#antibiotics : somebody should do something

I’m blogging from my iPhone while I wait for my car to be inspected. Expect imperfection, although, some of you may not notice a difference.

To those of you on the left who are finally paying attention to pharma research, head on over to In the Pipeline. Derek Lowe has another story that illustrates the state of R&D research in the era of shareholder value and its potential impact on the rest of us.

This recent event is about Merck acquiring antibiotic research company Cubist. Cubist in-licensed much of its pipeline and had a small early discovery research team of 120 people. It has now been announced that those 120 researchers have been laid off.

I guess you could say, well, Cubist in-licensed much of their stuff anyway. But those 120 people presumably have many accumulated years of experience from working on antibiotic research and that experience will largely be lost because companies are not really investing in antibiotic research. Where are they going to go?

Some of them are going to get a nice payout from Merck but even if they pool their resources, it’s not going to be enough to make a dent in the hole of antibiotic research. It will mean starting from scratch-again- for many of them. Or casting around for another hard to keep job in one of the most expensive housing markets in thtalee country.

In the meantime, there goes some badly needed talent to combat multi drug resistant bacteria.

If only there was an institution big enough to fund research in the public interest…

 

 

Stupid Drug Discovery Advice, $2 Billion dollar prizes and Antibiotics.

The NYTimes posted a column from Ezekiel Emmanuel, Vice Provost at the University of Pennsylvania, on the subject of antibiotic resistance and how to encourage more companies to develop antibiotics. He wants to reward the successful researchers with a $2B prize. BUT, he says: “no payment for research that fizzles. Researchers win only with an approved product.” Oh, and he says that the bragging rights would be great! Yes! That would make the starvation diet so much more meaningful. Funny, we don’t expect any other employed person to live on nothing for close to a decade on something that might not pan out or may need to be sold to a big company to keep our little startup from declaring bankruptcy.

He’s identified the problem. Companies don’t want to invest a ton of money in a treatment that’s only going to be used for a short period of time. By the way, that’s the new business model. Back in the olden days when I first started working in pharma, we had all kinds of therapeutic areas to choose from. But during the mergers and acquisition years during the 90’s to the mid Naughties, those therapeutic areas had to be eliminated to make room for shareholder value. Ok, I don’t want to get into this too deeply because it’s territory I’ve covered before but I might touch on it towards the end.

As I’ve discussed before, the antibiotic shortage problem was bound to come up. Bacteria mutate. It’s what they do. They are masters of natural selection, if you believe in evolution. If you don’t, an infection might just be one of those mysterious things that happen to people who do not pray enough. See, there’s another topic I don’t want to get into right now.

Here’s the problem: as Derek Lowe at In the Pipeline has pointed out, the molecule space around the typical antibiotic therapy has been exhausted. There are other targets than beta lactamases but they are not low hanging fruit anymore. There are new mechanisms that we have to learn, like quorum sensing for example.

When a new target is identified, it takes many years for that project to reach any semblance of what Silicon Valley industries would call fruition. In fact, the most promising project I was ever on started back in 2006. I don’t know what its status is at this point. It was promising enough that I think there was a drug there. But I’m betting it is still in the early phases of clinical development even now. That’s almost 10 years later.

This is the problem that a $2B prize does not solve. You can’t incentivize research like this. The reason is that the money has to be spent up front. That is the problem that almost all R&D, both academic and industrial, is grappling with right now. The scientists have to be hired and paid, the reagents have to be ordered and paid, the equipment has to be bought and maintained, and the people funding all of this have to have the patience of saints while the scientists churn through iteration of iteration of assays, high throughput screening, medicinal chemistry and drug design, pharmacology, ADME/T optimization and scale up. It takes a long time and it’s expensive. What will the R&D staff live on in the meantime? What are they supposed to use to get their work done? It’s like marooning a bunch of scientists on a desert island and telling them to come up with a drug using sand and chewing gum. Or hitting their “friends, families and fools” up for early funding as the American Chemical Society encouraged us to do when we first got laid off.

