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  • mattoddchem 9:33 am on March 24, 2015 Permalink | Reply  

    World TB Day 2015 – An Open Source Drug Candidate 

    In recognition of it being World TB day today, and to promote the development of urgently needed new medicines for this terrible disease I’d like to point people to a project they can be involved in from today. We very recently started Open Source TB – a project that will be similar in design to Open Source Malaria. The idea is that, eventually, anyone can run projects and take part in existing ones. No secrecy, no patents. Inclusive research. It’s early days, so please excuse the boxes and bubble wrap.

    The first set of compounds that were looked at were recently published. The second series of compounds is starting with a very nice looking molecule discovered by GlaxoSmithKline at their Tres Cantos site. It has potency against TB and is not toxic to mammalian cells. It’s an interesting compound – we’re not sure what it’s doing, and could use some help with that, starting from recent predictions of the target.

    Open Source TB Hit

    An Open Source TB hit from GSK – TCMDC143693

    We’re still working hard to set up the collaboration platform. Jessica Baiget is a postdoc with me working in Madrid, supervised by Julia Castro-Pichel from GSK. She’s recently resynthesised this compound (here’s the full lab notebook entry – working right now on sharing the whole notebook) so that she can study it further and make some new variations.

    This compound needs to be developed more, and any and all data generated will be put into the public domain immediately. We’ll set up more ways we can all work together. If you have a compound series you’d like to install as a new series on the wiki for consideration by the community, please just go ahead – e.g. any “abandoned” series from big pharma, or academic projects needing inputs. For now please check out the Twitter account and follow it for updates. If you’re working in the TB area and want to share ownership of the Twitter account to spread the word about anything open source that is related to TB, please just DM the account so we can be in touch. There’s also a Google+ Community so people can discuss anything.

    If you’re a medicinal chemist who would like to make some of these molecules, please get in touch (can use an email account we’ve set up: opensourcetb@gmail.com) – the chemistry for TCMDC143693 is *really nice* in fact, thanks to Jessica’s work. If you are a bioinformatics guru and want to help validate the target for the compound, please also get in touch. If you’d like some of these drug candidates for your own biological work, please just say.


    • Bheemara G. Ugarkar 2:33 pm on March 25, 2015 Permalink | Reply

      The molecule you have shown is an excellent Hit and if it has potent MIC against H37Rv and non toxic to mammalian cells, it is a plus. What else is done on this molecule? Any SAR and SPR information? Just curious. I am part of the Open Source Drug Discovery in India and we have pursued a couple of hits from GSK. Best wishes: Bheemarao

    • Jessica Baiget 11:19 pm on March 25, 2015 Permalink | Reply

      Hi Bheemara, thank you for your interest. This hit is our starting point and we are currently working towards obtaining data for some analogues that we may have access to. However, our initial work has been focused on the synthesis of some related compounds (see link) that have been sent recently for biological evaluation. This information and our lab notebook will be fully accessible in a few weeks. Best wishes


  • mattoddchem 1:20 pm on February 23, 2015 Permalink | Reply
    Tags: data exclusivity, economics, , , patents, TRIPS   

    The Economics of Open Source Pharma – What about data exclusivity? 

    This post is about something called data exclusivity. I’m asking whether data exclusivity might be a way to ensure the existence of a financial incentive for open source drug discovery and development.

    I am actually asking, since I’m not clear on the language of the relevant law.

    I was talking with some people at the SGC in Oxford recently about the possibility of some (any) kind of assurance to investors in open source drug discovery and development (e.g. the state) that they might make their money back when the medicine hits the market. I had been mulling over this idea of a retrospective patent (RP). I was thinking afresh about data exclusivity, which, unlike the RP, is already enshrined in law and which might achieve something similar. Instinctively I’m against exclusivity, but there’s something interesting here.

