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The Cyclofluidic Story

The recent post here on automation in chemistry (especially medicinal chemistry) is a good intro for this paper in ACS Med. Chem. Letters. It’s from David Parry, who led Cyclofluidic, and I’ve blogged about them a few times over the years. That was a company formed in 2008 in the UK to try to develop a “closed loop” of automated medicinal chemistry, where compounds would be synthesized, then tested in a primary assay on the same platforms, with the results fed back into the software to inform the next round of automated synthesis, etc. This has been a longstanding idea in the field, and there are no theoretical barriers to realizing it.

There are, however, plenty of practical ones. Fully automating the synthetic chemistry alone is not exactly trivial, given the variety of reactions and their different conditions. That problem by itself has kept several very capable research teams in both industry and academia busy for many years now, and it’s just the first step. Automating the assays, of course, has been the work of high-throughput screening teams for at least the last twenty-five years, so there’s a lot of experience to build on there – but connecting the output of the automated synthesis to such screening (without having some human operators in the middle of the process for purification and compound handling) presents a whole new set of challenges. And then you have the “evaluate and send back around” step, which calls for software that can suggest reasonable new analogs after evaluating screening data, which is yet another longtime goal that has kept many other folks fully employed for a long time now as well.

So Cyclofluidic had their work cut out for them. And Parry himself even more so:

Starting out at the helm of a new company on day one is both incredibly exciting and daunting in equal measure. The challenges were numerous, while both a business and technical plan were in place as part of the funding process that still left many open questions. I was very comfortable with the scientific and technical aspects to be undertaken having been increasingly involved with the evolution of the proposal but may have taken a slightly different stance on some of the more challenging technical milestones had I known I was going to be responsible for their delivery.

That last part will, I’m sure, bring on some shivers of sympathy among many readers, many of whom may have experienced some form of the “OK, whose problem is this going to be? Ah. I see. Mine” phenomenon. A big early decision was whether to build the machine from the ground up or adapt commercial equipment, naturally, and the company took the reasonable route of using available technology whenever possible, and doing its own development at the points where it was most needed. And it was certainly needed:

The assay platform initially utilized a custom glass chip for the assay with channel dimensions of approximately ca. 80 μm; early observations of laminar flow with colored aqueous dyes rapidly opened my eyes to the challenges of working in this environment. For practical reasons (lead time, cost, and ease of replacement) the glass chip was replaced with 75 μm ID capillary tubing, a simple switch that proved remarkably effective. Pumping at the very low flow rates with the required relatively high pressures determined by the assay chip or capillaries was not so straightforward. . .

. . .Much was learned along the way including the challenges of minimizing the adherence of reagents to glass surfaces, accurate pumping to achieve a gradient of reagents into the assay chip with time, and ensuring solubility of the reagents at all times.

I can well imagine, having done a fair amount of flow chemistry myself (and without the added twist of doing flow biology!) The paper goes into much interesting detail on both of these, and on the software needed to keep the whole system running. But there were even larger factors at work, which hadn’t been anticipated:

When Cyclofluidic was conceived, the business plan was to build a prototype platform and then sell the platform or its component parts to pharma and biotech companies. During the early years of the company, the pharma sector tended to be moving away from large internal technology platforms and not making significant investments in internal capabilities. With input from the shareholders and more widely, it was agreed that the business should look at alternative options for revenues based upon the rapidly evolving capabilities. This came down to a choice of two options, either become a technology integrator providing the expertise to tackle complex automation and integration projects in the life sciences or to provide services based upon the envisaged capabilities of the Cyclofluidic platform. . .

They opted for the latter, and were able to engage in a number of collaborations (only some of which have been published). The market for companies that want to assist in early-stage drug discovery is a large one, though, with pretty ferocious competition. And by this time, Cyclofluidic wasn’t just competing with other small service providers; they were, in many cases, competing with internal efforts at a number of large pharma companies to automate their own medicinal chemistry efforts. In general, these (at AbbVie, Lilly, Roche, and others) were devoted to increasing chemistry productivity or perhaps assay throughput: few (or perhaps none) were trying to close the compound-optimization loop completely with automation.

So that was the Cyclofluidic selling point, and the big question was whether that was enough. The all-in-one aspect was unique, but it also meant (as Parry notes) that at any given time, a good amount of the system was idle as things moved around the loop. The chemistry efforts at other companies were generally higher-throughput for a given fixed transformation, and could be combined in some cases in modular fashion. They weren’t integrated with assay technology for the most part, but how much of an disadvantage was that, practically? From what I can see, it came down to a choice between the Big Pharma model, where the individual parts of the process were highly optimized but not connected together as smoothly, versus the Cyclofluidic platform, which had far better connections but had limitations in each of the component parts. And those limitations were imposed by the connections themselves.

In the end, the company never reached takeoff speed: they had good feedback from their collaborators, but not enough of them seemed to feel that this was technology that was compelling enough to invest in further. Cyclofluidic ended up positioning itself as a service provider, but selling a service that people weren’t sure if they needed or not. As Parry mentions, it would have been very interesting to compare the progress of their platform versus a traditional med-chem team, and ideally to do this over several different projects.

