About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
February 28, 2007
Since I'm still on the job-hunting trail, after the events described here, I think I'd find it a bit therapeutic to complain about one part of the process that's a complete waste of time.
Now, there are open positions that are advertised, both online and in the various science and trade publications, and there are some that are handled mostly by recruiters. I'm working both of those, naturally, since at my level of experience it's generally harder to find a position. Friends of friends, former colleagues, company websites, online job boards, headhunters of every description - if this isn't the time to pull out all the stops, when is?
But there are recruiters, and there are recruiters. I've spoken with several who really seem to know their business, and I'm glad to have had the chance to contact them. But I've also spoken with several who don't seem to have the first idea of what they're doing. Let's just say that I've been pitched more than enough positions for "Formulations Chemist" and "Clinical Research Data Scientist" and God only knows what else. There are so many things wrong about these inquiries that I hardly know where to start.
For one thing, it shows that either the recruiter involved knows nothing about the industry, or they haven't even looked at my CV - and it's a good question as to which of those is a worse sign. I've had headhunters confidently forward me positions that focus on, say, developing generic injectables: what in my background makes that even remotely a match, unless all the other resumes they have on hand are from Linux developers and salespeople? The other day, I had someone pitch me a job that, while actually in medicinal chemistry, was at a level I wouldn't have interviewed for in 1992, much less now. And they seemed surprised that I wasn't considering it seriously.
Another problem with these is what's happening on the other end. Here's some company, paying a search firm to go out and beat the bushes for them, but the outfit's actually just randomly hitting up everyone who's walked across a drug company parking lot. You wonder what kind of progress reports these people are submitting on how their trained placement professionals are on the case, as in the background someone sits on the phone asking a cell biologist if they've ever considered running a mass spec lab. "Hello. . .hello? Cut off again. . ."
Well, at any rate, there are some good ones out there. But they sure stand out against the background.
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February 27, 2007
SciTheory has a post, complete with links to the relevant articles in Science, etc., on a recent batch of trouble in structural biology. Geoffrey Chang and his group at Scripps have been working on the structures of transporter proteins, which sit in the cell membrane and actively move nonpermeable molecules in and out. There are a heap of these things, since (as any medicinal chemist will tell you) a lot of reasonable-looking molecules just won't get into cells without help. It's even tougher at a physiological level, because (from a chemist's perspective) many of the things that need to be shuttled around aren't very reasonable-looking at all - they're too small and polar or too large and greasy.
Many of these transportersm especially in bacteria, fall into a large group known as the ABC transporters, which have an ATP binding site in them for fuel. (For the non-scientists in the audience, ATP is the molecule used for energy storage in everything living on Earth. Thinking of an ATP-binding site as a NiCad battery pack gets you remarkably close to the real situation). Chang solved the structure of one of these, the bacterial protein MsbA, by X-ray crystallography back in 2001, and it was quite an accomplishment. Getting good X-ray diffraction data on proteins which spend their lives stuck in the cell membrane is rather a black art.
How dark an art is now apparent - here's the original paper's abstract in PubMed, but if you look just above the abstract, you'll see a retraction notice, and it's not alone. Five papers on various structures have been withdrawn. As SciTheory says, anyone who doubted the original MsbA structure had some real food for thought last year when another bacterial transporter was solved at the ETH in Zurich. These two should have looked more similar than they did, to most ways of thinking, but they were quite divergent.
And now we know why. Chang's group was done in by some homebrew software which swapped two columns of data. In a structure this large and complicated, you can have such disruptive things happen and still be able to settle down on a final protein picture - it's just that it'll be completely wrong. And so it was. The same software seems to have undermined the other determinations, too.
This is important (as well as sad and painful) on several levels. For one thing, transporters are essential to understanding resistance to antibiotics and cancer therapies, and they're vital parts of a lot of poorly understood processes in normal cells. We're not going to be able to get a handle on the often-inscrutable distribution of drug candidates in living systems until we know more about these proteins, but now some of what we thought we knew has evaporated on us.