There are ways to reduce costs. For example, don’t make everyone live in Cambridge, MA or San Francisco. That right there would save the funding agent a bunch o’cash. Move people back to the mid-west from whence they came 25 years ago. You know, those places like Kalamazoo and Cinncinatti or even Pittsburgh. It’s cheap to live here and there is such a thing called the internet. We might even use web meetings to interact with each other. Wow, I believe I even used to do that with my colleagues in France and Germany once upon a time about 5 years ago! Let’s face it, there is not a big melting pot of exchange going on in Cambridge when everyone has signed confidentiality agreements. The only reasons to relocate there is 1.) it allows the MBAs who were once bio majors but sold out for the big bucks to live vicariously and 2.) I have absolutely no idea. No one I know actually wants to relocate to Cambridge. But I’m getting off topic.

My point is that the investment has to be made up front. It doesn’t do much good if it comes afterwards, especially if there are side effects and litigation that need to be covered. This is the case with all drugs. To get the drug discovery mechanism rolling, the fuel has to come early in the process and be committed to seeing the process through. That’s what we don’t have anymore. Once the drug is discovered and marketed, the profits can be reinvested in the next drug. That’s what used to happen.

Note that in this scenario, it is the R&D professionals who are important, not marketing, finance or shareholders. The researchers aren’t in it for the big bucks. You will have to take my word for this. Almost no one I ever worked with went into chemistry or biology with the intention of becoming an entrepreneur or cashing in big on their first blockbuster. Pushing us to become what we are not may be hampering the drug discovery process. Do you want someone in the lab making discoveries or do you want that person negotiating with contractors and venture capitalists? You can’t have both. There may be a few people who have the energy for both but they are exceedingly rare or exceptionally lucky.

And here is where I revisit the cause for why antibiotics, and other therapeutic areas like CNS, Cardiovascular and reproductive health, have been abandoned. It was the frenzy to merge that caused this to happen. All of those mid-size labs were joined and then a purging went on when the executive bonus class and shareholders took their cut. They created “efficiencies” by cutting out R&D and imposing cost cutting measures on research. They made research departments compete with outside vendors for services. They destroyed the collaboration between departments and exacerbated the complexity of the problem to be solved. They looked at their post-merger portfolios and said, “Antibiotics are not chronic therapies. We can’t make money on those. Let’s cut them.”. That’s what happened, Mr. Vice Provost.

And THEN, to top it all off, the mergers and acquisitors decided that academic researchers were so much less expensive. Why not scrap the R&D group altogether and let grad students do it?? Not that I have a problem with grad students but realistically, you have to do industrial research and follow a project from start to finish (if that’s possible without being interrupted by a merger or layoff) before you actually “get it”. Solving a drug discovery problem is one of the most difficult problems in science. Pretending it can be done on the cheap or rewarded afterwards when the vulture capitalists are going to demand their cut is not really understanding the nature of the problem.

A $2B prize is not a solution. It is the definition of success from a country that thinks the only reward is money. THAT is the bigger problem that we have not solved and the reason why new antibiotics are in short supply.

CROs, Temp Work and the future

These two reports go together. The first is from WRAL in North Carolina reporting on the research cuts at Glaxo Smith Kline in RTP, North Carolina. Says a company spokesperson:

“The aim of this program is to improve performance by taking unnecessary complexity out of our operations and establish a smaller, more focused, organization, operating at lower costs, that supports our future portfolio,” GSK spokeswoman Mary Rhyne said. “Each business unit is currently deciding how to respond to this challenge. When we do have proposals, we will first share those with our employees.”

Followed by:

Jobs affected are in the following categories:

• Chemist
• Engineer
• Biologist
• Clinical development scientist
• Statistician
• Other managerial, technical and support roles

Cuts “are not being made across the board but are strategic,” Rhyne added.

However, hundreds of affected workers could quickly find jobs at life science research firm Parexel, which has an office in Durham. GSK signed a letter of intent which would allow up to 450 workers work in a GSK-focused business unit at Parexel.

The second was found at Naked Capitalism. It’s a report on the nature of temp work and how it erodes the skills of the workers who have been forced into temporary contract work. The bottom line is that it is bad for your cognitive health. Temp workers do not develop the necessary skills to become experts in their field because they never last long enough to gain the experience and form the neural memories that allow them to extrapolate from their assigned roles.

Now, I’m sure that the people at Glaxo who made the decision to streamline and de-complexify their research units to save money have never actually done drug discovery work because the whole enterprise is very complex. Sometimes, a discovery effort gets more complex as you go along. The people who remain after their colleagues have been shunted off to a CRO with a poorer benefits plan and temp contracts, will have to spend more of their time negotiating with competitive outside vendors to get the resources they need to do the research work. That means more time finding the contractors, writing up secrecy agreements, asking for money from the MBAs to hire the contractors and preparing the projects to be offloaded to them. Before the layoffs, they might have walked down the hall to submit their sample to the queue or talked to a chemist about the next steps in hitting a specific cluster of amino acids in the binding site. Now, they’re going to have to arrange all of that stuff offsite. Instead of doing science, they’ll be doing paperwork.

