Giving Thanks

It is Thanksgiving Day here in the US, so I will do my own little thanks post.

First, thanks to everyone reading. This time last year, my subscribers and viewers was OK but it has grown steadily and now several hundred people will get to read my occasional utterances. My best ever single day was for a long time the day In the Pipeline added the blog to its blog roll, but that mark was exceeded by my 10 Nitrogens in a Row post. Mental note: include more stuff that blows up.

That brings me to another thank you: everyone and anyone who gave me the seed for a post. A couple of my co-workers in particular are often giving me ideas, including the 10 Nitrogens post and the series on the unidentified white powder. One lab mate will be telling me something and Will add “you should blog about that!” OK I will and thanks for the tip.

Thanks also to those who have commented or forwarded on the link to the blog. Beyond the odd tweet, I don’t really work that hard on drawing attention to it, relying on word of mouth (or tweet) to bring people here. So I really appreciate those who take the time, including Stuart Cantrill, Mr Nature Chemistry himself, as well as the irrepressible ChemJobber who has featured several of my posts on his own blog, all while somehow maintaining an impressive post regime of his own. Thanks, CJ for the links and all your efforts for the chem blogosphere.

Now it looks like it is time for dessert, so I will thank you all once more and hope to see you all tuning in for the foreseeable future.

10 Nitrogens in a Row

I’m sure Derek Lowe’s “Things I Won’t Work With” series is essential reading for most here (and for those that have missed out, take a look – my favorite was FOOF). He put one up a couple of years back on an interesting structure with 8 nitrogens in a row (two triazoles linked by 2 nitrogens). It was surprisingly stable, despite Derek’s title of that post. It also has a cool color effect where it changes color when you shine light on it (photochromism), due to the central double bond changing from trans to cis and back again.

My lab mates were talking about that and one pondered aloud what would happen if you used tetrazole instead? Luckily someone else has found out for us because, believe me, you didn’t want to be the one doing this particular piece of research.

Inevitably, it was Thomas M. Klapotke’s group that made it, published in 2011 in Inorganic Chemistry. Well, it was almost devoid of carbon by this point so why not? The graphical abstract tells the story eloquently: the structure with a back-drop of broken lab equipment. It was made in the exactly analogous fashion to the 8 nitrogen analog, but that is where the similarity ends. When the Klapotke group say this is one of the most sensitive materials they have handled, you better take notice.

Some choice comments from the paper:

The precipitated N10 compound 4 was not dried in the funnel
because attempts to manipulate the dry solid inevitably led to
extremely loud explosions and the destruction of labware.

we experienced several inadvertent explosions
during handling such as allowing the dry powder to slide down
the inside of a Raman tube or slowing down the rotation rate of a
rotary evaporator

Inadvertent explosions is a lovely expression.

They conclude that the formation of this compound leads to speculation that even longer nitrogen linkages might be possible but note that it “may present challenges for isolation”.

No kidding!

Chem Coach Carnival: My turn

The call was made for a post and I did heed it. Missed putting it on Mole Day, but what’s an order of magnitude between friends?

Your current job.

I work at RTI International, a non-profit research institute in the RTP area of North Carolina.

What you do in a standard “work day.”

It starts with a cup of tea (I’m a stereotypical Brit in that regard), but encompasses reading, writing and lab work. I am more in the lab than my supervisor, but he expects a certain amount of work on papers or grant proposals from me as well. My primary responsibility is keeping the project moving forward in terms of compound supply, so getting new data or scale-up so we have material for the next phase of the project. I’ll add we are more a basic research group than a drug discovery group, so tool compounds that pharmacologists can use to study receptors with is more our game than making a highly bioavailable drug. But many of the same skills apply – it needs to be soluble, for example.

What kind of schooling / training / experience helped you get there?

I have a PhD from the University of St. Andrews in Scotland. I post doc’d in the US at Georgia Tech. My original plan was to go back to the U.K. after that but jobs were scarce at the time and lining up one trans-Atlantically proved difficult. So I ended up staying. Got a job at a non-profit, then at a small contract research company here in RTP. As much as my qualifications, knowing people and being bold with contacting people got me here – I got an interview at my last job because they had hired a process chemist I knew, then I made a good contact with the recruiter who was hiring for this position, plus a number of former co-workers had post doc’d at RTI.

