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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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December 8, 2008

Enhancing the Brain: Here We Go

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Posted by Derek

Depending on what news sources you follow, you may have heard a lot about it already: taking cognition-enhancing drugs to improve normal brain function. An editorial in Nature has just come out in favor of it, so although I wrote about this back in April, it’s time to talk over the issue again.

Let's define what we're talking about first. We really don’t have anything to selectively affect memory or general intelligence per se, but we do know something about how to affect attention span and wakefulness. So right now, cognition enhancement is mostly going to be found via the stimulants used for attention-deficit disorders, along with Cephalon’s Provigil (modafinil) for narcolepsy. These are the drugs of issue.

Nature started off this latest debate on this a few months ago, when they took an informal survey to see how many scientists used these. The results came in as “more than you might think”, although still a decided minority. One got the impression that these were reached for during grant-writing time in academia, for the most part, which would make their usage pattern similar to what you’d find among the student population. My guess is that the number of people using these in industrial research would be far smaller, for several reasons. For one thing, our work moves in different rhythms. As opposed to academia, we rarely have situations where a Big Creative Work has to be produced (or a huge pile of facts memorized) under time pressure. We do have big reports and presentations that come due, of course, but by the time the big ones are due there have been a lot of smaller ones, and the slides and material are largely summaries of those. It’s not to say that many of us couldn’t benefit from some extra attention to our work, it’s just that the opportunities for such aid aren’t as clear-cut.

Any discussion of this topic has to start with the question of how much good such drugs do. I’m willing to stipulate that for situations like the ones I’ve been describing – a need for long, sustained periods of focus and attention to detail – that these compounds do indeed help. They may be more beneficial for some people than for others, but yes, I think that their effect is real. (If anyone has evidence to the contrary, I’d be glad to hear it – I should also mention that I have no personal experience to draw on).

And that brings up another question, the second big one that always comes up in such a discussion: is it right to do this sort of thing? Now that’s a tangle, because a value judgment has come into the room. And anyone who wants to take a hard line has to deal with the fact that we already have a legal, well-known, widely used drug for cognitive enhancement: caffeine. If that doesn’t increase wakefulness, I’d like to know what does.

The comparison with steroid use in sports will also come up, although I regard that one as partially a red herring. The whole point of athletic competition is different from the point of achievement in the arts and sciences. All sports are essentially artificial constructs that we agree on rules for, and doping makes people worried and/or furious that these rules are being bent. Science, on the other hand, is the real world. If Barry Bonds did indeed break home run records with chemical aid – personally, I think he did – then a lot of people (including me) have a problem with that. But if someone comes up with, say, a proof of the Riemann Hypothesis with the use of modafinil and methylphenidate, well. . .a proof is a proof.

But there is a competitive aspect that the sports analogy does bear on: several junior faculty may all be vying for tenure at the same time, for example. If they’re all roughly equal in ability, does the appointment end up going to the one who uses pharmacological help most effectively? That’s where the same uneasy feeling starts to set in. It’s when you look at head-to-head, human-to-human cases that the arguing really gets going.

We’re going to have more and more of this to deal with in the future. I don’t expect it any time soon, but we’ll eventually be able to do more for memory – and, for all I know, for higher cognition. There are too many therapeutic reasons to investigate such things, and too many reasons for any useful drugs not to quickly escape to the population that doesn’t necessarily have anything wrong with it.

All of these issues are addressed by the authors of the latest Nature commentary, naturally. For example:

"Consider an examination that only a certain percentage can pass. It would seem unfair to allow some, but not all, students to use cognitive enhancements, akin to allowing some students taking a maths test to use a calculator while others must go without. (Mitigating such unfairness may raise issues of indirect coercion, as discussed above.) Of course, in some ways, this kind of unfairness already exists. Differences in education, including private tutoring, preparatory courses and other enriching experiences give some students an advantage over others.

Whether the cognitive enhancement is substantially unfair may depend on its availability, and on the nature of its effects. Does it actually improve learning or does it just temporarily boost exam performance? In the latter case it would prevent a valid measure of the competency of the examinee and would therefore be unfair. But if it were to enhance long-term learning, we may be more willing to accept enhancement. After all, unlike athletic competitions, in many cases cognitive enhancements are not zero-sum games. Cognitive enhancement, unlike enhancement for sports competitions, could lead to substantive improvements in the world."

