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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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July 23, 2012

Science Fiction Gets the Upper Hand

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Posted by Derek

I wrote here about the Cronin lab at Glasgow and their work on using 3-D printing technology to make small chemical reactors. Now there's an article on this research in the Observer that's getting some press attention (several people have e-mailed it to me). Unfortunately, the headline gets across the tone of the whole piece: "The 'Chemputer' That Could Print Out Any Drug".

To be fair, this was a team effort. As the reporter notes, Prof. Cronin "has a gift for extrapolation", and that seems to be a fair statement. I think that such gifts have to be watched carefully in the presence of journalists, though. The whole story is a mixture of wonderful-things-coming-soon! and still-early-days-lots-of-work-to-be-done, and these two ingredients keep trying to separate and form different layers:

So far Cronin's lab has been creating quite straightforward reaction chambers, and simple three-step sequences of reactions to "print" inorganic molecules. The next stage, also successfully demonstrated, and where things start to get interesting, is the ability to "print" catalysts into the walls of the reactionware. Much further down the line – Cronin has a gift for extrapolation – he envisages far more complex reactor environments, which would enable chemistry to be done "in the presence of a liver cell that has cancer, or a newly identified superbug", with all the implications that might have for drug research.

In the shorter term, his team is looking at ways in which relatively simple drugs – ibuprofen is the example they are using – might be successfully produced in their 3D printer or portable "chemputer". If that principle can be established, then the possibilities suddenly seem endless. "Imagine your printer like a refrigerator that is full of all the ingredients you might require to make any dish in Jamie Oliver's new book," Cronin says. "Jamie has made all those recipes in his own kitchen and validated them. If you apply that idea to making drugs, you have all your ingredients and you follow a recipe that a drug company gives you. They will have validated that recipe in their lab. And when you have downloaded it and enabled the printer to read the software it will work. The value is in the recipe, not in the manufacture. It is an app, essentially."

What would this mean? Well for a start it would potentially democratise complex chemistry, and allow drugs not only to be distributed anywhere in the world but created at the point of need. It could reverse the trend, Cronin suggests, for ineffective counterfeit drugs (often anti-malarials or anti-retrovirals) that have flooded some markets in the developing world, by offering a cheap medicine-making platform that could validate a drug made according to the pharmaceutical company's "software". Crucially, it would potentially enable a greater range of drugs to be produced. "There are loads of drugs out there that aren't available," Cronin says, "because the population that needs them is not big enough, or not rich enough. This model changes that economy of scale; it could makes any drug cost effective."

Not surprisingly Cronin is excited by these prospects, though he continually adds the caveat that they are still essentially at the "science fiction" stage of this process. . .

Unfortunately, "science fiction" isn't necessarily a "stage" in some implied process. Sometimes things just stay fictional. Cronin's ideas are not crazy, but there are a lot of details between here and there, and if you don't know much organic chemistry (as many of the readers of the original article won't), then you probably won't realize how much work remains to be done. Here's just a bit; many readers of this blog will have thought of these and more:

First, you have to get a process worked out for each of these compounds, which will require quite a bit of experimentation. Not all reagents and solvents are compatible with the silicone material that these microreactors are being fabricated from. Then you have to ask yourself, where do the reagents and raw materials come in? Printer cartridges full of acetic anhydride and the like? Is it better to have these shipped around and stored than it is to have the end product? In what form is the final drug produced? Does it drip out the end of the microreactor (and in what solvent?), or is a a smear on some solid matrix? Is it suitable for dosing? How do you know how much you've produced? How do you check purity from batch to batch - in other words, is there any way of knowing if something has gone wrong? What about medicines that need to be micronized, coated, or treated in the many other ways that pills are prepared for human use?

And those are just the practical considerations - some of them. Backing up to some of Prof. Cronin's earlier statements, what exactly are those "loads of drugs out there that aren't available because the population that needs them is not big enough, or not rich enough"? Those would be ones that haven't been discovered yet, because it's not like we in the industry have the shelves lined with compounds that work that we aren't doing anything with for some reason. (Lots of people seem to think that, though). Even if these microreactors turn out to be a good way to make compounds, though, making compounds has not been the rate-limiting step in discovering new drugs. I'd say that biological understanding is a bigger one, or (short of that), just having truly useful assays to find the compounds you really want.

Cronin has some speculations on that, too - he wonders about the possibility of having these microreactors in some sort of cellular or tissue environment, thus speeding up the whole synthesis/assay loop. That would be a good thing, but the number of steps that have to be filled in to get that to work is even larger than for the drug-manufacture-on-site idea. I think it's well worth working on - but I also think it's well worth keeping out of the newspapers just yet, too, until there's something more to report.

