Pharmageddon continues

This time it’s Glaxo Smith Kline (GSK). You may remember that GSK was in the papers recently because it was one of the only big pharma companies with a potential vaccine for ebola. Well, now they’re cutting their R&D staff. According to the rumors flying over at In the Pipeline, the biggest cuts are going to happen at their research park in North Carolina.

How these things typically happen is the pharma in question just eliminates a whole research division or therapeutic area. Your job is not spared because you made your company a zillion dollars on the patent you sold to it for a dollar 10 years ago. I used to be in favor of this quid pro quo arrangement. You give me the means to do my research, I give you the fruit of my labor. But now, I’m not so sure. Like everything else, there are predators in the executive suites and on Wall Street who have zero appreciation for the amount of work it takes to create a new drug entity and plenty of people who think they own it. In some respects, researchers have only themselves to blame for not protecting their own interests, those being the need to earn a living in order to consume calories to sustain life and have a roof over their heads.

GSK’s cuts come on the heels of cuts at Astra-Zeneca, which decided to get rid of its antibiotics research unit. Yeah, try to figure that one out. And then there was Amgen that recently announced that it would cut up to 4000 jobs globally including at its research facility in Seattle. So, while the flood of layoffs in the US R&D industry has slowed down a bit since the high water mark of 2009-2010, it’s still not finished yet. After all, sooner or later, the industry will run out of people to lay off. But we’re still going to see pulses of carnage here and there, dumping more over-educated, over-qualified, experienced and talented chemists and biologists into the already saturated labor market. Fun, fun.

In other news, the left sometimes *almost* grasps what the problem is with pharmaceutical R&D but as soon as those of us who really know what’s going on turn our backs, we get more clueless BS from people like Dean Baker. Don’t get me wrong, I’d love to have him on my side. But he doesn’t seem to spend any time talking with people who have actually, you know, been there. There is something bizarrely automatic about the left’s misunderstanding of how drugs get invented and developed. Maybe this has something to do with the complexity of the process. Or maybe it’s just laziness.

Here’s the basic outline of the misunderstanding: The NIH, which we all pay for, does basic research. Then it collaborates with a big drug company and that big drug company turns around and sells that basic research for a ginormous profit. All the big company does is scales the sucker up, runs some admittedly expensive clinical trials, and then produces and markets the drug, delivered fresh and complete from the NIH labs, directly to you the consumer at an enormous markup.

There is just enough truth about the greed of the executive and finance movers and shakers to make this look plausible. Unfortunately, it is one of those beautiful theories easily destroyed by ugly facts.

I don’t want to go into this again because it will take at least several posts to unpack but the NIH rarely delivers a pristine drug to industry. No, the whole idea of basic research is that it is basic. That doesn’t mean it isn’t hard or not valuable. It means there is sometimes little more than a nugget of a something to follow up on. The “drugs” are sometimes nothing more than fragments or completely undruggable. (Undruggability is a whole different topic) Sometimes, there is no drug delivered to industry. Sometimes, it’s merely the suggestion that a specific protein target may or may not be involved in some undesirable endpoint.

The role of industry R&D is to take this very basic research and through many years of real, genuine, honest-to-god research, turn it into something resembling a drug. It is a very expensive process. I’m not surprised at the numbers being batted around. That is not to say that we can’t cut back on the amount of marketing that pharma does. At the end of the day, what is more valuable to you? The researchers that invent an ebola vaccine or the marketers that tell you why you need it? But to get real drugs from real research, a lot of money must be spent in order to pay for many trials and errors and reagents and lab equipment and researchers who need to be fed and housed.

That being said, it sure does look like there is a plan to exploit NIH and academic labs. If you get rid of all your R&D units in the name of shareholder value, or at least cripple them with endless, non-productive mergers and acquisitions and layoffs, you may end up without anything to market. And there are a lot of geeky students out there who are willing to work at subsistence wages to get a PhD. Why not use them as your new staff? That certainly looks like what is happening. It’s a bit of a self-fulfilling prophecy.

What is missing in the equation is the experienced R&D staff that will know “when to hold’em and when to fold ’em” when it comes to actually making the potential drugs. In other words, there will be a lot of reinventing of the wheel in academic labs as they sort through how to do it on limited soft money.

It’s a research strategy only a banker could love.

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One bright spot for the journal famished: Nature is experimenting with making its journal archive and current issue available as a free “read-only” version. That’s to circumvent the habit of some poor researchers who have to sneak around to satisfy their paper habit, a phenomenon known as “dark sharing”. You have to know someone who has inside access to a license, usually some friend who is still in industry or someone at a university. This is what we are reduced to: sharing illicit copies of nerdy papers like they’re banned versions of Tropic of Cancer. Read-only versions that you can’t save or refer to later is  better than nothing, I guess, though not quite as good as getting a subscription to Nature and Science for Christmas.

 

In which I differ with Derek Lowe over NIH funding

Typical private industry lab circa 2014

Derek Lowe, blogmaster over at In the Pipeline, took issue with NIH Director Frances Collins contention that if the NIH budget hadn’t been cut in the past decade, we might have had an ebola vaccine by now.  I remarked on the Vox article about this very same topic last week.  However, I’m siding with Collins on this topic.  True, he might be using the very scary disease of ebola to make his point but it is a valid one.