Note that this does not in any significant way reduce complexity. The complexity is inherent in the endeavor. We’re not talking about creating a new Facebook or Amazon. We’re talking about messing with cells and feedback and cross talk and reactions that yield tiny amounts of product and proteins that don’t fold right or won’t crystallize. Drug discovery is very, very difficult. It can still seem like an art than a science because there are still a lot of unknown unknowns. It’s not ever going to be like writing code.

Meanwhile, the poor researchers shuffled off to the CRO are now faced with a problem that may be as important as how long they’re going to get paid.  That is, have their years of education and experience resulted in nothing more than a dead end job where they will be treated as “just in time” workers who manufacture pieces parts of a project without any reference to those projects? There may be new restrictions on access to information. They may not be invited to team meetings. Their input will no longer be required. They will have the same status as factory workers, churning out compounds or proteins or analysis as directed from some external person who used to be their colleague. Thinking outside the box will no longer be required. All connections between the product and the project will be severed.

How long will it take before we have reduced their cognitive skills to irrelevancy?

By the way, ebola, drug resistant bacteria and schizophrenia are still out there.

One other post also comes from Naked Capitalism. It’s a mini-rant from Richard Wolff about how immoral it is for companies to offshore work and the havoc it has caused in American cities because wages have stagnated or fallen. He says there ought to be a law that prohibits companies from doing that, just like we have labor laws to prevent 4 and 5 year olds from working in factories.

You know, I get his point and understand that Germany and even France has stood up for its work force during this horrible recession (that’s looking more and more like a depression from where I sit). I find it remarkable that there was no one in our government who stood up for us when the pharmaceutical companies started to slash through the R&D units like a chainsaw homocidal maniac. But I don’t think Wolff’s suggestions are going to work. I think the corporate overlords would simply laugh at them.

What I think would work extremely well to curb the excesses of the finance and corporate unholy alliance is to eliminate the 401K system for the vast majority of workers. Because right now, the retirement savings of millions of working Americans is flowing into the system that has to turn around and gamble that money to return some of those earnings to the donors. There’s a lot to be skimmed and a lot more incentive to take risks both for the personal gain of the bonus class and in order to show some kind of return on investment. That in turn leads to excessive profit seeking, risk taking and layoffs.

So, the best thing that could happen to this country is a return to a defined pension plan and I will vote for the presidential candidate who proposes one along with the gradual elimination of the 401K.

 

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?

 

 

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:

Stuff that go together: How the rich are getting it wrong

Davos, Switzerland- Home of the World Economic Forum, the small evil group that runs the world to which no one we know belongs.

Chrystia Freeland discusses Plutocrats with Sam Seder on The Majority Report

Conjuring a High Tech Labor Shortage by Stan Storscher of Talking Union

Technology or Monopoly Power?, Paul Krugman, Conscience of a Liberal.

and the consequences:

The Drug Shortage No One is Talking About by Charles Pierce, Esquire

Study Ties Drug Shortage to Poorer Cancer Survival, Fox News (Ewwww)

Growing Drug Shortage Problematic for Patients, Doctors, ABC News

The drug industry in America has ceased to be.  It is an ex-industry.  It has joined the choir invisible.  The remaining multinational Pharmas’ strategy is to buy up the patents of struggling small biotechs and to use academic labs for the research they jettisoned.  But I’m reminded of something Mark Lynas said in his recent lecture on why he is no longer anti-GMO.  In our frenzy of making sure that big companies adhere to strangulating limits on their technology, we have allowed monopolies to thrive in the GMO industry while killing off emergent competition and potential diversity.