The editorial comes down to several main points: that we need more solid data on the benefits and risks of such drugs for normal individuals, that competent adults should have to option to use them, and that policies should be worked out to deal with issues of fairness, coercion, and the like.

My own thoughts on this are deeply confused and divided. That’s partly because I’m a weirdo: I don’t drink alcohol, and in fact, I don’t even drink coffee. That goes back to what I’d have to classify as a deep reluctance to mess with the way my brain works through chemical means, a trait that was already well in place by the time I was a teenager, but which was only reinforced as I learned more and more biochemistry. So on one level, I have to think that we really don’t know enough about how the existing cognitive enhancing drugs work, let alone what we’ll know about future ones, and that alone would keep me away from them.

But I can come up with plenty of thought experiments that shake me up: imagine that the risks are better known, and that they're as much as, say, caffeine (but with more benefits). What then? What if such things turn out, many years in the future, to be necessary to work at any reasonably high level in science, since everyone else will be taking them, too? Is part of my problem with drugs that alter brain function a streak of Puritanism - would I feel better about using such things if I knew that they were guaranteed not to be enjoyable? And so on. . .I have to confess, I found such issues a lot easier to deal with inside the confines of old science fiction stories.

Comments (20) + TrackBacks (0) | Category: General Scientific News | The Central Nervous System


COMMENTS

1. Hap on December 8, 2008 10:24 AM writes...

Were the effects of steroids (liver damage/cancer) known when they were being taken en masse by weightlifters and football players? If not, then steroids might not be a total red herring - we don't necessarily know if cognition/attention enhancers may do in the long-term. if they work, then there will probably be an arms race of sorts (either through direct academic competition or changing production goals) that would compel people in intellectual fields to use them in order to succeed. Knowing about their consequences would be helpful, but we probably won't know everything about them, and if their use becomes necessary for lots of people, the potential hazard (with unknown probability) becomes significant.

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2. drug_hunter on December 8, 2008 10:55 AM writes...

I'm with Hap. There is a great book by Edward Tenner called "Why Things Bite Back". It documents case after case where cool new technology led to horrible unintended consequences. I shudder at the thought of what we will learn about brain pharmacology when millions of geeks start messing around with their dopamine or norepinephrine transporters.

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3. Jose on December 8, 2008 11:07 AM writes...

Along the same lines, I shudder to think of what effects we are going to see now that mnay, many people have been on SSRIs for *decades.*

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4. asd on December 8, 2008 11:41 AM writes...

I occasionally took adderall for about a year as an undergraduate (I'm now a grad student in math). It was definitely quite effective at maintaining focus and wakefulness, but this did not necessarily lead to better outcomes. I think it lead to hyperfocus, which causes the first idea you think of to seem better than it is. This hurts creativity. Though perhaps this effect could be mitigated by waiting until you have a promising avenue, then taking adderall to help you work through it.

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5. Lucas on December 8, 2008 12:03 PM writes...

This is a subject I've been thinking about for some time, and I'd like to take the opportunity to ramble about Provigil a bit. This may get long enough to merit a post of its own, rather than a comment, but bear with me. (And a caveat: I haven't read the Nature article yet, so this may just be a rehash.)

I'm a BS organic chemist, formerly in medchem, now back in grad school (working on organic semiconductors, of all things). My wife has been on Provigil for about six months for "excessive sleepiness" - off-label, yes, but arguably not quite as far off-label as "cognitive enhancement." (Student health will prescribe grad students basically anything, which is both a blessing and a curse.)

As a pharma geek, I tend to obsessively look up all the research I can find on any drug she or I are prescribed. What I found on Provigil was both interesting and surprising.

First, modafinil is brick dust. Its oral bioavailability is unknown, because nobody has been able to come up with an IV formulation at any reasonable concentration. Its gut permeability is moderate, leading to the observed pharmacological activity, but the bulk of what patients take goes right on through the GI tract. The upshot of this is that the risk of acute overdose is basically nil; the NDA documents list accidental and deliberate overdoses of hundreds of times the max human dose - in one case something like 37 grams - in which no effect was observed that was any different from or more intense than regular side-effects.

Long-term safety, of course, is another can of worms. It's been around for a while, but not long enough to really know anything about long-term effects. This would probably be my biggest concern about use for performance enhancement.

