Note: this was a post on my old blog site, and never made the migration over to the current "In the Pipeline". I was reminded of it this morning, and thought I'd bring it more out into the light.

There are reports (updated here - DBL) that Mars may have hexavalent chromium compounds in its surface dust, which is already being brought up as a concern for future human exploration. I agree with comments I've seen that this is putting the cart in front of the horse a bit, but it also means that I probably wouldn't be a good candidate for the expedition. I've already had my lifetime's exposure to Cr(VI).

Back in grad school, I had an undergraduate assistant one summer, a guy who was pretty green. I'll refer to him by an altered form of his nickname, henceforth as Toxic Jim. I shouldn't be too hard on him, I guess: I was a summer undergrad in my time, too, and I wasn't a lot of help to anyone, either. But TJ did manage to furnish me with some of my more vivid lab stories in his brief time in my fume hood.

One morning I showed him how to make PCC. That's pyridinium chlorochromate for the non-organic chemists out there, an oxidizing agent that doesn't seem to be used as much as it was 15 or 20 years ago. Even in '85, you could buy it, but the freshly-made stuff was often better. It certainly looked nicer. Like all the Cr(VI) salts, it has a vivid color, in this case a flaming orange. I shouldn't say "flaming;" that's getting ahead of the story. . .

It's not hard to make. You take chromium trioxide, a vicious oxidant in itself which comes as clumpy fine purple crystals, and dissolve it in 6N hydrochloric acid. That's an easy solution to whip up, since it's just concentrated HCl out of the jug cut 1:1 with water. I had Toxic Jim do all this - weighing out the chromium compound, making the HCl. During that part I couldn't resist quoting the ancient adage, which works well in the East Arkansas accent of my youth: "Do like you oughter, add acid to water." Most chemists either remember that one, or they remember the syrupy conc. acids splattering all over their arm when they did it (once!) the other way around.

We set up a three-neck flask with an overhead stirrer to run this in. That's just a motor mounted above the flask, turning a shaft with a paddle on the end of it. Works well for really thick mixtures, which this was supposed to turn into. As things turned out, it was even thicker than planned, for a brief exciting interlude.

In went the HCl, out of a big Erlenmeyer flask, and in went the chromium trioxide. Here's where the wheels began to come off. Instead of a vivid red-orange solution, the stuff got dark and began to thicken. I could tell it was getting hot, too, since you could see the clear wavery solvent vapors coming out of the open necks of the flask. And that was wrong, too - you don't get that so much with water vapor. It's the mark of organic solvent fumes, with their different density and refractive index.

And so it was. TJ had indeed grabbed the wrong Erlenmeyer. Not the one he'd just mixed up the HCl in, but one from another part of the bench that contained ethyl acetate from a big chromatography run the night before. Ethyl acetate is a pretty poor substitute for hydrochloric acid, most of the time, when you stop to think about it.

Then the overhead stirrer began to bog down, which takes a mighty thick mixture to achieve. I hadn't added up what had happened at this point, but I knew that things were going wrong in all directions at once. I pulled the glass hood sash down some more, saying "I think you better stand back -" WHOOOOMPH!

And there it went! The whole reaction went up in a big fireball, which filled a good part of the hood and came roaring out of the gap in the front sash. I felt the heat roll over me, yelled something incoherent, and bolted for the safety shower. I didn't have to run up Toxic Jim's back, either: he was making for the door in championship time. Pulling the chain of the shower dumped a hundred gallons of ice water on me immediately, not that I needed any more waking up.

When I opened my eyes and took inventory, things weren't as bad as I thought. Limbs and appendages all present, head and facial hair still attached - though lightly singed and frizzed - skin not even sunburnt, although it (along with my lab coat) was generously splattered with green. That was what remained of the chromium trioxide. It was now the Cr(III) oxide, having given up three oxidation levels by turning the ethyl acetate into carbon dioxide, most likely. There were a few orange-brown spots of the Cr(VI) stuff, but those were mostly confined to the front of the lab coat, in a vivid line that showed where the hood sash had gotten pulled down to.

My hood wasn't looking its best. There was smoke hanging in the air, although that was getting pulled out. There was a huge stain of the green and brown chromium mixture all over the inside, thickest in the directions of the three open necks of the flask. Which was still intact - if I'd been foolish enough to set this up in a closed system, the whole thing would have gone up as Pyrex shrapnel. Even the ceiling had a line of gunk on it, from the thin gap in the hood sash assembly.

While I was taking this in, wondering what the hell had gone wrong, and wondering what I could possibly do to TJ that was worse than what he'd just gone through, the emergency crews arrived. It was a Saturday morning, but Bob across the hall saw the explosion and immediately dialed 911. In came the fire crews, trying to talk through their breathing apparatus: "Mumph heff deff umphh cafulteff. . " "What?" "We hear there's a casualty up here"

I put my hands on my hips, and gave them the full effect of my green spots, frizzed hair, and soaking wet lab coat: "That would be me."

Thanks to Lisa Jarvis at C&E News, here's a chart (PDF) of the 39 drugs approved last year by the FDA. Last year was a good year, by almost any measure. The question as we go on will be whether this was a one-time spike, or the start of a long-awaited turnaround. If the latter, I think it will be as much of a regulatory phenomenon as a scientific one (faster reviews, etc.)

John LaMattina takes off after PhRMA's effectiveness here at Forbes. His two points are release of clinical trial data and openness about consultant payments to physicians. And I agree with him on both of those - as I've said here many times, we're not going to regain anyone's trust until we stop giving people reasons to think that we're trying to hide things from them.

The problem, though, as LaMattina shows, is PhRMA (the biggest industry association) doesn't seem especially interested in taken on these issues. Are they stupid, or short-sighted? Possibly. But when I see something like this going on, my assumption is to assume that the people involved are rational actors, who have made an informed decision. And that means that I'm somehow not looking at things the same way that they are.

My guess is that PhRMA's sees the public perception of the drug industry as a comparatively minor problem. The thing is, even if everyone liked the drug industry just fine, sales of prescription drugs would be about the same. They're not purchased because people have good feelings about the companies; they're not all that discretionary. People take medicines grudgingly, for the most part, because they're trying to correct something that's gone wrong.

So what's PhRMA's major concern? Regulatory and legislative affairs. Our industry is absolutely, crucially dependent on government's attitude towards it. We are regulated heavily at every point once we start to close in on an actual drug. So if you're trying to spend your time and effort in the most cost-effective way, you will go to Congress, to the regulatory agencies, to anyone at any level in government who can make and modify the rules that you have to live under. And you will spend your time and money making sure that the rules you like stay in force, that ones that you like even better are on the table, and that ones you don't like get slowed or watered down.

It's true that doing this would be somewhat easier if everyone had a better opinion of us. That's especially true for avoiding the regulations and laws that you don't like; that would be helped if you could go to the people involved with a big groundswell of public support behind you. But trying to influence the public to the point where that would reliably affect legislation is a very large undertaking. The same amount of effort (and money) will have far more impact if applied directly to the legislators and regulators themselves, rather than trying to use public opinion as a lever on them. It's just not cost-effective. This is especially true if you've already worked yourself into a situation where your industry is unpopular; trying to reverse that becomes a bigger and bigger proposition, which makes the alternatives look even more effective. And this is, after all, the way that every other interest group (well, every effective one) works in a highly regulated environment. What else would one expect?

That's my answer, then, to the question of why PhRMA doesn't do more to improve the industry's image. It's not a priority. Thoughts?

Notes: LaMattina's post is also partly a reponse to Ben Goldacre's book "Bad Pharma". I have been meaning to take that one on, but it's also a large undertaking. Book-length arguments are often best addressed at book length, unfortunately. But I do plan to do a big roundup on the subject.

Here's an excellent article at Slate on "natural" medicines versus pharmaceuticals. You won't see too many mainstream articles that suddenly break out into chemical structures, but this one does, and to excellent effect.

In case anyone's wondering, I'm not even at work today - no one at my company is; they announced last night that they were closing down for the day, which was welcome news. For those of you not living in the Northeast US, it's been snowing merrily along since earlier this morning, and by the time it finishes tomorrow, we look to have about two feet of the stuff.

Research will be slow today in this part of the country. I'm sure to see that in the traffic figures for the site - there's always a spike at lunchtime EST, a slight dip, and then another spike at lunchtime on the west coast. I think that the Central and Pacific zones will win out this time!

The largest single snowfall I've ever experienced was in January 1996, back in New Jersey, where we had 39 inches (one solid meter) in a single storm. I remembering opening one of those doors at the bottom of the apartment-complex building and staring in amazement at a drifted wall of snow that came up past the middle of my chest. This was one of those hunt-for-the-cars kind of storms. And I well remember the winter of 1977-78, which is still a standard in many parts of the country. I experienced that one in high school back in Arkansas, so I didn't get the apocalyptic snow mountains, but it was certainly impressive enough by the standards of the area (complete with a record amount of missed school!)

So for those of you not getting snowed on, well, you have to make up for the rest of us today. I think I'll get everyone to start on the Elements Jigsaw Puzzle, myself. Note: corrected this from the earlier "crossword". If anyone has a periodic table crossword puzzle, though, I'd be glad to hear about it).

There's a fascinating paper out on the concept of "drug-likeness" that I think every medicinal chemist should have a look at. It would be hard to count the number of publications on this topic over the last ten years or so, but what if we've been kidding ourselves about some of the main points?