To get an idea of what the NIH has been up against, I recommend that readers review the congressional testimony on the ebola outbreak from last week.  I believe it was Anthony Fauci who laid out the problem.  It goes like this:

1. The NIH identified the need for an ebola vaccine about a decade ago.
2. (This is the crucial part) The NIH is engaged in basic research.  We are talking very, very basic research.  Like, identifying the genes and sequences and making them available to other researchers, or studying how the virus works and propagates, or figuring out which enzymes chop up the viral proteins, or how the viral proteins are exposed to the rest of the body.  That’s the kind of research the NIH does.  And sometimes, the research is so preliminary that there are mistakes that get published that industrial labs have to figure out when they try to replicate the results in the lab.  Not a criticism.  It happens.  You only have so much money to do the research and sometimes, it’s not enough to double check your results.  I get it.  But it does make it harder for your private industry partners to figure out what’s going on and sometimes means that projects need to take detours to unpack mechanisms and rerun assays and such.  In other words, REAL RESEARCH.  That’s just the way science works, much to the finance industry’s chagrin.
3. So, the NIH tried to get a private industry partner to help finish the research on the vaccine and develop it.
4. But during the same decade, private industry was going through a chaotic destructive process brought on by the “patent cliff”.  That is, the blockbuster drugs that fueled industry research suddenly went off patent.  In response, the shareholders who were not about to take a haircut just so some lab rats could continue to do research for them, decided to take the money and run.  That precipitated Pharmageddon, where I and my colleagues got tossed out of corporate labs by the hundreds of thousands.
5. The NIH couldn’t find a private industry partner until the last couple of years when Glaxo Smith Kline (GSK) decided it would take a risk and start working on one.
6. In the meantime, in the last couple of years, the Republicans have lost their freaking minds over the budget and would rather let every government institution rot in hell before they would approve any funding.  This is about the same time we wrote a blank check to AIG, and other lords of the finance industry (see Neil Barofsky’s book).  Then the Democrats came up with this great idea of a sequester, you know, to call the Republicans bluff.  And the raving mob that calls itself the Republican party took the deal and slashed NIH funding by 20%.  The Democratic leadership that came up with the boneheaded, backfiring sequester idea should be kept away from sharp objects for their own safety.
7. So, to recap: NIH needed a vaccine but couldn’t find a private partner for nearly a decade.  Private industry contracted at a time when additional research and development is crucial.  Regular NIH funding is not sufficient for it to develop a vaccine on its own.

This would probably be a good time to insert some Paul Krugmanesque graph that shows the equilibrium between private and public investment in scientific research.  This one should show that when private industry stopped funding research, the corresponding expected increase in public spending was notably absent.

Derek has a libertarian streak and works for one of the last small molecule drug discovery companies in Cambridge.  That’s not necessarily a bad thing but it does skew his perspective just a tad.  Not only that but Derek is operating in the old world order when we tested every therapeutic treatment to death.  That’s clearly not happening with the ebola treatments.  Those suckers have been fast tracked like nobody’s business.  We are treating ZMapp like it’s a cure for ebola when it’s nothing of the sort.  It’s just that it’s the only thing we’ve got.  ZMapp is so early in development that back in the old days of real drug discovery, it might have been killed in a project portfolio review before it ever made it to development.  And the vaccines?  Well, normally, they’d go through many stages of development and testing for safety, efficacy, and side effects with an expanding number of trial recipients at each stage before it was approved by the FDA.  Forget that.  In this epidemic in West Africa, with number of exposures increasing exponentially, no one has time for these niceties (though I can just see some lefties screaming about how we killed West Africans with an untested vaccine that triggered a cytokine storm or autoimmune disease.  Wait for it.  You know it’s going to happen.  There will probably be a movie about it featuring some ruggedly handsome Liam Neesom type and a earnestly beautiful lady scientist detective out to uncover the awful truth of corporate exploitation of poor third world citizens.).

The real world is not so simple but there definitely is money at the bottom of this mess.

I’ve worked on both sides of the problems in both industry and in academia, if only briefly.  But I got a good look at what it’s like to do research on NIH grant money and it’s not pretty.  Most of a principal investigator’s time is spent preparing grant applications.  It’s very bureaucratic and, I suspect, very political.  If there isn’t a retrospective analysis on the amount of grant money that goes to the Ivies that leave the rest of the academic labs starving for funds, there really should be.  Not every breakthrough has to happen at Harvard.  The polio vaccine, for example, was developed in Pittsburgh.  Oh, yeah, how many of you knew that Jonas Salk worked for the University of Pittsburgh? True story.

And yet, it was about a year ago that I got a call in my office at Pitt from a researcher in the immunology group who had just lost her job because of the sequester.  It was last year at about this time that we had to cut back sharply on ordering chemicals and lab supplies for my lab because grants were on hold, also due to the sequester.  Even today, I see positions at Pitt for the kind of work that I used to do but the hours are part time.  Really??  You expect scientists to do protein production, extraction and crystallization experiments on a part time basis?  That’s the craziest thing I have ever seen.  You can’t just interrupt an experiment half way through the week because you’ve run out of hours.  That makes me think that the people posting the positions aren’t serious about how many hours they expect the researcher to be available.  It’s deceptive and weird and unrealistic.  But that’s life on soft money.  Here today, gone the next.  Yet the cells still need to be fed, lysed, protein collected, spun, purified, etc, etc, etc.

Friends, Americans, countrypersons, this is no way to run a research infrastructure.  Ok, sure, it’s the way to run a research infrastructure if you don’t want to do it like Americans used to do it.  If you are content to run a research infrastructure like Bolivians do it, fine, do it this way.  But don’t complain later that nothing of significance happened on the science front from 2008 onward.  Don’t complain that the NIH is not telling the truth about funding.  It can’t be all things to all people without a steady funding mechanism that isn’t going to be subject to violent shocks brought on by crazy people who get elected to Congress.

Here’s the bottom line.  If liberals expect the NIH to do all of the things that they *think* it already does, it needs more funding.  It needs waaaaaaaay more funding than it already has.  It needs as much funding as private industry used to pump into its own research coffers but no longer does.  It needs billions and billions more.  It has to become what private industry used to be but no longer wants to be.