Another point that people shouldn't miss is the trouble with relying too much on computational methods. There's really no alternative to them in protein crystallography, of course, but there always has to be a final "Does that make sense?" test. The difficulty is that many perfectly valid protein structures show up with odd and surprising features. Alternately, it's unnerving that the data for these things can be so thoroughly hosed and still give you a valid-looking structure, but that just serves to underline how careful you have to be.
And we're talking about X-ray data, which (done properly) is considered to be pretty solid stuff. So what does this say about basing research programs on the higher levels of abstraction found in molecular modeling and docking progams?
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February 26, 2007
F. Albert Cotton's recent demise brings up a question that traditionally comes up in the fall, during Nobel season. Cotton himself never won the prize, although his name came up constantly in the list of contenders. There's a group of scientists (a select one) in every Nobel-bearing discipline that fills this role. Some of these people eventually get Nobel recognition, of course, and when that happens a good number of onlookers are relieved that ol' So-and-So finally got it, and another host are surprised, because they'd already sort of assumed that ol' So-and-So had received one years before.
But as time goes on, it seems to become clear that some eminent people are just not going to win, and I'd have to have put Cotton in that category. The Nobel committee had years in which to act on his behalf; they never did. The question then is why. Theories abound, some of them conspiratorial (and thus unprovable for another hundred years or so), but most trying to discern what makes some work Nobelish and some not.
One of the strongest arguments is that doing a lot of good work across several areas can hurt your chances. It seems to help the committee settle on candidates when there's a clear accomplishment in a relatively well-defined field to point at. Generalists and cross-functional types are surely at a disadvantage, unless they can adduce a Nobel-worthy accomplishment (or nearly) in one of their areas. That's not easy, given how rare work at that level gets done even when you've devoted all your time and efforts to one thing.
The current example in organic chemistry is George Whitesides at Harvard. He's an excellent chemist, and has had a lot of good ideas and a lot of interesting work come out of his group. But it's all over the place, which is something I really enjoy seeing, but the Nobel folks maybe not as much. Just look at this bio page from Harvard, and watch it attempt to pull all his various research activities under some sort of canopy. It isn't easy.
To drag the late Isaiah Berlin into it again, Whitesides clearly seems to be a fox rather than a hedgehog. Hedgehogs tend to be either spectacularly wrong or spectacularly right, and that last category smooths the path to greater formal recognition. For more on fox/hedgehog distinctions in other disciplines, see Daniel Drezner (international relations), Andrew Gelman (statistics), and Freeman Dyson (physics), and for an application of the concept to drug research, see here. Which sort of creature does Whitesides stock his research group with? Paul Bracher would know.
(Readers are invited in the comments to submit their own candidates for scientists who always seem to be on the Nobel list, but haven't won, and any alternate theories about why this happens).
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February 25, 2007
The other day I made a quick comment that I wasn't sure which would have a higher rate of return - biotech stocks or lottery tickets. Some folks liked the comparison, and others didn't, naturally. But there are some points worth thinking about in it.
For one thing, we have to distinguish between the gains realized by the companies themselves, versus those realized by their stocks. The former figures have already been calculated fairly recently (2004) by David Hamilton in the Wall Street Journal (subscriber link here), and I wrote about their figures at the time.
The best estimate was that since the first biotech company went public, total operating losses in the industry have amounted to some 40 billion dollars. Genentech and Amgen do what they can with all the black ink that they generate, but they're overwhelmed each year by the tide of the red stuff. I can only imagine what this figure would be if it included non-public biotechs, every single one of which (as far as I know) has run at a loss. After all, when you start to look like you're going to turn a profit someday, you're already public, right?
During this period, investors have put about 100 billion into the public companies, so we know where 40% of that money has gone, at any rate. Ah, but you're saying, these investors got stock in return, and how's that done, eh? Undeniably, some of the issues have made people fantastic amounts of money - Amgen, for example, has returned several hundred-fold on an investment at its IPO price in the early 1980s, although surely no human being has held it for that entire time. Of course, somewhere around 15 or 20 per cent of all the biotech companies that have gone public over the years turn out to have returned nothing at all, having disappeared in a blizzard of worthless stock, so that does cut into things. Still, biotech has been up over that time - but compared to what? As a whole, the article suggested, the sector has failed to even come close to the S&P 500's rate of return over the last 25 years. (And I'm not sure if that comparison includes transaction costs, which because of all the turnover in the sector would skin you alive over time).