In the case of the drug industry, we have demanded so much hoop jumping in order to create the most perfect, side effect free, litigation proof drug that the only companies that can afford to get a drug through the approval process are the largest ones with the deepest pockets.  And even those companies can’t do it after having invested billions of dollars in research.  If you are a small biotech, the costs of verifying that your lead compound meets the increasingly more stringent safety profiles is cost prohibitive.  No matter how hard you work for how long, it is more and more likely that you will have to sell your miracle drug patent to a large pharma at a fraction of its potential earnings just in order to recoup your investment.  The drug industry news is full of small biotechs having to lay off their entire research staff in order to take their discovery through the next phase of development.  That throws the research community into ever increasing precariousness, diminishing the prospects of young scientists and discourages students from pursuing science as a career.  And that, in turn, is eventually going to affect the quality of academic research upon which many big multinationals now intend to feed.  I’m still predicting that the brains are going to go to western Europe to do research because governments there still have a commitment to education and protecting their workforce.

Our research capabilities in this country have shrunk profoundly in the last 5 years.  We don’t introduce many drugs to the market anymore.  What is in research are new, even more expensive technologies.  But since the research community is much smaller, there is a bottleneck we have imposed on research.  Only a tiny fraction of the potential is being investigated now.  It’s primarily centered around cancer, which is very important, of course.  But what if your problem isn’t cancer?  What if you just need your thyroid medication?  Or your generic ADD medication?  Well, there’s no money in generics and to repair the plants is expensive and that eats into “shareholder value”.  So, the cost of generics is going to have to go up.  The result will be more expensive generics as patents expire, more older generation drugs for everyone, a few very expensive newer drugs for those that can afford them and the cost borne by all of us.

The plutocrats and their political allies have allowed this to happen.  They have overvalued their own importance and undervalued the importance of everyone else.  They have put the attainment of money and the acquisition of power at the pinnacle of the greatest of human achievements and have demoted the quest for knowledge.

Chrystia Freeland makes some interesting points in her discussion with Sam Seder on the nature of money and plutocracy.  She has talked to plutocrats of the Bill Gates, Mark Zuckerberg variety.  And they have told her that to the billionaire and the mailman, a Big Mac is still a Big Mac.  In other words, you can only consume so much in your lifetime.  Even if you buy the best of everything and search out the most perfect experiences, you may have more money than you will ever be able to use in your life.  Of course, a perfect experience to one person may not be a perfect experience to another.  For example, I’ve lived close enough to NYC to see many Broadway plays in the 20+ years I’ve been in New Jersey.  At this point, Broadway is no big deal to me anymore.  Oh, sure, I’d love to see the Book of Mormon but I could be content to see the touring company at a opera house in a smaller city.  The performances are going to be pretty much the same.  Maybe I would miss the lights of Times Square afterwards but I’ve been there so many times that it’s not a heartstopping thrill anymore.  There are other things that are interesting that don’t cost much money.  I still like Big Macs.

A similar observation can be made about the nature of work.  I understand that billionaires these days are the “working rich” and that their days are filled to the brim with lots of thinking and decision making and that those thoughts and decisions affect thousands of people.  But then I think about how hard my colleagues and I worked in the last year we were employed and those days were also filled to the brim with thoughts and decision making that affect thousands of people.  Just because we did a lot of it on our feet or with our hands as well as our minds does not make it less important to the world.  It is hard to see how Mark Zuckerberg could be working harder than we did in absolute terms.  In other words, to the billionaire and the drug discoverers, there are still only 24 hours in a day and some of those hours are taken up with sleeping, eating and excreting.  I suppose you could eat your lunch at your desk while you multi-task.  Yep, we did that too.

So, it’s not consumables that set us apart except in quantity and quality because taste and temperament may play a role.  And it’s not the degree of hard work or time because we all face the same time constraints.  And it’s not genius because I worked with a lot of extraordinarily smart people who were not rich and know some extraordinarily rich people who are not smart.

What it seems to be the crucial component is being, or being born, in the right place at the right time with the right idea for which you can capture a market or schmooze your way to the top of the corporate ladder or gamble away other peoples’ money at the global casino.  It is this elusive property of being struck by lightning at least once in your lifetime that counts.  And with that once in a lifetime experience, you can dictate the lives of others, elevate your own contributions and denigrate theirs.

And ruin the drug supply.

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.

Science Careers: Run Away, Little Children, Run Away!

Unemployed scientists at last week's BioNJ Expo at Rutgers Univerisity

Derek Lowe’s blog from inside the pharma industry, In the Pipeline, highlighted an Op/Ed piece by Josh Bloom in the New York Post yesterday titled, “America’s Vanishing Science Jobs”.  I don’t know Bloom (and this is weird because we have a past company in common.  Collegeville?  Pearl River?) but he nails the problem facing the unappreciated American scientist in the first paragraph:

The folks at Scientific American have launched “1,000 Scientists in 1,000 Days” — a program to bring together scientists, teachers and students to improve America’s “dismal” showing among wealthy countries (27th out of 29) in graduating college students with degrees in science or engineering. I’m sure they mean well — but, at least as it applies to the field of chemistry, “1,000 Unemployed Scientists Living With Their Parents at Age 35 While Working at the Gap” would be a better name.