And if Republicans are committed to free enterprise at all costs, it’s going to have to get tough with private industry drug discovery and force it to take on research that it sees as unprofitable.  It needs to have a serious talk with the bonus class and shareholders about greed at the expense of public health.  Isn’t that what the GOP is all about?  Morality?

That’s just the honest truth.  The NIH is not private industry.  If we want the NIH to replace private industry, which has abandoned certain, critical research areas because it can’t make the kind of profits that shareholders demand nowadays, we need to put more money into the NIH and fund researchers properly and seriously.  That is the point that Frances Collins has been trying to make.

Liberals have a complete misunderstanding of what the NIH does or is capable of doing.  Libertarians have an inflated view of what private industry can do, sometimes because they are living in one of the last holdouts of productive private industry drug discovery (that could end at any time, so don’t get too comfy, Derek).  But once you have lived in both worlds, you can see what a shambles the whole system is.  It’s unsettling and alarming.

Why Ebola spread in Dallas: Americanism

Lorenzetti’s Allegory of Good Government, 1339

We’re number one.  That’s what we always tell each other.

We have the best health care in the world.

Our public safety institutions are number one in the world.

We  are the richest country in the world.

We are supremely over confident.

How many people know that when Dr. Kent Brantley and Nancy Writebol returned from Liberia with ebola that their care was paid for by Samaritan’s Purse?  I’ll bet a lot of us just assumed that the US government picked up the tab for the flight, biocontainment units, ZMapp doses and hospital stays.  Not so.  So, who is paying for the transport and treatment of Nina Pham and Amber Vinson?

Probably a few more of us have questioned whether money was behind the shoddy care that Mr. Duncan got in Texas.  I have.  I’m betting that his lack of insurance and status as a foreign national had a lot to do with why he wasn’t immediately isolated when he first came to the hospital and why he was left in the ER for hours, some nurses say days, before he was transferred to a critical care unit.

As for the best health care in the world, the nurses were very unprepared for ebola.  The biggest chunk of the blame goes to the hospital.  It’s a hospital for the middle class and those who can afford the best health care in the world.  That’s where people go to have their babies and bypass operations.  Maybe they didn’t associate their kind of hospital with an epidemic in a third world country.  Bad things happen to THOSE people over there in Africa.  Not their kind of people in Dallas.  At best, that’s a benign form of American narcissism.  We’re so used to having clean water and streets and good food.  So, why should the hospital get all Girl Scouty and be prepared for a situation that will never happen to it?  Training for such an eventuality takes time from nurses doing their duties and time is money.  It’s the American way.

The CDC seems to have vastly overestimated the outcomes of our educational institutions, especially our K-12 schools, where everyone should have a pretty good understanding as to where Liberia is.  But then again, Liberia was a state created by former American slaves in the 19th century and Texas is a state notorious for trying to rewrite the past when white Americans might have done bad stuff to anyone.  But still, don’t these ER intake people, nurses and doctors watch the news??  At least one nursing supervisor seems to have been on the ball and insisted on moving Mr. Duncan to an isolation unit instead of letting him shed viruses all over the ER but she was shot down by her administration.  Still, you’d think that a hospital so concerned with its reputation and profits would have been more proactive in limiting the damage that his presence was causing.  Not so, apparently.

And what was the hospital thinking when they gave antibiotics to Duncan when they hadn’t bothered to find out whether he  had a bacterial infection that required them?  Does Texas Health Presby Hospital routinely overprescribe antibiotics?  Is this a hospital or a student health center?

What were Republicans and Democrats thinking when they cut the budget for the CDC by 12% and the NIH by 20%?  Friedan said yesterday that $30 million was restored earlier this year in an “anomaly”.  How the hell are you supposed to prepare for emergencies if you never know what your budget is going to be from one year to the next?  We complain about administrators making decisions for our health care instead of physicians but our bigger problem is that we have politicians making decisions for our disease fighting institutions.  Should the CDC and NIH know in advance what diseases are going to become epidemic on some kind of 5 year plan and ask for the right budget money in advance?  Or are their functions compromised by their unreadiness brought on by this reckless political posturing?

And everyone, politicians, journalists and people who should know better, is under some mistaken belief that the private sector is going to step up and perform the tasks in research and disease prevention that the CDC and NIH were created to do.  But they’re too busy trying to reap profits for the shareholders to engage in such money sucking activities like research. Meanwhile, we underfund the NIH and CDC.  Is that so Republicans can point to what a sh*%%y job government does?  Are they paying no attention to how our scientific infrastructure is being dismantled in this country and concentrated on a few narrow therapeutic areas?  They are leaving a gap that no one is able to fill.

This may be the richest country in the world but the riches are hoarded by some pretty selfish individuals and we don’t seem to be able to get our act together to force them to give up their loot for the greater good.

A little ray of hope came through yesterday when I saw that some television content providers are breaking away from the package deals offered by cable companies to allow viewers ala carte channel selection.  That’s great because eventually I will no longer have to subsidize right wing propaganda from Fox News or be forced to pay for Fox to mislead unsuspecting American viewers.  I’m betting that a lot of like minded individuals across the country will drop Fox from their lineup the second they are able to do it.

But the damage may already be done.  The Senate may fall into Republican hands this November and in the next two years, the predators who have been stalking us since FDR got us out of the Great Depression will finally be able to finish us off.   The willfully ignorant elderly and angry white males will finally stick a fork in us, and allow the extremists to carelessly destroy Social Security, roll back women’s rights and plunge us back into recession with unrestrained austerity.  The only thing that will stand between the power extremists and us will be Barack Obama.  That right there is a very depressing scenario.  But maybe he will have the courage to stand aside when we finally pick up our torches and pitchforks.