    Data exclusivity is a period following a clinical trial where the funder of the trial (i.e. the people bringing the drug to market) have several years grace to market the medicine: to sell the medicine, you have to have generated the clinical trial data. This exclusivity is nothing to do with a patent – so for example generic versions of a medicine can be produced following the expiry of the period of exclusivity, unless a patent prevents that. Here’s a useful PDF background document. Other miscellaneous background can be seen here, here, a PDF from WIPO, and an argument that data exclusivity is a better incentive for invention than patents.

    So: is the 5-10 year exclusivity on the use of clinical trial data a means of protection for an open project? Imagine we run an open source drug discovery/development project, and we run a clinical trial as part of that. We disclose all the data as soon as possible. Would we have some period of exclusivity to act on the data? Would that permit a fully open project to set the drug’s price at a level that covers costs? i.e. can one think of the exclusivity as a positive enabler of an open project, rather than as a necessary evil?

    This hinges on whether the data can be public and still not acted upon by anyone else. In other words if you wanted to register your own version of the drug, you’d need to pay for your own trial. You’d have to pretend the original data aren’t there.

    You could of course go ahead and pay for your own trial anyway – after all you’d have some confidence that the trial would work out OK.  You could then release a competing medicine. But I can’t imagine any shareholders thinking it would be a good idea to go up against an open consortium, committed to low prices and with a multi-year headstart. (Unless your country’s laws mandate you do this – which is the case in India – in which case the open data would undoubtedly make the trial a lot simpler and cheaper.)

    So my conception here of “exclusivity” equates with a “manufacturing license” rather than “secrecy”. The ability to recoup costs might mean there is no need for patent protection and the associated secrecy.

    What does the law say? The sticky part is whether the “exclusivity” means that nobody else can see the data or whether nobody else can use the data. The TRIPS agreement on this seems unclear. Article 39.3 of TRIPS says data should be “disclosed” if the disclosure is accompanied by steps to ensure that the data are protected against “unfair commercial use.” It seems to me that this caveat means that the data could be disclosed openly, and that you’d need regulatory vigilance to make sure nobody uses the data to undercut the exclusivity granted to the open project. That shouldn’t honestly be that hard.


    1) Is this stupid, or has someone made this point before?
    2) Is anyone an expert on the letter of the law here? Can the data be seen but not used?

  • mattoddchem 9:46 am on January 13, 2015 Permalink | Reply  

    Retrospective Patents as an Incentive to Open Research 

    Why do we say we need patents?

    A patent is a public declaration of knowledge in return for a form of exclusivity. The deal is that by revealing to others what you have achieved, you have some time to profit from the invention, allowing you to recoup expenses incurred in development without being overly pressured by fast followers. Patents are usually promoted as a way to encourage innovation because they are currently a way towards a guarantee that offsets the financial risk of R&D. This seems reasonable. We should all support public disclosure and risk-taking. However, only those who have read a lot of patents will understand how far from the ideal (of being useful documents) patents usually are.

    The offset of risk means that patents are seen by many in pharma and global health as a way to guarantee access to new drugs by the greatest number of people – i.e. as being an essential part of equitable access to essential medicines. Thus despite patents often being perceived (I think) as a tool that benefits big pharma, they are seen as being necessary if we want to see medicines developed and distributed. I understand this is broadly the current position of the Gates Foundation, for example.

    Yet there is a significant downside to patents, which is the associated need for secrecy. To patent something requires that that something has not previously been revealed in the public domain. This means that the novelty in the patent is not merely a novelty, but is a novelty that has not been previously described anywhere. So it is not possible to make something new, start using it, and then later on (when it’s clear that the invention works well) to apply for a patent.

    In other words, there is no way to be rewarded for an invention if you have already revealed it to people. “Well done on developing something new that works – here’s a period for you to make your money back.” Colloquially, there is no such thing as a “retrospective patent”.

    The terminology of course makes no sense. Why would you need to patent something if it’s already public? Correct. So maybe there is another word for a retrospective patent. A license? A monopoly? What? Does this already exist?