So, how's that lottery ticket comparison look? If you're looking for the next Amgen or Genentech, well, those are two stocks out of several hundred that have gone public. Those are far better odds than the jackpot in a state lottery, true (although the jackpot has an even more insane rate of return). How about the overall odds of winning, though? Looked at more broadly, most state lotteries will cause you to lose about half of every bet that you put into them (a rate which casino operators can only envy). The figures above suggest that (on an operating basis), biotech has done worse, splitting about 41/59. On a stock investment basis, it appears that you'll make money overall, but not as much as you'd make by parking the same cash in the indices, and I'd call that a loss, myself. You may not think so, but if you don't, please send the difference to me so I can give it to Vanguard myself.
I should mention that the original WSJ article is itself full of comparisons to casinos, Las Vegas, and lotteries. The point, unfortunately, is well taken. Next time, we'll talk about probability of ruin, and things will really start looking grim.
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February 23, 2007
F. A. Cotton died this week, and another gigantic name in chemistry departs. As an inorganic chemist, he was technically outside my field, but no one's really outside the range of influence of someone like that. If you're an organic chemist, you use organometallic reagents and catalysts, and if you use those, you owe F. A. Cotton some appreciation. 50 years of research, 1600 papers, some extremely influential books - he really cleared some brush, and we're unlikely to see his kind again.
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February 22, 2007
An undergraduate reader sends along this request:
I was wondering if you had some recommended readings for a second year student, eg books that you have read and made a palpable impression on you when you were my age.
That's a good question, despite the beard-lengthening qualification of "when you were my age". The books that I would recommend aren't the sort that would require course material that a sophomore hasn't had yet, but rather take a wider view. I would recommend Francis Crick's What Mad Pursuit, for one. It's both a memoir of getting into research, and a set of recommendations on how to do it. Crick came from a not-very-promising background, and it's interesting to see how he ended up where he did.
Another author I'd recommend is Freeman Dyson. His essay collections such as Disturbing the Universe and Infinite in All Directions are well-stocked with good writing and good reading on the subject of science and how it's conducted. Dyson is a rare combination: a sensible, grounded visionary.
Another author to seek out is the late Peter Medawar, whose Advice to a Young Scientist is just the sort of thing. Pluto's Republic is also very good. He was a fine writer, whose style occasionally comes close to being too elegant for its own good, but it's nice to read a scientific Nobel prize winner who suffers from such problems.
I've often mentioned Robert Root-Bernstein's Discovering, an odd book about where scientific creativity comes from and whether it can be learned. I think the decision to write the book as a series of conversations between several unconvincing fictional characters comes close to making it unreadable in the normal sense, but the last chapter, summarizing various laws and recommendations for breakthrough discovery, is a wonderful resource.
Those are some of the ones that cover broad scientific topics. There are others that are more narrowly focused, which should be the topic of another post. And I'd also like to do a follow-up on books with no real scientific connection, but which are good additions to one's mental furniture. I have several in mind, but in all of these categories I'd like to throw the question open to the readership as well. I'll try to collect things into some reference posts when the dust eventually clears.
+ TrackBacks (0) | Category: Book Recommendations | General Scientific News | Who Discovers and Why
There's a whole list of posts below live-blogged from the CMPI conference that I attended on Wednesday, and I think that the organizers will be putting up some audio files of the proceedings soon. It was an enjoyable meeting, and I met a number of interesting people. Since it also involved politics (on which everyone's an expert), the discussion was often livelier than at many scientific conferences. The entry barrier for speaking up about (say) the effect of efflux transporters on toxicokinetics, fascinating subject though that is, is higher than for talking about where the FDA should get its money and how they should spend it.
While in DC, I also got a chance to meet Megan "Jane Galt" McArdle, and we had a nice talk on economics, scientific research, academia, kitchen implements and the eighteenth-century novel. (Get yourself a liberal arts education, and you'll never run out of conversational topics, is my advice). Next time I'm in the area, she threatened to get Tyler Cowen to show up, who will probably take us to some Papuan or Zanzibarean restaurant in a decrepit strip mall. (Not that he's wrong about those being reliable places for good ethnic food).