We have been living a myth of our greatness.  We’ve been in denial about how government works.  We have told ourselves lies about how we can “starve the beast” that once made our country a formidable force of good around the world.

I’m only glad that the ebola crisis here will be under control before the next session of Congress begins and before the gung-ho, American exceptionalists who take over show us just how unexceptional we are to the hunters who prey on the young, old, and weak.

Section from Lorenzetti’s Effects of Bad Government, 1339

 

More speculation and budget numbers at Angry Bear Blog.

Another thing that irks me

Vox has a new post about Frances Collins remark that if the NIH had better funding, we would have an ebola vaccine by now.  Vox says this isn’t true.  I think this was addressed briefly during the hearing.  The NIH went for years looking for a partner for vaccine research in the private sector and couldn’t find one.  Finally, they got GSK and another company interested in development.

Here’s what Vox doesn’t understand about drug discovery research and I have seen this repeated time and time again until it has become ingrained and hard to dislodge:

The NIH is not the only player necessary to take vaccines to market. The agency’s role in pharmaceutical development is usually basic research, giving scientists grants to look at how diseases function and what can stop them.

When it’s time to use that science to build a vaccine, that’s where drug companies typically come in, paying for the trials and manufacturing. We don’t know whether, in a world where the NIH had more funding, a pharmaceutical company would have stepped forward to do this. There’s decent reason to believe there wouldn’t have been; a vaccine to treat Ebola, an infrequent disease that hits low-income areas of the world, is hardly a blockbuster.

This is the conventional wisdom but it is incorrect.  The NIH does provide valuable basic research but the key word here is basic.  It’s not like the NIH develops a vaccine that just needs to be “built” by private industry.  It’s the same thing with drugs for cancer or any other illness.  The NIH provides very basic starting points.  After that, private industry has to pour massive amounts of money into research to fill out the details to get it to the point where it can be built.

What Vox and others do not understand is that private industry research is Real RESEARCH.

Now, if Vox wants the NIH to do the same kind of research that private industry is doing, starting with basic nuggets performed in NIH sponsored labs and publishing work that frequently can not be reproduced in private industry labs (I have been there, Ezra Klein), then it will need a lot more funding.

And this may be necessary anyway because private industry has decided that Real RESEARCH is way too risky and it would prefer not to do it anymore. (Hence the hundreds of thousands of layoffs that we refer to as Pharmageddon)  So, if we want a vaccine for anything, it may eventually have to come from the NIH.  That is what Collins is referring to.  NIH can only go so far without a private partnership.  If the partnership isn’t there and funding is cut, guess  what?  No vaccine.

This has been another episode of a former drug discovery researcher fruitlessly trying to correct the record.

Clueless scientist asks a very dangerous question

How the world sees scientists. Thank you, Underdog.

Note: Congressional hearings on the US Ebola efforts are going on right now with representatives from CDC, NIH, BARDA, FDA and others.  You can watch it here.  If anyone wants a live blog, let me know.  I invite other geeky types to watch and summarize, especially those of us with knowledge of the drug discovery/biotech area.

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No, it’s not me.  I admit to being clueless sometimes but not when it comes to the distribution of information.

I’m talking about Leonard Adleman who wrote an Op/Ed in the NYTimes about how easy it would be to revive smallpox.  The reason it would be theoretically easy is because the sequence for the smallpox virus is available online.  So, some really clever evil genius with a garage lab could potentially order up a copy of the gene from one of the synthetic gene specialists in South San Francisco and piece the sucker together using, oh, I don’t know, a variola, vaccinia or orthopox virus just hanging around.  It sounds complicated and might take some time, and if the independent researcher was born in the 80’s, there’s a good chance he’ll die of the disease if he’s not careful.  But it is possible.

Personally, I’m more concerned about reviving the 1918 influenza strain and getting it to go airborne, which, if I recall correctly, was successfully done a few years ago in Europe.  From what I remember, the researchers on that team suppressed the sequence.  Funny, I can’t seem to google that info.  Hmmm…

But getting back to Adleman, he’s not so keen on us just publishing the sequences on public databases.  Maybe it would be better if we just restricted access and only let the professionals see them.  That’s just nuts for a couple of reasons.  The first is that through the years, I have noticed that the sciences are full of people with psychopathic tendencies.  Fortunately, most of them get promoted out of the lab into management.  But just because they might be working at a prestigious lab with unrestricted access to information doesn’t mean they’re not out to get us.  After all, we still don’t know who did the anthrax attacks and I’m pretty sure it wasn’t a garage biologist.

The second reason is, referring to smallpox especially, we have a vaccine for that.  Oh sure, there will be plenty of thirty year olds who may be at risk but an outbreak would be limited.

And for the people who have extraordinary skill in making lethal viruses, I have a perfect solution: HIRE THEM!  Jeez, why in god’s name would you lay off hundreds of thousands of talented people and have them stew over the MBAs and shareholders who wrecked their careers??  Especially when there are auction sites where they can buy discounted equipment from mothballed labs?

I can’t see a teenager doing this, although we do have a lot of malicious computer viruses so who knows.  But they would have to be trained.  Just getting the sequence is not enough.  It’s not like writing code and you can’t get all your information from a book.  Maybe grad students would be capable if they’re motivated, so you tyrannical PIs out there should be on your guard.  But cooking up stuff in a lab takes practice and some good mentors to teach you how to do it.

In other words, it is possible that some well funded hostile country could fund this kind of work by sending some grad students to study in Dr. Adleman’s lab, for example.  He and his students would always have access to sequence data. But smallpox is not a threat and the other diseases are not so easily made.