The big concept in this area is, of course, Lipinski criteria, or Rule of Five. Here's what the authors, Peter Kenny and Carlos Montanari of the University of São Paulo, have to say:

No discussion of drug-likeness would be complete without reference to the influential Rule of 5 (Ro5) which is essentially a statement of property distributions for compounds taken into Phase II clinical trials. The focus of Ro5 is oral absorption and the rule neither quantifies the risks of failure associated with non-compliance nor provides guidance as to how sub-optimal characteristics of compliant compounds might be improved. It also raises a number of questions. What is the physicochemical basis of Ro50s asymmetry with respect to hydrogen bond donors and acceptors? Why is calculated octanol/water partition coefficient (ClogP) used to specify Ro50s low polarity limit when the high polarity cut off is defined in terms of numbers of hydrogen bond donors and acceptors? It is possible that these characteristics reflect the relative inability of the octanol/water partitioning system to ‘see’ donors (Fig. 1) and the likelihood that acceptors (especially as defined for Ro5) are more common than donors in pharmaceutically-relevant compounds. The importance of Ro5 is that it raised awareness across the pharmaceutical industry about the relevance of physico- chemical properties. The wide acceptance of Ro5 provided other researchers with an incentive to publish analyses of their own data and those who have followed the drug discovery literature over the last decade or so will have become aware of a publication genre that can be described as ‘retrospective data analysis of large proprietary data sets’ or, more succinctly, as ‘Ro5 envy’.

There, fellow med-chemists, doesn't this already sound like something you want to read? Thought so. Here, have some more:

Despite widespread belief that control of fundamental physicochemical properties is important in pharmaceutical design, the correlations between these and ADMET properties may not actually be as strong as is often assumed. The mere existence of a trend is of no interest in drug discovery and strengths of trends must be known if decisions are to be accurately described as data-driven. Although data analysts frequently tout the statistical significance of the trends that their analysis has revealed, weak trends can be statistically significant without being remotely interesting. We might be confident that the coin that lands heads up for 51 % of a billion throws is biased but this knowledge provides little comfort for the person charged with predicting the result of the next throw. Weak trends can be beaten and when powered by enough data, even the feeblest of trends acquires statistical significance.

So, where are the authors going with all this entertaining invective? (Not that there's anything wrong with that; I'm the last person to complain). They're worried that the transformations that primary drug property data have undergone in the literature have tended to exaggerate the correlations between these properties and the endpoints that we care about. The end result is pernicious:

Correlation inflation becomes an issue when the results of data analysis are used to make real decisions. To restrict values of properties such as lipophilicity more stringently than is justified by trends in the data is to deny one’s own drug-hunting teams room to maneuver while yielding the initiative to hungrier, more agile competitors.

They illustrate this by reference to synthetic data sets, showing how one can get rather different impressions depending on how the numbers are handled along the way. Representing sets of empirical points by using their average values, for example, can cause the final correlations to appear more robust than they really are. That, the authors say, is just what happened in this study from 2006 ("Can we rationally design promiscuous drugs?) and in this one from 2007 ("The influence of drug-like concepts on decision-making in medicinal chemistry"). The complaint is that showing a correlation between cLogP and median compound promiscuity does not imply that there is one between cLogP and compound promiscuity per se. And the authors note that the two papers manage to come to opposite conclusions about the effect of molecular weight, which does make one wonder. The "Escape from flatland" paper from 2009 and the "ADMET rules of thumb" paper from 2008 (mentioned here) also come in for criticism on this point - binning averaged data from a large continuous set and then treated those as real objects for statistic analysis. Ones conclusions depend strongly on how many bins one uses. Here's a specific take on that last paper:

The end point of the G2008 analysis is ‘‘a set of simple interpretable ADMET rules of thumb’’ and it is instructive to examine these more closely. Two classifications (ClogP<4 and MW<400 Da; ClogP>4 or MW>400 Da) were created and these were combined with the four ionization state classifications to define eight classes of compound. Each combination of ADMET property and compound class was labeled according to whether the mean value of the ADMET property was lower than, higher than or not significantly different from the average for all compounds. Although the rules of thumb are indeed simple, it is not clear how useful they are in drug discovery. Firstly, the rules only say whether or not differences are significant and not how large they are. Secondly, the rules are irrelevant if the compounds of interest are all in the same class. Thirdly, the rules predict abrupt changes in ADMET properties going from one class to another. For example, the rules predict significantly different aqueous solubility for two neutral compounds with MW of 399 and 401 Da, provided that their ClogP values do not exceed 4. It is instructive to consider how the rules might have differed had values of logP and MW of 5 and 500 Da (or 3 and 300 Da) had been used to define them instead of 4 and 400 Da.

These problems also occur in graphical representations of all these data, as you'd imagine, and the authors show several of these that they object to. A particular example is this paper from 2010 ("Getting physical in drug discovery"). Three data sets, whose correlations in their primary data do not vary significantly, generate very different looking bar charts. And that leads to this comment:

Both the MR2009 and HY2010 studies note the simplicity of the relationships that the analysis has revealed. Given that drug discovery would appear to be anything but simple, the simplicity of a drug-likeness model could actually be taken as evidence for its irrelevance to drug discovery. The number of aromatic rings in a molecule can be reduced by eliminating rings or by eliminating aromaticity and the two cases appear to be treated as equivalent in both the MR2009 and HY2010 studies. Using the mnemonic suggested in MR2009 one might expect to make a compound more developable by replacing a benzene ring with cyclohexadiene or benzoquinone.

The authors wind up by emphasizing that they're not saying that things like lipophilicity, aromaticity, molecular weight and so on are unimportant - far from it. What they're saying, though, is that we need to be aware of how strong these correlations really are so that we don't fool ourselves into thinking that we're addressing our problems, when we really aren't. We might want to stop looking for huge, universally applicable sets of rules and take what we can get in smaller, local data sets within a given series of compounds. The paper ends with a set of recommendations for authors and editors - among them, always making primary data sets part of the supplementary material, not relying on purely graphical representations to make statistical points, and a number of more stringent criteria for evaluating data that have been partitioned into bins. They say that they hope that their paper "stimulates debate", and I think it should do just that. It's certainly given me a lot of things to think about!

Addex Therapeutics has been trying to develop allosteric modulators as drugs. That's a worthy goal (albeit a tough one) - "allosteric" is a term that covers an awful lot of ground. The basic definition is a site that affects the activity of its protein, but is separate from the active or ligand-binding site itself. All sorts of regulatory sites, cofactors, protein-protein interaction motifs, and who knows what else can fit into that definition. It's safe to say that allosteric mechanisms account for a significant number of head-scratching assay results, but unraveling them can be quite a challenge.

It's proving to be one for Addex. They've announced that they're going to focus on a few clinical programs, targeting orphan diseases in the major markets, and to do that, well. . .:

In executing this strategy and to maximize potential clinical success in at least two programs over the next 12 months, the company will reduce its overall cost structure, particularly around its early-stage discovery efforts, while maintaining its core competency and expertise in allosteric modulation. The result will be a development-focused company with a year cash runway. In addition, the company will seek to increase its cash position through non-dilutive partnerships by monetizing its platform capability as well as current discovery programs via licensing and strategic transactions.

That is the sound of the hatches being battened down. And that noise can be heard pretty often in the small-company part of the drug business. Too often, it comes down to "We can advance this compound in the clinic, enough to try to get more money from someone, or we can continue to do discovery research. But not both. Not now." Some companies have gone through this cycles several times, laying off scientists and then eventually hiring people back (sometimes some of the same people) when the money starts flowing again. But in the majority of these cases, I'd say that this turns out to be the beginning of the end. The failure rates in the clinic see to that - if you have to have your compounds work there, the very next ones you have, the only things you have on hand in order to survive, then the odds are not with you.

But that's what every small biopharma company faces: something has to work, or the money will run out. A lot of the managing of such an outfit consists of working out strategies to keep things going long enough. You can start from a better position than usual, if that's an option. You can pursue deals with larger companies early on, if you actually have something that someone might want (but you won't get as good a deal as you would have later, if what you're partnering actually works out). You can beat all sorts of bushes to raise cash, and try all sorts of techniques to keep it from being spent so quickly, or on the wrong things (as much as you can tell what those are).

But eventually, something has to work, or the music stops. Ditching everything except the clinical candidates is one of the last resorts, so I wish Addex good luck, which they (and all of us) will need.

I'm not the first person to complain about these things, of course. Even by 2003, there were sixteen different clinical trials in the literature with the acronym HEART. It appears that the cardiovascular field picked up the acronym bug early, probably due to the size and length of their clinical programs. It also may been the first field to think up the jazzy clinical trial name first, and find something half-sensible to match it afterwards. But who can doubt that this is what goes on most of the time now? For those who still want to run the algorithm the other way, there's the Acronym Generator, which, wouldn't you know it, is run out of a cardiac hospital unit in Liverpool.

I wonder if the FDA would ever consider requiring drug companies and other research organizations to tone all this down, in the interest of sanity. If you're studying a drug called, say, kevorkirol (a generic name I invented a few years back, and hereby give freely to the scientific community), couldn't the clinical studies just be named "Kevorkirol Efficacy Trial #1", and "Kevorkirol Expanded Efficacy Trial #2" and so on? That would actually help people to keep them straight, instead of having to make a chart of bizarre trial names and their actual purpose. Anyone up for this idea?

We will file this one under N, for Nerve, Lots Of. Readers will probably remember the cancer research scandal at Duke a couple of years ago, where Anil Potti turned out to have faked a wide range of results in the clinic. This led to his leaving Duke rather abruptly, with a trail of retracted papers, all sorts of unpleasant complications with the funding agencies and so on. Retraction Watch covered this business extensively, as well they might have, since it's just the sort of thing that site helps to spotlight.

