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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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January 5, 2012

Lead-Oriented Synthesis - What Might That Be?

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Posted by Derek

A new paper in Angewandte Chemie tries to open another front in relations between academic and drug industry chemists. It's from several authors at GSK-Stevenage, and it proposes something they're calling "Lead-Oriented Synthesis". So what's that?

Well, the paper itself starts out as a quick tutorial on the state and practice of medicinal chemistry. That's a good plan, since Angewandte Chemie is not primarily a med-chem journal (he said with a straight face). Actually, it has the opposite reputation, a forum where high-end academic chemistry gets showplaced. So the authors start off by reminded the readership what drug discovery entails. And although we've had plenty of discussions around here about these topics, I think that most people can agree on the main points laid out:

1. Physical properties influence a drug's behavior.
2. Among those properties, logP may well be the most important single descriptor,
3. Most successful drugs have logP values between 1 and perhaps 4 or 5. Pushing the lipophilicity end of things is, generally speaking, asking for trouble.
4. Since optimization of lead compounds almost always adds molecular weight, and very frequently adds lipophilicity, lead compounds are better found in (and past) the low ends of these property ranges, to reduce the risk of making an unwieldy final compound.

As the authors take pains to say, though, there are many successful drugs that fall outside these ranges. But many of those turn out to have some special features - antibacterial compounds (for example) tend to be more polar outliers, for reasons that are still being debated. There is, though, no similar class of successful less polar than usual drugs, to my knowledge. If you're starting a program against a target that you have no reason to think is an outlier, and assuming you want an oral drug for it, then your chances for success do seem to be higher within the known property ranges.

So, overall, the GSK folks maintain that lead compounds for drug discovery are most desirable with logP values between -1 and 3, molecular weights from around 200 to 350, and no problematic functional groups (redox-active and so on). And I have to agree; given the choice, that's where I'd like to start, too. So why are they telling all this to the readers of Angewandte Chemie? Because these aren't the sorts of compounds that academic chemists are interested in making.

For example, a survey of the 2009 issues of the Journal of Organic Chemistry found about 32,700 compounds indexed with the word "preparation" in Chemical Abstracts, after organometallics, isotopically labeled compounds, and commercially available ones were stripped out. 60% of those are outside the molecular weight criteria for lead-like compounds. Over half the remainder fail cLogP, and most of the remaining ones fail the internal GSK structural filters for problematic functional groups. Overall, only about 2% of the JOC compounds from that year would be called "lead-like". A similar analysis across seven other synthetic organic journals led to almost the same results.

Looking at array/library synthesis, as reported in the Journal of Combinatorial Chemistry and from inside GSK's own labs, the authors quantify something else that most chemists suspected: the more polar structures tend to drop out as the work goes on. This "cLogP drift" seems to be due to incompatible chemistries or difficulties in isolation and purification, and this could also illustrate why many new synthetic methods aren't applied in lead-like chemical space: they don't work as well there.

So that's what underlies the call for "lead-oriented synthesis". This paper is asking for the development of robust reactions which will work across a variety of structural types, will be tolerant of polar functionalities, and will generate compounds without such potentially problematic groups as Michael acceptors, nitros, and the like. That's not so easy, when you actually try to do it, and the hope is that it's enough of a challenge to attract people who are trying to develop new chemistry.

Just getting a high-profile paper of this sort out into the literature could help, because it's something to reference in (say) grant applications, to show that the proposed research is really filling a need. Academic chemists tend, broadly, to work on what will advance or maintain their positions and careers, and if coming up with new reactions of this kind can be seen as doing that, then people will step up and try it. And the converse applies, too, and how: if there's no perceived need for it, no one will bother. That's especially true when you're talking about making molecules that are smaller than the usual big-and-complex synthetic targets, and made via harder-than-it-looks chemistry.

Thoughts from the industrial end of things? I'd be happy to see more work like this being done, although I think it' going to take more than one paper like this to get it going. That said, the intersection with popular fragment-based drug design ideas, which are already having an effect in the purely academic world of diversity-oriented synthesis, might give an extra impetus to all this.