Blogging will now resume its one-a-day pace here: five per day in real time is about my limit (particularly in a room where there's no place to plug in the laptop - although the CMPI people did well by us in getting wireless access set up outside the hotel's usual exorbitant charges).
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February 21, 2007
The last panel of the day (I missed a good part of one in between, unfortunately) is on the FDA's Critical Path initiative and personalized medicine in general. It's moderated by Greg Simon of FasterCures, and features Michelle Hoffman of Drug Discovery and Development, Robert McBurney of BG Medicine, Gualberto Ruaño of Genomas, John Swen of Pfizer, and Janet Woodcock of the FDA.
Hoffman makes the point that some of the hyper-sceptical reporting of drug and medical issues is a reaction to the genomics hype of a few years ago. (I know, some of you out there who've seen stories that were ripped right from an idiotic press release are wondering where this sceptical reporting is, but I think she's talking about, say, the New York Times.
McBurney spoke about his academic background, saying that he cares even more about data now than he did back then, since millions of dollars are riding on the results. He also mentions the genomic craze, using a good analogy - that a caterpillar and the corresponding butterfly have exactly the same genetic sequence. "I have the same genome I did when I was born," he said, "but some things have changed along the way". His company has recently signed a deal with the FDA to look at preclinical liver toxicity, wirh funding from several large drug companies.
Ruaño is speaking about reverse genomics, "bedside to bench" work for figuring out drug and tox mechanisms. He's summarizing a recent paper in Mol. Psych. on the metabolic effects of antipsychotic drugs - the weight gain and prediabetic symptoms seen in a subset of patients. He and his company did a large parallel search for DNA markers between the patient populations on the two ends of the weight-gain distribution. As it turned out, in olanzapine-treated patients, an ApoE marker was higher in the heavy group, and and ApoE4 one was higher in the lean. For risperidone-treated patients, the leptin receptor and the NPY5 receptor fit the same pattern. They're starting to use their markers prospectively to predict how new patients will respond.
That leads into John Swen's view from Pfizer. He makes the point right at first that he doesn't blame the media for the overhyping of new technologies, as opposed to the people promoting them. (He's got a point, although I'd share the blame out a bit more - compare Michelle Hoffman's view at the beginning of this post). His view of the Critical Path initiatives is that it's going to be long slog to get biomarkers and transitional medicine to work out - worth it, certainly, but not something that's going to start delivering in a short time frame. (No argument here!) He also thinks that we could be doing a lot better than we are in things like new clinical trial designs (which is interesting coming from a company that's run the first large published Bayesian clinical trial).
And finally, Woodcock of the FDA is being asked about how the whole Critical Path initiative is going to fare at its current level of funding. She also feels that the media are very cynical about the sorts of technologies that are being promoted, which corroborates the over-reaction theme. She also says that the parts of the scientific community that are "more vested in the reductionist model" are also pushing back a bit. (My take is that the minute something useful comes out of the whole personalized medicine field, most of the critics will shut up with great alacrity. Success has a thousand fathers, for sure, and nowhere more than in a drug company). She largely dodges the funding question, saying that's it not really the agency's job to lobby for funds, but says that the biggest obstacle she faces right now is getting enough reviewer time to evaluate proposals properly. She thinks that the single best use of the money, though, is personalized medicine (which I find a bit arguable at this point, but eventually she may well be right).
+ TrackBacks (0) | Category: Current Events | Press Coverage | The Central Nervous System
The third conference is on the CATIE and ALLHAT trials, the large comparative studies of antipsychotic and hypertensive medications. These studies are taking a real beating, I have to say. Herbert Meltzer of Vanderbilt took on the CATIE work, saying that its design was too complex and tried to do too many things at once. He pointed out that the study's results - that older and newer antipsychotics were essentially equivalent - is very much at odds with evidence-based medicine. He says that its conclusions haven't had that much effect with clinicians, because it's so at variance with their experience.