The campus newspaper (the Duke Chronicle) noted at the time that Potti had hired some sort of online reputation management firm. (I should mention in passing that I owe a debt to that newspaper, whose crossword puzzle got me through an electron spin resonance course while I was a grad student in the 1980s. Without it I would have been forced to listen to the lecture material, and who knows what would have become of me then?) It looks like these reputation-polishers are still in business. That's why that link to Retraction Watch goes to their front page instead of one of their posts on the scandal itself.

Those posts have been taken down, you see. Oh, yes. Copyright problems, don't you know - why, one of the most famous news sites in the world, one "Newsbulet.in" turns out to have published all that stuff on its own, and has filed a DMCA takedown notice with Wordpress to have the posts removed.

It must be bovine waste products week around here at In the Pipeline. because that's another big steaming load of the stuff. Here, take a look at the request itself:

Myself Narendra Chatwal Senior editor in NewsBulet.In, a famous news firm in India. All the news we publish are individually researched by our reporters from all over India and then we publish them on our site and our news channel. Recently we found that some one had copied our material from the category Medical Reviews and published them on their site. So we request you to help us in protecting our content and copy right.

Ah, but if you take a look at that domain, you find that it didn't even exist until October 2012, well after all but one of the posts that they're complaining about. And as the commenters to the Ars Technica post on this noticed, the address given in the WhoIs records corresponds to a nightclub in London. Peachy. So not only is this a spurious copyright complaint, it's a stupid, incompetent spurious copyright complaint. Whoever is providing this sort of service to Anil Potti is ripping him off - not that that bothers me much after reading the facts in the Duke case.

And the thing is, this sort of effort is futile. It's the very definition of futile, because getting the internet off of you is impossible. That Duke Chronicle story says (at the time of its writing) that the first page of Google results about Potti contained no mention of the scandal, just social media sites and glowing statements. That sure didn't last long, though - now the front page contains lots of details about the Duke imbroglio, and (as of this morning) several discussions of this current ridiculous DMCA effort.

After reviewing the facts of the earlier case, and these new attempts at reputation-burnishing being done on his behalf, I'm sticking with my earlier statements about Dr. Potti: I would not hire him to mow my lawn. Has Newsbulet.in published that before?

My grad school work was chiral-pool synthesis; trying to make a complex natural product from carbohydrate starting materials. There was quite a bit of that around in those days, but you have to wonder about its place in the world by now. It's true that everyone likes to be able to buy their chiral centers, especially if they're from the naturally-occuring series (nobody's keen to use L-glucose as their starting material if they can avoid it!) We certainly love to do that in the drug industry, and we can often get away with such syntheses, since our compounds generally don't have too many chiral centers.

But how developed are the multicenter methods? I certainly did not enjoy manipulating the multiple chiral centers on a sugar molecule, although you can (with care and attention) do some interesting gymnastics on that framework. But I think that asymmetric synthesis, especially catalytic variations, is more widely used today to build things up, rather than starting with a lot of chirality and working it around to what you want. The synthetic difficulties of that latter method often seem to get out of hand, and the methods aren't as general as the build-up-your-chirality ones.

Is my impression correct? And if so, is this the way things should be? My tendency is to say "yes" to both questions, but I'd like to see what the general opinions are.

Here's a report on employment in the biopharma industry that will cause some pretty strong emotions in those of us who (still) work there. PriceWaterhouseCoopers (PwC), in their annual CEO survey finds (here's the good news) that:

Nearly three-quarters (72 percent) of executives said their organizations are looking to increase R&D capacity over the next 12 months, and six in 10 intend to increase investments over the next three years to create a more skilled workforce.

So far, so good. But would you like to know what the executives said was one of the biggest problem in doing all this? Honestly, you'll never guess:

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.

Well, now. One's first impulse is to refer, with deep feeling, to bovine waste products, but one mustn't jump to conclusions about whether the industry might just possibly have heaved too many people over the side over the last ten years or so. As Pharmalot points out, the people that are allegedly being sought are not always the ones that have already been ditched:

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. . .

Now, that one I can believe. An uncharitable summary of many of those outside partnership managerial positions would be "Keep track of what all the cheap overseas contract workers are doing". And there is indeed a demand for that relatively thankless task. Another task that appears to be strongly in demand is for scientists who can deal with regulatory affairs. Fine. But what about actual research, not actually in China or beyond? There are possibilities, but things still don't look so good if you're a chemist. Pharmalot again:

As for job growth among scientists, not surprisingly there is only a 4 percent increase forecast for chemists, who were thrown overboard in large masses in recent years, and 13 percent for microbiologists. Conversely, a 62 percent boost is predicted for biomedical engineers and 36 percent for medical scientists. Biochemists and biophysicists trail at 31 percent.

PwC seems to be taking a broad view of biopharma if "biomedical engineers" are the top category. That's a flexible-sounding category, but I'd guess medical devices, at the very least. "Medical scientists" is also the label on a rather large bin, and this gives only a fuzzy picture of where the hiring will supposedly be taking place.

Looking through the PwC material, you can tell that it's addressed largely to HR folks, trying to gear them up for all this talent-searching and position-filling. It spends, for example, some time sharing sympathy for the HR departments who don't, somehow, feel as if they're key parts of the organization on the front lines of discovery. (Which they aren't, usually, but that's another story). But there's some useful advice for them in there, too - see what you make of this:

Scientists want career paths that recognize and reward their passion and commitment to research, not just additional responsibilities. Too often, scientists are pushed out of what they do best – research -- and saddled with management chores that distract them.

Finally, senior executives must act as a powerful motivating force for their people. Companies with decades-long legacies have lost their edge due to repeated layoffs, wearing down the morale of scientific staff.

Ain't that the truth. But how many senior executives are in a position to act as a "powerful motivating force"? Well, OK, some of them have been, but with a negative sign in front, which isn't the idea. In many organizations, the sorts of behavior that the scientists would find motivating on the part of a top-level manager are often not the sorts of behavior that lead people into top managerial positions. So you get people who are, at the very least, rusty on those skills (if they ever had them in the first place). And that leads to things like (in my own experience, some years ago) hearing a high-level guy exhort various research teams while mispronouncing the names of some of their projects. Which neither bred confidence, nor raised morale.

Overall, I find this PwC report irritating, perhaps because of its HR-centric worldview. And the message of "Shortage of top talent!" is rather hard to take, no matter how you spin it. It also brings thoughts of the perennial "America's critical lack of scientists" headlines, which have only slightly abated. I'm waiting for someone to tie those two together into one annoying headline. . .

Note: I'll get back to that out-of-the-science-and-into-the-management topic again; it's come up here before, but it's an important one.

Here's a rather grim analysis from the AP of Merck's current status. The company's stock was recently downgraded by two analysts after last Friday's earnings call didn't go very well (links added by me below):

Future sales of Vytorin, a controversial combination drug on sale since 2004 that includes Zocor, and prospects for a crucial experimental osteoporosis drug called odanacatib were thrown into question Friday as Merck announced its fourth-quarter results. Company executives made some cryptic comments, suggesting significant problems with both drugs. . .

Merck said Friday that it won't apply for approval of odanacatib, a new type of osteoporosis drug, until 2014 instead of by this June. Management said it was reviewing safety and efficacy data from one study and now won't apply for approval until they have longer-term data from an extension study.

Executives also said a committee monitoring its 18,000-patient study of Vytorin, called IMPROVE-IT, had requested a new interim analysis of patient data in March. The study is meant to determine whether Vytorin reduces risk of heart attack, stroke and death in heart disease patients — the ultimate purpose of cholesterol drugs — but Merck executives, grilled by analysts on a conference call, wouldn't say that they're confident the study will show that benefit.

I wouldn't, either, if I were in their shoes. The Vytorin story has been long and complex, and that complexity comes from two sources: the drug's unique mechanism of action (at least the ezetimibe part), and the uncertainties of human lipid handling and its relationship to cardiovascular outcomes. Honestly, these things could go any way at all, and the same goes for Merck's high-profile push in CETP. A lot of the company is riding on some very uncertain science.

But I wonder, as I was speculating on in that last link, if that isn't where the whole industry is these days. By now, we've attacked all the things that we believe we really know something solid about. What's left is often big, important, potentially very profitable. . .and risky enough to make you leave fingernail marks in the armrests of your chair. The higher up you sit, and the nicer the material that chair is made of, the more damage is being done to it.

I wrote here and here about Luca Turin's theory that our perception of smell is partly formed by sensing vibrational modes. (Turin is the author of an entertaining book on the subject of olfaction, The Secret of Scent, and also co-author of Perfumes: The A-Z Guide). His theory is still controversial, to say the least, but Turin and co-workers have a new paper out trying to shore it up.

A previous report from Vosshall and Keller at Rockfeller University had shown that human subjects were unable to distinguish acetophenone from its deuterated analog, which is not what you'd expect if we were sensing bond vibrations. Interestingly, this paper confirms this result. (References to all these studies are in the original paper, which is open-access, being in PLoSONE):

In principle, odorant isotopomers provide a possible test of shape vs. vibration mechanisms: replacing, for example, hydrogen with deuterium in an odorant leaves the ground-state conformation of the molecule unaltered while doubling atomic mass and so altering the frequency of all its vibrational modes to a greater or lesser extent. To first order, deuteration should therefore have little or no effect on the smell character of an odorant recognized by shape, whereas deuterated isotopomers should smell different if a vibrational mechanism is involved.