As far as the enhancement it offers, it isn't the wonder-drug a lot of people seem to think. Everyone has heard stories of fighter pilots staying awake for 80 hours using Provigil. You can find a few studies of this sort in the literature, and what most people don't realize is that maintaining prolonged wakefulness means taking 200 mg every 2 hours, and after 80 hours you're still operating as if you'd been awake for 40 or 50 hours. Maybe I could do that as an undergrad, but nowadays I'd just go to sleep and let the plane crash, thanks.

And from my wife's experience, I can vouch for the fact that it isn't a wonder drug. It certainly helps her, but it's not a cure-all. I'm sure this varies a lot between individuals, and might vary even more between people who "need" it (to achieve normal levels of wakefulness) and people who don't (i.e. are taking it for enhancement).

As far as boosting performance vs. enhancing learning, from our experience it seems to be a combination of both. My wife's performance can certainly be improved by a single dose, but in her case this is primarily because it reduces the "brain fog" associated with sleepiness. Whether or not this effect would disappear in normal individuals, I have no way of knowing. But I can say for certain that it does significantly improve her long-term learning ability, for basically the same reason. Increased alertness, more time for reflection, and reduction of the constant brain fog has made a huge difference for her in learning- and memory-oriented functions.

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6. CMC Guy on December 8, 2008 12:12 PM writes...

Besides the potential for hidden side effects I would perhaps question the true intelligence of anyone who required "artificial" means to reach peak mental performance. Even during times of great demands or stress the ability to handle it effectively is a good measure of being able to apply the inherent smarts which is important.

I had a friend in college who was pre-med and would smoke marijuana to help study for exams as claimed it gave him focus (and calmed nerves). Although admittedly book smart and he did make it to med school I would not wish him to treat me or anyone else because that extra boost he needed to function at a high level.

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7. Fargo on December 8, 2008 12:23 PM writes...

I don't drink much, maybe a couple beers every few months, and I've actively sworn off caffeine, which I've only lapsed on a few times in the last couple years. As with every chemical I've ever tried, if you use it a lot (a lot varying by the substance involved), you end up feeling like crap, and any benefit you may have been deriving comes back to bite you. Like caffeine, for instance. Take in a little, and you're more "awake", better able to focus, and whatnot. Take a lot and you're jittery and have an attention span perhaps best described as stroboscopic. Take a little, but take it as though it were the counter-poison Thufir had to milk from that cat, which for non-Dune fans is to say constantly, and eventually you'll just feel used up. Getting high to get normal, as I heard in more severe circumstances.

My point is that while I'm sure chemicals to enhance brain performance, in one way or another, may be beneficial, I think that for a long time to come it'll really only change the curve during crunch time projects, because even if there aren't serious risks the rewards won't be sustainable on a prolonged basis.

That's all just based on personal experience though, I freely admit to understanding little of the actual chemistry involved. I'm just a computer tech with a penchant for reading blogs that lie far afield of what I know about already.

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8. Roadnottaken on December 8, 2008 12:36 PM writes...

I fail to see how this is any different from caffeine. We should all admit that we don't really know the long-term effects of a lifetime of chronic caffeine-use except that they're not catastrophic. Similarly, I have no doubt that caffeine would improve test-scores in a double-blind study (coffee v decaf) yet because it's so common nobody objects. Does it provide an "unfair advantage"? Do we question the "true intelligence" of people that "require" coffee? These questions sound silly, but for some reason people take them seriously when talking about mild stimulants that come in pills (instead of beans).

Derek's perspective is unusual because he abstains from all psychoactive substances and is therefore largely free of the hypocrisy found in most people's opinions on the subject. I think it's totally reasonable to be wary of psychoactive substances but I cringe whenever I hear someone argue that there's some sort of moral difference between using caffeine vs. amphetamine or alcohol vs. marijauna.

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9. Sili on December 8, 2008 1:36 PM writes...

asd's comment is interesting, since it implies that what 'we' need - or take - is complete antipodal to the artists. Of course you can make great art while being a puritan, but you can also do so under the influence.

It's a tough question, though. Was Erdős joking when he said that maths had been set back a month after he gave up speed on a bet?

I think all we can do is the research and then leave it to people to weigh the costs and benefits individually. Would I take up an addiction that gave me the shakes, made me impotent or more like to have kidney stones if it meant I could move into a slightly higher paybracket? Not likely, I think. Would I give fifty years of my life to be the one to find an answer - one way or another - to the RH? In the blink of an eye!