Comments (34) + TrackBacks (0) | Category: Chemical News | Drug Assays | Drug Development | The Scientific Literature


COMMENTS

1. Capek on January 5, 2012 9:16 AM writes...


I find it interesting and worthwhile to learn about the type of chemistry that is critical to advancing the goals of researchers in the pharmaceutical industry. But I balk at the notion that academic researchers should shift their priorities accordingly. We typically pursue synthetic strategies and targets that will elucidate fundamental principles or will be otherwise instructive and enabling. Perhaps these don't necessarily overlap that often with the attributes required to feed a drug discovery pipeline. That troubles me not one whit. If GSK wants to develop synthetic methodologies that will provide an additional 30,000 compounds to fall within the criteria that they deem important, they should certainly hire the chemists to enable those discoveries.

So I'm glad to learn that GSK doesn't find my research of particular value. That's fine. To be honest, our incoming graduate students have not been expressing much desire to obtain training for drug discovery anyway. I wonder why.

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2. marcello on January 5, 2012 9:34 AM writes...

UGI

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3. marcello on January 5, 2012 9:39 AM writes...

If you are in academic in the synthetic methodology business than you will be recognized in the future (e.g. Nobel prize) for methodologies that were useful and simple, but very atom efficient in the same time: Heck, Diels and Alder, Ugi, Suzuki, etc. etc.

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4. Tim McDaniel on January 5, 2012 10:08 AM writes...

Drat! From the headline, I was expecting Things I Won't Work With with new results on Pb and other toxic heavy metals.

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5. h21n on January 5, 2012 10:15 AM writes...

As #1 said, perhaps they should spend their money on hiring chemists instead of firing them. Oh, I forgot, that's what gets you a knighthood these days...

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6. Biotechtranslated on January 5, 2012 10:28 AM writes...

Anyone concerned about the fact that medicinal chemistry is now so burdened with rules on what a drug should look like (especially among the big pharmas) that we're missing out on important new discoveries?

It's called drug "discovery", not drug "find another similar one". I just wonder if you spend all your time under the streetlight looking for the money you dropped that you never notice the $100 bill in the shadows.

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7. LeadEyeDee on January 5, 2012 10:35 AM writes...

Wonderful paper, it makes many excellent points. A few thoughts:

1) The poor profiling of the arrays really ought to concern us, since these in theory are made with an eye towards Lead ID. The problem arises from the way chemists become enamored by complex and beautiful scaffolds, which consume most of their MW allowance. This in turn flows from the scaffold diversity arguments made by folks at Serono among others: that scaffold diversity is the main driver of shape diversity and hit rate. Yes, more scaffolds is better than less, but capping groups also play a large role in determining shape, and they are available in incredible numbers and diversity. But rather than tap into that resource, the academic libraries often will use a handful of fairly simple monomers to elaborate their complex scaffolds. Use of bigger and more complex monomers would blow up the property profile since the scaffold is already so big. Incidentally, hats off to Krchnak at Notre Dame for making several arrays that score well in this analysis. His group really focuses on elegant, atom-economical array chemistry.

2) The whole concept of logP drift is a good one, but we should remember the underlying assumptions: property drifts arise largely from yield and purity constraints. The lower logP compounds fall out because they cannot be isolated in the required purity and yield. These constraints in turn arise from the sensitivity of high-throughput assays to impurities, reagents, reactive intermediates, etc, basically from the long sorry history of mixture screening of combichem libraries. But direct affinity-based methods do not suffer from the same limitations. Mass-encoding, fragment screening by x-ray or NMR, and DNA-encoding are just a few of the methods in which the identity of a compound is determined directly by its interaction with target, rather than by its position on a plate. These methods ought to be more tolerant of mixtures and impurities. Therefore, if we changed our screening paradigms, we could afford more flexibililty on the synthetic end, and get a lot more shots on goal with nice-looking compounds. Only if they hit would we have to go find an efficient way to synthesize them.

Anyhow, it was thought-provoking paper, kudos to the GSK team for putting it out there.

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8. anchor on January 5, 2012 11:24 AM writes...

#6 spot on! Medicinal chemists are not obliged to follow a "picky way" to make drug discovery happen. There are rules, do’s and do not and the rest is to find his/her way out. When the smoke clears and, If your drug molecule shows efficacy without any AE, who cares?

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9. drug_hunter on January 5, 2012 1:00 PM writes...

Is there anything new in this paper? What's the key new insight?

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10. anon the II on January 5, 2012 1:19 PM writes...

As I was reading this article, I got that old déjà vu all over again It reminded me of the DOS article that Schreiber wrote a long time ago in that there was a lot of talk to restate the obvious. I don't really see them asking for anything new except to get credit for a new acronym, LOS.