    I started looking around at the early history of patent law. I wondered whether, when patents were first created, they were awarded (e.g. by a monarch) for a clearly demonstrated invention already of public/commercial value, and one which needed rewarding through a little market exclusivity. But I can’t find anything of this kind. Was it the case that the first patents were awarded on already-operating objects? I’d love to know.

    Nobel Patent

    Nobel Patent, via Wikimedia Commons


    So as it stands patenting cloaks scientific research in secrecy. This means R&D in pharma and, increasingly, in academia, is a secretive process. The secrecy is infecting university research, where many patents are sought on the off-chance that discoveries could be profitable later. Indeed quite generally patents are seen as necessary if we are to capitalize on discoveries made using public sector funds by using downstream private investment.

    The secrecy of this process is the most significant barrier to open research. In many cases people are reluctant to share because there is the expectation that we must patent if we are to avoid jeopardizing the financial structure of the whole research system.

    Let’s drill down to pharma for a moment. The secrecy means we don’t share the failed R&D campaigns, the current bottlenecks, the early successes. If a drug will fail, it can fail several times, expensively. There’s much duplication in research, wasting money.

    There are non-traditional ways to fund drug discovery that offset some of the risk. One can make a guarantee that funding is available later on in development by amassing commitments up-front, and such things (GAVI, HIF) are being used particularly in the area of neglected tropical diseases. These are not yet mainstream, and the funding just isn’t yet there to replace the current pharma R&D system. But in any case, such instruments are still being used within an inherently secretive R&D system. Patent pooling also clearly requires patents, which are generated using the same secretive R&D system.

    So: how can we combine an incentive to work openly (and share all our work) with the possibility we can recoup R&D expenses later?

    The retrospective patent (RP) (or whatever it’s called) would mean one could invent something using a completely open R&D process where everything is shared publicly as it’s done, improving efficiency in various ways. Indeed that would be a precondition of being granted the patent – a solid paper trail that demonstrates invention (in much the same way we require this with the current patent process where a patent is challenged). Once the invention is shown to function correctly (and perhaps even to function well) the RP is written as a full, static definition of the scope of the invention (to summarize all the work that has been done and clarify the claim) then a period could be granted of financial exclusivity, by some means i.e. a licensing arrangement, with a period that might depend on the degree to which the invention innovates. Those providing the contributions that led to the invention (rather than those just swooping in at the end) would be granted proportional shares of the exclusivity agreed in the written document. Interestingly this means the State could be an awardee, allowing financial kickback for public investments in research, of the kind argued for by Mariana Mazzucato in her book.

    Trying to determine who should benefit from this process (who was responsible for the innovation) when the invention was carried out openly will generate a lot of arguments. But we already have a lot of arguments about patents in the current system.

    So an RP wouldn’t be a prize* (just as a patent is not a prize) since it would be something with a value that is determined by market forces during a period of exclusivity.

    This proposal for “retrospective patents” is naive, but it gets to the core of the problem: the current need for financial exclusivity promotes secrecy which lowers the efficiency of the research process. If financial return could be guaranteed on condition that the research process is revealed openly in full detail in real time, and that the research needs to be demonstrably effective, and that all who contributed could be eligible for financial reward, we would actually incentivize openness.

    So my question is: Does this legal/financial instrument already exist by some other name?


    (*A note on prizes: Interestingly the kind of post hoc determination described above of who was responsible for past breakthroughs would allow prizes to be run openly, and would allow postmortems on prize funds – i.e. who should get how much of the prize and for what. So the prize could be run with a transparent workflow as a precondition for entry – and after a critical point is reached and a prize awarded the funds could be distributed according to achievement. This would significantly change closed prizes like the Longitude Prize (where people work in isolation in a way that does not change the way the research is done vs. the current system). The need for demonstrating one’s competence as part of an open R&D process should lead to a rather intense level of competition since there is disadvantage to being secretive or doing work that is not reproducible. Open competitions in coding are not mainstream as far as I know, but have shown these intense bursts of creativity. For those used to closed competitions, where one can mull on a problem at leisure without revealing one’s progress, this would be unsettling.)