The experimental evidence on this question to date is contradictory. Drosophila appears able to recognize the presence of deuterium in odorant isotopomers by a vibrational mechanism. Partial deuteration of insect pheromones reduces electroantennogram response amplitudes. Fish have been reported to be able to distinguish isotopomers of glycine by smell. However, human trials using commercially available deuterated odorants [benzaldehyde and acetophenone] have yielded conflicting results, both positive and negative. Here, using GC-pure samples and a different experimental technique, we fully confirm Keller and Vosshall’s finding that humans, both naive and trained subjects, are unable to discriminate between acetophenone isotopomers.

But the paper goes on to show that humans apparently are able to discriminate deuterated musk compounds from their H-analogs. Cyclopentadecanone, for example, was deuterated to >95% next to the carbonyl, and to 90% at the other methylenes. It and three other commercial musks were purified and checked versus their native forms:

After silica gel purification, aliquots of the deuterated musks were diluted in ethanol and their odor character assessed on smelling strips. The parent compounds have classic powerful musk odor characters, with secondary perfumer descriptors as follows: animalic [Exaltone], sweet [Exaltolide], oily [Astrotone] and sweet [Tonalid]. In all the deuterated musks, the musk character, though still present was much reduced, and a new character appeared, variously described by the trained evaluators [NR, DG, LT and Christina Koutsoudaki, Vioryl SA] as “burnt,” “roasted,” “toasted,” or “nutty.” Naive subjects most commonly described the additional common character as “burnt.”

They found, by stopping the deuterium exchange early, that this smell showed up even at around 50% D-exchange or less. For more rigorous tests, they went to a "smelling GC", and double-blinded the tests. This gave clean compound peaks, and they were able to diminish the need to keep a memory of the previous smell in mind by capturing the eluted peak vapors in Eppendorf tube for side-by-side comparison.

This protocol showed that people are indeed unable to discriminate deuterated acetophenone from undeuterated - the Keller and Vosshall paper stands up, which will come as a relief to the author of the unusually celebratory editorial in Nature Neuroscience that accompanied it. To be sure, it also makes moot Turin's own objections to their work at the time, which questioned its experimental design and rigor.

But the deuterated musk experiment done this way are quite interesting. I'm going to just quote the entire section here:

All trials were performed with GC-pure catalytically deuterated [D fraction >90%] cyclopentadecanone [See Methods]. Each trial consisted of the assessment of 4 pairs of odorants, one deuterated and one sham-deuterated. The subjects were presented with a deuterated sample and their attention was drawn to the “burnt, nutty, roasted” character of the deuterated compound. Several other sample pairs were presented until the subjects were sure they could tell the difference between the two sample types.

The Eppendorf tubes were heated in a solid heating block to 50C. The samples were arranged in rows according to their type. The experimenter randomized the order of the tubes within the rows by means of two flips of a coin (first flip: first or second two positions, second flip: first or second spot within those). The rows were then mixed randomly by a further coin flip per d/H pair (heads: swap positions, tails leave in situ).

Subjects were first given a training pair and told which was deuterated and which sham-deuterated. The experimenter then left to watch the experiment through a window. Subjects were then presented with the unlabeled, position-randomized pairs of deuterated and sham-deuterated GC-pure samples and asked to say which was which.

The subject, wearing nitrile gloves to avoid contamination, smelled first one and then the other sample. Multiple sniffs at each sample were allowed. The subject was asked to identify the deuterated sample and to place it to one side. After four trials the tubes were placed under the UV light source and identified. The subject was not informed of the outcome. To avoid habituation, the subject then rested for 15 minutes before attempting the next trial.

The results are shown in table 2. Eleven subjects were used. Two subjects tired before reaching the desired number of 12 trials. Two were able to go beyond to 13 and 17 trials respectively. The binomial p values range between 0.109 [6/8 correct] to 7.62×10−6 [17/17 trials]. These are independent trials, and an aggregate probability for all trials [119/132 correct] can be calculated: it is equal to 5.9×10−23.

As it happens, musks are at nearly the top of the molecular weight range for odorant compounds. The paper mentions a rule of thumb among fragrance chemists that compounds with more than 18 carbons rarely have any perceptible odor, even when heated (and different people's noses can top out even before that). Musks tend to smell quite similar even with rather different structures, which suggests that a small number of receptors are involved in their perception. Here's Turin's unified theory of musk:

We suggest therefore that a musk odor is achieved when three conditions are simultaneously fulfilled: First, the molecule is so large that only one or a very few receptors are activated. Second, one or more of these receptors detects vibrations in the 1380–1550 cm-1 range. Third, the molecule has intense bands in that region, caused either by a few nitro groups or, equivalently, many CH2 groups. A properly quantitative account of musk odor will require better understanding of the shape selectivity of the receptors at the upper end of the molecular weight scale, and of the selection rules of a biological IETS spectrometer to calculate the intensity of vibrational modes.

It's safe to say that this controversy is very much alive, no matter what the explanation might be. Leslie Vosshall of Rockefeller has already commented on this latest paper, wondering if compounds might be enzymatically altered in the nose (which would also be expected to show a large difference with deuterated compounds). I'll await the next round with interest!

Two different research teams have reported a completely different way to run NMR experiments, one that looks like it could take the resolution down to cellular (or even large protein) levels. These two papers in Science have the details (and there's an overall commentary here, and more at Nature News).

This is not, as you've probably guessed, just a matter of shrinking down the probe and its detector coil. Our usual method of running NMR spectra doesn't scale down that far; there are severe signal/noise problems, among other things. This new method uses crystal defects just under the surface of diamond crystals - if a nitrogen atom gets in there instead of a carbon, you're left with a negatively charged center with a very useful spin state. It's capable of extraordinarily sensitive detection of magnetic fields; you have a single-atom magnetometer.

And that's been used to detect NMR signals in volumes of a few cubic nanometers. By comparison, erythrocytes (among the smallest of human cells) have a volume of around 100 cubic micrometers. By contrast, a 50 kD protein has a minimal radius of 2.4 nm, giving it a volume of 58 cubic nanometers at the absolute minimum. This is all being done at room temperature, I might add. If this technique can be made more robust, we are potentially looking at MRI imaging of individual proteins, and surely at a detailed intracellular level, which is a bizarre thought. And there's room for improvement:

By implementing different advanced noise suppression techniques, Mamin et al. and Staudacher et al. have succeeded in using near-surface NVs to detect small volumes of proton spins outside of the diamond crystal. Both authors conclude that their observed signals are consistent with a detection volume on the order of (5 cubic nanometers) or less. This sensitivity is comparable to that of the cryogenic MRFM technique and should be adequate for detecting large individual protein molecules. Both groups also project much smaller detection volumes in the future by using NVs closer to the diamond surface. Staudacher et al. expect to improve sensitivity by using the NV to spin-polarize the nuclei. Mamin et al. project that sensitivity may eventually approach the level of single protons, provided that the NV coherence time can be kept long enough.

I love this sort of thing, and I don't mind admitting it. Imagine detecting a ligand binding event by NMR on an individual protein molecule, or following the distribution of a fluorinated drug candidate inside a single cell. I can't wait to see it in action.

I've written here about the strange-sounding conferences that keep sending out invitations to all and sundry. They tend to be in provincial Chinese cities, have grandiose names like the "First International Summit Meeting of Advanced Medical Science", and feature so many sections, sessions, tracks, and breakouts that you wonder if anyone attends who isn't giving a talk. And you get invitations to submit invited talks in fields you've hardly even touched on in your career; that's another reliable sign.

Well, I've had one this morning whose title really rises to the top of the list. I present to you the "1st Annual Symposium of Drug Designology". No, I did not make that up - if I had, I wouldn't tell anyone, believe me. And I'm not about to provide a link to the conference site. If you want more, I'm willing to bet that a search for "drug designology" will yield only highly relevant hits, since I'm not aware of that phrase ever appearing in English until this morning. Here's hoping it submerges again.

The short answer is "by looking for compounds that grow beta cells". That's the subject of this paper, a collaboration between Peter Schulz's group, the Novartis GNF. Schultz's group has already published on cell-based phenotypic screens in this area, where they're looking for compounds that could be useful in restoring islet function in patient with Type I diabetes.

These studies have used a rat beta-cell line (R7T1) that can be cultured, and they do good ol' phenotypic screening to look for compounds that induce proliferation (while not inducing it across the board in other cell types, of course). I'm a big fan of such approaches, but this is a good time to mention their limitations. You'll notice a couple of key words in that first sentence, namely "rat" and "cultured". Rat cells are not human cells, and cell lines that can be grown in vitro are not like primary cells from a living organism, either. If you base your entire approach this way, you run the risk of finding compounds that will, well, only work on rat cells in a dish. The key is to shift to the real thing as quickly as possible, to validate the whole idea.

That's what this paper does. The team has also developed an assay with primary human beta cells (which must be rather difficult to obtain), which are dispersed and plated. The tricky part seems to be keeping the plates from filling up with fibroblast cells, which are rather like the weeds of the cell culture world. In this case, their new lead compound (a rather leggy beast called WS-6) induced proliferation of both rat and human cells.

They took it on to an even more real-world system, mice that had been engineered to have a switchable defect in their own beta cells. Turning these animals diabetic, followed by treatment with the identified molecule (5 mpk, every other day), showed that it significantly lowered glucose levels compared to controls. And biopsies showed significantly increases beta-cell mass in the treated animals - all together, about as stringent a test as you can come up with in Type I studies.

So how does WS6 accomplish this? The paper goes further into affinity experiments with a biotinylated version of the molecule, which pulled down both the kinase IKK-epsilon and another target, Erb3 binding protein-1 (EBP1). An IKK inhibitor had no effect in the cell assay, interestingly, while siRNA experiments for EBP1 showed that knocking it down could induce proliferation. Doing both at the same time, though, had the most robust effect of all. The connection looks pretty solid.