I think maybe I'm just becoming an old curmudgeon over this drug discovery stuff. It's gonna get harder and harder to discover new drugs with fewer people making molecules. What we need is More Organic Synthesis, done by more people. I'll call it MOS

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11. Brian JW on January 5, 2012 2:41 PM writes...

anon the II # 10

But Schreiber isn't a medicinal chemist! The dross that is often DOS has been discussed many times on this blog to be as useless for drug discovery as combinatorial chemistry ever was (ie big, ugly, reactive molecules that you just can't turn from a micromolar hit into a drug). I like your idea of MOS, but it has to be the right sort of MOS - no point in making more rubbishy compounds...maybe try making ones that are actually useful for drug discovery, which is what I think they mean by LOS.

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12. Hap on January 5, 2012 2:56 PM writes...

GSK certainly has lots of their own money, both for internal research and for collaborations with outside groups. For research projects that don't necessarily have general applicability or utility (in a manner of speaking) as fundamental science, either of those would seem to be a more reasonable option.

With the jobs that the people currently in school doing research migrating elsewhere, it seems like an unfortunate time to recruit more students to do research that doesn't seem to have a future here (and to spend part of a likely-to-be-shrinking pot of money for biomedical applications to do it). In addition, if the researchers elsewhere are good enough to discover and make your drugs, why can't they solve your research problems?

On the other hand, funding methods for synthesis of leads would probably be more useful than making maitotoxin, and we're already spending that money. I just tend to be cynical about companies hoping for someone to socialize their costs (while in all likelihood keeping their benefits private).

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13. Myma on January 5, 2012 3:39 PM writes...

@4 Tim
I was also a sentence and half into when I realized the blog was not going to be about "lead" as in Plumbum.

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14. Dumbing Done on January 5, 2012 4:17 PM writes...

An inevitable outcome of the progressive outsourcing of synthetic expertise - GSK is left cajoling academia into acting as a pliant component-provider to its own internal "drug-assembly" chemistry. The comparison with modern car manufacturing seems appropriate.


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15. Boghog on January 5, 2012 4:19 PM writes...

#1: I think you have missed the point. At least in the US, a lot of funding for synthetic organic chemistry has come from the NIH with the implicit assumption that this research will "enable" medicinal chemistry. "Elucidation of fundamental principles" is more in the realm of physical organic chemistry which is typically funded by other agencies like the NSF.

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16. Puzzled on January 5, 2012 4:30 PM writes...

I must be missing something.

These type of articles often hark back to a Golden Age when medicinal chemists made molecules with great physical properties and were duly rewarded with successful drugs....

So what Chemistry was used to synthesise those?



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17. Boghog on January 5, 2012 4:35 PM writes...

#6 and #8: The evidence at this point is overwhelming that lower molecular weight and lower log P compounds have a lower attrition rate in clinical trials. You may find a molecule that breaks these rules and looks great in animals models, but taking this molecule into clinic increases the chance it will fail. These clinical failures are killing the industry and therefore it is quite understandable why big pharma is paying more attention to physicochemical properties.

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18. Recyling on January 5, 2012 4:44 PM writes...

Re. the observed "cLogP drift" within Industry labs...

I blame the universal adoption of automated reverse-phase chromatography. Defaulting to purification using a C18 stationary phase was always going to favour more lipophilic products.

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19. Capek on January 5, 2012 9:20 PM writes...

Boghog:

I don't care if the funding comes from the NSF, NIH, DOE, or OTB. My priority is to guide my students towards projects that reveal broad physicochemical principles and conceptual insights, not narrow physicochemical properties and commercial outcomes.

We call it graduate *school* for a reason. We're supposed to be teaching something. Or maybe you missed that point.


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20. pharmadude on January 5, 2012 9:47 PM writes...

In the world of big pharma this paper counts as intellectual thinking.

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21. Anonymous on January 6, 2012 1:24 AM writes...

Conveniently, the authors make a point of saying the molecules found in several ACS, ElSevier, and Thieme journals are not useful, but only include a single journal from Wiley (and none from RSC). Coincidence, I'm sure.

I agree with Capek. What motivation might students possibly have to try and get into pharma these days? Gearing academic research towards drug discovery would only give trolls like Sir Witty an opportunity to lay off more scientists in favor of inexpensive homegrown labor (ie; grad students). All the cost savings of outsourcing without the troublesome distance in between.