  • mattoddchem 9:51 am on December 15, 2014 Permalink | Reply
    Tags: academia, Electronic Laboratory Notebook, ELN, open access, , publishing, tuberculosis   

    Anatomy of an Open Science Paper 

    We use lab notebooks to record research. Why not publish lab notebooks alongside papers?

    My lab just published a paper on some chemical methodology towards some potential tuberculosis drugs we finished last year. The chemistry was carried out by Kat Badiola, with bio testing courtesy of my colleague Jamie Triccas at Sydney Uni.

    In some senses it’s a traditional paper, but it has an interesting feature.

    Standard, brief papers are like press releases, conveying the choicest bits of the science. Most manuscripts we often read are a little like this.

    Which is useful but of course ridiculous – like icing with no cake. So we often prefer to publish larger pieces of work, where the choicest bits are accompanied by a “Supporting Information” section – stuff you consult if you want to know more. Usually this is a PDF file, usually containing pictures of datasets – in Chemistry this is usually copies of NMR spectra, for example.

    Which is also ridiculous on its own, since it’s 2014 and megabytes are cheaper than milk now, so we’re able to include raw data files too (though people seldom do, I don’t know why) and we’ve done so with this paper. So you can download the files and reprocess spectra for yourself if you like. Useful for all sorts of obvious reasons I won’t list here.

    Which is great but not enough.

    What about all the “failed” reactions? What about the repeats, so that one can assess reproducibility? What about the comments and ideas we all put in lab notebooks, such as things to try next? What about the strands of the projects that didn’t quite work out, but may yield to another investigator? What about photos of the science (genuinely useful in organic synthesis), or other data that would help someone wanting to take this research on?

    In other words, wouldn’t it be useful to include the lab notebook as part of the paper?

    That’s what we’ve done here. The electronic lab notebook Kat used – it’s been zipped up and put on our Uni’s institutional repository. You can download it, unzip it and explore it as a snapshot using a web browser – all the links work, and every experiment is in there.

    Components of a Paper

    Components of a Paper

    Useful, and easy to do. Very easy for open projects, since you are already sharing everything so why not zip up the notebooks and include them? It’s probably more difficult for closed projects only because if a lab notebook is closed it’s probably not necessarily in the best shape to be shared with others – openness in record keeping can encourage (not guarantee) a way or recording activity that is understandable by others outside the team. Including the notebook is essentially impossible if you’re still using a paper lab notebook (for shame!)

    Thanks to the Labtrove team at the Uni of Southampton for capturing the snapshot and generally being great.

    (Related links: Some suggestions as to how we might change journal articles in future are here. More on the browser-based notebook Labtrove here and here. Please comment below if I’ve missed anything.)

  • mattoddchem 10:31 pm on October 3, 2014 Permalink | Reply
    Tags: , Crowdsourcing, Education, , MMV, , , Open Source Malaria, ,   

    Crowdsourcing Drug Discovery 

    Open Source Malaria has completed an experiment in crowdsourcing for open drug discovery.

    Identifying and developing medicines is a labour-intensive process, particularly in the discovery and optimization phases, and most particularly in the physical preparation of samples of new molecules for testing: a phase that consumes large amounts of time and money and is often a roadblock. One of the obvious things to do is to crowdsource the synthetic chemistry using students.

    In open source projects there is the tantalizing additional possibility that student teams can assemble to work on those problems because what’s needed can be fully described in the open. The openness means that the teams could learn from each other, share data and receive peer review and mentorship from interested experts based elsewhere, such as in the pharmaceutical industry.