But the best reason for not restricting access is that it once again takes out of the public domain millions of sequences for genes and proteins that the independent benevolent researcher has access to.  I think it’s great that the US publishes to the NIH PubMed and the European Mol Bio Organization provides this information for free to anyone who wants it.  Without sequence information, and the tools to process it, small, entrepreneurial companies would not have access to it without paying a fee.  That fee, like the high costs of accessing journal articles, could be a substantial barrier to admission to new businesses and new cures for diseases.

Think of it this way, without the information from sequence databases, Mapp Biopharmaceuticals, the company that discovered ZMapp, might never have gotten off the ground.

It’s unlikely that I’m going to produce an ebola protein in the lab but I’m glad that someone published the sequence data so that another lab could make them, crystallize them and publish 47 different protein crystal structures to the web for anyone to access, including a former drug designer in Pittsburgh.  That means a lot to me.  And maybe some crazy kid out there who likes looking at these things and enjoys protein folds and modeling as much as I do will be inspired to find a cure for ebola and other diseases.

What worries me is that the fear that Adleman is producing will lead to those sequences being locked away forever so that only the rich and well connected have access to them.  It would be the equivalent of the Patriot Act.  We wouldn’t know what we had lost until the new Dark Ages descended on science.  Do we really want to leave this information in the hands of only those who can afford to access it?

 

 

Freaky Weird Prescience (Ebola Post)

Well, it’s not looking good on the ebola front.  We still don’t know why the nurse in Dallas has ebola despite all of her precautions but I’m still not panicking.  My relatives in Houston are probably safe, though what did they say during the Black Death?  Run fast, go far, stay long?  Ok, that’s not really funny and is only encouraging a kind of hysteria that isn’t helpful.  Two ebola patients in Texas does not an epidemic make.  Then again, it’s Texas.

Nevertheless, there is a some speculation that the virus has become more virulent.  Peter Jahrling of the National Institute of Allergy and Infectious Diseases says this may be due to the increased viral load in infected individuals:

You’re seeing all these patients getting infected, so people think there must be aerosol spread. Certainly, it’s very clear that people who are in close contact with patients are getting a very high incidence of disease and not all of that can be explained by preparation of bodies for burial and all the standard stuff. But if you are to assume that the differences in virus load detected in the blood are reflected by differences in virus load spread by body secretions, then maybe it’s a simple quantitative difference. There’s just more virus.

Jahrling says that HIV was actually a hotter disease, primarily because carriers weren’t obvious and were able to spread the disease easily.  It also helped that HIV attacks cells in the immune system, which prevents a vigorous response.  But it’s a little hard to make this argument when comparing it to ebola.  HIV is a long, slow death and we now have drug cocktails to treat it.  Ebola is quick, excruciating, bloody and the lethality is alarming, especially because the treatment options are so few.

Which brings me to the next bit of bad news.  Frances Collins of the NIH says we might have had a vaccine for ebola except our politicians, with anti-governmental fervor, cut funding to those very institutions that might have helped to develop one.  I’d heard from researchers I met in Cambridge who had recently been to the CDC that morale was pretty low and disorganization was high.  Then, I lived through the summer of sequester when university research groups lost a sizable chunk of their funding as grants became more and more unattainable.  Layoffs quickly ensued.

One of the reasons I have been reluctant to pursue a job in research is because the money isn’t there anymore and I’m really sick of layoffs.  And let me make it clear that while scientists like to get paid fairly for the work they do, they don’t work for the money, for the most part.  They just like the work.  It can be frustrating and maddening and discoveries take a long time.  But it is also intensely rewarding in a way that money isn’t.  That’s not to say that we don’t have our own caloric requirements and shelter needs.  Also, no one likes to be exploited.  But bankers and Jack Welch types don’t understand the nature of science or the vast majority of people who do it for what is turning out to be a vanishing living.  But I digress.

The problem is that the patent cliff spooked pharma shareholders and they abandoned American research in search of get-rich-quick schemes and foreign research that isn’t ready for prime time.  At the same time, rabidly anti-government Republicans, abetted by complacent Democrats, have been slashing research budgets.

This is not the same America that we had in the post World War II days.  This is an infrastructure that is rapidly being gutted.  If you have any doubt of how bad things are, consider that Mapp Pharmaceuticals is virtually the only company on the planet with a possible treatment for ebola (we won’t know how the GSK vaccine is doing for awhile yet) and it is a small company in San Diego facing a logistical nightmare.  How does it grow the monoclonal antibodies and purify them on a scale to meet the urgent need of thousands of patients around the world?  Where is the CDC/NIH/Private Industry SWAT team that can get this off the ground?  We are asking this company to do the impossible on a massive scale in such a way that would attract every class action lawyer in the country if there wasn’t a health care emergency.

But it’s even worse than that.  As Collins says, ebola is only the tip of the iceberg.  The vast majority of us will not die of ebola.  We’re going to suffer from other maladies that no one is studying right now.   The funding is low on antibiotics, certain central nervous system disorders, heart disease, etc.  Companies just stopped working on these diseases because the research was expensive and shareholders didn’t think the profits were high enough.

All of this is happening when there is a revolution in biology.  The most ironic aspect of this problem is that thousands of trained researchers have been sidelined right at the same time that there is more than enough work to keep every one of them extremely busy for the rest of their lives.  There’s a profound disconnect between the people who are experienced enough to do the work and the funding mechanisms, either private or public, that will allow it to get done.

I see a lot of fuming on the ebola twitter feed about how scientists should just step up and get it done.  We’re all going to be saved by scientists.  How this is going to happen without funding is anybody’s guess.  It takes money to buy the equipment and reagents and research the papers and feed these scientists who everyone seems to think are going to be self-sacrificing for the betterment of mankind and to save their asses from some exotic African disease.  But as soon as the crisis is over, will we go back to chain sawing through the NIH budget?

