for lack of trying.  Researchers have seemingly endless dogged determination to preserver in  the face of failure after failure.  The problem is that research has to deal with *two* impossible systems: the complex biology and the self-serving, clueless managerial/finance class.  And the underfunded and politicized FDA.  Make that THREE impossible systems.  And the class action law industry.  FOUR! It all adds up to unnecessarily and ridiculously expensive drugs.  But I digress.

So, according to Derek, Astra had some really rough years, laid off a ton of people in Delaware and all around the world, but hired a new guy in 2012 to turn the ship around and has plans to consolidate a tiny fraction of their research unit in Cambridge, MA where no one really wants to work because it’s a.) expensive, b.) a pain in the ass commute and c.) an insecure career environment for researchers.  MBAs really are a bunch of status snob lemmings, I swear.  Or magpies chasing the latest shiny thing.

My bad, that’s Cambridge, UK where AZ wants to set up its stripped down R&D division.  It’s probably just as attractive to the relocated researchers (You happy few!  You band of brothers!) as the American Cambridge.

Derek makes a good point in that Pfizer has a lot of money to spend on the small, nimble biotech startups that MBA types have told the analysts are supposed to be able to generate a s^&*load of drugs to inlicense.  They’re like unicorns, these little startups, or like perfectly elastic collisions of particles in a box.  Theoretically, they exist but in the real world?  ehhhhh, not so much.  Drugs rarely emerge from these tiny incubators fully formed because, helloooooo, Silicon Valley, drug discovery is NOT like writing code for a new Facebook.  But you’ll find out in the next couple of years.  Just sit in on one of the project teams while the biologists drone on and on and on about how much to tweak the components of their confirmatory and cell based assays to make them reproducible and it will quickly dawn on you that drug discovery makes coding look like Chutes and Ladders.  Even so, we’ve got to wonder why Pfizer is choosing to forgo spending some of their billions on the biotech startups in order to sit on a pile of cash.  Where is the drive for innovation we’re always hearing so much about?

Anyway, where was I?  After pondering the problem for awhile, Derek hypothesizes that Pfizer is buying Astra-Zeneca, a foreign owned company, to hide its taxable profits from the US government.  Or the British government.  It’s like some British, Swedish, American threesome, which initially sounds like a good time for everyone except the citizens who actually count on corporations to respect them. It’s a rather strong accusation but Derek says he never wants to work for Pfizer anyway.  That’s Ok for him but my pension was acquired by Pfizer when it gobbled up Wyeth and then proceeded to lay off every one of the people I used to work with.  I’m kind of concerned with this wobbly third leg of my rapidly disappearing retirement stool so if Pfizer is up to something, I’d like to know what the heck it is.

The remaining survivors in research at Astra-Zeneca can see what’s coming.  They must be busily rewriting their CVs and networking instead of finishing that reaction or fishing the crystals out of solution to send to the synchrotron.  What a lovely way to spend your hours in the lab.  And the industry wonders why there is nothing in the pipeline after 20 years of this crap.

What this research project team really needs is a financially nerdly Yves Smith type who can look at the details of the proposed takeover and report back in a meeting to tell us what’s up.  More to the point, what does the UK’s new tax rates for foreign profits say about whether the conservative government is trying to make Britain into a sleeker global tax haven?  I’m just a chemist.  Money is not my area of expertise.  This project team needs a finance specialist.

 

 

More on Drug Discovery and public funding

Following up on the last post on Virtually Speaking’s recent episode featuring Dean Baker and his comments on drug discovery, I’ve had a nice conversation with Jay and I think we are a little closer to understanding what’s going on here.  In some sense, we may have been talking past each other, in another sense, there are still some engrained biases there that the left will need to fight its natural impulses in order to contain.  But it is all good.

So, in the interest of fairness, I am posting a link to Baker’s proposal to a public funding mechanism for drug discovery.  I confess that I haven’t had time to read it yet, what with moving and work related activities, making sure Brook is studying for her finals, and driving back and forth between PA and NJ, so I’m going to hold off critiquing it until I do.  However, I will say that any policy proposals that don’t involve the input of people who actually have the experience of drug discovery are probably not going to work very well.  After all, we’ve had a couple of decades of the MBA class restructuring on a regular basis without the input of their R&D staff and how did that work out?  We do have opinions and are well trained in the scientific method, so, you know, take advantage of our expertise before you set up some new system that might be as unworkable as the old one was.

Here’s the link to Dean’s Financing Drug Research: What are the Issues?   I just noticed that it was written in 2004.  At this point, given the last decade of craziness, it’s out of date and due for a rewrite.  I mean, for one thing, there really isn’t an American drug discovery industry anymore.  There are only remnants and a whole lotta unemployed chemists with lots of time on their hands.

And here is a recent post from Derek Lowe on the subject of The Atlantic’s recent article, How Drug Companies Keep Medicine Out of Reach.  Derek touches on some of the mythology surrounding the drug discovery process. Says Derek:

At some point, the article’s discussion of delinking R&D and the problems with the current patent model spread fuzzily outside the bounds of tropical diseases (where there really is a market failure, I’d say) and start heading off into drug discovery in general. And that’s where my quotes start showing up. The author did interview me by phone, and we had a good discussion. I’d like to think that I helped emphasize that when we in the drug business say that drug discovery is hard, that we’re not just putting on a show for the crowd.

But there’s an awful lot of “Gosh, it’s so cheap to make these drugs, why are they so expensive?” in this piece. To be fair, Till does mention that drug discovery is an expensive and risky undertaking, but I’m not sure that someone reading the article will quite take on board how expensive and how risky it is, and what the implications are. There’s also a lot of criticism of drug companies for pricing their products at “what the market will bear”, rather than as some percentage of what it cost to discover or make them. This is a form of economics I’ve criticized many times here, and I won’t go into all the arguments again – but I will ask:what other products are priced in such a manner? Other than what customers will pay for them? Implicit in these arguments is the idea that there’s some sort of reasonable, gentlemanly profit that won’t offend anyone’s sensibilities, while grasping for more than that is just something that shouldn’t be allowed. But just try to run an R&D-driven business on that concept. I mean, the article itself details the trouble that Eli Lilly, AstraZeneca, and others are facing with their patent expirations. What sort of trouble would they be in if they’d said “No, no, we shouldn’t make such profits off our patented drugs. That would be indecent.” Even with those massive profits, they’re in trouble.