Michael Weber of SUNY-Downstate has a lot of bad things to say about the ALLHAT study, too. He points out that the HAT part stood for "Heart Attack Treatment", and that although the diuretic treatment group showed somewhat better blood pressure data, the heart attack outcomes were no different. His other surprising claim was that a large number of African-American trial subjects ended up in groups that did not meet the best standard of care for that population, and asked what would have happened if a drug company ran a similar trial. He was clearly frustrated with the initial coverage of the results in places like the New York Times, which he said were the result of a very well-planned press offensive by the study's authors.
Ralph Snyderman of Duke spoke about the problem of working on complex diseases that aren't driven by a single molecular defect (which, more and more, is what we're left to work on). These things are terribly heterogeneous, on more than one level - for instance, referring to his specialty, he said that as far as he's concerned rheumatoid arthritis is at least three diseases, and perhaps as many as six or seven.
Susan Horn of the Institute for Clinical Outcomes Research made the case for "practice-based medicine", trying to work out the real-world effects of compounds after they've been launched. Meltzer wasn't so sure about how well these sorts of studies replicate, though.
In other news, Matt Herper of Forbes has reluctantly admitted that he doesn't find medical journals to be the most exciting reading in the world - his challenge is turning these results into things that people will read voluntarily. He had a great quote about the difficulty of turning ambiguity into a story, mimicing an editor: "What you you mean these experts don't know? Call them back and get them to tell you!"
Post updated in sections - I've been recharging my laptop batteries - DBL
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Now I'm listening to Andy von Eschenbach, the new FDA commissioner, who's giving a speech on communication and regulation. I think I can refer to him as "Andy", since I'm eating a ham and cheese sandwich in front of him (not to mention blogging his speech).
The main thing I've taken away is that the agency plans to announce some new outlets and methods to disclose information - he's not ready to say what those are yet, but promises that details will be forthcoming. Now questions are coming from the floor - the first one is on direct-to-consumer ads and the recent recommendations by the Institute of Medicine. von Eschenbach answers by saying that the FDA has to recognize the right to free speech, but has to make sure that things are factual. (Not the time to get into a discussion of commercial speech, clearly).
Answering another question, von Eschenbach seems to want to move the FDA away from a reactive stance on drug-safety issues. That's probably a good idea, but considering the kinds of events that bring these things to the front page, reaction is surely always going to be a big part of the process.
Now there's a question about the adverse event reporting system - how to make it useful without overloading people. (This was a feature of the second panel discussion). He's answering that adverse events are only part of the problem - there's unexpected efficacy as well, and any system needs to be able to pick up on all sorts of events. (I agree, but I think that the former will always far outweight the latter).
Now a representative of PhRMA is asking about transparency - as an MD, he's contrasting the open discussion at at mortality and morbidity conference among physicians with what takes place at the FDA/national press level. von Eschenbach replies that acquiring the data is only the first step, and that transforming raw information into knowledge needs to be more transparent. He's saying that the general public wants the end product, not so much all the raw data. (I'd add that these days there will always be people, far between but very committed and vocal, who will want to see the raw numbers, too).
An attendee from Pharmaceutical Executive magazine asks about making sure that different points of view are considered, and on whistleblowers in general. von Eschenbach's reply is that he'd like to have things run so that people wouldn't feel the need to go outside the usual processed. "If people wanted Andy von Eschenbach to do everything himself," he says, "there would just be the Andy Agency". He expects people to adhere to the way the FDA does business, and wants them to come to him if they have a problem.
Steve Projan of Wyeth is now saying that the FDA doesn't seem to have the resources to do what it wants to do, and asks about the renewal of the PDUFA legislation. (There's a whole panel on that in the afternoon). von Eschenbach's reply isn't very specific, as probably befits an issue that's the subject of current legislative wrangling. He regards PDUFA fees as straight fee-for-service, and regards them as useful, but only one part of his resourcing.