Comments (29) + TrackBacks (0) | Category: Academia (vs. Industry) | Chemical News | Drug Assays


COMMENTS

1. cookingwithsolvents on July 23, 2012 9:16 AM writes...

I don't know about in your house but point fabrication of substances (e.g. at the local drug store) certainly is a possibility in the future.

It won't be as simple as getting a custom paint at home depot but certainly it's within the realm of possibility. Whether or not it's within the realm of regulatory possibility, for drugs at least, is a whole other discussion. Pills are worth a lot more and are a lot lighter than paint+cans and an almost-magic synthesizer won't be cheap either, so the economics will also weigh in.

Totally the kinds of things that visionary, long-term research should be exploring, though.

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2. Twelve on July 23, 2012 9:34 AM writes...

If somebody offers to bet you that this is how drugs will get to the patient in a few years or so, take the bet - any odds. To paraphrase a famous New Yorker cartoon (albeit on a different topic): "Is never a good time for you?".

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3. David Formerly Known as a Chemist on July 23, 2012 9:50 AM writes...

"There are loads of drugs out there that aren't available," Cronin says, "because the population that needs them is not big enough, or not rich enough. This model changes that economy of scale; it could makes any drug cost effective."

Spoken like a true academician that has never stepped foot in a pharma research environment. These "loads" of drugs aren't available because the cost of discovering and developing them are hard to justify given the limited market sizes. As WE all know, the cost of physically synthesizing such a drug is nearly negligible, it's all the lab research and clinical development (especially the latter) that results in these loads of drugs not being available.

Hyperbole on a grand scale!

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4. cirby on July 23, 2012 9:51 AM writes...

Of course, the first step by the government will be to ban or heavily restrict these things.

I they're even vaguely useful, the first real-world applications will be more like "Breaking Bad" than anything.

"Hey, we can make all sorts of potential new drugs. Or we can just crank out a whole bunch of meth to pay the bills."


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5. Tom Phillips on July 23, 2012 10:09 AM writes...

"I think it's well worth working on - but I also think it's well worth keeping out of the newspapers just yet, too, until there's something more to report."

Indeed. My first thought after reading the article was "who wrote this?" because the it doesn't really challenge anything Cronin says. Turns out it was an Observer staff writer who doesn't normally write about science (based on some Googling). I think we would be reading a very different article if it had been written by science journalists.

(As a pedantic aside, I personally wouldn't call them microreactors because that would imply that they have the benefits of miniaturisation, e.g. fast mass and heat transfer, but the reactors are actually centimetres in dimension, so basically a small RBF.)

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6. processchemist on July 23, 2012 10:16 AM writes...

"he wonders about the possibility of having these microreactors in some sort of cellular or tissue environment, thus speeding up the whole synthesis/assay loop"

What's the problem? Whith the right nanotech we can do anything, and we can engeneer the right stem cell or venter's bug line to take care of the details...

The true problem is that hype addiction has two sides (scientists and the public), and for media operator selling junk it's a lot easier than anything else...

About point fabrication, it's a fascinating concept mindlessy mutuated by point energy production by solar power or wind. But while the light of the sun and the wind are universally available at no price (and so the only cost is the hardware), the unit cost of the simplest drug substance you may think of (where starting materials are not for free and not ubiquitous) is subject to scale economy.
BTW a 50 ml round bottom flask is cheaper than any 3-D silicone printed reactor you can think of... maybe not so cool, but cheaper, for sure.

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7. DLIB on July 23, 2012 10:28 AM writes...

It's fun to create problems then create the solutions to them.

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8. noname on July 23, 2012 10:57 AM writes...

--which would enable chemistry to be done "in the presence of a liver cell that has cancer, or a newly identified superbug"--

So all I need to do is add some E. coli. to my next Buchwald coupling and the product will be an antibiotic?

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9. Distantdiamond on July 23, 2012 11:12 AM writes...

Key quote in the piece...

"there is no reason at all – beyond a certain level of funding – why it all couldn't happen very soon." Cronin is impatient to get on with it as quickly as possible.

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10. G-Dog on July 23, 2012 1:01 PM writes...

Having been taught by Cronin I can definitely attest to his rather slippery grasp on the space between science fact and science fiction but frankly I think his approach with the media is nothing short of genius.

I don't want to get too heavy on the debate of this actual research since I agree that while the work shows potential his sales pitch on it does stretch reality to an uncomfortable degree. However, if there's one thing Cronin can do it is sell his work. By capturing the imagination of the public and those who may see fit to fund him, his group grows and his research flourishes.

What he's suggesting might not be true now and it may never come true, but if people who believe it might come true decide to back it then it gets closer to being possible.

While in some ways he always struck me as being like a bit of a dodgy car salesman, he seems like one who genuinely, whole-heartedly and passionately believes the clapped out vectra he's selling you could save your life.