Not drinking, smoking or drugging really isn't all that unusual.

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10. Sebastian on December 8, 2008 6:46 PM writes...

"Consider an examination that only a certain percentage can pass. It would seem unfair to allow some, but not all, students to use cognitive enhancements, akin to allowing some students taking a maths test to use a calculator while others must go without."

The more interesting but less examined social question is "why do we have examinations that only a certain *percentage* can pass"? And I know that takes it out of the realm of pharmacology, but still...

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11. satan on December 8, 2008 8:15 PM writes...

I agree.. if the top "failed" candidate is within 10% of the last "pass" candidate on a given day, the decision to pass/fail has no relevance to future job performance.

"The more interesting but less examined social question is "why do we have examinations that only a certain *percentage* can pass"? And I know that takes it out of the realm of pharmacology, but still..."

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12. Anonymous BMS Researcher on December 8, 2008 9:38 PM writes...

Hmmm, much ahem food for thought here.

Like Derek I basically don't use alcohol or caffeine, but my wife drinks lots of tea (and imports exotic varieties from companies that talk about tea the way wine enthusiasts natter on about THAT, but fortunately the cost of world-class tea is orders of magnitude less than the cost of world-class wine). I like my brain as it is and prefer not to muck aboot with it.

As for the issue of competitive examinations, grant study sections, etc., my own take is in many cases we are doing something statistically invalid when we attempt to make finer distinctions than our tools for comparison really permit. A more intellectually honest approach would first decide what "true" score would constitute our standard for "excellence." Then we determine on statistical grounds the range of scores for which the difference from our ideal score is not significant. THAT should be our cutoff score. If it happens that "too many" people meet our cutoff, and forces beyond our control mandate we select fewer winners, then we pick the final winners AT RANDOM from among all who meet the statistically valid criterion.

This line of reasoning may also have application in drug development, actually! Many times we have a number of candidates that seem equally promising so we have difficulty picking which to select for the next stage of our pipeline. *I* think we should pick randomly from among those that appear equally good, but since we are unwilling to acknowledge the reality that we have no valid basis for selection what we actually do is examine the data over and over until we manage to dream up some argument for picking THIS one today...

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13. Kay on December 9, 2008 9:22 AM writes...

Please do note that the majority of the doses being consumed at the university are stolen or otherwise diverted from a legitimate prescription fill.

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14. CMC Guy on December 9, 2008 11:06 AM writes...

Roadnottaken if some one "requires" caffeine for their brain to function I would also question how to properly measure their intelligence as even though a natural source it still has temporary (and inconsistent) effects plus many side effects. I was attempting to make a point that difficult circumstance typical will demonstrate the true character of most people, including intelligence, and if one has to use an external stimulant then may be not as smart as it appears.

Although I was thinking more of the physical responses from caffeine than mental impacts would suggest in general caffeine harder to abuse (and maybe less additive?) which I think is the distinction between other "drugs" mentioned. Not to ignore that caffeine can be used improperily at times, and amphetamine appropriately in treatments but in degree of response intensity and potential addiction power they are different. Lines less clear between alcohol and marijuana however if a person "needs" either it is a sign of a problem. Not sure would view as morality but as practical consequences that can start road to establish ethical aspects,

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15. Gen X on December 9, 2008 10:33 PM writes...

"That’s partly because I’m a weirdo: I don’t drink alcohol, and in fact, I don’t even drink coffee. "


So that's why you're a libertarian! It has nothing to do with messing with your brain chemistry (it is an excuse for abstaining from human contact). Coffee and drinking are social things. Possibly you are even autistic.

You've shown you are:

1. Antisocial
2. Have great disdain for your fellow man
3. Feel no pressure (because drinking that cup of coffee would help you perform if you were a real human being. Sociopaths and the autistic feel no such pressure.
4. Care nothing about bonding with your fellow man, hence you do not drink.

-Fantastic. Many insects and other ravenous carnivores adhere to your kind of behavior.
My general impression is that 50% of all chemists are autistic.

I see your blog as a desperate cry for hope. Keep hitting those keys, maybe one day you'll wake up!

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16. Anon on December 10, 2008 1:31 AM writes...

I work in the pharmaceutical industry as well, and my wife is also prescribed Provigil to combat excessive sleepiness. In the midst of long & labor intensive projects, I must admit to occasionally stealing a dose after an all-nighter, when my stomach can no longer handle the flow of coffee. So I thought I'd add a few personal observations on the effects of the drug.