The last two questions are on drug labels - the questioner is asking about the inclusion of genomic information on warfarin and tamoxifen labels. And the final question is on regulation of diagnostic test regulation, and the burden on direct-to-consumer genetic tests - the questioner is saying that many primary care physicians aren't that well trained in genetics, and that these tests might as well go to the consumer rather than using the MD as a gatekeeper. "Uh. . .how much time do I have left?" says von Eschenbach, mock-nervously.
He answers that drug labels are changing constantly, and that the agency has to be certain that any infomation that's given out so broadly is really accurate and valuable. He says that the various "omic" disciplines are going to have to make sure that they've got very well established data before it can go on a drug label, but that he knows that this is coming on. As for the regulatory burden on tests, he seems leery of turning these things loose on the public, and would rather have these "integrated into the medical model".
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The second panel is going on now, moderated by Steve Usdin of BioCentury, and featuring Helen Boucher of Tufts, Frank Burroughs of the Abigail Alliance, Scott Gottleib of the American Enterprise Institute, and Steve Projan of Wyeth.
One subject that's coming up a lot (as it did in the first panel) is the associate of SSRI therapy with suicide (or suicidality). That's a good example of the tricky nature of drug regulation, crossing over from pre-approval to marketed compounds. Some of the earlier panelists (and questioners from the audience) bemoaned the media coverage on the issue - the current panel is talking about it as an example (some parts good, some bad) of how to study ongoing safety issues, with a big problem being who's going to pay for such things. Surveillance, everyone agrees, is probably the best way to get useful data on drugs and their performance in the real world, but (as has been pointed out), no one wants to hear about how that's surely going to drive up drug costs.
Other areas coming up are antibiotics (and the dearth of new ones) and off-label use of cancer therapies (and other drugs) and how much to regulate it.
The conflict between openness and giving lawyers bait to sue everyone is also being discussed - tort reform has been referred to more than once, as you'd figure. The debate about whether you want to report only data that's reached statistical significance has shown up as well (I think that the alternative is chaos, personally, but not everyone agrees).
Steve Projan made a good point about the problems with Ketek (which, as others have noted, haven't had anywhere near the coverage that the Vioxx problems did). As he says, if you drop Ketek and switch to ampicillin, you'll end up killing more people through anaphylactic shock.
Note: post edited after original version, to incorporate more info - DBL
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Well, I'm sitting in the audience now at the CMPI conference. My panel was the first of the day, and was pretty lively. Moderated by Rob Pollock of the Wall Street Journal, it featured Ed Silverman of the Newark Star-Ledger (and now of the very useful Pharmalot, Paul Coplan (who does risk managment at Wyeth), Tim Hunt (public affairs at Biogen-Idec), and Paul Seligman (safety policy at the FDA), and Diedtra Henderson of the Boston Globe.
Vioxx was a big point of discussion, as an example of media reporting on medical and pharma issues. There was a noticeable split between the reporters on the panel and the pharma people on this - the discussion was civil, but you could see the differences in opinion on how well the issue had been covered. With Biogen represented, the Tysabri withdrawal (and return) was also a big topic.
I suppose the main point I'd make in reference to that split came when Ed Silverman mentioned that a good thing that came out of the Vioxx coverage was that it started debate, and that that was always a good thing. I agreed with him, up to a point, adding, though, that I thought that informed debate was more useful. My problem with much of the Vioxx coverage was (as I said about that Michael Crichton op-ed the other day) that it made people feel as if they'd been informed when they hadn't been.
There was general agreement that risk/reward (especially absolute risk versus relative risk) was a key concept in reporting these things, but that it could be difficult to get across to a general readership. The other agreement was the companies should try to be as open as possible about clinical data and adverse events, with (naturally) different ideas about where the cutoff of possibility would fall.
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February 20, 2007
I have some down time here at the Hartford airport, which gives me a chance to talk about one of the routine, but pleasurable, things about doing organic chemistry: making stuff. By that I mean making something that most certainly wasn't there when you started.
For example, in the post the other day about the odors of various lab solvents, someone mentioned 2,2-dimethoxypropane. That's not in my top five, but it is pretty nice, and certainly distinctive. You can buy it by the liter, but it's also not hard to make (as grad students in underfunded academic labs know). You take some acetone, which as I mentioned the other day has a clear, strong solvent smell to it, and some me