And that brings up another point: we also get the “Drug companies only spend X pennies per dollar on R&D”. That’s the usual response to pointing out situations like Lilly’s; that they took the money and spent it on fleets of yachts or something. The figure given in the article is 16 cents per dollar of revenue, and it’s prefaced by an “only”. Only? Here, go look at different industries, around the world, and find one that spends more. By any industrial standard, we are plowing massive amounts back into the labs. I know that I complain about companies doing things like stock buybacks, but that’s a complaint at the margin of what is already pretty impressive spending.

The point is that drug discovery ain’t rocket science.  It’s much, much harder.  Are there ways to make it easier and less expensive to the average consumer?  Yeah, probably, but it’s still bloody hard and in some respects, the left has as much to answer for as the right does when it comes to the cost and expense of developing drugs.  If we’re all in this together, then the left has an obligation to learn all that it can about the mechanisms of drug discovery and who is making a fortune on drug failures as well as successes because we know that the right isn’t going to do it.  Let’s be better than them.  M’kay?

 

 

Talking us down from the glyphosate ledge

Glyphosate. Not keeping me up at night.

Glyphosate is now the new cyclamate and we’re all supposed to be terrified to use it in agriculture.  Oh, please.  Check out this analysis of the glyphosate study by Derek Lowe at In the Pipeline, Is Glyphosate Poisoning Everyone?.  Here’s the money quote:

Now, that presumably sounds extremely detailed and impressive if you don’t know any toxicology. What you wouldn’t know from reading through all of it is that their reference 121 actually tested glyphosate against human CYP enzymes. In fact, you wouldn’t know that anyone has ever actually done such an experiment, because all the evidence adduced in the paper is indirect – this species does that, so humans might do this, and this might be that, because this other thing over here has been shown that it could be something else. But the direct evidence is available, and is not cited – in fact, it’s explicitly ignored. Reference 121 showed that glyphosate was inactive against all human CYP isoforms except 2C9, where it had in IC50 of 3.7 micromolar. You would also not know from this new paper that there is no way that ingested glyphosate could possibly reachlevels in humans to inhibit CYP2C9 at that potency.

In the pharma lab, if a compound had an IC50 of 3.7 micromolar against a target, we’d have to be desperate to call it a “hit”.  That level of activity means you’d have to choke down a lot of chocolate cookies before you’d be even mildly affected.

So, you can stop worrying about glyphosate poisoning.  That doesn’t mean everything in the world is safe to consume.  It’s just that glyphosate is no dioxin and you won’t have to superfund site a farm that uses it.

Lowe also has a post on the cost of cancer drugs that is worth reading.  It gems fairly nicely with my cynical theory of the current pharma business model, which goes like this: Once upon a time, big pharma made drugs for all kinds of ailments, like heart disease, schizophrenia, depression, reproductive health, antibiotics, diabetes, pain, inflammation, etc.  But over the last 30 years, it has become increasingly more difficult to get those drugs to market for a variety of reasons I won’t go into here.  Suffice it to say that the FDA doesn’t approve very many small molecule drugs anymore.  Like virtually none.  A pharma can spend a lot of money on research only to have a drug shot down at the approval stage.  So, how does a drug company make money if it can’t sell drugs?

Easy.  It concentrates on cancer and orphan drugs.  Orphan drugs are for diseases that are relatively rare.  For cancer drugs, the path to profit is pretty straightforward.  The patients are desperate. They’ll pay what the market will bear and then some.  Will they mortgage their houses?  Yeah, probably.  So, the market is there.  But it gets better.  Cancer drugs are fast tracked for approval and no one is overly concerned with toxicity.  In other words, there won’t be class action lawsuits because patients are grateful for any extension of life they get.  Even if the patient dies, their families are likely to consider their treatment as advancing the knowledge of science.  No one complains.  If you’re a bean counter, oncology drugs are as good as it gets.  They’re profitable, quickly approved, they don’t have to be perfect and no one will hold you accountable.  It’s probably the same situation for orphan drugs.

This is the financier’s mindset at work.  R&D people don’t think like this.  But in the end, there is a ceiling to the amount of money we as a society are willing to pay for potentially lifesaving drugs and  we are now up against it.  Meanwhile, if you are suffering from any other ailment, like bipolar disease or osteoporosis or some flesh eating bacterial infection, you’re going to be stuck with older drugs that are quickly becoming generics.  The good news is that the generics will be cheaper, well, at least for a little while longer.  I don’t think that can last as there won’t be enough profit in generics to keep the production facilities up to FDA standards. I can easily imagine some production facilities being taken offline a la the rolling blackouts of the California energy crisis 10 years ago.  Some jerk generics traders are going to be yucking it up about Granny not being able to afford her cholesterol lowering drugs.  Call me paranoid but as far as I know, there’s nothing to stop such scenarios from taking place and I wouldn’t be surprised if it’s already happened.

At some point, the price of generics will start to rise and in some cases, they haven’t really dropped all that much yet.   There won’t be a steady stream of new and improved drugs coming from the pipeline.  It will be more of a thin trickle.  The public has spoken.  It doesn’t want me-too drugs even if they are better than what’s already on the market, and it doesn’t want any drug that’s less than 100% perfect and free from all side effects.  Whether this combination of financier morality and public skittishness is good for medicine, science or society are questions we haven’t even considered yet.  No one, it seems, except the displaced scientists from Pharmageddon seem to be discussing those issues.  Someday, the Ezra Kleins and Duncan Blacks will wonder how that happened but it’s already almost too late to do anything about the coming Dark Ages of pharmaceutical medicine.

So, if you’re rich and you have cancer, you’re probably going to be Ok.  If not, well, it’s just another symptom of being in the 99%.

Pharma can’t find post-doc STEM graduates to do incredibly boring paperwork jobs, hiring managers say

Derek Lowe at In the Pipeline asked for an eye catching headline to summarize a new labor report on the dismal fate of STEM graduates so I thought I’d give it a shot:

The knowledge-intensive pharmaceutical industry had the highest reported difficulty in hiring top talent of the 19 industries featured in PwC’s 2012 Global CEO Survey. CEOs identified talent gaps as one of the biggest threats to future growth prospects.

Research conducted by HRI, including a survey of human resource and R&D executives at U.S. biopharmaceutical companies found (that) fifty-one percent of industry executives report that hiring has become increasingly difficult and only 28 percent feel very confident they will have access to top talent.

Of course, the workplace is not stagnant and the demand for certain skills is always evolving. Seen this way, the data suggest that pharma execs may want the sort of talent that is not on the sidelines or simply clamoring for a different opportunity. For instance, 34 percent say that developing and managing outside partnerships is the most important skill being sought among scientists. . .