An ideal test would be to hand the same starting set of potential lead compounds to several traditional med-chem teams (not in communication with each other!) and to a Cyclofluidic-style effort as well, and to compare the results. What were the compounds they arrived at after (say) a year of work, and how good were they? You’d want to do this several times (as mentioned, given the natural variability of drug discovery) and honestly I’m not even sure how many trials you’d want to run before drawing firm conclusions. I am quite sure, though, that it would be more than anyone would be willing to fund. The human-team versus human-team aspect would be fascinating enough even without the man-versus-machine aspect; I’m sure that nothing like this has ever been run under controlled conditions. Bored billionaires apply here.

 

10 comments on “The Cyclofluidic Story”

  1. Anon says:

    We can call it more bite than chew! I have in my life time (of doing medicinal and organic chemistry) seen so many technology come and and go with a whimper! At the end of the day how much data can we digest and make meaningful conclusions thereof? Cyclofludic-RIP!

  2. Nick K says:

    Is Cyclofluidics defunct? (I have no access to the article). The website is still up, but seems to to be no more than a shell.

    1. A Nonny Mouse says:

      They attempted a rebirth as Aidiscovery, but I don’t think that it got off the ground

  3. Me says:

    Doesn’t surprise me: most of the management there were jettisoned from GSK followed by Pfizer for producing solutions that needed problems. I know the tech. Dev. Unit at gsk produced a pile of high tech garbage that nobody used and were all pulling in vp money for it. Next step was always to sweet-talk someone into giving them venture capital. Looks like they achieved more of the same.

  4. Anonymous says:

    Derek wrote: “An ideal test would be to hand the same starting set of potential lead compounds to several traditional med-chem teams (not in communication with each other!) and … compare the results.”

    Haven’t we had a version of that going on for a century or more? Albeit without supervisory control, time limits, and the ability to compare resources used, etc..

    Aspirin was the common starting point for researchers before and after Bayer. Penicillin was a common starting point for everyone after WWII. Mevinolin set off the whole race of a crowded field to make statins … and many of them have a certain similarity. Erythropoietin (Epogen) has been whacked, cracked [truncated] and modified by many groups of researchers. None of that research was done in COMPLETE isolation from others due to meetings, pubs, patents, etc..

    It would be quite an effort to look at those and other histories to approach Derek’s test (minus Cyclofluidics) but I think there are interesting stories there.

    (I was going to mention Epogen the other day on the “money” part of Derek’s “Where Drugs Come From” blog. Amgen sold ~$40B to $50B of Epo over 22 years. They pushed drug usage to other applications and higher doses to hit those numbers. Some of those uses (dialysis patients) and doses did not produce the promised outcomes. It turns out that post-hoc analysis showed that usage of Epo as an adjunct to chemotherapy did more harm than good. Oops. (The “Thought Leader” expert opinions were that chemo lowers RBC counts bordering on anemia; Epo would help restore a “normal” RBC level. What could possibly go wrong?) Epo for cancer was around 50% of sales; $20+B of Medicare – tax – insurance payments to Amgen that will never be returned to society or the ultimate payers, us. One story linked in my handle.)

    1. cynical1 says:

      The scenarios that you outline discounts what an important factor IP space played in all those drug discovery efforts, mostly limiting. Being a great chemist doesn’t get you past the generic claims of a competitor no matter how brilliant you are. So no two groups usually start with the same leads unless they discovered them independently and both (or more) teams are working in the same IP space unbeknownst to the other. And then the patent applications issue and it’s all tears for the other group(s). That happened many times in my 30 years. Doesn’t matter whose compounds were strictly “better”. It mostly mattered who filed first. If you know what you’re doing, your patent application covers a lot of chemical space basically to screw your competition. At the end of the day, patent busting (sadly) plays a rather large role in drug discovery. That’s just a reality.

      1. fasterthanyou says:

        not only drug discovery, everything from car parts to cell phones to pumps for excrement.

        The only thing a patent does is show the competition what you’re working on, it’s far better to be faster to market and gain so much market share that you become the go to product.

        Take a look at the garbage Microsoft produced and we are all stuck with today.

  5. nolongerachemist says:

    The trick to automating more discovery chemistry is to make a device that brings the vials to the pump that dispenses the reagents, not the other way around as you see done with a fluid handler.

    This will allow reagents to be prepared in inert vessels and pumped into the vial with a very short plumbing path.

    Imagine a table where the chemist could setup numerous solutions with peristaltic pumps using viton tubing, or syringe type pumps.

    Underneath is a table that holds the vials, with the ability to move around and position each vial under the needle that comes from the reagent pump.

    1. Chris Phoenix says:

      Sounds good, but what about adding two reagents at once?

  6. Bob the Chemist says:

    I got the impression (correct?) that a lot of their early work only came their way through ex-colleagues/friends etc….

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