From what I can see, neither private industry or our political leaders are taking the threat seriously.  So, I stand by my earlier prediction.  It’s going to take a plague to focus the nation’s attention on our crumbling research infrastructure.  It might as well be ebola.

 

Once upon a time…

Merck chemists go into exile

Once upon a time in New Jersey about 20 years ago, there was a company called Merck that everyone I knew wanted to work for.  The streets of Rahway were paved with gold.  We jokingly referred to our own company as a training facility for Merck and Bristol Myers.  The best of the best worked there for two years and then went to Merck.

At local conferences, the Merck people showed up in a pack, smug, condescending, and cast an otherworldly pool of light around them.  THEY wrote their own proprietary modeling software.  Even as late as two years ago, when Pharmageddon got its groove on, there was something magical about Merck people.  They were like fading elves.

Alas, all good fairy tales come to an end and so it was with Merck this week where the rumor is that medicinal chemistry, that is the research part that makes your drugs from scratch, oh best beloveds, has been decimated at Merck.  The rest of the story at Merck is unclear at this moment.  We’re still trying to piece together whether Merck is going to outsource their synthesis to poorly paid foreign PhDs or whether management, who hasn’t synthesized anything but performance standards and political fantasy baseball for years, is going to don their too tight lab coats and nitrile gloves and go back to the lab.  That should be interesting.

Once upon a time, the US had world class public research.  Then the big companies decided they didn’t want to do research anymore and they would pharm out their research to academic labs.  And they wrote policies about how this would be accomplished and the politicians said it was good because many of them didn’t know what the heck they were voting for.  And then the Republicans decided to “drown government in a bathtub” and because they are like Godzillas in Tokyo, they were pretty indiscriminate about what they were knocking down.  It turns out that the NIH keeps getting hit pretty hard and grants are harder and harder to come by with higher and higher bars to jump over and endless hours slaving over documents.  That time could be used to invent new techniques but research is very expensive and someone has to pay for it.  So the academic scientist spends much of his or her time begging to keep the reactions going and the lab rats paid.

Recently, during the government shutdown, Francis Collins, the head of the NIH, said this about the sequester and the tragedy of what is happening to this country’s life sciences infrastructure:

The sequester hitting as it did in the middle of the year meant that about 640 grants that would have been supported and highly regarded by peer review are now not going to receive funds. And those ideas are not going to happen. And breakthroughs that they might have represented will not occur. We will not know what we’ve missed because it’s gone. Imagine 640 bright, motivated scientists on the brink of doing something powerful that could have changed the way in which we diagnose, treat, and cure cancer or influenza or diabetes or some rare disease that desperately needs an answer; it’s just not going happen. I would argue with anybody who says that’s a minor consequence. It’s not; it’s a major negative outcome and a tragedy for what had been the world’s most successful search-engine in biomedicine.

Other countries, meanwhile, have read our play book and see their future in trying to do what we used to do. As we seem to be backing away, they are increasing their support. And if people care about American leadership, they should be worried.

Unless something (it’s called C-O-N-G-R-E-S-S) stops the next set of cuts in the sequester, the problem is going to get a lot worse.

I don’t see a happily ever after ending to the story right at this minute but, you know, I’m a Tolkienist so I’m not ready to give up hope yet. The situation at the present time is this. We have private industry pulling out of research because the shareholders are like opium addicts who expect bigger and bigger quarterly hits.  Long term investment doesn’t play nicely in the sandbox with an “ownership society” where everyone and their grandma is expected to put their savings into mutual funds that analysts and managers can gamble with.  And we have idiots like Rush Limbaugh who yee-haw that the sequester is the best thing since sliced bread because liberals are sucking on it.  I wouldn’t wish a Charlotte Corday situation on my worst enemy but I wouldn’t think twice about wishing a drug resistant version of Fournier’s Gangrene on Rush Limbaugh.

In the meantime, some of us still can’t quit science.  After two years in the desert, I have to pinch myself because I now have access to all the journal articles I can eat.  I’m afraid to click on the “Full Journal Article” button sometimes.  It’s almost not real, like ruby slippers.  {{Oh, wow, oh, wow!}}  But it’s almost cruel too because it’s so uncertain these days.   What is granted can so easily be taken away, like coaches that turn into pumpkins at midnight.  Sometimes, I think I might have been better off if I’d taken my academic advisor’s advice and studied law.  Then I think I’d rather eat glass than study torts.

So, science, yeah.  You can barely make a living at it anymore and yet can’t quit the habit. The best I can do at this point is try not to frighten the new, untested, warriors in training that there be dragons out there and to pass on what a wizard once told me, “Don’t let anybody steal your bliss.”

 

Calling all medicinal chemists, time to contact Virtually Speaking

I was mulching my flower beds, listening to the latest Virtually Speaking with Dean Baker and Jay Ackroyd when I heard the same moronic bullshit about how drugs are REALLY all discovered in academic labs using government money and the drug companies just put the finishing touches on them, develop them and charge a small fortune.

I’ll give you the fortune bit, for sure.  There’s no doubt that the marketers and finance guys are charging what the market will bear and then some.  They’re greedy, ruthless and cruel.  The whole drug industry has pivoted to serve the owners and the owners want money.  That affects what gets researched, promoted and sold and at what cost.

BUT

There is absolutely no truth to the idea that academia passes on almost fully formed drugs to industry where we researchers add our special sauce flourishes and then cash in big.

I repeat.

There is absolutely no truth to the idea that academia passes on almost fully formed drugs to industry where we researchers add our special sauce flourishes and then cash in big.

If Dean Baker and Jay Ackroyd and Yves Smith want to propagate this myth, they can knock themselves out.  But it’s no more true that the idea that Bill and Hillary Clinton did something nefarious with a land deal in the Ozarks.