Back in the 90’s, I thought we were going to be eclipsed by China and India as well.  Then, I realized that China, and Russia too, had let its creme de la creme emigrate to America.  America benefitted from that wave.  Graduate level classes were full of Asian students.  It was a bit intimidating.

And then they blended in and we came to realize that although they are extremely hard working, focussed and fanatically well prepared in math, there is just as much variation in talent among Asian scientists as American scientists.  That’s because to be well trained in math and science is necessary but not sufficient.

In his book, Outliers, Malcolm Gladwell points to an observation that to master a subject, whether it is a field of study, profession or musical instrument, and to become an expert, requires 10,000 hours of practice.  The ability to discover drugs also develops over many years of practice.  A scientist doesn’t arrive in a lab ready to find a new drug simply because he/she comes from a country whose kids rank number one in math.  Even newly minted PhDs need a few years of seasoning before they’re useful and they’re still only novices.  Gladwell is right.  It takes a good 10 years before you develop a degree of comfort in doing drug discovery after you’ve seen many different kinds of problems and have tried various approaches to solving them, lathered, rinsed, repeated, over and over again.  It is very rare to find someone who gets it the first time.  In fact, I have never met any such person.  It’s a journey for even the brightest.

It wouldn’t even be correct to say that advanced technology can speed up the process.  We’ve seen many different new technologies like high throughput screening robotics, genomics, transgenic animal models and combinatorial chemistry.  Each one of these technologies did produce results but sometimes, we are left with more data and unanswered questions.  Speeding things up created new problems to be solved and sometimes lead us down new avenues of inquiry.  All of that information has to be processed, categorized, understood.  It takes time.

So, now China and India are going to jump on the drug discovery bandwagon.  As more and more companies outsource not just the routine tasks but whole research units, we may indeed see discovery speed up and it might look miraculous.  But that would be ignoring the groundwork that was laid here in America. And it will still take time, perhaps decades, for the Chinese to catch up.   In the meantime, the people who did the gruntwork for the past couple of decades are being asked to step aside and sacrifice their careers for the good of the shareholders.  Those scientists have seen their research stop/started frequently since the 1990’s.  Mergers and acquisitions and management schemes from business administration majors and consultants have interfered with the ability of scientists to process the information coming out of this amazing era of biological breakthroughs.

It won’t be long before the executives and shareholders realize they’ve made a mistake and that new drugs *can’t* be designed like new Intel chips.  They also can’t be discovered by breaking the discovery process into neatly manageable “on-time” bits, each component made in a tedious, routine manner to be assembled at some American endpoint by a handful of designer/engineers.  Biological systems are not like cars or new high tech gadgets, and understanding those biological systems is aided by an economy of scale that is destroyed by atomization into neatly manageable “on-time” bits that can be turned on and off following the whimsies of the business cycle. Bussiness types intuitively know this right about their undergrad sophomore year when they’re forced to pick a major but they forget it by the time they graduate from Wharton.

That leaves us to tell our children that their lives are going to change.  No more vacations, piano lessons and daytrips to the city.  Get used to parents who are constantly worried about money, dental appointments that must be saved for in advance and how they are going to pay the mortgage on vastly reduced salaries.  The children of scientists see their parents, weighted down with degrees, some of the smartest people they know, deprived of the means to make a living.  The parents have heard their children ask, “What’s the point of all this work and college?  Where did it get you?”  We still make our kids study like fiends but we tell them,

Don’t go into science, there’s no economic security in it.

The Scientific American initiative is a futile one.  The places where those 1000 scientists are located have also seen the most devastation.  The scientists that have lived to see another day in smaller companies with less economic stability and longer hours know that the job they love today could be gone in a flash tomorrow when the venture capital runs out or the management decides capriciously to make a change.  We tell our kids to learn to live with less or go into finance, become a spy or study plumbing.

Don’t waste your time learning molecular biology and organic chemistry.  Resist the siren song of the lab.  Run away, run away!

Well, this is interesting. US Gov’t to dabble in drug discovery?

