After I posted on, what was in my opinion, a poor use of Nuvigil, several people referred to caffeine as being peddled as a wakefulness enhancer and stimulant for centuries.  True, but caffeine is different neurobiologically than amphetamine like stimulants. 
Amphetamine modulates neurotransmitters in the brain, with the majority of amphetamine effects being exerted on the monoamine neurotransmitters dopamine, serotonin, and norepinephrine. Amphetamine most likely has a much broader effect on the brain and central nervous system dopamine, serotonin, and norepinephrine are just  the most noticeable ones. Amphetamine activity throughout the brain appears to be site-specific. Certain receptors that respond to amphetamine in some regions of the brain tend not to do so in other regions, such as memory formation in the hippocampus. Amphetamine's influence on  neurotransmitter activity specifically in regions implicated in reward explains the behavioral implications of the drug, mainly the  euphoria characteristic of use.

Caffeine is the most widely used psychoactive drug in the world.  I enjoy it in the form of a nice cup of dark roasted coffee of Indonesian or Ethiopian origin.  It is one of those GRAS compounds (generally recognized as safe) that has some pleiotropic effects.

Thus spake Wikipedia: "Adenosine acts as an inhibitor neurotransmitter that suppresses activity in the central nervous system. Consumption of caffeine antagonizes adenosine and increases activity in neurotransmission including acetylcholine, epinephrine, dopamine, serotonin, glutamate, norepinephrine,cortisol, and in higher doses, endorphins which explains the analgesic effect to some users. At very high doses (exceeding 500 milligrams) caffeine inhibits GABA neurotransmission. This evidence explains why caffeine causes anxiety, insomnia, rapid heart and respiration rate."

So instead of bathing my brain in a bath of dopamine, I'll stick to my coffee.  It has other health benefits as well.   I leave you with Voltaire's response to a comment that coffee was a slow poison.  "It must be.  I've drunk 40 cups a day for the last 50 years and I'm not dead yet"

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So I am now mildly annoyed.  This advertisement for Nuvigil (a stimulant that has legitimate uses for narcolepsy indicates that if you have a patient that is overworked (go to the site there are other examples where the answer to the condition is for the employers of said individuals to let them lead normal lives) don't tell them to rest and listen to their bodies, give them Nuvigil! 

I get very nervous when I see things like this.  I've been fortunate enough in my career to only work on important problems: cancer, cancer adjuvant therapy, inflammatory disease, severe neuropathic pain, and degenerative neurologic disorders.  I would be very unhappy if my labor were being used to drug overworked  people into ignoring their circadian rhythms. 

Our society is broken.  Now we are beginning to turn to drugs to (I guess people have always self medicated with alcohol) deal with societal problems that should be dealt with at societal level. I personally am against the Affordable Healthcare act.  Not because of what it does, because of what it does not.  We are at a point in the development of our civilization where we should care enough about our fellows that we do not allow someone to die if we can do something about it.  It is something that is too important to be left to private industry.  Drug discovery is something too important to be left to government.  We should have a national health care like every other developed nation. 

 I love the pharmaceutical industry.  It has given me an interesting life where I could work on interesting problems.  I love it so much that I think there should be many more companies.  Lets do an AT&T like break up on the big pharmaceutical companies and return to the state of the 1980's when Merck was respected and innovative and GSK was Glaxo, Smith-Kilne and Beecham. 

Here endeth the lesson.

Journal papers get retracted all the time.  It's not always a case of scientific fraud.  Sometimes it is.  Sometimes massive fights erupt in the literature.  Then, on the other hand, every once-in-awhile something really weird happens.  Now gentle readers I present to you a file from files of Retraction Watch and the Twilight Zone. 

There has been controversy about this 1994 paper which I had been completely unaware of, but now it turns into a cloak and dagger story where one of the principal authors was caught breaking into a lab freezer and tampering with one of the samples of the students tasked with reproducing the results. By a hidden camera. Really.  I'm speachless. 

Should any of you, dear readers, be seeking employment.  This article has a list of international pharma companies that are actively hiring. 