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22. Anonymous on January 6, 2012 2:25 AM writes...

Repackaging old medicinal chemistry concepts to patronise academics. We should lead by example rather than sit on side lines and criticise what others do. What exactly have these authors delivered? Perhaps they should read some more literature and see what groups like McMillan are doing to generate lead structures in relevant phys.chem space.

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23. Molecule on January 6, 2012 4:24 AM writes...

I have often seen people from industry and also many from academics talking against DOS and saying ´one should make right kind of molecules´...do you know what is right kind? had the industry or you guy known this..you won´t be wasting time in bashing other howsoever useless approaches to target howsoever boring chemical space. By the way, I am not a Schreiberphile for your information and how does it matter.....

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24. Anonymous on January 6, 2012 5:56 AM writes...

Capek: Graduate school has two purposes: (1) teaching/training and (2) producing research discoveries that will benefit society. Of course, the applications of a particular discovery are often unforeseen, and hence a portion of research funding should be devoted to more basic science where the applications may not be immediately obvious.

Like it or or not, organic synthesis is largely an applied science, and the reason most organic synthesis research is funded is to provide enabling technology to support specific applications in areas such as drugs, foods, plastics, explosives, and paints.

One of the points of the Angewandte Chemie paper is that the types of compounds that academics produce tend to have a narrow physicochemical range as measured by log P (i.e., mainly high log P compounds). The authors suggest that academics develop new reactions (and per LeadEyeDee #7 purification procedures) that will broaden the range of compounds that can easily be synthesized.

Finally I do not see why revealing "broad physicochemical principles and conceptual insights" and developing chemistry to produce more lead-like compounds is mutually exclusive.

# 16 Puzzled: Excellent point.
A significant portion of early total synthesis work was devoted to making low molecular weight polar natural products which just happen to be lead-like. One of the reasons (and admittedly a minor reason) why the pharmaceutical industry is currently in such a mess is that modern organic synthesis has become very adept at making greasy molecules that have high attrition rates in clinic.

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25. noname on January 6, 2012 11:17 AM writes...

Man, a lot of haters out there. People can connect the lay-off situation to just about any post nowadays. I mean really, connecting a discussion of phys-chem properties to Sir Witty and layoffs smacks of obsession.

I'm surprised to see there are still people who seem to believe that the property rules are creativity-stifling, bureacratic causes of the industry's woes. The data is the data my friends, attrition is expensive and its odds increase with bad properties. There are exceptions, but anecdotes cannot defeat statistics. To think otherwise is unscientific.

Why all the resistance? I think it's the dominanace that nat prod synthesis has had over the o-chem community for the last 50 years. If your target doesn't have 10 stereocenters, a macrocycle, and a few quats, then it's just not sexy. Too bad that molecules like that just don't have a lot of value to society, except (as Capek readily admits) as training exercises. (I can hear everyone screaming Taxol! Rapamycin! Artimesinin! Tools! But compared to the countless total syntheses out there these are drops in the ocean).

The branches of chemistry that actually deal with polar and highly functionalized compounds are peptide and carbohydrate chemistry. These branches of synthesis have much more focus on seemingly boring handling logistics, like solubility, protection/deprotection, purification, etc. than the nat prod folks, whose compounds are most likely soluble in ether. But practitioners of these branches, particularly the peptide folks, are viewed as "lesser chemists" by most of the community (you know it's true).

Perhaps if the industry stopped hiring yet another Corey post-doc, and started people who've actually purified a compound by ion-exchange, they'd see their properties improve.

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26. Boghog on January 6, 2012 12:17 PM writes...

(note: #24 is my post which I forgot to sign. Sorry.)

#25 noname: Concerning attrition and bad properties, very well put. I would also agree that peptide and carbohydrate chemistry, while looked down on, has provided valuable methods and training for working with polar compounds. Also the comments (#3 and #7) concerning atom efficient chemistry less dependent on protecting groups is very relevant. Development of green chemistry that can be run in aqueous conditions which by definition must be tolerant of reactive functional groups (i.e., water). This same chemistry should in principle assist the synthesis of compounds with improved physchem properties.

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27. Capek on January 6, 2012 1:51 PM writes...


I was instructed, and firmly believe, that the role of PhD students is not to identify and develop new drugs. That is the role of the pharmaceutical industry. Our role is to conduct the scientific inquiries that will lead to new paradigms in drug discovery.