Well, it all makes sense to me.  What pharma wants is not scientists, they want lawyers to negotiate contracts and efficiency experts to break down each experiment into a set of easily digestible tasks.  That’s not really science anymore because the ability to think for oneself, analyze procedures and take advantage of serendipity is lacking but nevermind the counterintuitiveness of it all. Chemists and molecular biologists didn’t spent 12 extra years doing lab work in order to push papers around.  They planned to actually work in a lab, not that there’s anything wrong with that.

Funny how you have to tack that apology onto the end of the sentence when you are referring to people who actually get their hands dirty.  We’re working with someone else’s values when it is assumed that the thing scientists would prefer above all things is to work their way out of the lab and never have to touch a chemical or wear a labcoat again.  Well, anyway, they said they don’t want people like that anymore.  You know, those scientific malingerers who hide out in university corridors waiting for a hit of the Journal of Medicinal Chemistry or whiff of stewing e.coli.

This is what happens to an industry that gets taken over by the brain trusts on Wall Street.  They think that any industry that’s not finance can be outsourced and managed by people a little bit like them but who simply have more experience in the lab.  I hope they’re not counting on fresh out of school Harvard PhDs to this work because even they need about a decade’s worth of seasoning before they even know who to manage or what to do to make a project work.

Come to think of it, you don’t need PhDs to do this stuff.  Why not just hire any science type sucker who needs to make ends meet?  We all know how to use Excel and PowerPoint and we’ve all got experience slogging through the badly implemented SAP systems that the executive branch is so proud of.  You don’t need to go to an Ivy League university for 12 years to be a scientifically literate corporate drone.  A BS level employee with a 2 month crash course in drug discovery could probably do it.  I mean, that’s how it’s done on Wall Street, right?  You take some overprivileged  23 year old recent graduates from Princeton and teach them how to do finance in 2 months before they’re set loose on the world.  What could possibly go wrong?

Flee from science majors, little children!  Flee!

In another sign of the times, Derek posts on yet another company that’s had to lay off early stage discovery staff in order to move their two lead projects into development and clinical trials.  That means, the dedicated chemists, drug designers, biologists, pharmacologists, etc will have to pack up their pipettes and find another job.  They probably *won’t* be able to work on the same kind of project again and use their expertise. There goes the mortgage on the house, the car payments, the college funds.  Imagine having to do this every couple of years- if you’re lucky enough to actually work in a lab and not tied to a chair in Massachusetts managing people in Shanghai.

I hope it’s not to much longer before our nation’s leaders realize they’ve been lied to about the promise of “entrepreneurship” in biotech.  The initial overhead costs are among the highest of any industry and a payoff is unlikely.  The big pharmas that are preying like vultures on the promising tidbits on the skeletons of little start ups are the same companies that couldn’t get blockbusters to market after several rounds of M&A and sinking billions of dollars into very badly managed R&D departments.

Believe it or not, there are lot of scientists who are not dying to relocate to Cambridge to work in the offices of big pharma.  The ones who do go to Cambridge and South San Francisco are just postponing the inevitable.  The rest of us would rather take pay cuts for some modicum of stability or get out of science altogether.

Whatever.  What the world needs now is a good plague to wipe out the aristocrats and middle men and let the scientists get on with it without any further interference.

************************************

Zombie Symmetry shows what’s involved in drug discovery these days:

Big Pharma and the power of a union

French union scientists at Toulouse do a haka to protest salary and position cuts.
{{sniff}} I am so proud!

Derek Lowe at In The Pipeline wrote recently about French drugmaker Sanofi’s recent plans to close some sites in France.  I’ll get to that in a minute but first a little background.

A few weeks ago, Sanofi announced that it would be closing some French sites, the biggest site would be at Toulouse.  The closure would have put approximately 2300 scientists out on the unemployment rolls.  The Ministry that handles labor and unemployment had a fricking fit:

Besides unions, Sanofi has gotten an ear full from some government officials. With France’s economy struggling, the fact that Sanofi’s mother country was absorbing more of the pain, has not set well. French Productive Recovery Minister Arnaud Montebourg told senators when the cuts were first leaked: “Sanofi showed up at the ministry to tell us they were planning several thousand job cuts. Couldn’t you have said that earlier on? Last year you made €5 billion ($6.1 billion) in profits.”

And I’m sure that Sanofi would have cut elsewhere, if they had anywhere else to cut.  Last year, the company laid off all of the scientists at their main site in the US that was located in Bridgewater, NJ.  A couple dozen jobs were rescued and sent to the Cambridge, MA site, which is small, cramped and inadequate.  The rest of the projects were distributed to the French sites.  And do you want to know WHY the work went to the French sites and not to China (at least not yet)?  I’ll tell you why:

THE FRENCH SCIENTISTS ARE PROTECTED BY A UNION

Their union is pretty damn good too.  You could take every project away from them and have them just occupying the sites and playing tetris all day and the company would still have to pay them.  So, any time the company felt like research was being too much of a money pit, they took it out on the US workers until there weren’t any left.

This time, the unions threatened to strike and the French Productive Recovery Minister told the company that dumping French scientists on the labor market and relying on the government was not an option.  Usually, the companies who do business in France lay scientists off through attrition or generous early retirement packages.  A straight layoff , although rare, is still heavenly by American standards with terminated employees getting up to 80% of their salaries for 2 years and then able to go on the French public assistance program after that.  AND you don’t need to shell out half your unemployment on COBRA.  So, pretty sweet deal even if you’re being laid off.  You have time to find something else or go back to school for retraining or emigrate to Canada.  Your life isn’t thrown into an instant and chronic crisis.  And THAT, in turn, helps stabilize the rest of the economy.  The more people who can spend and keep demand up, the less of a hit the economy takes in newly unemployed people.

Anyway, it was still looking pretty grim for the French scientists until this week.  It looks like the Productive Recovery Ministry and the unions had an impact.  From Derek’s post:

here’s the announcement itself. And maybe this is my first impression, but compared to what’s gone on in other Sanofi sites (like Bridgewater), this one comes across like a shower of dandelion fluff. No reduction in the number of sites, no actual layoffs – just 900 positions to phase out, mostly via attrition, over the next two years. The Toulouse site is the only loose end; that one is the subject of a “working group” to figure out what it’s going to do, but I see no actual language about closing it.

Here’s more from FiercePharma’s article on the cutbacks in France:

A key official in France is keeping up pressure on Sanofi about its planned work force reductions in the country, sticking to the position that the drug giant ($SNY) hasn’t done enough to protect jobs. And French Industry Minister Arnaud Montebourg makes clear in reports today that he isn’t satisfied with how the company plans to secure the future of its R&D site in Toulouse.