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11. Nick K on July 23, 2012 1:28 PM writes...

Cronin would have a good point if he was suggesting the microencapsulation and controlled release of an API from a 3D-printed device. The idea that actual synthetic chemistry could be performed in such a device is ludicrous (air- and water-sensitive reagents, high temperatures, corrosives etc?). In any case what advantages are there compared with current practice?

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12. DrSnowboard on July 23, 2012 2:17 PM writes...

Isn't Cronins point that to get synthesis at the point of need, all you need is a 3D printer, a set of reagents and a software recipe to combine them all into a 'drug producing' system?
Essentally, it's skill-less drug synthesis, a zero delivery chain product.
At least it has no impact on R+D, unlike the outsourcing fairy tale.

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13. G-Dog on July 23, 2012 2:27 PM writes...

Having been roped in, as I promised myself I wouldn't be to the argument of the actual research I must admit I was playing not only Devil's advocate but the team of solicitors, barristers, the 4 bribed jury members and the blackmailed judge.

1. To say that there are better "economies of scale" in shipping every reagent is backwards. It's not like having a fridge that prepares jaimie oliver meals, it's like every house having a tiny factory that makes toothpaste. That is the opposite of economies of scale.

2. Drugs that are out of patent are made on mass in bulk in a fashion cheaper than anyone else could do, in fact in increasingly cheaper ways.

3. This would allow people to "pirate" patented drugs. I mean, okay, we all dream of a world where hand-holding hippies pump the cure for cancer freely from their flowing dreadlocks but this isn't the music industry, pharmanapster or drugkazaa would crush the pharma industry because people don't make drugs for fun.

As to my original point though, I can't fault his marketing strategy. Funding is the difference between lying and trying.

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14. vanad on July 23, 2012 2:40 PM writes...

cronin would have a good point if...

ok and you can fill in the blank all you like but who's laughing. he is laughing at you actually.

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15. Bruce Hamilton on July 23, 2012 3:33 PM writes...

The target market could be high-value illicit drugs where investors probably don't require multi-page research proposals. Unfortunately, such funders may reward failure with a 9mm headache.

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16. chips on July 23, 2012 3:59 PM writes...

@10
It's a shame that this is what gets a lab well funded these days. Ultimately, this sort of thing damages the field. There seems to be a lot of this in the area of 'synthetic technology' in academia - Peter Seeberger being another example of the 'science fiction' approach

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17. chips on July 23, 2012 4:00 PM writes...

@10
It's a shame that this is what gets a lab well funded these days. Ultimately, this sort of thing damages the field. There seems to be a lot of this in the area of 'synthetic technology' in academia - Peter Seeberger being another example of the 'science fiction' approach

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18. Anonymous on July 23, 2012 10:42 PM writes...

Voodoo Science always goes to public media!

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19. lip on July 24, 2012 8:39 AM writes...

It appears that everyone agrees that Cronin is very good at to put lipstick on a pig.

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20. TCP on July 24, 2012 9:34 AM writes...

Having met and worked in the same department as Cronin in the past, I can definitely attest to his, erm, rather enthusiastic approach to getting a story out before everything's done and dusted in the lab.

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21. BTM on July 24, 2012 10:57 AM writes...

As someone in the polyoxometalate community, this is just par for the course from Cronin. "Gift for extrapolation" puts things far too mildly - he's gotten papers published in Angew. Chem. and Inorg. Chem. that are based on what would charitably be called "poorly interpreted" data. They're not out-and-out wrong, but they lean quite heavily (and somewhat improperly) on improper uses of ESI-MS to infer reaction mechanisms. So take this with a saucer of salt.

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22. Lee Cronin on July 24, 2012 11:35 AM writes...

BTM, I take exception to your comment. My work is rigorously peer reviewed and some of the self assembly stuff we do is quite challenging, but well defined. Since you are claiming I have poorly interpreted data I would like you to defend your comment openly or ask me for further clarification. I also feel the nature of the phrase 'somewhat improperly' seems without a peer reviewed basis. This is the first time I have entered this debate but I think there comes a point where people can criticise the ambition of an idea, but perhaps should also debate if the idea is worthwhile - what would it mean if? e.g. Kennedy said the USA wanted to go to the moon and they tried and succeeded to go to the moon. I am suggesting there are some interesting converging technologies. My inorganic chemistry work is both well received and well published. There have been no requests for clarification on the mass spec work and for you to cast doubts on my work without evidence is unfortunate. I ask you to retract your comment and apologise or back it up with facts. With best wishes, Lee Cronin, Glasgow.

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23. Lee Cronin on July 24, 2012 11:53 AM writes...