It looks like the NIH is going to start screening for new drugs.  Here’s a quick and dirty primer on how drug discovery works (via me):

There are two different paths to discovering a drug.  In the first path, a database of gene sequences are scanned for a potential “target”.  The target gene codes for a protein or receptor that is implicated in a disease state.  Biologists make the protein and use robots to test a library of potential “ligands”, drug compounds, against the target.  These libraries consist of hundreds of thousands and possibly millions of compounds.  When  a compound interacts with the target and elicits the right response, it is called a hit.  The hits are passed to a project team of biologists, chemists and drug designers who examine the hits, select the most promising ones, ie, the ones that look like they won’t be toxic or too hard to work with and which provide places for modification.  The team then engages in a years long struggle of iterations.  The drug designers propose modifications, the chemists make the modifications the designers suggest (or not, as the case may be.  Convincing a chemist to make a drug is the most challenging aspect of the whole endeavor, IMHO.) and the biologists test the new compounds and say “hotter” or “colder”.

There is a lot of other stuff going on in the background.  There are structural biologists who can sometimes crystallize the protein in question and make it a lot easier for the chemist and designers to see what the hell they’re doing.  Also, there are groups that test the compounds for properties other than how effective they are against the target.  Those things include toxicity, mutagenicity (how likely they are to cause cancer and birth defects), bioavailability (how easily they get into your system through the gut, stomach or blood-brain barrier), solubility (how easily they dissolve), metabolism (how your liver breaks them down and into what byproducts) and cardiotoxicity (does it make your heart spazz out).  Note that this list is not exhaustive.  The FDA is very strict about what goes into your body and drug discovery takes these regulations very seriously.

Once the potential new drug is ready, it gets passed to a development group for scale up and clinical trials.  This whole process takes a long, long, LONG time and there are many failures along the way.  It is also extremely expensive.

The other path is to bypass the gene target identification route and simply test a bunch of compounds, that are already sitting around, against a desired endpoint.  This is known as a phenotypic screen or high content screening.  In this case, the drug company does not know what the target is, well, not at first.  Instead, the tests that are conducted against cells and a desired outcome is noted.  After the phenotypic screen finds hits, it is sometimes possible to deconvolute the pathway that the compound affected and identify the targets.  In this scheme, the discovery process presumably starts out with drug compounds in the library that are already known to have desirable or promising safety profiles because they might have been worked on before for different projects but they weren’t active enough against the target they were made for.  But that doesn’t mean they can’t be used for something else.

The last pathway is what I think is going on with this new initiative at the NIH or at least that’s the way I interpret it.

There’s a lot of factual data in the NYTimes article about what the drug industry is up against.  It remains to be seen whether this new initiative will be good or bad for the industry or the public.  I can imagine many possible scenarios as to how it might turn out and some worry or encourage me more than others.

In any case, go read it and when you’re done, I’ll try to answer any questions you might have in a broad, general way.  I can’t speak for my industry or company and wouldn’t want to anyway.  But general information I can do.

Update:

Here’s a weird comment from the same article:

Great. So now taxpayers will be liable when there’s a problem. I hope there’s some kind of handoff program to private industry at some point in the program to avoid problems like that.

Soooo, let me get this straight.  The ability to sue is still of utmost importance.  Did I get that right?  Because, from where I sit, the class action lawsuits are part of the problem.  Everyone complains about not reining in the big finance guys but ambulance chasers looking for big bucks who glom onto adverse drug reaction reports like blood sucking ticks are all ticketyboo?  It’s *not* ok to curb the lawyers?  I mean, presumably, the government would not be interested in deliberate negligence and injury brought on by a joint venture, right?

Just curious.

Another commenter who doesn’t quite get how the industry works or didn’t check the graphs on the side of the page (they are pretty accurate):

Its about time. Our drug companies have lost focus on what is really important. All they concentrate on is profit and the FDA is complicit in its approval process. New drug application fees should be abolished also. One drug turns into 5 or 6 all with patents and huge costs are passed on to the US consumer. We do not need over half of these meds for they really do not benefit anyone other than the profits of big pharma. Do we actually need dozens of antidepressants or drugs for male impotence?