Montebourg has been a thorn in the side of Sanofi. Early this week Sanofi softened its stance on job cuts in France, saying the company would seek to shrink its work force in the country by 900 jobs through early retirements and voluntary moves and transfers in the next few years, as opposed to the 2,300 to 2,500 jobs at the company previously estimated to be on the chopping block. Yet the minister and others keep harping on Sanofi’s unresolved plan for its Toulouse site, where 600 additional jobs hang in the balance.

Sanofi wants to part ways with research in Toulouse, and said earlier this week that it would work with stakeholders in the coming months to solidify plans to keep the operation alive, Reuters reported. That too fell short with Montebourg and unhappy Sanofi workers and labor officials.

“Trade unions are right to say this is too much,” Montebourg told BFM television, as reported by Reuters. “The government thinks this is too much and we want guarantees for Toulouse.”

Sanofi CEO Chris Viehbacher, who has reportedly met with the industry minister, has found resistance in his strategy to double down on productive R&D centers while making cutbacks at those that fail to meet expectations.

You know, if Chris Viehbacher wanted to preserve the company’s most productive sites, maybe he should have kept the US scientists on their tree-lined campuses instead of keeping them in a high state of suspense for several years, terminating their projects and then stupidly laying them off and closing the site.  No wonder the French Ministry doesn’t believe a single thing he says.

So, there you go, folks.  If you want to stand up to the bonus class and save your jobs, you need to get a union and the government behind you.  Or maybe just the government behind you.  You don’t need to work 24/7 like a maniacal drone on crack, cranking out work and trying to impress everyone working like crazy, singing, “I really need this job.  Oh, God, I need this job” to guys on Wall Street who don’t give a shit anyway.  No, you have your union representatives negotiate a contract that makes it extremely painful for the company to drop its commitment to you.

Not only that, but the union has to be very, very active and visible, like standing outside the cafeteria, handing out grievance pamphlets and making its presence very known to the management.  Imagine going to lunch to eat your company subsidized baguette, custom prepared omelet and glass of red wine and being greeted at the door by a union person dissing the management and getting away with it.  (Oh, yes, it really happens, I saw it with my own eyes.)  Take a look at that picture.  Does that look like a bunch of broken human beings, cowering under the whip they’ve been forced to kiss, cringing in fear of being fired for speaking up or fighting for their rights?  Damn straight it doesn’t.

That’s why I keep saying that drug discovery will survive in Europe. They’ll have an infrastructure in France and Germany and the expertise that is acquired from having stability and continuity of uninterrupted research.  They’ll be able to keep pace with this rapidly changing explosion of biological discoveries while thousands of US scientists will be trapped in routine, unchallenging CROs or having their expertise rotting from disuse.  Maybe they won’t be as productive as the US researchers used to be or as ingenious as possible but, by golly, they may be all the world has left unless and until the Chinese and Indians can stabilize their business environment and take the lead in research.  It’s not easy and it will take some time before that happens.  The finance guys are going to have to take an old, cold tater and wait, not something they’re good at.  They’re going to be mad that they can’t transform our salaries into their bonus gold, but such is life.  The French government is finally standing up to them and saying “Non”.  In this case, the unions are actually doing them a favor, giving them an excuse to keep the technological expertise in the country and giving it an edge when the recession finally eases up.  The government will soak the corporations for salaries, not the workers for absolutely everything.

The bad news is that now that Sanofi has been forced to scale back their cutback plans in France, they’re going to have to take it out on their remaining employees elsewhere, like their site in Cambridge, which is already tiny, and their exploratory facility located in Tucson, Arizona.

So, for those of you professionals who are watching in horror at what happened to the scientists in this country, take note: get a union.  The problem of unemployment among us is not structural.  There are plenty of us and many of us are willing to relocate or work from home.  The problem is that the big guys don’t want to pay us for our expertise.  So, they’re going to keep spreading this lie that they can’t find enough qualified workers.  The real problem is that OUR government is not on OUR side.  The Obama administration would rather this country lost its technological edge and make precariats of us all than to stick up for us when the finance guys calculate their bonuses based on how many R&D bodies they can chop.

Sad but true and this story is proof.

Debunking the myth that the NIH discovers drugs and industry just exploits it

Derek Lowe describes how the drug discovery process really works and why critics who perpetuate the myth that the NIH discovers targets and drugs before the pharma industry ruthlessly exploits the taxpayer don’t know what the hell they’re talking about.  Here’s a snippet but if you’re interested in this kind of thing because you don’t know much about it, you should read the whole post:

 I think I’ve hit on at least one fundamental misconception that these people have. All of them seem to think that the key step in drug discovery is target ID – once you’ve got a molecular target, you’re pretty much home free, and all that was done by NIH money, etc., etc. It seems that these people have a very odd idea about high-throughput screening: they seem to think that we screen our vast collections of molecules and out pops a drug.

Of course, out is what a drug does not pop, if you follow my meaning. What pops out are hits, some of which are not what they say on the label any more. And some of the remaining ones just don’t reproduce when you run the same experiment again. And even some of the ones that do reproduce are showing up as hits not because they’re affecting your target, but because they’re hosing up your assay by some other means. Once you’ve cleared all that underbrush out, you can start to talk about leads.

Those lead molecules are not created equal, either. Some of them are more potent than others, but the more potent ones might be much higher molecular weights (and thus not as ligand efficient). Or they might be compounds from another project and already known to hit a target that you don’t want to hit. Once you pick out the ones that you actually want to do some chemistry on, you may find, as you start to test new molecules in the series, that some of them have more tractable structure-activity relationships than others. There are singletons out there, or near-singletons: compounds that have some activity as they stand, but for which every change in structure represents a step down. The only way to find that out is to test analogs. You might have some more in your files, or you might be able to buy some from the catalogs. But in many cases, you’ll have to make them yourself, and a significant number of those compounds you make will be dead ends. You need to know which ones, though, so that’s valuable information.

That’s just the start of the problem as Derek goes on to point out.  This is usually where the drug designers get involved, sifting through the information that comes from the screens, clustering the compounds that show activity, doing searches on in-house and commercial databases, finding the common features of the hits to determine if there’s a reason why they’re active, and proposing modifications to those lead series (that the chemists will ignore).  You do this on enough projects and you become a very good pattern spotter without really trying.  But that was only a small part of my job.  Most of the projects I’ve been involved in go on for years.  It’s a very iterative process and sometimes, the project takes off on tangents  It’s like untying a giant knot with lots of little subknots that sometimes need to be solved first.

The bottom line is that as valuable as the NIH contribution is, it’s usually the 1% inspiration that leads to the drug industry’s 99% perspiration.