How does chemistry inform your work?

I work in the lab doing synthesis most of the time so it is pretty central to my job and that is how I like it.

Finally, a unique, interesting, or funny anecdote about your career

I could note how my PhD was book-ended by building evacuations due to ammonia release from the lab next door. But that isn’t really about me.

When in school, we were working on making a Grignard reagent. I forget the details, but it was magnesium turnings, a bromide of some sort, maybe some iodine to activate things. We were heating it. The guy behind me (doing the same thing) suddenly cried out and I turned around at saw his reaction spouting out of the top of his condenser. I chuckled turned around and mine did the same thing, shooting out of the top with enough force to mark the ceiling with a nice brown spot.

If I were just coming into the field, would I learn something useful from your story?

I hope so. The lesson I take from my own journey is that it is rarely as smooth as you imagine, you have to adapt and be flexible, be ready to take on things that you did not expect. But also it is possible to make your career into something you enjoy and want to do long term.

Pharma Bashing

Ben Goldacre writes the Bad Science column for the Guardian newspaper in the U.K. and mostly he writes about pseudo-science because, as he puts it, “pulling apart bad science is the best teaching gimmick I know for explaining how good science works”. He has just put out a book called Bad Pharma, putting the foreword on his blog, an excerpt appeared in the Guardian and he put up a video of a TED talk he gave. So he is getting it out there.

The book, as a brief summary, takes the pharmaceutical industry to task for its clinical trial practices, wherein it skews the trials to favor their candidate, hides the results of unfavorable trials, covering up side effects and persuading doctors to prescribe their drug once it comes to market with misleading data published in industry sponsored journals. The game is rigged in favor of the big companies who then rake in the enormous profits.

Some people dispute this claim and John LaMattina put up his own take on the book and its contents.

So before my comments, my disclaimer. I suppose I am one involved in the pharmaceutical industry , though I have never worked for one directly, working for a industry contractor on research projects for several years, but these days I am more an interested observer, as I am at a non-profit research institute. I am also not by any means an expert on how clinical trials are run, exactly how things get approved for use or indeed very much at all about the ins and outs of the process. But I have a general idea.

Now the pharmaceutical industry have not done themselves any favors here. They have done all the things that Dr. Goldacre accuses them of, but the blanket statement that the whole industry is out to trick doctors and patients into taking their drugs is extreme to say the least. Pharmaceuticals in various forms have improved the lives of millions of people, saved them from death. Drug candidates are carefully vetted for efficacy and safety – more and more these days as there are so many treatments already available. Clinical trials are not just run against placebo but for approval, drugs need to show an improvement over a standard treatment. In short, that the system is occasionally circumvented does not mean the system does not fundamentally work.

If you look at it from the pharmaceutical company’s view, you can see why these sorts of things happen. Projects begin because there is a medical need for a treatment – essentially a gap in the market. So scientists work to come up with something that will meet that need. But the process of working that out is long and difficult and so many things can go wrong along the way. Worse still, the further along the path you get the more expensive the next step. A phase I failure is a disappointment for sure but it is a minor inconvenience compared with a late stage Phase III failure. Drug development is a high risk venture and there is no pay-off without a final marketable product. So at a certain point, the aim becomes the finish line of FDA approval. Anything that can lower the obstacles in the way would seem like an obvious route to take. Far from the drug companies preying upon the vulnerable and pushing through drugs that should not be, they suffer some dramatic failures – ask anyone in the Alzheimer’s field. Indeed if the system is set up to favor the drug companies, why is there so much talk of the barren drug pipelines and lack of new drug approvals? Pharmaceuticals have always been a high risk high pay-off investment but the risk seems to have risen and the prospect of a big pay-off seems to be receding.

Interestingly, as I was writing this (and re-writing it – curse that wordpress log-off), I came across Matt Herper’s post on Glaxo’s greater clinical trial transparency. This shows two things to me: firstly, that the pharmaceutical industry is aware of its image problem and are prepared to do something to counteract that perception. But also, that there are the problems talked about by Dr. Goldacre, with prominent doctors paid to talk up a new drug from GSK or pushing unapproved uses. That they are taking steps to reassure the general public can only be a good thing.