Robert Lustig was talking at the Aspen Ideas Conference last week. He has been on a crusade against fructose for some time.  He is one of the leading proponents that all calories are not created equal. He claims that sugar is one of the most toxic substances we can consume and wants it regulated like alcohol.  I tend to react poorly to alarmist phraseology.  I do not believe that  sugar causes cancer any more than I think that police cause highway accidents.  The is a clear confusion of correlation (some cancer cells selectively metabolize sugars, you always see a police car at an accident scene) with cause.  

However there is a significant amount of truth that humans were opportunistic omnivores.  We ate meat, vegetables, nuts, berries, but no significant amounts of grain.  we got fructose in our diet from fruit, but it wasn't constant and it was most likely an episodic binge.  When we learned agriculture, our life spans, cranial capacities and overall measures of health decreased. The source of this information is the very fascinating book: "Paleopathology at the Origins of Agriculture (Bioarchaeological Interpretations of the Human Past: Local, Regional, and Global)" it's recommended reading. 

Clearly we didn't evolve to eat so much grain. A more reasoned approach to the problem can be found in the work of Dr. Peter Attia, who was an obese and pre-diabetic surgeon turned nutrition researcher who, I think quite rightly shows that people confuse acute with chronic toxicity.  He explains the issue quite well here. 

Personally I was a vegan (for moral, not health reasons) and was very obese.  I have lost 65 pounds consuming more calories than I ate before on a slow carb diet.  I'm still losing, but now I'm just fat, not obese. I resumed eating meat (grass fed, organic and also game meat.  (tip: wild boar makes a great burger)) and all of my blood markers are better than they were whilst vegan.  You can chalk that up to anecdotal evidence.  But I do believe all calories are not equal. 

Stay healthy out there. Take what I say with a grain of salt, but do look into the concept of caloric difference.

In antiquity purple was the color of royalty.  Cloth dyed with the purple dye made in Phoenicia was highly prized throughout the ancient world.  It was colorfast (i.e. it did not  fade) and it was difficult to make and only available in small quantities.  Pliny the elder discuss the dye in chapters 60 to 65 of "The Natural Histories": 

"The most favourable season for taking these fish  is after the rising of the Dog-star, or else before spring; for when they have once discharged their waxy secretion, their juices have no consistency: this, however, is a fact unknown in the dyers' workshops, although it is a point of primary importance. After it is taken, the vein  is extracted, which we have previously spoken of, to which it is requisite to add salt, a sextarius about to every hundred pounds of juice. It is sufficient to leave them to steep for a period of three days, and no more, for the fresher they are, the greater virtue there is in the liquor. It is then set to boil in vessels of tin, and every hundred amphoræ ought to be boiled down to five hundred pounds of dye, by the application of a moderate heat; for which purpose the vessel is placed at the end of a long funnel, which communicates with the furnace; while thus boiling, the liquor is skimmed from time to time, and with it the flesh, which necessarily adheres to the veins. About the tenth day, generally, the whole contents of the cauldron are in a liquefied state, upon which a fleece, from which the grease has been cleansed, is plunged into it by way of making trial; but until such time as the colour is found to satisfy the wishes of those preparing it, the liquor is still kept on the boil. The tint that inclines to red is looked upon as inferior to that which is of a blackish hue. The wool is left to lie in soak for five hours, and then, after carding it, it is thrown in again, until it has fully imbibed the colour."

The fish Pliny is referring to is the Murex snail now called Bolinus brandaris.  One can imagine the smell of the dye works at Tyre as tons of shell fish fermented in the vats.  The rest of the mollusc was discarded when the hypobranchial gland (the vein Pliny was referring to). Zvi Koren has reconstructed the process and successfully dyed cloth using the ancient techniques.  

This is the structure of the purple dye and interestingly it is showing up as an interesting lead in GSK inhibition. If you enjoy the weekend forays into the chemistry of antiquity let me know and I will make it a regular feature. 

Leibniz argued we live in the best of all possible worlds.  I realize that looking at what goes on around us causes pause at this statement, but ask yourself, what percentage of our problems are caused by human frailty and not an inherent conditional aspect of the universe as a whole.  I'll stop the philosophical meanderings now, and switch to my plan to fix the pharmaceutical industry.