Politicians should spend a little time interviewing the drug discovery people.  I don’t mean the executives or the lobbyists.  I mean the people who actually do the work.  It appears that there is a lot of mythology to dispel still.  And without a more complete concept of how drug discovery works, it’s difficult to craft policies to make pharma research work for patients, government and businesses.

If I might make a suggestion to Derek, visual aids might be useful.  Just dig a couple of slides from your latest pre-project team meeting and modify the names of the targets.  People will not really grasp what is involved until they see it.

Stuff that only looks random

Worlds largest woodpile, Byholma, Sweden.

Update: Is it possible that the firing of Teresa Sullivan from the University of Virginia is part of a ratfucking operation to get Elizabeth Warren in Massachusetts?? See this post at Brietbart (Ewww) for details.  Firing Sullivan may be the first step in making Warren look like she is guilty of scientific misconduct.  Regardless, the Board of Visitors should be investigated.  Who are they taking orders from?

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I’m cleaning out the Instapaper queue this morning.  Let’s take a look:

Derek Lowe writes a response in Slate to a recent Slate article that claims that we need more scientists and mathematicians.  No, what we really need are more jobs for the hundreds of thousands of STEM majors who are out of work right now.

Derek also has a post about the future of Organic chemistry in this country.  Bottom line: there is no future in this country for organic chemists and a recent National Research Council Committee study confirms this:

Whitesides believes that the question should be asked whether PhD theses are narrow technical presentations for jobs that no longer exist. Should U.S. graduate students be doing organic synthesis if most organic synthesis is being done in China? “That’s not to say that these aren’t really important activities, but we need to connect our investment in graduate school with what’s actually needed to give jobs to students.”

That’s really sad.  America has produced some of the finest chemists of the modern era but if there are no jobs after graduate school, why bother studying a dead field? You might as well get a PhD in Alchemy for all the good it will do you.  Our country hasn’t felt the full effects of all of the industrial slashing and burning on our scientific infrastructure yet but it’s coming and it won’t be pretty.  Meanwhile, our wealth of scientists are forced to pursue other careers…

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Theresa MacBain, the Methodist pastor who recently came out as an atheist, gave a short interview on Fox News radio.  It’s only 9 minutes.  Well worth the time. She did very well and held her own.  Good job, Theresa.  It’s not easy taking on the blowhards at Fox.  Let’s hope some of this interview percolated into the minds of the listeners.

Theresa is presently directing the Clergy Project, an initiative to help non-believing pastors make the transition into the civilian world.  The purpose of the Clergy Project is not to deconvert practicing pastors.  The pastors that join the project are already past the point of deconversion.  They just want out of the pulpit because they want to stop living a lie and they need to make a safe landing.  The number of clergy who have joined the project has swelled dramatically since McBain and another graduate, Jerry DeWitt, have barnstormed the country in the past couple of months.  They have almost 300 members and many more clergy who are on a waiting list to be screened before they can join.

In another sign of the atheist apocalypse, Linda LaScola, a researcher on religion, gave an interview to CNN about the rate of deconversion and its future effects on politics. The days of the religious right strangling the country and squashing modernity are numbered.

As more people turn away from religion, there is an associated trend that shows they are becoming more liberal.  So, you have to wonder why Democrats seem scared to death of the religious right.  If they just hang in there and stop ceding ground to the conservatives, in a few election cycles, the pendulum will have swung the other way.  In fact, Republicans seem to be frantically throwing everything but the kitchen sink at the electorate this year because they know they are rapidly running out of time.  Before long, there won’t be enough elderly, conservative religious voters who they can conscript for the plutocrats.

By the way, did you know that up until recently, most people stayed with the religion traditions they were brought up in?  And according to Bob Altemeyer, author of The Authoritarians, “amazing apostates”, those individuals who reject their  fundamentalist upbringings and become secular do so at the rate of about 1%.  What the data shows recently is that the rate of deconversion is picking up with greater access to the internet.

Previously, that 1% shared some common characteristics, such as being good in school and valuing truth.  In other words, we don’t just accept what people tell us unquestioningly no matter how much our parents isolate us.  Altemeyer also found that there are a few people who go the other way from secular households to religious conversion but these people tend to be less well educated and they make their conversions after some life-changing event like an illness, unemployment or relationaship failure.  In other words, religious conversions happen when people are most vulnerable to persuasion and to individuals who are least able to reason their way out of it.  These findings are similar to my own experience.  I never believed the fundamentalist crap I was fed and to get me to believe it now, after I have seen the proof of evolution in my research and now know the historical facts behind the bible, would require me to undergo a lobotomy.

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Something very weird is going on at the University of Virginia.  Last week, the President Teresa Sullivan, was asked to resign abruptly by the University’s Board of Visitors, which is like the Board of Regents everywhere else.  The reasons for the resignation are not clear.  Even Sullivan herself is not actually sure why she was fired and the board is not answering questions to anyone’s satisfaction.  This move came 2 years after Sullivan was appointed and has, by all accounts, done an admirable job.

I first read about this a few days ago from a history professor there, Siva Vaidhyanathan, who wrote about the dismissal in Salon.  What Vaidhyanathan describes sounds oddly familiar to those of us in the pharmaceutical industry who have lost our jobs due to cost saving measures of the shareholders:

In the 21st century, robber barons try to usurp control of established public universities to impose their will via comical management jargon and massive application of ego and hubris. At least that’s what’s been happening at one of the oldest public universities in the United States—Thomas Jefferson’s dream come true, the University of Virginia.

On Thursday night, a hedge fund billionaire, self-styled intellectual, “radical moderate,” philanthropist, former Goldman Sachs partner, and general bon vivant named Peter Kiernan resigned abruptly from the foundation board of the Darden School of Business at the University of Virginia. He had embarrassed himself by writing an email claiming to have engineered the dismissal of the university president, Teresa Sullivan, ousted by a surprise vote a few days earlier.

[...]

“The Board believes that in the rapidly changing and highly pressurized external environment in both health care and in academia, the University needs to remain at the forefront of change,” [Board of Vistors chair] Dragas wrote in her initial email announcement. I have no idea what that means or why it pertains to Sullivan’s dismissal. I guess it means that stuff is changing. So the university must change. Firing a president is change.

On Monday Dragas, sensing that the university community might want some explanation for such a radical act, sent out a second message: “The Board believes this environment calls for a much faster pace of change in administrative structure, in governance, in financial resource development and in resource prioritization and allocation. We do not believe we can even maintain our current standard under a model of incremental, marginal change. The world is simply moving too fast.”

OK, then. It’s all about pace. I suppose this means the board will appoint a new president every two years. Or maybe more frequently, because that’s the only way to keep up with the pace of change.