Now, is WS6 a drug? Not at all - here's the conclusion of the paper:

In summary, we have identified a novel small molecule capable of inducing proliferation of pancreatic β cells. WS6 is among a few agents reported to cause proliferation of β cells in vitro or in vivo. While the extensive medicinal chemistry that would be required to improve the selectivity, efficacy, and tolerability of WS6 is beyond the scope of this work, further optimization of WS6 may lead to an agent capable of promoting β cell regeneration that could ultimately be a key component of combinatorial therapy for this complex disease.

Exactly so. This is excellent, high-quality academic research, and just the sort of thing I love to see. It tells us useful, actionable things that we didn't know about an important disease area, and it opens the door for a real drug discovery effort. You can't ask for more than that.

I wanted to thank everyone who comes here for making January the biggest traffic month ever on the site: just over 480,000 page views. That seems like a lot for a site that features no cat videos (not that there's anything wrong with cat videos), no partially clad women (not that there's anything wrong with them, either), and no continually raging flamewars in the comments section. Actually, the comments section here has one of the highest signal-to-noise ratios in the whole blogging world.. Other blog owners have asked me many times how I do that last part, and I just have to tell them honestly that I don't - the people who read the site are responsible. So thanks again to everyone who visits!

Thanks are also due to those who have hit the various Amazon links that I put up from time to time. The affiliate payments those bring in get spent in, among other things, swelling the book collections around here to even more alarming levels.

Courtesy of the vital site that is TOC ROFL, I wanted to highlight this graphic from this paper in MedChemComm. I always pictured the liver as sort of a sawmill or shredding machine for our drug candidates, with the hepatic portal vein being the conveyer belt hooked up on the front end. But I have to admit, this is a pretty vivid representation.

Update: See Arr Oh has a few issues - rightly so - with the molecule being munched on. . .

So everyone watching the pharma business has been hearing about how AstraZeneca has all kinds of problems - drug failures, big patent expirations, too much spending on too little output, one damn thing after another. Well, here's the evidence today. Everyone knew that numbers like these were coming, and here they are.

Sales will fall by a “mid- to high-single digit percentage” at constant exchange rates in 2013, the London- based company said today in a statement. Analysts had estimated a decline of about 3 percent, according to data compiled by Bloomberg. The company also said earnings fell for a fourth straight quarter and left the annual dividend unchanged. The stock fell the most in nine months.

And things will continue to be. . .challenging:

AstraZeneca has ended nine drug development programs since June 30, including selumetinib for solid tumors, AZD4017 for glaucoma and AZD9773 for severe sepsis, which were in mid-stage trials. In December, the company said fostamatinib, its experimental drug for rheumatoid arthritis, failed to show a benefit against AbbVie Inc. (ABBV)’s Humira in a mid-stage trial.

On the one hand, you want to get rid of such programs before they chew up still more time and money. But on the other hand, you do need something to sell. All this makes a person think that if you're a small company with an asset to sell, that you're going to want to give AZ a call. I think that they'll be ready to deal.

So Isis and their partner Sanofi have received FDA approval for mipomersen (branded as Kynamro). Late last year, the European Medicines Agency turned them down, which has people wondering about the drug's future, but here they are, albeit with a warning on the label about liver toxicity.

Mipomersen is designed to lower the Apo-B lipoprotein in people with the most severe (homozygous) form of familial hypercholesterolemia. That's a small patient population, but they're definitely in need of help. The really significant thing about this approval, in my mind, is that it's a pure antisense therapy, and it comes about twenty years after there was supposed to be a world-changing flood of them. (Isis did get one through the process back in 1996, fomivirsen, but it's never had much of an impact). It was a standing joke back in the late 1980s/early 1990s that everyone had heard from a headhunter recruiting for one antisense company or another. (Sheesh, those were the days, eh? There still are search firms, right? When's the last time a headhunter rang your phone?)

I don't think that mipomersen will ever reach the heights that Isis thought it might a few years ago; the liver tox problems will see that it's only used in life-threatening situations. (I note that one time when I wrote about the drug, fans of ISIS showed up rolling their eyes at the mistaken notion that liver tox could ever be a problem). But I'm divided between congratulating them on finally getting something onto the market, and wondering about how difficult it's been to get there. As far as I know, the liver tox seen in this case is largely (completely?) thought to be due to the mechanism of action on lipid handling in the liver itself.

So how about the other antisense compounds in the clinic? As of that 2010 link above, we had trabedersen, for TGF-beta2, which is actively being tried against pancreatic cancer. Alicaforsen, for Crohn's et al., has shown disappointing efficacy in Crohn's, but is still alive for ulcerative colitis.. Aganirsen, for various vascular conditions in the eye, is still in development, with more funding having arrived recently. Oblimersen has shown some effects in the clinic, but CLL is a crowded area, and its current status is unclear, at least to me. And custirsen is in Phase III, with mixed results in Phase II trials.

Actually, that lineup looks a lot like drug development in the rest of the industry, to be honest. Some stuff looks OK and is moving along, some not so OK, and some has wiped out. It's important to realize that even if liver tox is not some general feature of the mipomersen-generation antisense compounds, that we still have efficacy failures. Oh, that we do. The indications where we can really laser right in on a key target do not make a long list. Many of those are orphans, too. In contrast, the list of giant-unmet-medical-need indications where we can laser right in on a key target is, I think, waiting for something, anything, to be written on it.

Here are some angry views that I don't necessarily endorse, but I can't say that they're completely wrong, either. A programmer bids an angry farewell to the bioinformatics world:

Bioinformatics is an attempt to make molecular biology relevant to reality. All the molecular biologists, devoid of skills beyond those of a laboratory technician, cried out for the mathematicians and programmers to magically extract science from their mountain of shitty results.

And so the programmers descended and built giant databases where huge numbers of shitty results could be searched quickly. They wrote algorithms to organize shitty results into trees and make pretty graphs of them, and the molecular biologists carefully avoided telling the programmers the actual quality of the results. When it became obvious to everyone involved that a class of results was worthless, such as microarray data, there was a rush of handwaving about “not really quantitative, but we can draw qualitative conclusions” followed by a hasty switch to a new technique that had not yet been proved worthless.

And the databases grew, and everyone annotated their data by searching the databases, then submitted in turn. No one seems to have pointed out that this makes your database a reflection of your database, not a reflection of reality. Pull out an annotation in GenBank today and it’s not very long odds that it’s completely wrong.

That's unfair to molecular biologists, but is it unfair to the state of bioinformatic databases? Comments welcome. . .

Update: more comments on this at Ycombinator.

One more on quackery, and then back to science. You may have seen this story, which broke in Sports Illustrated, on a strange little outfit that called themselves Sports With Alternatives To Steroids, or S.W.A.T.S. They seem to have had a long list of professional and college athlete customers looking for some sort of (legal) performance edge. And who wouldn't sign up when there are cutting-edge therapies like this on offer?

(S.W.A..T.S.) prescribed a deluxe program, including holographic stickers on the right elbow; copious quantities of the powder additive; sleeping in front of a beam-ray light programmed with frequencies for tissue regeneration and pain relief; drinking negatively charged water; a 10-per-day regimen of the deer-antler pills that will "rebuild your brain via your small intestines" (and which Lewis said he hadn't been taking, then swallowed four during the conversation); and spritzes of deer-antler velvet extract (the Ultimate Spray) every two hours.

"Spray on my elbow every two hours?" Lewis asked.

"No," Ross said, "under your tongue."

We never do find out what's in the "powder additive". My guess is sugar-free drink mix, but perhaps I'm just small-minded. I don't think as big as the founders of S.W.A.T.S., that's for sure - these guys are way out in front of the rest of us:

The theoretical underpinning offered by Key is that radio waves can be stored in fluids (the spray) and in holograms (the chips), and that when an athlete consumes the fluid or wears the holograms, the radio waves are re-emitted and prompt his body to create specific nutrients and hormones -- from vitamin B to testosterone. Key says that it's not unlike the way particular wavelengths of sunlight cause the human body to produce vitamin D. In the musty storage room, the holographic stickers and bottles of deer-antler spray are irradiated for 24 straight hours or more in what Ross and Key say is an effort to program them with performance-enhancing frequencies

You know, that reminds me a lot of Nativis, the odd little biotech company I wrote about here, and who threatened me with legal action here. They went on about "photonic signals" stored in water, that were somehow stored and released later. The people at S.W.A.T.S. should look into this technology; it sounds like it would be a good fit. When last heard from, the Nativis folks were touting some sort of radio-frequency cancer zapper - slap some holographic stickers on at the same time, and who knows what might happen?

The SI article is well worth a read, just to show you that the process of separating the gullible from their money is timeless. There are gloomy thoughts to be had about the state of science education, that such things are believed, but education is a thin spray-painted layer on the surface of a brain that wants miracles and wants to believe. The proper response is the one that NBA owner Mark Cuban had to a very similar scam, the Power Bracelets that would, er, align your energies or something. Cuban found the right alignment for them, as far as I'm concerned - check the video clip at that link. I hope the trash can is big enough for all this stuff.

Red palm oil. Green coffee beans. Raspberry ketone. Some of you are wondering what the heck I'm making for dinner, but some of you will recognize the common characteristic: all of these have been promoted by Dr. Mehmet Oz, the most famous physician in the country.