First we must agree on some points.  Number one is that the pharmaceutical industry, while a business which exists to make money, is a very different business than others.  Why discover drugs when you could make tyres, or tacos? Presumably because you want to apply to scientific training to something that will help humanity in some small way. Consequently, point number two follows. Drugs are not tacos.  Creating a demand for drugs is inherently not the point of the business. Drugs that make a significant difference in peoples lives create their own market. Lipitor became a huge seller before all the massive market-creating direct to consumer advertising started.  Therefore we should strive to create drugs that solve problems that exist, not find a use for a drug that your have.

Point three is that all of the major blockbuster drugs were created before the merger mania.  it is impossible to be innovative in a crushing bureaucracy.  Just ask any of your Russian colleagues about being innovative in the Soviet Union. Consequently, the mergers need to be undone. Pfizer, Novartis, etc.  need to be broken up into smaller companies where a drug that produces $350 - $400 million in revenue would be significant enough to make a difference.  

A corollary to point three is that is drugs are not tacos, you can't let managment come from the same business background that is created in most business schools.  Research can not be viewed as an expense.  It costs about a billion dollars and takes ten to fifteen years to create a functioning research group.  Cutting, or shutting down a research site is equivalent to shooting your dairy cows for meat, or eating the seed corn. The steak may taste good, but when you realize you need milk, you will need to go buy cows that you really should already have.  

Pfizer has admitted that it can't do research and is looking around for innovative products from small companies that employ the scientists that Pfizer fired when they shut down all the research sites that they acquired in the mergers.  To quote a Pogo comic strip, "we have met the enemy and they are us!".

The problems in the pharmaceutical industry can be solved by reversing the results of merger mania.  Also require that the shut down facilities be turned over to a non-profit foundation (Hey Bill and Melinda Gates, I'm talking to you)  where companies can be incubated for free for a period of time.  Be very loose on the criteria to get in and get started and then do a two year review and be very harsh on the criteria to stay. Let the non-profit be involved in getting funding and make sure it has enough clout to keep the Harvard MBAs out. Let them then license the products out to recoup the costs.  Core functionality like scale-up, Preclinical and clinical research can be centralized so the scientists can focus on research. 

we have to get small or all we will have are 3rd generation Viagras and more invented conditions like "low testosterone".

I welcome feedback. Contact me, follow on twitter (@VictrixCMC).  Particularly if you are Bill Gates. 

This graphic roughly shows the structure of the pharmaceutical industry when I joined it in the last gasps of GHW Bush's administration. There were 34 companies that were large enough to merit the title of big pharma.  In that legendary time, Merck was the largest raking in a cool $5.2 billion a year.  Pfizer was number 14 making $1.4 billion a year.  There were many blockbuster drugs on the horizon. I worked at American Cyanamid which was bought by American Home Products.  I left and went to biotech and watched as AHP shed the Cyanamid Agricultural Chemicals business and passed it off to BASF, closing the only agricultural chemical division that was making more money than the pharmaceutical division (Lederle Labs).  The the mass orgy of cannibalism began. As the graphic shows, 34 companies became 7. In 2011 Pfizer had moved to number one with a whopping $56.4 billion in revenues. Merck had dropped to #3 with a still huge $40.1 Billion in cash flow. Novartis which formed when Ciba-Geigy and Sandoz merged.  Ciba-Geigy, itself a merger of Ciba and Geigy. I guess Ciba-Geigy-Sandoz wouldn't fit on business cards, so a new creature emerged named Novartis. 

In the graph below, you can see that 39 drugs were approved in 2012, which is fairly large compared to previous years.  It is important to note that 14 of those were new biologics.  In 1990, 23 drugs and 30 the following year, 1991 were approved.  If you look at the graph at the bottom of the page, one obvious factor is that the cost of developing a new drug (chemical) has risen to $800 million in 2000 from $300 million in 1990.  The best estimate for last year was $ 1.8 billion for 2012.  So where are all those savings that were supposed to come from the consolidation of the industry?  Well, they obviously don't exist. 