Earlier in the statement Dragas wrote that “the board feels strongly and overwhelmingly that we need bold and proactive leadership on tackling the difficult issues that we face.” So we can derive from Dragas’ statements that Sullivan was not bold enough, fast enough, or “proactive” enough to guide a bucolic 193-year-old institution founded by a stocking-wearing guy who studied Greek and Latin for fun.

We were all baffled. So Sullivan did nothing wrong? The board would not even hint at the reason she was fired. Conspiracy theories quickly circulated to fill the vacuum. And they got worse after Kiernan’s letter unleashed an unfounded fear that an MBA “cabal” was in cahoots with Goldman Sachs to loot the university.

It sounds like the financiers’ values have come to the University of Virginia because they loves them some change! The bizspeak jargon is always a bad sign.  No one knows what it really means, not even the speakers.  This leaves a lot of leeway to interpret the jargon on the fly to justify just about anything.  Vaidhyanathan suggests that donors to the university want more control over how their donations are used.  Maybe they want more influence over the curriculum or benefits or hiring.  Whatever it is, they want to impose change on their timetable and in their way without some capable university president who specialized in class dynamics and the sociology of debt getting in the way.

Did I mention that the University of Virginia has pretty reasonable tuition compared to its peers?  How much do you want to bet that that’s going to Change!™ now that the bonus class has got its grubby mitts on the steering wheel?  Cut back on wages benefits here, hire some more poorly paid adjunct professors there, get more companies to foot the bills for research, raise tuition 30% over a few years and voile!  This is not a charitable institution, after all.  Why should University of Virginia students and their parents get off easy?

The students and faculty have turned out for Sullivan and latest reports say that 4 of the 12 members of the Board of Visitors have approached Sullivan to ask her to stay.  But this is not a good working environment for anyone at the University and Sullivan warns that the faculty may be poached by other universities looking to pick up spooked researchers and professors.  Researchers need to be able to plan and require a contiguous and stable environment and this crap from the Board of Visitors is undermining that.  They’ll get their change for sure but what they will be left with won’t be worth anything after they’re done.  The university’s faculty need only look at the smoking hulks of our empty industrial labs and extraordinarily well compensated former MBA overlords to know what will come next.

Another disaster brought to you by the Goldman Sachs family of assholes.

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More office chairs.  I’m still pining for the white leather one from West Elm but the damn thing never goes on sale.

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Le Pacman:

Wall Street + Stock Buy Backs => Cookies of the Apocalypse

Greed has consequences.  The definition of success also has consequences.  When people judge their success in life by how much money they are making instead of what they contribute to the well being of the society they live in, they can have unintended consequences for other people who they don’t even know in fields they couldn’t care less about.

Let’s follow this trail, shall we?

Matt Taibbi writes another scathing critique on the lack of character on Wall Street.  This is where the worldview is developed and the flawed value system starts.  In this little snippet about John Paulsen and his incredible haul of obscene gobs of cash, we are to feel sympathy for the pain he has suffered for all the gobs of cash he lost on bets that didn’t pan out last year:

Look, the financial services industry should be boring. It should be quaint. Let’s take the municipal debt business. For ages, it was a simple, dull, low-margin sort of industry, in which banks arranged municipal bond issues and made small but dependable profits as cities and towns financed improvements and construction projects.

That system worked seamlessly for decades, until people like Sherman’s interview subjects suddenly decided to make the business exciting. You know what happens when you make municipal debt exciting? Jefferson County, Alabama happens. Or, on a macro level, Greece happens.

When making a few points on mere bond issues stops being enough, and you have to cook up crazy swap schemes and indices to bet against those schemes, ingenious scams allowing politicians to borrow billions of dollars that they will never in a million years be able to pay back, you might end up getting a few parks, schools, and subways in New York.

But what you get everywhere else is a giant clusterfuck that costs the rest of us years and even more billions of tax dollars to remedy.

This is what the protests are all about – it’s anger that Wall Street has been profiting from an imaginary economy that leaves bankers overpaid, but creates damage everywhere else. Sherman doesn’t get this. He seems to subscribe to the well-worn straw-man position that protesters are simply upset that bankers and financiers make a lot of money. Take for example his view on John Paulson, the hedge fund titan who was involved in Goldman’s infamous Abacus deal:

In October, a thousand protesters stood outside John Paulson’s Upper East Side townhouse and offered the hedge-fund billionaire a mock $5 billion check, the amount he earned from his 2010 investments. Later that day, Paulson released a statement attacking the protesters and their movement …. The truth was, Paulson was furious that the protesters had singled him out. Last year, he lost billions of dollars on bad bets on gold and the banking sector. One of his funds posted a 52 percent loss. “The ironic thing is John lost a lot of money this year,” a person close to Paulson told me. “The fact that John got roped into this debate highlights their misunderstanding.”

Hey, asshole: nobody misunderstands anything about John Paulson. They’re not mad that he made billions the year before, and they’re not happy that he lost money this year. They’re mad that the way he made his money in previous years – which involved putting together a born-to-lose portfolio of toxic mortgage bonds and then using Goldman Sachs to dump them on a pair of European banks, who in turn had no idea that Paulson was betting against them.

Matt Taibbi is using harsh curse words.  How declasse.  The fundies react with shock and horror.  Is there no civility on the internet?  Paulsen is rich.  Surely this man deserves respect.

Moving on.

Derek Lowe at In the Pipeline wrote a rather longish post for him about the pharmaceutical companies buying back stock in what looks like a desperate attempt to push up the stock price and keep more for the executives.  Lovely.  And this is made easier by assuring investors that they have cracked down on research costs, by golly.  We’ll have none of that wasteful spending here:

He has some figures from our own industry: From 1997 to 2009 “Amgen did
repurchases equal to 99 percent of R&D expenditures, Pfizer 67 percent, Merck 62
percent, and Johnson & Johnson 57 percent.” It could be worse – companies in the IT sector have often managed to spend even more than their R&D budgets on repurchases, partly because they increased the number of shares outstanding so hugely during the dot-com boom years.

One complication with the market-manipulation view is that stock buybacks don’t correlate very well with total stock returns. If anything, the correlation is negative: companies (and sectors) that spend the most on repurchases have lower returns. Of course, there’s a correlation/causation problem here – perhaps those returns would have been even lower without the buybacks. But there’s clearly no slam-dunk financial case to be made for repurchases.

Except one: that they’re often the easiest and least controversial use of the money. Companies get criticized if they sit on cash reserves, and they get criticized for missing earnings-per-share numbers. Why not try to address both at the same time? And without having to actually think very hard about what to invest in? I think that Pfizer’s Ian Read is being truthful when he says things like this:

Pfizer declined to make an executive available to discuss its policy. But in a statement, the company said it “remains committed to returning capital to shareholders through share buybacks and dividend payments.”