I'm prompted to write about him by this New Yorker profile, which is excellent reading. It author, Michael Specter, tries his best to figure out why a talented, well-trained cardiac surgeon is sitting down on his own television show with psychic healers, fad-diet pushers, and the likes of Joseph Mercola. (In case you haven't run across him, consider yourself fortunate. His eponymous web site, which I will certainly not link to, is a trackless fever swamp of craziness. If you want to hear about how vaccines are killing you, or how cancer is actually a fungus, or how to heal your ulcers with vinegar and your melanoma with baking soda, well, Mercola is your man).

When Oz says that Mercola is “challenging everything you think you know about traditional medicine and prescription drugs,” it’s hard to argue. “I’m usually earnestly honest and modest about what I think we’ve accomplished,” Oz told me when we discussed his choice of guests. “If I don’t have Mercola on my show, I have thrown away the biggest opportunity that I have been given.”

I had no idea what he meant. How was it Oz’s “biggest opportunity” to introduce a guest who explicitly rejects the tenets of science? “The fact that I am a professor—one of the youngest professors ever—at Columbia, and that I earned my stripes writing hundreds of papers in peer-reviewed journals,” Oz began. “I know the system. I’ve been on those panels. I’m one of those guys who could talk about Mercola and not lose everybody. And so if I don’t talk to him I have abdicated my responsibility, because the currency that I deal in is trust, and it is trust that has been given to me by Oprah and by Columbia University, and by an audience that has watched over six hundred shows.”

Well. . .I'm not sure that that's much of an answer. In fact, if the currency that Dr. Oz deals in is trust, then you'd think that he has a responsibility not to abuse that trust by giving his imprimatur to lunatics. To his credit, the New Yorker's Specter also finds this response lacking, so he tries again. What he doesn't realize is that he's traveling up the river to the heart of darkness:

I was still puzzled. “Either data works or it doesn’t,” I said. “Science is supposed to answer, or at least address, those questions. Surely you don’t think that all information is created equal?”

Oz sighed. “Medicine is a very religious experience,” he said. “I have my religion and you have yours. It becomes difficult for us to agree on what we think works, since so much of it is in the eye of the beholder. Data is rarely clean.” All facts come with a point of view. But his spin on it—that one can simply choose those which make sense, rather than data that happen to be true—was chilling. “You find the arguments that support your data,” he said, “and it’s my fact versus your fact.”

Chilling is right. The man's a nihilist. Here we have a massively famous doctor, the public face of medicine to millions of television viewers, and he apparently believes that well, it's hard to say what works, because everyone has their own facts, you know?

A word with you, Dr. Oz, if I may. I know that you're very busy, and that your TV show takes up a lot of your time, and that whatever time you have left is probably occupied with being famous and everything. This won't take long. I only wanted to remind you that you got to wear your scrubs and your stethoscope by virtue of an excellent medical education. But the people who provided it to you (and the people who provided the knowledge that they were passing on) did not get there by assuming that everyone had their own facts. If we'd stayed with that attitude, we'd still be waving bags of magic chicken bones over the groaning bodies of cancer patients. But then, you'll probably have that on your show next week. Why not?

I say all this as someone who has spent his career digging for facts and searching for insight. I'm a scientist, Dr. Oz, and I actually don't think that medicine, at least my end of it, is such a religious experience, at least, not the way you're defining one. My colleagues and I spend our days in the labs. Our facts had better be the same for everyone who looks at them, every time, and if they're not, well, we go back to work until they are.

We can't just go on TV right after we've dosed a few rats, you know. We'd go to jail. The FDA won't listen to anything we come up with unless it's been done under rigorously defined conditions, unless it's been repeated (over and over), and unless we tell them every detail of how we did it all. We can't come in waving our hands and telling everyone how great we are - we have to spend insane amounts of money, time, and effort to put together enough data to convince a lot of very skeptical people. Thank goodness you're not one of them. You're either the easiest person to convince that I've ever seen, or (more likely), you don't worry much about being convinced of anything. Why should you? It would limit your opportunities. That TV show isn't going to produce itself - if you stuck to people who could actually back up their assertions, what would your guest list look like?

But here's a suggestion: get someone on your show who actually knows where medicines come from, and what it takes to find one. Instead of telling people about magic beans, tell them the truth: discovering anything that will treat a sick patient is hard, expensive work. The reason we don't have a Cure For Cancer isn't because there's a conspiracy; it isn't because the Powers That Be are too stupid and greedy to recognize the wonderful healing powers of the latest miracle berry. It's because cancer is really hard to figure out. That would be a lot more of a public service than what you're becoming, which is this:

Most days, Oz mines what he refers to as his go-to subjects: obesity and cancer. . . Cancer, Oz told me, “is our Angelina Jolie. We could sell that show every day.”

I'm sure you could, Dr. Oz. But what you're really selling is yourself. How much is left?

Update: John LaMattina actually did get the Oz experience, as recounted here. And he certainly knows what drug discovery is like, but it doesn't seem to have had much effect on the show, or on Dr. Oz. . .

Well, it is a hard question, and I don't know the answer, either. On Twitter, See Arr Oh wonders:

Know that tangy smell that LAH / NaH give off? Is that oil volatiles, or trace H2 being formed from room moisture?

I'm not sure, but I'd be willing to bet that hydrogen has no smell at all - it would seem too small and too bereft of interactions to see off the nasal receptors. So my guess is mineral oil constituents in the case of sodium hydride, which I usually handle as the dispersion. Now, the lithium aluminum hydride is a dry powder, so in that case, I'd say that I'm smelling the real stuff, which can't be improving my nose very much. That lines up with Chemjobber's explanation: "It's the smell of your nose hairs being deprotonated." Any other guesses?

We medicinal chemists talk a good game when it comes to the the hydrophobic effect. It's the way that non-water-soluble molecules (or parts of molecules) like to associate with each other, right? Sure thing. And it works because of. . .well, van der Waals forces. Or displacement of water molecules from protein surfaces. Or entropic effects. Or all of those, plus some other stuff that, um, complicated to explain. Something like that.

Here's a paper in Angewandte Chemie that really bears down on the topic. The authors study the binding of simple ligands to thermolysin, a well-worked-out system for which very high-resolution X-ray structures are available. And what they find is, well, that things really are complicated to explain:

In summary, there are no universally valid reasons why the hydrophobic effect should be predominantly “entropic” or “enthalpic”; small structural changes in the binding features of water molecules on the molecular level determine whether hydrophobic binding is enthalpically or entropically driven.

Admittedly, this study reaches the limits of experimental accuracy accomplishable in contemporary protein–ligand structural work. . .Surprising pairwise systematic changes in the thermodynamic data are experienced for complexes of related ligands, and they are convincingly well reflected by the structural properties. The present study unravels small but important details. Computational methods simulate molecular properties at the atomic level, and are usually determined by the summation of many small details. However, details such as those observed here are usually not regarded by these computational methods as relevant, simply because we are not fully aware of their importance for protein–ligand binding, structure–activity relationships, and rational drug design in general. . .

I think that there are a lot of things in this area of which we're not fully aware. There are many others that we treat as unified phenomena, because we've given them names that make us imagine that they are. The hydrophobic effect is definitely one of these - George Whitesides is right when he says that there are many of them. But when all of these effects, on closer inspection, break down into tiny, shifting, tricky arrays of conflicting components, can you blame us for simplifying?

The brand names of drugs are famously odd. But they seem to be getting odder. That's the conclusion of a longtime reader, who sent this along:

I was recently perusing through the recent drug approval list and was struck by how strange the trade names have become. Perhaps it is a request from the FDA so that there are fewer prescription errors, but some of these are really bizarre and don't quite roll off the tongue. USAN names I can understand, but trade names, to me anyway, used to be much more polished (Viagra, Lipitor etc). Could it have to do with the fact that most of these are for cancer? I have a list below comparing trade names from 2004 to those from the past year or so.

2004:    Vidaza;   Avastin;  Sensipar;  Cymbalta;   Tarceva;   Certican;   Factive;   Sinseron;   Alimta;  Lyrica;  Exanta

2012:   Fulyzaq;  Bosulif;  Xeljanz;  Myrbetriq;  Juxtapid;  Iclusig;  Fycompa;  Zelboraf;   Xalkori;  Jakafi;  Pixuvri

He's got a point; some of those look like someone rested an elbow on the keyboard when they were filling out the form. I'd be willing to bet that the oncology connection is a real one - those drugs don't get mass-market advertising at all, so they don't have to be catchy. This Reuters article also notes the trend in cancer drugs, and brings up the need for novelty. Not only is it good to have a name that stands out in the memory, it's a legal requirement to have one that can't be easily confused with another drug. That goes for handwriting as well:

"Regulators want a lot of pen strokes up and down that provide a much more unique-looking name. It is more readable or interpretable if it has a lot of (Zs and Xs)," said Brannon Cashion, Addison Whitney's president.

Whether anyone can actually pronounce the name is of less concern.

That's for sure, when you're talking about things like Xgeva (edit: fixed this name to eliminate the extra "r" I put into it. Can anyone blame me for getting it wrong?). But that one's a good case in point: the generic name is denosumab. That's a good ol' USAN name, with the "-mab" suffix telling you that it's a monoclonal antibody. It's sold in the oncology market as Xgreva for bone-related cancer complications, but it's also prescribed for postmenopausal women to halt loss of bone tissue. There, the same drug goes under the much more consumer-friendly name of Prolia. Now, that's a blandly uplifting name if I've ever heard one, whereas Xgeva sounds like the name of an alien race in a cheap science fiction epic ("An Xgeva ship has been detected in the quadrant, Captain!").