I’ve seen many good drugs taken off the market because of unexpected side effects.  It happens to all of the companies in the industry.  I’ve also seen drugs that the industry has spent billions of dollars and years to develop go before the FDA and get shot down.  There goes a huge investment.  It’s hard to justify taking that kind of risk with shareholders’ money, especially when money making drugs are going off patent and there’s nothing in the pipeline that can get approved.  If the FDA and the pharmaceutical companies are colluding with each other, you would expect a whole lot more drugs getting approved and the numbers simply don’t bear that out.  Sooo, I would safely ignore this commenter as dreadfully uninformed.

Tuesday Morning: Melange

There’s no consistent theme in this collection of posts.  Or maybe there is but I can’t find it yet.

To start off, let’s say for a moment that Democrats actually get their $#@% together and decide to primary Obama.  (not exactly a fantasy and not nearly as remote as it was last week at this time)  Who is the most likely person to succeed, I mean, besides the obvious?

My guess is Jim Webb, Senator from Virginia.  Now, Webb has a few liabilities and I’ll get to them in a minute.  But with Webb versus Obama, you would get the classic matchup between the Stevensonian and Jacksonian parts of the Democratic party.  The Stevensonians have their hands on power right now, or what’s left of it, since they’ve made a total mess of things.  But the Jacksonians have the votes the Democrats need to win next time.

RealClearPolitics featured a conversation with Webb yesterday about how to win back the Reagan Democrats.  I actually don’t like the term “Reagan Democrat”, which is why the media is probably going to use it every chance they get.  I’m certainly no fan of Reagan and have been a liberal all my life.  But Webb actually gets it better than most people who are sticking a label on disaffected Democrats:

We’re talking about why voters didn’t come around. Webb is weighing my report the morning after the election: Democrats won the smallest share of white voters in any congressional election since World War II.

“I’ve been warning them,” Webb says, sighing, resting his chin on his hand. “I’ve been having discussions with our leadership ever since I’ve been up here. I decided to run as a Democrat because I happen to strongly believe in Jacksonian democracy. There needs to be one party that very clearly represents the interests of working people … I’m very concerned about the transactional nature of the Democratic Party. Its evolved too strongly into interest groups rather than representing working people, including small business people.”

[…]

Webb seems less at home today. He identifies himself as a Democrat. But he has few Democratic leaders to identify with. He won’t say this. His criticism is discernibly girdled. He begins to tell a story about a conversation with a Democratic leader and pulls back. “I don’t want to talk about that,” he mutters. “I have had my discussions. I’ve kept them inside the house. I did not want to have them affect this election, quite frankly. I didn’t want to position myself in the media as a critic of the administration.”

But criticism is in order. Democrats’ suffered historical losses from Congress to the state houses last week. It’s an apt moment for Webb to step in. He is an atypical politician. Politics is not his alpha or omega. He’s authored more than half a dozen books, succeeded as a screenwriter and won an Emmy for his coverage of the U.S. Marines in Beirut. This success outside politics empowers him to be less political. Yet what suits Webb to criticism is not that. It’s the political sociology he embodies.

Webb represents an endangered species. It’s more than his red state Democratic stature, although that would be reason enough. The moderate House Democratic coalition lost more than half its lawmakers last week. But that Blue Dog set is still more common than Webb.

Webb’s one of the last FDR Democrats. An economic populist. A national security hawk. His Democratic politics are less concerned with social groups than social equality (of opportunity, not outcome). His values were predominant in the Democrat Party from FDR to JFK, the period in the twentieth century when Democrats were also dominant.

Before we go on, notice how the conventional wisdom saturated media, in its quest to shape a narrative (or under orders from someone else) positions Blue Dog Democrats as “moderates”.  Anyone who has been paying even a minimal amount of attention to politics knows that Blue Dog Democrats are just as conservative as their Republican colleagues.  But I digress.

In some respects, Webb is similar to Hillary Clinton.  (He could have lifted that last paragraph right out of our credo.) He’s got enough governmental experience to make Obama look completely unqualified: Combat vet, former Secretary of the Navy, Congressional liaison, novelist, journalist, Emmy winner, lawyer, Senator.  His son enlisted and served in Iraq, yet he is not an Iraq War proponent.  In 2008, there were rumors that he was up for consideration as Obama’s VP.  But he made it clear that he wasn’t interested in the VP position.  Is it because he had concerns about Obama or because he wanted the top position some day?  As far as superdelegates go, I think he held out as uncommitted for a long time.  Actually, I wish all of them had waited but that’s besides the point.  Karma will take care of the ones who jumped aboard the Obama bandwagon early.

Now, for his liabilities.