Firstly, I'd say the drug is not a wonder in terms of enhancement of cognitive abilities. As near as I can measure, it doesn't boost performance significantly over a well-rested baseline. You might be able to pick out minor effects on formal performance testing, but this isn't going to turn a patent clerk into Einstein.

That said, the drug is fairly impressive in what it does do - namely, it all but eliminates the feeling of cognitive fatigue from lack of sleep. There's really not a better way to describe it than feeling normal and well rested. You don't feel "up," per se, and don't feel jittery as with coffee or (presumably) the amphetamine alertness agents (haven't had any desire to try those, but folks with ADHD have often described the hyperfocus and jitters that accompany excessive NE transmission). You just feel normalized.

The overall AE profile is relatively benign, at least in my experience (n of 1, of course). I have noticed that one does lose a bit of appetite - I tend to look down and realize it's already 1:30 and I have forgotten to take lunch, but when I do remember portion size is relatively unchanged (wonder if Cephalon has an interest in the obesity market). The only other side effect I've noticed is, well, a bit curious: it tends to make one's urine smell odd, and smell quite a bit. So (and I hope not to get too personal here) if anyone is ever in-disposed and notices a smell somewhere between marijuana smoke and almond extract, there's a good chance a coworker has experience with the drug.

So, to bring it back to Derek's larger discussion, i think the analogy between anabolic agents and cognitive enhancers does bear some though, but modafinil is probably not the standard-bearer of that charge. It certainly does expand ones capacities in some sense, but I'd say the benefits are more in total output, rather than work quality.

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17. Derek Lowe on December 10, 2008 10:26 AM writes...

Gen X, you've nailed me, all right: autistic sociopath. That's what everyone says who's been around me for a while, and I applaud your powers of long-range diagnosis. If only you'd warned my wife in time!

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18. Roadnottaken on December 10, 2008 11:15 AM writes...

Anon,
For what it's worth, your description of modafinil is VERY similar to my experiences with amphetamine (Adderall). You don't feel noticeably different, just not-tired. I used to pull all-nighters in college a lot and sometimes I used coffee and cigarettes and other times Adderall and the only appreciable difference is that eventually you start getting jittery and unfocused with coffee. After taking Adderall for a while you feel basically normal, alert, and rested, which is amazing because you've been awake for 36+ hours. That said, I always took pretty low-doses (~5-10mgs at a time) so perhaps larger doses are more dramatic. I had similar experiences with Ritalin.

Ultimately, it's the sheer "mild-ness" of all of these drugs that makes my opinion what it is. If there were truly drugs available that added 30 IQ points to one's intelligence, this would be a more difficult ethical and social dilemma, I think.

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19. Anonymous on December 10, 2008 12:25 PM writes...

There's zero dilemma, IMO. Most drugs are arguably quality-of-life improvements (heart burn, migraine, cholesteroal lowering, erectile disfunction), in that they don't IMMEDIATELY save your life (like an antibiotic, e.g.) If it's ethical to take those drugs, what's wrong with taking something to raise intelligence?

Make the efficacy and safety results available, I can decide for myself what risk I want to take to improve my quality of life.

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20. anonymous coward on January 12, 2009 7:13 PM writes...

Every time I see this whole debate, I think about my personal use of Ritalin.

Have to use it. Would love to stop using it. Either way, I'm fairly bright, it's just that with Ritalin, I can actually get stuff done at work. So every 30 days or so, I have to pick up a new prescription for it and fill it.

Hyperfocus, IMHO, seems to be characteristic of the ADHD sufferer on or off the drugs. And when I accidentally took a double dose, I can assure you that the clinical effects of ritalin on ADHD are dramatically different than the accidentally recreational effects. They are also markedly different than caffeine.

But I really wish I could unscrew the top of my head and let you hear the thoughts that are going around in my head. About how we really don't know all of the details about what happens after 50 years of usage. How my blood pressure is just a smidge higher on the drugs than off, which then makes me worry about dying young. About mysterious fears of biochemestry screwups that will turn me into a mental vegetable or emotional simpleton one day.

And this is the result of a good amount of medical and psychological evaluation bestowed upon me. The second I either move into the sort of job position where I don't need this crap or find a better way to avoid ADHD problems, I'm dropping 'em.

And some folks want to just be able to take this stuff when it's not necessary?

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