Or, like its recent peers, it also sounds like an excellent Scrabble word, were it to be allowed, which it wouldn't. Me, my proudest moment was playing "axolotl" one time for seven letters. Come to think of it, Axolotl would make a perfectly good drug name under the current conditions. . .

Update: I notice that the comments are filling up with alternative definitions of some of these names, many of which (not all!) sound more sensible.

Here's the latest big picture, from Chemjobber. Note, though, that on Twitter he said that after writing this post he felt as if he could press KBr pellets with his jaws. That should give you some idea.

Have I mentioned recently what a pain the rear the Ullmann reaction is? Copper, in general? Consider it done, then. I'm trying to make biaryl ethers, not something I'd usually do, and these reactions are the traditional answer. One of my laws of the lab, though, is that when there are fifty ways of doing some reaction in the literature, it means that there's no good way to do it, and the Ullmann is the big, hairy, sweaty example of just that phenomenon. Even when it works, there are worries. But you have to get it to work first. . .

CETP, now there's a drug target that has incinerated a lot of money over the years. Here's a roundup of compounds I posted on back last summer, with links to their brutal development histories. I wondered here about what's going to happen with this class of compounds: will one ever make it as a drug? If it does, will it just end up telling us that there are yet more complications in human lipid handling that we didn't anticipate?

Well, Merck and Lilly are continuing their hugely expensive, long-running atempts to answer these questions. Here's an interview with Merck's Ken Frazier in which he sounds realistic - that is, nervous:

Merck CEO Ken Frazier, speaking in Davos on the sidelines of the World Economic Forum, said the U.S. drugmaker would continue to press ahead with clinical research on HDL raising, even though the scientific case so far remained inconclusive.

"The Tredaptive failure is another piece of evidence on the side of the scale that says HDL raising hasn't yet been proven," he said.

"I don't think by any means, though, that the question of HDL raising as a positive factor in cardiovascular health has been settled."

Tredaptive, of course, hit the skids just last month. And while its mechanism is not directly relevant to CETP inhibition (I think), it does illustrate how little we know about this area. Merck's anacetrapib is one of the ugliest-looking drug candidates I've ever seen (ten fluorines, three aryl rings, no hydrogen bond donors in sight), and Lilly's compound is only slightly more appealing.

But Merck finds itself having to bet a large part of the company's future in this area. Lilly, for its part, is betting similarly, and most of the rest of their future is being plunked down on Alzheimer's. And these two therapeutic areas have a lot in common: they're both huge markets that require huge clinical trials and rest on tricky fundamental biology. The huge market part makes sense; that's the only way that you could justify the amount of development needed to get a compound through. But the rest of the setup is worth some thought.

Is this what Big Pharma has come to, then? Placing larger and larger bets in hopes of a payoff that will make it all work out? If this were roulette, I'd have no trouble diagnosing someone who was using a Martingale betting system. There are a few differences, although I'm not sure how (or if) they cancel out For one thing, the Martingale gambler is putting down larger and larger amounts of money in an attempt to win the same small payout (the sum of the initial bet!) Pharma is at least chasing a larger jackpot. But the second difference is that the house advantage at roulette is a fixed 5.26% (at least in the US), which is ruinous, but is at least a known quantity.

But mentioning "known quantities" brings up a third difference. The rules of casino games don't change (unless an Ed Thorp shows up, which was a one-time situation). The odds of drug discovery are subject to continuous change as we acquire more knowledge; it's more like the Monty Hall Paradox. The question is, have the odds changed enough in CETP (or HDL-raising therapies in general) or Alzheimer's to make this a reasonable wager?

For the former, well, maybe. There are theories about what went wrong with torcetrapib (a slight raising of blood pressure being foremost, last I heard), and Merck's compound seems to be dodging those. Roche's failure with dacetrapib is worrisome, though, since the official reason there was sheer lack of efficacy in the clinic. And it's clear that there's a lot about HDL and LDL that we don't understand, both their underlying biology and their effects on human health when they're altered. So (to put things in terms of the Monty Hall problem), a tiny door has been opened a crack, and we may have caught a glimpse of some goat hair. But it could have been a throw rug, or a gorilla; it's hard to say.

What about Alzheimer's? I'm not even sure if we're learned as much as we have with CETP. The immunological therapies have been hard to draw conclusions from, because hey, it's the immune system. Every antibody is different, and can do different things. But the mechanistic implications of what we've seen so far are not that encouraging, unless, of course, you're giving interviews as an executive of Eli Lilly. The small-molecule side of the business is a bit easier to interpret; it's an unrelieved string of failures, one crater after another. We've learned a lot about Alzheimer's therapies, but what we've mostly learned is that nothing we've tried has worked much. In Monty Hall terms, the door has stayed shut (or perhaps has opened every so often to provide a terrifying view of the Void). At any rate, the flow of actionable goat-delivered information has been sparse.

Overall, then, I wonder if we really are at the go-for-the-biggest-markets-and-hope-for-the-best stage of research. The big companies are the ones with enough resources to tackle the big diseases; that's one reason we see them there. But the other reason is that the big diseases are the only things that the big companies think can rescue them.

Chemistry World has really touched a lot of nerves with this editorial by economics professor Paula Stephan. It starts off with a look back to the beginnings of the NIH and NSF, Vannevar Bush's "Endless Frontier":

. . .a goal of government and, indirectly, universities and medical schools, was to build research capacity by training new researchers. It was also to conduct research. However, it was never Bush’s vision that training be married to research. . .

. . .It did not take long, however, for this to change. Faculty quickly learned to include graduate students and postdocs on grant proposals, and by the late 1960s PhD training, at least in certain fields, had become less about capacity building and more about the need to staff labs.

Staff them we have, and as Prof. Stephen points out, the resemblence to a pyramid scheme is uncomfortable. The whole thing can keep going as long as enough jobs exist, but if that ever tightens up, well. . .have a look around. Why do chemists-in-training (and other scientists) put up with the state of affairs?

Are students blind or ignorant to what awaits them? Several factors allow the system to continue. First, there has, at least until recently, been a ready supply of funds to support graduate students as research assistants. Second, factors other than money play a role in determining who chooses to become a scientist, and one factor in particular is a taste for science, an interest in finding things out. So dangle stipends and the prospect of a research career in front of star students who enjoy solving puzzles and it is not surprising that some keep right on coming, discounting the all-too-muted signals that all is not well on the job front. Overconfidence also plays a role: students in science persistently see themselves as better than the average student in their program – something that is statistically impossible.

I don't think the job signals are particularly muted, myself. What we do have are a lot of people who are interested in scientific research, would like to make careers of it, and find themselves having to go through the system as it is because there's no other one to go through.

Stephan's biggest recommendation is to try to decouple research from training: the best training is to do research, but you can do research without training new people all the time. This would require more permanent staff, as opposed to a steady stream of new students, and that's a proposal that's come up before. But even if we decide that this is what's needed, where are the incentives to do it? You'd have to go back to the source of the money, naturally, and fund people differently. Until something's done at that level, I don't see much change coming, in any direction.

Here's a structure that caught me eye, in this paper from Georgia State and Purdue. That's a nice-looking group stuck on the side of their HIV protease inhibitor; I don't think I've ever seen three fused THF rings before, and if I have, it certainly wasn't in a drug candidate. From the X-ray structure, it seems to be making some beneficial interactions out in the P2 site.

This is an analog these are analogs of darunavir, which has two THFs fused in similar fashion. That compound's behavior in vivo is well worked out - most of the metabolism is cleavage of the carbamate. Both with and without that, there's a bunch of scattered hydroxylation and glucuronidation; the bis-THF survives just fine. (That's worth thinking about. Most of us would be suspicious of that group, but it's pretty robust in this case). I'd be interested in seeing if this new structure behaves similarly, or if it's now more sensitive to gastric fluid and the like. No data of that sort is presented in this paper (it's an academic group, after all), but perhaps we'll find out eventually.

So Daniel Vasella, longtime chairman of Novartis, has announced that he's stepping down. (He'll be replaced by Joerg Reinhardt, ex-Bayer, who was at Novartis before that). Vasella's had a long run. People on the discovery side of the business will remember him especially for the decision to base the company's research in Cambridge, which has led to (or at the very least accelerated the process of) many of the other big companies putting up sites there as well. Novartis is one of the most successful large drug companies in the world, avoiding the ferocious patent expiration woes of Lilly and AstraZeneca, and avoiding the gigantic merger disruptions of many others.

That last part, though, is perhaps an accident. Novartis did buy a good-sized stake in Roche at one point, and has apparently made, in vain, several overtures over the years to the holders of Roche's voting shares (many of whom are named "Hoffman-LaRoche" and live in very nice parts of Switzerland). And Vasella did oversee the 1996 merger between Sandoz and Ciba-Geigy that created Novartis itself, and he wasn't averse to big acquisitions per se, as the 2006 deal to buy Chiron shows.

It's those very deals, though, that have some investors cheering his departure. Reading that article, which is written completely from the investment side of the universe, is quite interesting. Try this out:

“He’s associated with what we can safely say are pretty value-destructive acquisitions,” said Eleanor Taylor-Jolidon, who manages about 400 million Swiss francs at Union Bancaire Privee in Geneva, including Novartis shares. “Everybody’s hoping that there’s going to be a restructuring now. I hope there will be a restructuring.” . . .

. . .“The shares certainly reacted to the news,” Markus Manns, who manages a health-care fund that includes Novartis shares at Union Investment in Frankfurt, said in an interview. “People are hoping Novartis will sell the Roche stake or the vaccines unit and use the money for a share buyback.”