As for the cut in research spending in February, Pfizer said it has “accelerated our research strategy and made important changes to concentrate our efforts to deliver the greatest medical and commercial impact.”

In a conference call with analysts this month, Pfizer’s chief executive, Ian C. Read, said his company would “continually look” for acquisitions that would increase revenue growth. But in deciding how to use the proceeds from recent asset sales, he said “the case to beat is share repurchase.”

And that, truly, is a shame.

Oh, well, it’s not like the executives are going to stick around to see what a shame it is.  As the following animation suggests, they will be sitting on a beach in the Cayman Islands ideating and leaving the company to hobble toward some finish line on its own:

{{catching breath, wiping eyes, clearing throat}}  Ahem, geek humor and all that.  Too funny, or it would be if so many of us “ancient ones” weren’t out of work.

Good Morning

Cue the music

Some more bad news on the research front.  Earlier this week, Merck laid off a number of employees from the parent company and Schering-Plough, the company it merged with a couple years ago.  I can’t find a firm number for the total layoffs.  In some reports, it’s 17,000, in others it is 17,000 plus an additional 13,000.  That’s worldwide.  And while Merck has something like 91,000 employees worldwide, when it comes to laying off research, it comes primarily from the US side because American research workers have zero labor protections.  I would expect the loss from Western European research facilities to be light.  Estimated cost savings are $400 million out of a budget of $7.9 billion.  That is a huge research budget but that’s what it takes these days.  Drug discovery is very expensive.  Merck and Schering-Plough have facilities in the Northeast, particularly in Rahway, NJ, West Point, PA and Kennilworth, NJ.  Derek Lowe at In the Pipeline says he is getting heavy casualty reports in from the research professionals at Schering Plough (Kennilworth).  I know people who work at both companies and I’m very sad for them.  This is not a good time to be untethered from a steady income.  I hope they’ve prepared themselves.  The loss to the states of NJ and PA in tax revenue from cutting these well-paying jobs is going to be pretty bad.  So, this month we have Novartis, Amgen and Merck-Schering-Plough.  Wait, wasn’t there another one?  Too many to keep track of.  And more competition for me.  Well, I am in good company.  Some of the smartest people in the country, no, the *world* are now out of work.

Jay Ackroyd thinks that the desire to globalize is driving this and calling it “centrism”.  Jay’s anger and disgust is pretty clear but coming from the corporate world that most lefties hate, hate, HATE with all their souls, I see this a little differently.  For example, take the way Steve Jobs was pushed out of Apple back in the 80′s.  I’m listening to the biography by Walter Isaacson.  Jobs was no saint.  Back in the 80s, he was the heartless boss from hell.  I guess you could chalk that up to youthful immaturity but when the precariousness of his position at Apple hit him, he got a sense of how companies would work in the future.  John Sculley, the president Jobs hired to run Apple, was a marketing guy.  He didn’t understand the product he was manufacturing.  He wanted to spin off the creative part of Apple to a unit called Apple Labs, that would be run by Jobs.  It was a way to get rid of Jobs and his loyal creative types who wanted to act like pirates.  Sculley wanted employees to put Apple, the company, first.  People like Jobs wanted to put the product first.  It’s too bad that he acted like such an obnoxious, insulting immature brat because Jobs was right.  Most companies have followed the Sculley route.  They put sales and marketing and making money first.  And that’s what companies are for, to make money.  You’d have to be stupid if you had any altruistic aspirations for having a company.  But what marketing people fail to see is that without a product, you have nothing to sell.  If you short your R&D division, you’ll be cutting your own throat. It won’t happen overnight but it will happen.  And then you’ll be busily eating your seed corn to make those quarterly earnings, like Merck, Pfizer, Novartis, Amgen…  After Jobs grew up a bit and came back to Apple, he put the focus back on innovative products and now, the company is the most profitable in the world.

So what does this have to do with Ackroyd’s piece?  Well, if pharma is any indication of what is really going on, globalization is a fad.  That’s what the business people do.  They chase fads and trends.  They rarely follow up on their initial enthusiasm to see if the fads actually add to their bottom lines.  It’s the initial savings that they care about because that’s immediate, it’s quarterly and they think better in 3 month increments.  Pharma went through a period of mergers and acquisitions that did nothing for research and only enriched executives’ pockets.  But there have been other fads, like combinatorial chemistry, proteomics, siRNA, and genomics.  None of them turned out to be the panacea the Sculley class was looking for because the nature of biology is such that these technologies were just tools that we used to dig up more problems to solve.  They were never intended to be solutions all by themselves.  The newest fad is to relocate all of research (or what is left) in the bay areas, Cambridge,MA and San Francisco and San Diego, CA.  Presumably, the smartest people in the world graduate from MIT and Harvard and Stanford and UCSD.  That may be true.  But it may also be the case that only the wealthy and well connected can get into those schools anymore.  It also ignores the fact that for years, biomedical researchers came from all over the country, prestigious and unprestigious schools alike.  I’ve known excellent researchers who graduated from schools in Indiana, Colorado, New Jersey and Louisiana.  But this idea of educational exclusivity and capturing the elite is the new fad.  They will do the brain work and the hands on stuff will be carried out by a bunch of drones in China and India.  The corporate guys are marketing and sales and business school guys.  They think research and innovation can be broken down to a list of mind numbing chores and “just in time” off the shelf solutions while the “better people”, people like them in their social class, are graduating from ivy league schools and those people have the natural talent to manage the innovation process.  The corporation will take the profits gained by outsourcing.

And they are following this course of action and business not because it is good for the companies they serve but because they can.  The rules don’t apply to them anymore.  I’m not sure the goal was always globalization but now that there’s nothing to stop them, that’s what they’re going to do even if it ruins the product line.  The Sculleys of this world do not understand what motivates people who do research and who are inspired to innovate.  Here’s a clue: the most profitable product line of the world was designed by a college drop out and his rag tag bunch of unorthodox pirates who were left to their own devices.

So, Jay, I wouldn’t worry too much about the desire to globalize.  At some point, the grasshoppers will stop eating their seed corn because there will be nothing left, the big corporations you hate will find themselves smaller and their research divisions located in Western Europe and the fascination for the elite universities will be tempered by the reality that real innovation takes time and dedication and getting the right people *together* in one place.  At some point, the researchers in China and India will get fed up with studying hard for years only to be treated like cheap assembly line workers by the Sculley class.  It would also help if lefties took some time to understand pharma so they would stop contributing to the demise of biomedical research through bone headed ignorance.  But that’s another post.  Yeah, it may mean that the innovation infrastructure of the US is decimated.  But I wouldn’t be looking for meaning in any of this.  Think of it like water flowing in the path of least resistance.  There’s nothing intelligent about this, as in sentient beings planning to gut their product lines for the sake of a quick buck.  There’s no giant conspiracy to globalize.  It’s happening because we allowed it to happen.