Dear TCP, Thanks for your comment. I do agree that I am enthusiastic and want to engage people with ideas. In fact I am really interested in being honest with people about the big idea / ambition as the science is unfolding and this is all I am trying to do. This stuff is going on in my lab right now and we are often focussing on new ideas and approaches to doing science and using technology to ENABLE new science. Now, nothing is perfect but my reasoning for this is to perhaps transfer the real sense of excitement for that discovery moment and I want to be throw myself open to comment and criticism by my peers - that is immensely important. I guess the question is: why you rather have a running commentary on the Higgs particle that we already know exists or an open discussion about new ideas / possibilities that we are just setting out to investigate and what it could mean if we were successful? I think we owe it to the public to be open about our research motivations and ideas. This should not be at the expense of rigour or make outrageous promises. But there again, if Kennedy had not openly said ‘we are going to the moon’ would the USA have really gone?

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24. Derek Lowe on July 24, 2012 1:14 PM writes...

I'm glad to see Prof. Cronin here in the comments section. I also want to make sure that things don't get too ad hominem. Criticisms of the work should be distinct from criticisms of the person doing it. . .thanks!

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25. BTM on July 25, 2012 1:09 AM writes...

Lee, Derek - I apologize for getting a bit too aggressive there, especially over what is a fairly minor criticism.

Professor Cronin, to your point: I agree that much of the work your group does in this area is quite challenging, and I'm a big fan of most of it. In this one case, however, I do feel that the POM community (in general) is insufficiently circumspect about ESI data. My issue with ESI data as presented in your papers is that observation of the fragments of MS/MS processes, while informative, are a very large step removed from the conditions under which a Lindqvist ion would form in a "bottom-up" manner. In this case the issue I take is that not that the experiments were incorrectly performed or the data misinterpreted, but rather that too close a parallel is drawn from observations of gas phase fragmentation products to unobserved aqueous condensation products. Again, you aren't alone in this. I'm at least equally displeased with the ESI work in JACS, 2012, 134, 1810, though more for their lack of discussion of the results (in general) and for not mentioning if any intermediate species were observed (in particular).

Please, if you'd like to discuss any of this further, contact me. I'd love to be proven wrong. Maybe I'll learn something.

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26. Lee Cronin on July 25, 2012 3:14 AM writes...

BTM. Thanks for the correction and retracting the suggestion that the work is wrong or poor. I do however understand your concern and the challenge. In this work we use bottom up and top down molecular assembly in solution and directly sample in the MS. That means we both do the self assembly reaction in the mass spec (we define as bottom up) AND we dissolve the crystals of the preformed materials (we define as top down) and compare them and also have theoretical data. i.e. we have two different approaches. The first is to SAMPLE the reaction as it is happening and directly infuse into the mass spec, and look at dissolved crystals of the products.

We only present this and ask if a connection can be made with solution. That is a legitimate question and nothing in the article is over analysed or over sold. In fact I was approached from the theory guys in Tarragona to do this so we actually carefully crafted the manuscript to reflect this challenge THIS WORK IS HARD and is at the cutting edge hence care and hence we must be rather mindful of the challenge and not over sell the significance whilst highlight our achievements.

Please read the paper again and try and contact me my email (happy to publish the results of our discussion on this blog) if you want to discuss and I would be happy to walk you through it. Your question here is much better put but and I really do like to hear all criticism. In science this correct process and something I take very seriously. Cheers, Lee.

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27. Charlie Stross on July 25, 2012 10:08 AM writes...

Just guessing here, but I suspect if this is possible at all, the likely first place we'll see such devices is in hospital pharmacy departments, used to prep short-shelf-life infusion products -- possibly nuclear medicines with short half-life isotopes (either for use as imaging media for gamma cameras or as anti-cancer agents). Hospitals have been making up radiological agents on site for decades (I did a training course on radiopharmacy back in the mid-eighties); this might permit more elaborate products.

But ibuprofen? Can sit on the shelf for years and is dirt cheap in bulk. Not going to happen until this technology is so mature it's voted in the past six elections.

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28. Vern on July 25, 2012 4:39 PM writes...

"earl grey, hot", can't wait for the Star Trek synthesizer. It's great to be aspirational so kudos to the Cronin lab. I had a little experience with how microfluidic reactors were going to revolutionize medchem at GSK. Unfortunately, the aspiration was too far from reality to ever get traction with most scientists - upper management, nonchemists were the big fans. PET ligands etc seem the application to me - high value, shortlived, only need a smidge

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29. Henrik Olsen on July 29, 2012 2:47 PM writes...

Science fiction stage indeed.
I'm just reading Charles Stross' "Rule 34" (first published 2011) in which one of the illegal items the police are trying to control are fabber plans for making micro flow reactors geared at producing illegal drugs.

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