Quick addition: Ben Goldacre posted his response to GSK’s proposal and he voices some doubts about whether they will actually go through with it.

Local Guy Makes Good

Despite my stance as a Nobel curmudgeon, I will still stand up and salute a local scientist who did OK. Dr. Robert Lefkowitz of Duke Medical Center and Howard Hughes Medical Institute picked up the Nobel prize in chemistry today, along with Stanford’s Brian Kobilka for their work on G Protein-Coupled Receptors (GPCRs), an area of immense importance in the drug development area and also one that intersects with my own current work.

Congratulations to both men.

The Value of a Chemistry PhD

There has been a number of articles wondering if there are too many or not enough people studying science in general and chemistry in particular. Last week it was Daniel Lametti’s Slate piece, saying basically that unemployment among PhDs is much less than the general populace so we shouldn’t worry about them. ChemJobber did a very nice job rebutting that article but I wanted to add a little to what he said.

Chemistry unemployment is at a high level, with many jobs eliminated from the U.S. to go overseas or maybe just eliminated by the “synergy” created by the latest merger. But more than that, the type of jobs that are available has changed. A lot of chemistry folks have gotten out of chemistry, either out of need or disillusionment. I myself considered options beyond the laboratory when I was let go. After some soul-searching, I decided that I most wanted to stay in the lab and sought out a position, but the range of jobs of that type out there was very low indeed. The typical job in synthetic chemistry or medicinal chemistry is either a contract or, if you are lucky, with a small start-up or a more academic drug discovery effort (such as the Broad Institute in Boston or the Vanderbilt Center for Neuroscience). While good jobs, these are typically either short-term, lower paid or dependent on grant funding (in other words, could also be short term). Permanent medicinal chemistry jobs such as were the typical destination of a semi-decent Ph.D. synthetic chemist are now in very short supply and are savagely competitive, with many hundreds of applicants.

So to to get back to the title of this post, what is it worth to be a chemistry Ph.D.? If I wanted to be rich, I would have done something else; I did chemistry because of its challenges but also because I was interested and relatively good at it. I also followed it because it seemed like it was a degree that led to a career, rather than a qualification that would then need further training to start on the career path. So that latter consideration might cause me not to advise a young student of science to go into chemistry – the career path is much murkier now than it was when I started. And the advice I got around that time was lacking in many respects: what would set me on a true course toward a steady career? Getting a degree in a good school for a well-known professor was the basic advice (and the professor mattered more than the school). I think that remains true to this day, though it is more treacherous than it was then.

But still, things can change and today’s nadir could be tomorrow’s zenith. Labor differences between China and the US are narrowing, the US economy does at least appear to be recovering, albeit slowly. There will still be a need for new medicines. There is some kind of future for the pharmaceutical industry even if we don’t know exactly what that will look like. So if you were passionate about the subject, if it was something that you really wanted to do, then I would tell you to pursue that dream. I haven’t regretted it. But if you are looking at it as an easy way to a career, then it might bear some serious thought, because that easy path is no longer so straightforward. Pure research is a narrowing market, though if you are interested in chemical engineering, a talented engineer is still in demand (as seen by their consistently higher average salaries). Plus, further down the drug development track there is room, in drug formulation for example, but this rapidly becomes more clinical studies rather than medicinal chemistry. Something beyond benchwork is also a possibility – law or teaching or scientific writing for example. Some of those can be pursued without a PhD, though teaching, for example, can be easier to get into if you have a higher qualification, partly due to a lack of teachers in some subjects and science tends to be one of those.

I have had periods where I have questioned the value of doing a Ph.D., where we collectively wondered how easy it would be to erase that part of our life from our resume and take on the life of an associate. It is hard to separate all the things that have happened to you such that you could remove one facet and still remain the same person. But I have enjoyed the challenges of becoming a Ph.D., it gave me opportunities I never would have had otherwise. If I was to do it all over again, I might do it a little differently, apply myself a little more to some things, but as youth is wasted on the young, maturity can’t be granted retroactively. So I’d do it all over again, but if it were someone else, I would make sure they knew what they were getting into.