When we block the path to a quick buck at the middle class’ expense, it will stop.  And we know this is possible because there are countries where the government has protected their innovative infrastructure.  When the dust settles and the corporations come to their senses, it will be the middle class in places like Germany and France who will be able to carry on.  If we want to be one of those countries, we have to decide that we want to reimpose the rules.  There’s no need to over analyze.  But I would like to point out that saving innovation here does not mean that we as a country will not be taking advantage of cheap labor elsewhere.  As Nucky Thompson says, “We all need to decide how much sin we can live with.”

In other news, if the election were held today, guess which politician would have the best chance of beating the Republicans?  It’s Hillary.  Yep, sorry lefties who hate Hillary, in a recent Time Magazine poll she beats the Republicans by larger margins than Obama does and she’s not even in the race (yet):

A national poll conducted for TIME on Oct. 9 and 10 found that if Clinton were the Democratic nominee for President in 2012, she would best Mitt Romney 55% to 38%, Rick Perry 58% to 32% and Herman Cain 56% to 34% among likely voters in a general election. The same poll found that President Obama would edge Romney by just 46% to 43%, Perry by 50% to 38% and Cain by 49% to 37% among likely voters.

Read more: http://swampland.time.com/2011/10/27/hillary-clinton-and-the-limits-of-power/#ixzz1cBO8BDMj

It always amuses me when the left starts to hyperventilate about the prospect of a Republican president next year and how evil that would be.  But when you give them a perfectly acceptable alternative of someone with a lot of experience, who is excelling in foreign policy, runs a global executive branch and has been able to stay away from domestic issues to emerge fresh as a rose, while being widely admired by world leaders and voters of both parties, they flinch when it turns out to be Hillary.  Apparently, they are MORE afraid of Hillary Clinton in the White House than Mitt Romney or Herman Cain or, gawd help us, Governor Rick “Good Hair” Perry.

No?  That’s not how it is?  There’s something I’m missing?  Oh, her Iraq War Resolution vote.  Yeah, she single handedly brought on the Iraq War.  Of all 99 senators who voted for that POS in 2003, HER vote counted more than anyone elses.  It was even more powerful than John Edwards’ IRW vote.  It had to be because the left was perfectly happy to forgive and forget that reckless phony.

I can just see them gearing up to spew some anti Hillary hatespiel.  No, no, save your breath.  No one cares what you think of Hillary anymore.  Your opinions are not more important than the rest of the electorate.  She should have her opportunity because the Democrats don’t really have anyone better, not even Obama.  No one is entitled to a second term.

But if you get stuck with a Republican in November 2012, you have no one to blame but yourselves.  Hillary wins over all of them, you passed anyway.

Psych! Prions and Ice Nine

3D structure of amyloid fibrils

I saw this post about the possibility that Alzheimer’s is an infectious disease at Derek Lowe’s blog, In the Pipeline.  There’s a new paper out that reports that animals whose brains were exposed to misfolded amyloid-β protein extracted from patients with Alzheimer’s disease will go on to also develop amyloid plaques while control animals do not.  While there is a reputed genetic component to the development of Alzheimer’s disease, this study suggests that it can be induced by the transmission of a prion from one animal to another.  Prions are infectious bits of protein.  They’re teensier than viruses even.  In the case of amyloid disease, the protein under investigation is about 42 amino acids long, which is tiny.

The principle is this: in order to function properly, proteins need to fold into distinct secondary patterns and then a specific 3D shape.  If the protein is misfolded, it doesn’t work properly or it can aggregate, ie form clumps.  The sneaky think about prions is that they can induce other proteins to misfold.  The misfolded protein is in a lower energy state than the properly folded state so the protein can’t unfold itself and refold properly.  It’s stuck.

If any of you have read Kurt Vonnegut’s novel, Cat’s Cradle, and can remember anything beyond spritual footrubs and Bokononism, you may recall that one of the characters created a substance called Ice-9.  A single crystal of Ice-9 had the potential to freeze all contiguous bodies of water.  Throw it into a bathtub, the bath water freezes.  Throw it into an ocean, the ocean freezes.  I can’t recall if it stayed that way permanently but after Ice-9 was released, the world started to die of thirst.

The introduction of amyloid-β prions into a healthy brain may be doing an analogous thing by inducing newly formed amyloid protein to misfold.  And an excess of misfolded protein tends to aggregate, triggering inflammation and, down the road, dementia.  Mad cow disease is also a prion disease that in sheep manifests itself as scrapies.

Er, no one knows how to fix it yet.  One of the problems with developing a drug for Alzheimer’s disease is that the enzyme that normally would be targeted for inhibition, γ-secretase, is also used to cleave a protein called Notch, which the cell can’t really do without.  So, there’s that.  Drug discovery is much harder than it sounds, as Derek says in this recent podcast that he did with Paul Howard from the Manhattan Institute.

The frustrations of the drug discovery process that Derek describes reminds me of the central tenet of Bokononism:

Beware of the man who works hard to learn something, learns it, and finds himself no wiser than before. He is full of murderous resentment of people who are ignorant without having come by their ignorance the hard way.

Well, we *are* learning but the truth comes slowly and the answers to the questions are frequently accompanied by a whole new set of questions that must be answered.  This is in part why the pressures of the financial industry have been particularly harmful to the pharmaceutical industry and may have contributed to the high price of drugs.  Drug discovery is a long term process.  It can’t be sped up just to meet the numbers on a spreadsheet for the bean counters.  Cost controls that are intended to whip researchers to pick up the pace are bloody useless and counterproductive when applied to the complexity of the cell, something that the guys with executive hair may just now be realizing.  There’s not a whole lot more of mergering, cutting and restructuring that can be done at this point.  And the patent cliff still looms.  It’s going to be a rough ride for the drug industry for the next couple of years.

Derek also points out that the drugs that are now being approved were probably first discovered or synthesized in the mid 1990′s.  That means the patent clock has been running down for some of them and if there’s not a lot of time left to recoup the costs of discovery, it gets passed on to the consumer as higher prices.  There are other contributing factors to the cost of drugs but the length of the process is a significant one.

I encourage readers to check out the podcast.  Derek also discusses a new therapy for cancer that involves harnessing the immune system.  Fascinating and promising.

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