One huge problem is that a company the size of Pfizer needs multi-billion dollar earning drugs and those are hard to come by.  They weren't a particularly innovative company so in the 1990s they went on a merger and acquisition binge that destroyed Warner-Lambert, Pharmacia-Upjohn, Wyeth.  All were much more innovative companies than Pfizer.  Pfizer dismantled the research infrastructure of these companies, turning out the chemists responsible for producing the blockbuster drugs, that they acquired the companies for.  Now what?  We have several Brontosauruses that can't find enough food to survive.  As we have learned from the housing crisis, that "too big to fail" translates into "too big not to fail".  The cost savings of mergers are paper economies.  Mirages of accountants ledger books. The industry was in much better health in the late '80s and early '90s that it is now.  What are the big guys doing?  Looking for innovation in the small company arena, buying the small companies, so they can get innovative products and destroy the culture of innovation that brought the new drugs in the first place.  

"Well, what is to be done?" you ask? I'm glad you did.  Fortunately, I am arrogant enough to believe I have the solution.  Tune in tomorrow for part three, in which I solve all the world's problems. 

Merck always was the epitome of what a pharmaceutical company should be.  Growing up, I knew about what a good company it was.  This reputation was largely based on the research organization that was built by Max Tishler. He led the teams that worked out the total synthesis of ascorbic acid, riboflavin, cortisone, miamin, pyridoxine, pantothenic acid, nicotinamide, methionine, threonine, and tryptophan. Tishler stepped outside his synthetic organic background and developed the fermentation processes for actinomycin, vitamin B12, streptomycin, and penicillin. Tishler also invented sulfaquinoxaline for the treatment for coccidiosis. This man basically invented the discipline of modern medicinal chemistry. He stands next to Paul Ehrlich in the discipline as one of those towering figures that looks down on the medicinal chemists of today.  I wonder if he would be pleased.

Now Merck's new head of research, Roger Perlmutter, has announced plans to revamp research at Merck with a plan that will involve cuts to R&D. I have no access to the organizational structure of Merck, or it's costs or infact any inside information. However, I do know that when a research organization has problems, it almost never resides in the foot soldiers who carry out the day to day research.  The choice of therapeutic areas, staffing, funding basically everything but the day to day research is a senior management problem. 

Bringing in a new head of R&D is a start, but laying off the researchers will do nothing to make the pipeline more robust.  The issues at Merck are deep.  The shareholders should consider the way the military handles problems with performance in the field.  They fire generals, not privates. If a division fails, the commander is gone.  They don't cashier 10% of the privates to make a "leaner more efficient" division keeping the chain of command intact. 

I firmly believe that no one has ever reorganized themselves to greatness.  I believe that this is why most organizations fail over time.  There is too much power in the upper echelons and the tendency to shift blame downward is too entrenched.  Even the shareholder activist investors, when they wrest control from an ossified senior management, gut the company to see how they can get the largest sum, for the best parts of an organization and the devil take the hindmost.  Tomorrow I will continue this thread with why I feel the merger and acquisition mania that has swept the pharmaceutical industry over the last two decades has caused this problem of weak pipelines and low levels of innovation.

I am fortunate person. I really have a life filled with tremendous blessings.  My wife, who had cancer, is cancer free, healthy and starting her own business venture. When I was laid off, I had sufficient funds to start this consulting business, which is getting traction and attracting high quality clients.  

I am really impressed with one new client in particular: Collaborative Drug Discovery.  They truly are collaborative.  I have become involved with one of their collaborative efforts and am enjoying it tremendously. We had our first meeting on Monday and lets just say that people from all over the world were involved. While the jetpacks we were promised never materialized, we have something that makes them unnecessary. The true power of the internet is being realized.  We can communicate with people all over the world, work together, and securely share data all from the comfort of our homes.  

I have been able to assemble a computational chemistry work suite for under $2,000.  The negotiated software license agreements were easy to negotiate.  The ability of a decentralized team of experts to put together a dynamic program are now in place.  We are in a position to reap the benefits.  This is particularly important for my discipline.  Computational chemistry used to be expensive and require a company to hire a full time expert.  Now you can bring one on (me for example) and have the benefit of decades of experience for a reasonable price and only pay for the services you actually need.  Pretty cool, huh? I think so.  Distance is no longer a barrier.  I can work with anyone in the world. Web meetings make it possible to sit in on meetings in Moscow, or Brisbane.  Your can get project information and share results with people in Buenos Aires, or Naples. 

The future is here, and I like it!