Maybe it’s what they want to be true, maybe it fits their worldview, maybe it’s wishful thinking but it not true.  And I should know because I’ve worked in both industrial and academic settings and I actually DO the kind of drug discovery that Jay and Dean talk about so confidently but have no clue about.

The truth is that academia rarely submits a fully realized drug entity to industry for development.  What it submits is frequently just an idea.  Sometimes, that is just a target (a protein, receptor, gene, etc) and sometimes, it consists of some very basic building blocks.  Those building blocks will not resemble the final drug product until industrial medicinal chemists spend years and years rescaffolding it, making new appendages for it, and developing whole libraries of potential drug compounds that may not resemble the initial compound in the least when they are finished.

So, yes, the NIH funds a lot of research but, no, that research does not result in anywhere near effective or consumable drugs until industrial chemists get their hands on it and bend it to their wills.  By the way, those industrial chemists used to be academic chemists.  It’s not supposed to be an adversarial relationship.

Anyway, for all you pharma researchers out there who are pissed off by the “everybody knows” truthiness and yet more dissing of your shrinking profession and want to set the record straight, let Jay Ackroyd at Virtually Speaking know.  God only knows why Jay won’t simply invite someone like Derek Lowe on his show to tell it like it really is.  It’s almost like they don’t want to hear the truth, that somehow by sticking their fingers in their ears and singing “la-la-la, I can’t HEAR you”, that that’s going to make the poor graduate students working for peanuts into unsung heroes and pump lots of righteous indignation into the put upon American people.  Well, those graduate students ARE unsung heroes, but so are many of my former industrial colleagues in medicinal chemistry and drug design who have slaved tirelessly for years wrestling some academic’s decidedly un-druglike molecule into a real drug that can be developed.

I’m really insulted by this poor performance by Ackroyd and Baker.  The left deserves people who are not lazy and who will actually go out of their way to get to the truth.  Otherwise, the drug industry will continue to fail, drugs will continue to skyrocket in price and no one will be able to do anything about it because they’ll all be off chasing wild geese or red herrings or whatever it is you call it that is just a waste of time and energy.

Jay and Dean aren’t even seeing through a glass darkly at this point.  If they would only come and actually, you know, talk to us, we could tell them what’s really going on so they could talk more intelligently about a subject they clearly know nothing about at the present time.  I’m not sure what is holding them back.  Is it the absurd notion that those of us who work(ed) for industry  are as greedy, ruthless and conservative as the guys who laid us all off?  Even if that were true, (it’s not, not by a long shot) is that a good reason for ignoring what we have to say?

You can’t fix a problem if you are totally ignorant.

Here’s Jay’s links if you want to set the record straight.

Jay on Facebook

Jay on Twitter

VS Guests on Twitter

VS in Second Life

VS Ning

VS on BlogTalkRadio

VS on Facebook

VS on Itunes

And here is Dean Baker’s twitter feed.

 

 

 

 

Hacks and thwaks

Yesterday, for some bizarre, unknown reason known only to Yves Smith, I was accused of spouting PR for the pharmaceutical industry.  It appears that it goes against left of center dogma to say that the NIH does not just hand over perfect drug entities to the drug industry, already tested and bioavailable and efficacious, and that all the industry “R&D” divisions (well, what’s left of them) do is add a few finishing touches and charge everyone an arm and a leg for them.  Yes, that is what pharmas do.  They don’t really do research.  We just accept these gifts of government largess and when they arrive on our front door steps all glistening with ingenuity and brilliance, we stand around and marvel at them like they are alien creations.

Ok, the chemists can stop laughing now.  No, really, you’re going to hurt yourselves.

The truth is that NIH grants allow for some good science and many new discoveries.  But very rarely do they get to the stage where a new drug is delivered to a pharmaceutical company as a fully formed entity that requires no modification.  My experience (>20 years in the industry) is that NIH grants fund a lot of basic science on targets.  Then, if those targets (not drugs, protein targets) look interesting, they’re picked up by a pharmaceutical R&D, or more likely, several pharmaceutical R&Ds because the information is public, and all those different companies work on the target at the same time.  That’s how you get “me too” drugs. Just because someone beat you to market doesn’t mean you can trash all your hard work. Besides, your drug might actually be better.  It is strange that it is only in the pharmaceutical industry that “new and improved” is looked on as a bad thing.

Now, I am not going to argue that the pharmaceutical industry doesn’t charge an outrageous amount of money for new drugs these days.  And I won’t argue that they haven’t done much of anything to put new drugs on the market.  Or that they haven’t gone back into their old compound libraries  or that they reformulate things.  Sometimes, those reformulations are meaningful and sometimes they are not.

But I do know that research is expensive.  Ridiculously expensive.  That’s why big pharma has been cutting back on research as a counterintuitive business model.  That’s why there’s nothing coming out of the labs.  They are spending less money these days and they are relying on academic groups more often now.  The reasons are many but chief among them is that after having spent many billions of dollars on research, very few new drugs were approved by the FDA.  And that could be a result of higher safety standards that didn’t exist when the project was started or the constant mergers and acquisitions and bad management and the explosion in biology in the past couple of decades and the new and trendy things that snake oil salesmen corporate ladder climbers sold to their bosses as the next big thing that weren’t ready for prime time.  In fact, if Yves had been reading the posts I have written in the past several years on the pharmaceutical industry, or Derek Lowe at In the Pipeline has been writing (check the archives, Yves) or even someone like Anthony Nicholls at Openeye has been writing, she would have gotten a more complete picture of what is really going on.

What is really going on is that the big pharmas are going “weightless”.  They think they can exploit little start up companies and academic groups and turn those compounds into drugs.  And they want a cheap workforce.  I mean REALLY cheap.  Like $37K/year is their ideal top of the salary band for post docs who will never find a job in industry.  So they have been pushing this nonsense to the White House and Congress that what we need is more students who will sacrifice themselves to STEM professions and forget about having a stable job or family life because it is the patriotic thing to do.