It's important for me to know what compounds are currently considered suitable to funnel into the drug discovery pipeline. It's not my mission, or my students' obligation, to feed that pipeline. We are probably doing our job best when we make compounds that *don't* look like drugs to industry scientists. If and when we convince the community that they are suitable drug candidates, we should probably move on to another field of inquiry.

I would have a much less jaundiced view of the landscape if there wasn't such massive disinvestment in basic research. I don't appreciate being summoned to fix a broken business model. Ideally, we would be addressing our objectives, while the industrial chemists would nimbly be generating compounds that meet their commercial criteria. Even more ideally, we would be able to appreciate our mutually complementary goals.

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28. Boghog on January 6, 2012 2:37 PM writes...

@Capek: Again, I think you have missed the point. I totally agree with you that the primary role of academic organic chemistry is not to fill the pipeline. However a new "paradigm in drug discovery" could legitimately include development of more robust reactions (e.g., green chemistry) that industrial medicinal chemists could later apply to produce compounds with better physicochemical properties.

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29. Martin on January 6, 2012 3:30 PM writes...

@Capek - I'd be flattered: it seems to me that pharma has finally realized it can't do everything itself and is asking us clever academic chemists to consider turning our intellectual talents to think of ways of making diverse, physchem-constrained molecules affordably.

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30. Hap on January 6, 2012 3:41 PM writes...

But that requires money and people - if you're cutting the jobs that attract people to research, and playing in a funding environment which is (or will shortly become) a zero-sum game, then you have to take them from somewhere else. Total synthesis might be a good place, if you can convince the people on grant boards that lead-oriented synthetic methods are a better place for utility, money, and glory than TS.

The layoffs factor into the equation twice. Trying to attract people to do the research which pharma seems to be counting on to deliver useful methods for drug development is much more difficult when jobs that use the skills developed there seem to be disappearing. In addition, the tax money that would be funding that research is going away, either because the payrolls generating that tax money are decreasing or because the tax incentives necessary to keep payrolls stable cost money that can't be spent there.

Crich seems to have made a decent career in carbohydrates, and other people (Nicolaou) have done decent work there - I don't know if their students are getting jobs. though. Alkaloids attract lots of synthetic talent but handling them is (apparently) a PITA (hence the "add one year to your PhD for every nitrogen in your molecule" for TS people). Hudlicky, in particular, has complained about the poorly defined isolation and purification techniques for alkaloids.

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31. Realist on January 7, 2012 4:27 PM writes...

I agree with Boghog and Martin that some people have missed the point. The article's pointing out a need for the discovery of new types of chemistry to make more drug-like molecules, not asking you to identify drugs. Seems to me that'd be a perfectly proper thing for academics to do and that they'd be better at doing this kind of exploratory stuff than industry. It's also fair enough for industry to point out the need. I don't see the problem and I don't see the need for all the bitchy comments and juvenile remarks insinuating that one side is cleverer than the other.

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32. DrSnowboard on January 9, 2012 4:15 PM writes...

The dirty little secret that this paper does acknowledge is that array synthesis with a common methodology leads to enrichment in less polar products as the polar functionality 'tends' to make those analogues fail / difficult to purify.
So make what you NEED/WANT to make rather than just what you CAN make, easily. Invest the time in the difficult analogues, that tell you something when you've made them.

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33. Professor Salt on January 10, 2012 10:22 PM writes...

Like it matters? We'll still all be unemployed soon anyway.

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34. Hap on January 12, 2012 12:33 PM writes...

I'm wondering if the authors are barking up the wrong tree - it's hard to develop chemistry for polar compounds when your methods don't allow you to isolate and purify them easily. Perhaps spending some money in analytical chemistry would help to develop better detection and purification techniques for polar compounds, or make the techniques more available and user-friendly if they do exist. If you can develop the methods, you can more easily apply combinatorial reaction discovery methods with them, develop reaction methodologies useful to make things they can detect and purify, and sic natural products chemists on heinous alkaloids, depsipeptides, or carbohydrates to get better chemistry.

Chemistry mattered when it was the side project of wealthy people, and it will matter even after/if our jobs have gone elsewhere. It'll matter until we've found everything or until the world ends, and even then maybe it'll matter somewhere else. Whether we'll be able to make a living doing it (or will want to) and whether we can use its skills to do something else worthwhile is no longer so certain, but even then chemistry will matter to someone.

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