Oh yes indeed, that's what we're all hoping for, isn't it? A nice big share buyback? And a huge restructuring, one that will stir the pot from bottom to top and make everyone wonder if they'll have a job or where it might be? Speed the day!

No, don't. All this illustrates the different world views that people bring to this business. The investors are looking to maximize their returns - as they should - but those of us in research see the route to maximum returns as going through the labs. That's what you'd expect from us, of course, but are we wrong? A drug company is supposed to find and develop drugs, and how else are you to do that? The investment community might answer that differently: a public drug company, they'd say, is like any other public company. It is supposed to produce value for its shareholders. If it can do that by producing drugs, then great, everything's going according to plan - but if there are other more reliable ways to produce that value, then the company should (must, in fact) avail itself of them.

And there's the rub. Most methods of making a profit are more reliable than drug discovery. Our returns on invested capital for internal projects are worrisome. Even when things work, it's a very jumpy, jerky business, full of fits and starts, with everything new immediately turning into a ticking bomb of a wasting asset due to patent expiry. Some investors understand this and are willing to put up with it in the hopes of getting in on something big. Other investors just want the returns to be smoother and more predictable, and are impatient for the companies to do something to make that happen. And others just avoid us entirely.

Reader Andy Breuninger, from completely outside the biopharma business, sends along what I think is an interesting question, and one that bears on a number of issues:

A question has been bugging me that I hope you might answer.

My understanding is that a lot of your work comes down to taking a seed molecule and exploring a range of derived molecules using various metrics and tests to estimate how likely they are to be useful drugs.

My question is this: if you took a normal seed molecule and a standard set of modifications, generated a set of derived molecules at random, and ate a reasonable dose of each, what would happen? Would 99% be horribly toxic? Would 99% have no effect? Would their effects be roughly the same or would one give you the hives, another nausea, and a third make your big toe hurt?

His impression of drug discovery is pretty accurate. It very often is just that: taking one or more lead compounds and running variations on them, trying to optimize potency, specificity, blood levels/absorption/clearance, toxicology, and so on. So, what do most of these compounds do in vivo?

My first thought is "Depends on where you start". There are several issues: (1) We tend to have a defined target in mind when we pick a lead compound, or (if it's a phenotypic assay that got us there), we have a defined activity that we've already seen. So things are biased right from the start; we're already looking at a higher chance of biological activity than you'd have by randomly picking something out of a catalog or drawing something on a board.

And the sort of target can make a big difference. There are an awful lot of kinase enzymes, for example, and compounds tend to cross-react with them, at least in the nearby families, unless you take a lot of care to keep that from happening. Compounds for the G-protein coupled biogenic amines receptors tend to do that, too. On the other hand, you have enzymes like the cytochromes and binding sites like the aryl hydrocarbon receptor - these things are evolved to recognize all sorts of structually disparate stuff. So against the right (or wrong!) sort of targets, you could expect to see a wide range of potential side activities, even before hitting the random ones.

(2) Some structural classes have a lot more biological activity than others. A lot of small-molecule drugs, for example, have some sort of basic amine in them. That's an important recognition element for naturally occurring substances, and we've found similar patterns in our own compounds. So something without nitrogens at all, I'd say, has a lower chance of being active in a living organism. (Barry Sharpless seems to agree with this). That's not to say that there aren't plenty of CHO compounds that can do you harm, just that there are proportionally more CHON ones that can.

Past that rough distinction, there are pharmacophores that tend to hit a lot, sometimes to the point that they're better avoided. Others are just the starting points for a lot of interesting and active compounds - piperazines and imidazoles are two cores that come to mind. I'd be willing to bet that a thousand random piperazines would hit more things than a thousand random morpholines (other things being roughly equal, like molecular weight and polarity), and either of them would hit a lot more than a thousand random cyclohexanes.

(3) Properties can make a big difference. The Lipinski Rule-of-Five criteria come in for a lot of bashing around here, but if I were forced to eat a thousand random compounds that fit those cutoffs, versus having the option to eat a thousand random ones that didn't, I sure know which ones I'd dig my spoon into.

And finally, (4): the dose makes the poison. If you go up enough in dose, it's safe to say that you're going to see an in vivo response to almost anything, including plenty of stuff at the supermarket. Similarly, I could almost certainly eat a microgram of any compound we have in our company's files with no ill effect, although I am not motivated to put that idea to the test. Same goes for the time that you're exposed. A lot of compounds are tolerated for single-dose tox but fail at two weeks. Compounds that make it through two weeks don't always make it to six months, and so on.

How closely you look makes the poison, too. We find that out all the time when we do animal studies - a compound that seems to cause no overt effects might be seen, on necropsy, to have affected some internal organs. And one that doesn't seem to have any visible signs on the tissues can still show effects in a full histopathology workup. The same goes for blood work and other analyses; the more you look, the more you'll see. If you get down to gene-chip analysis, looking at expression levels of thousands of proteins, then you'd find that most things at the supermarket would light up. Broccoli, horseradish, grapefruit, garlic and any number of other things would kick a full expression-profiling assay all over the place.

So, back to the question at hand. My thinking is that if you took a typical lead compound and dosed it at a reasonable level, along with a large set of analogs, then you'd probably find that if any of them had overt effects, they would probably have a similar profile (for good or bad) to whatever the most active compound was, just less of it. The others wouldn't be as potent at the target, or wouldn't reach the same blood levels. The chances of finding some noticeable but completely different activity would be lower, but very definitely non-zero, and would be wildly variable depending on the compound class. These effects might well cluster into the usual sorts of reactions that the body has to foreign substances - nausea, dizziness, headache, and the like. Overall, odds are that most of the compounds wouldn't show much, not being potent enough at any given target, or getting high enough blood levels to show something, but that's also highly variable. And if you looked closely enough, you'd probably find that that all did something, at some level.

Just in my own experience, I've seen one compound out of a series of dopamine receptor ligands suddenly turn up as a vasodilator, noticeable because of the "Rudolph the Red-Nosed Rodent" effect (red ears and tail, too). I've also seen compound series where they started crossing the blood-brain barrier more more effectively at some point, which led to a sharp demarcation in the tolerability studies. And I've seen many cases, when we've started looking at broader counterscreens, where the change of one particular functional group completely knocked a compound out of (or into) activity in some side assay. So you can never be sure. . .

Has anyone happened to read this paper, from 2009, or this one, from this year? Well, Shawn Burdette of WPI has, and he noticed that (to a significant extent) they're the same paper. Prof. Valerie Pierre of Minnesota, author of the first paper, is reportedly not too amused, and I don't blame her. But hey, the 2013 authors did at least cite her paper. . .in reference 14d. So at least there's that.

Update: but wait, there's more!

OK, folks, time to choose: would you rather be downwind of an industrial-scale spill of butyl mercaptan (which started in Rouen and is already being smelled in London), or. . .would you rather deal with a twenty-seven tons of burning goat cheese in Norway?

Tough call. I think, though, that I might go with the devil I know, which means the mercaptan. I've never encountered a Goat Cheese Inferno, and I live in fear of discovering even more revolting odors than I've already experienced. Good luck to the Norwegians, I say.

Update: for the curious, natural gas odorant mixes are usually t-butylthiol and isopropyl thiol, with perhaps some other lovelies (dimethyl sulfide) thrown in for that special je ne sais quoi. Although across northern France today, I'll bet they can tell you quoi for sure at the moment.

There's a new Viewpoint piece out in ACS Medicinal Chemistry Letters on academia and drug discovery. Donna Huryn of Pittsburgh is wondering about the wisdom of trying to reproduce a drug-company environment inside a university:

However, rather than asking how a university can mimic a drug discovery company, perhaps a better question is what unique features inherent in an academic setting can be taken advantage of, embellished, and fostered to promote drug discovery and encourage success? Rather than duplicating efforts already ongoing in commercial organizations, a university has an opportunity to offer unique, yet complementary, capabilities and an environment that fosters drug discovery that could generate innovative therapies, all the while adhering to its educational mission.

A corollary to this question is the converse—what aspects of drug discovery efforts within a university might be inconsistent with its primary goal of education and research, and can solutions be found to allow success in both?

Her take is that a university should take advantage of whatever special expertise its faculty have in particular areas of biology, pharmacology, etc., which could give it an advantage compared with the staff of a given pharma company. This isn't always easy, though, for cultural reasons:

While it seems that a university should have the tools to make significant contributions to drug discovery by taking advantage of the resident expertise, a cultural change might be required to foster an environment that values the teamwork required to make these efforts successful. Certainly funding agencies are moving in this direction with the establishment of multi-Principal Investigator designations that are designed to “maximize the potential of team science efforts”. Additionally, internal grants offered by academic institutions often insist that the proposed research involve multiple disciplines, departments, or even schools within the University. However, it seems that a concerted effort to “match-make” scientists with complementary expertise and an interest in drug discovery, finding ways to reward collaborative research efforts, and even, perhaps, establishing a project management-type infrastructure would facilitate a university-based drug discovery program.

She also makes the case the universities should use their ability to pursue higher-risk projects, given that they're not beholden to investors. I couldn't agree more - in fact, I think that's one of their biggest strengths. I'd define "high-risk" (by commercial standards) as any combination of (1) unusual mechanism of action, (2) little-understood disease area, (3) atypical chemical matter, and (4) a need for completely new assay technology. If you try to do all of those at once, you're going to land on your face, most likely. But some pharma companies don't even like to hear about one out of the four, and two out of four is going to be a hard sell.

And I think Huryn's broader point is well taken: we already have drug companies, so trying to make more of them inside universities seems like a waste of time and money. We need as many different approaches as we can get.