Meanwhile, there really are academic groups that are trying to create new drugs.  They consist of former industry professionals who have taken incredibly steep cuts in their salaries and work in facilities where their resources are vastly reduced compared to their formerly corporate lab environments.  The pharma industry has them right where they want them, using their decades of expertise to cobble together drugs out of shoestrings and bubblegum.  And those dedicated scientists spend a lot of time applying for grants from the NIH but the money is very hard to come by and can’t pay for all the things and people they need to do their jobs.  These people are amazing and I can’t say enough good things about them.

But they are the exceptions, not the rules.  The rule is that the vast majority of NIH funded research provides germs of ideas.  They are hints of possibilities, a bunch of gel slides and some correlations.  I have been on many projects that started with a few interesting papers from NIH funded research.  We spend a lot of time on these shiny little nuggets setting up assays and crystallizing proteins and screening millions of compounds and synthesizing new compounds only to find out that the NIH funded studies did NOT have all of the answers.  The initial studies had only part of the answers and didn’t know about all of the other pathways and upregulation or the initial study was just off and the assays don’t work like they should and the project has to solve a different problem before it circles back to the original problem.  In the process, the industry research uncovered many aspects of the biology that the NIH scientists didn’t have the time, money or urgency to discover by themselves.  Many millions of dollars have been spent chasing NIH beginnings that ran into brick walls and had to be abandoned.  In any pharmaceutical company, there were dozens and dozens of these kinds of projects going on all at the same time.  Many projects are started but bloody few succeed and the vast majority of drugs that are produced from the germ of an idea that came out of an NIH study originated in the compound library of the pharmaceutical company itself.

Those are just the facts, Yves.  You can talk to anybody who has ever worked in pharma in the past 20 years and they will confirm this.  Yes, some remarkable things have come out of academia but very few of them  came directly from some academic lab untouched.  All of the other drugs were industry generated.

The reason why drugs are so expensive and are going to get more expensive is because more companies are abandoning their small molecule drug discovery efforts, because they couldn’t get approvals and recoup their investments before the patent clock expired, and are now moving into biologicals, the next big thing.  Oh sure, there will be some small molecule efforts in areas like oncology but this is due to a very cynical calculation on the part of the bean counters.  Oncology drugs are fast tracked and the safety profile is relaxed. People with death sentences on their heads are more than willing to become human guinea pigs and put up with a lot more toxicity than average non-sick people. They’re less picky about formulations.  Sure it would be great if the drug is oral and easily bioavailable but if you have to take it by IV, that’s OK too. If the drug extends life by even a few months, some families would consider that a success and they’d be willing to pay whatever the market wants.  And best of all, patients don’t complain and file class action lawsuits.  If the treatment succeeds, everyone is happy no matter how much the liver is shot.  If it fails, well, the patient was going to die anyway.  The relatives chalk it up to fate. The shareholders are happy.

Biologicals are a whole different animal with their own share of problems from humanizing mouse antibodies and aggregation problems to all kinds of new and different things that no one even knew about the cell.  It’s going to be interesting and very expensive.

The rest of the non-wealthy people will have to live with generics, which are bound to get more expensive.  Yves is smart enough to figure out why because she understands scarcity, supply and demand.  But these will be older, less efficacious drugs.  Well, the public put it’s foot down about “me too” and demanded a higher level of perfection than any small molecule drug is likely to ever deliver and this is what happens.  No more new small molecule drugs.

There are many facets to this problem.  Everyone sees the issue they are closest to.  If you only consult one “expert”, you only see one part of the problem.  There is no reason to distrust those of us former industry professionals who have a different version of events.  Believe me, we are not going to tell you a lot of flattering things about the pharmaceutical industry that stupidly laid off all of its expertise.  But unless you find out what is really going on and who is doing what with which resources and how successful those resources are, you can’t develop a complete picture of the landscape of this problem.  And more importantly, you can’t *solve* the problem. That smacks of a very unscientific approach to solving problems and, in the end, it doesn’t serve the patients or American citizens well at all.  In fact, not gathering as much information as you can from different sources is precisely what Big Pharma wants you to do.  It’s asymmetrical information at its best.  You only have one part of the picture and they just sit back and laugh at your righteous indignation while you rail against them.  How is this different from the finance industry?

By the way, I am no finance person and I didn’t much care for economics.  But I took the time to read books and ethnographies and visited wonky sites and read Yves and waded through all this money crap that interests me not even in the slightest.  And although I don’t know everything, I know much more than I did four years ago.  I know what motivates the bastards now and what incentives need to be changed to make the system function again.  That’s a positive step, right?

So, maybe closing your ears to differing points of view is not a good thing, Yves.  You’re not helping us beat this thing.  And that is something no pharma PR rep would ever say.

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

And now for some IKEA hacks!

This first one is from one of my new favorite YouTubers, goodbrowngravy, who despite being a white southern male with an accent, appears to be not the ignorant redneck that some lefties think all white southern men are.  (Do we condescend and stereotype much?  I think we do.)

Here’s goodbrowngravy’s IKEA hack of a Rast dresser into a campaign style side table.  Nice work!

And here is a hack of an Expedit unit turned into a stereo system from Apartmenttherapy.

Speaking of IKEA, if you are in the area tomorrow of the Elizabeth, NJ IKEA, you can drop off some badly needed items for the NYC/NJ survivors of Hurricane Sandy. IKEA is teaming up with the RedCross and other organizations to provide furniture and funds and also to collect items from customers who are shopping on Sunday. Check here for a list of items that would be much appreciated.  The collection will start at 11:00am.  And I really need a Rast…

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.