    There have obviously been examples of crowdsourcing in various scientific arenas such as genomics (e.g., 1, 2) and there have been closed groups of students operating in the area of drug synthesis. There are examples of crowdsourcing initiatives in attempts to identify biologically active natural products (1, 2), Joerg Bentzien ran a Kaggle competition in in silico small molecule modeling, Urmi Bajpai is working with students in her lab on some biochemical projects (see also this earlier story) and there are other preparative activities of many kinds dating back to things as diverse as the AIDS quilts. I wasn’t aware of any students participating in crowdsourced synthetic chemistry as part of a project that was open source, though Patrick Thomson provided a spectacular example of how openness can lead to high quality scientific contributions from individuals. Mass recruitment of synthetic expertise is going to be one cornerstone of any scaled-up vision for Open Source Pharma, and I was very keen to see if we could complete this exercise in OSM as a precedent, and maybe learn how to make sure it works most effectively.

    We just completed this precedent. Around 50 students from Lawrence University in the US midwest worked on the synthesis of six new analogs in the “Near Neighbour” (NN) branch of Series 1 of OSM. The compounds were mailed to a different lab in the US for biological evaluation. Active compounds were discovered – one of them new to the project and quite potent. I find the closure of this loop tremendously exciting.

    Data for the Lawrence University Compounds - check out the red value for OSM-A-3!

    Data for the Lawrence University Compounds – check out the red value for OSM-A-3!

    Here’s how it worked. I was contacted a few days before the end of 2012 by two US-based academics asking whether their undergraduate cohorts could contribute to OSM. This had been an aim of the project way back in the design phase and not something we’d gotten round to. For one of the academics, Stefan Debbert, Murray Robertson and I wrote up a description of a synthetic route we’d been using for the NN compounds. The chemistry is not trivial, but possesses the advantage that the compounds are typically solids that can be easily purified and are stable under ambient conditions. Stefan looked into this and came up with some analog structures he felt his students would be able to access, and without any further input from us he got this working in his lab class in early 2013. Around June/July he wrote to say his students had finished the syntheses, and in November he uploaded all the data to the online lab book. After some quality control checking of the data by others, the compounds were shipped to Kip Guy’s lab at St Jude’s where Julie Clark performed the assessment of potency and the data were put up online last month, thereby closing the loop on this part of the project. This whole process took longer than it should have since we were all feeling our way a little on this one.

    The data have come in just in time for the writing of the first OSM paper, which is at an advanced stage. We are now faced with the interesting challenge of how to credit this student cohort with authorship. What a great problem to have.

    A Student Hard at Work in the Debbert Undergrad Lab

    A Student Hard at Work in the Debbert Undergrad Lab

    The take-home: a cohort of undergraduates successfully made new molecules that are potent in killing the malaria parasite. The data are valuable as part of a larger project of current research that will be published in the peer-reviewed literature.

     The students were able to make an impact because:

    1) A current/future research need was openly described

    2) The rules behind the project clearly stated that anyone could participate

    3) The student team was locally and carefully mentored by a dedicated individual (Stefan) willing to engage in an unusual activity

    4) The details of what was needed were described in full, i.e. previous, related research that made it clear the activity would not be open-ended

    5) The outputs were actively used, i.e. data deposited in the relevant lab notebook for the benefit of the wider project and molecules tested by a laboratory willing to do so.


    This is scaleable. Any team of undergraduates can engage in real research in this way, and perform scientific activities that are valuable to a “live” project and which might result in the undergraduates being able to publish their work. The work could be out-of-hours or, more excitingly (and as in Stefan’s case) part of a formal lab class for which the students receive credit – more on this below. I don’t know about you, but if I’d had the chance to make real molecules for a real research project as an undergrad, I would have found that quite motivating.

    One of the neatest aspects about doing this openly is the quality control. A cynical onlooker might say “Well, these are just a bunch of undergrads – how can we trust the work?” You don’t have to. In an open source project, you have access to the raw data, so you can check the quality for yourself. Many people don’t trust data in synthetic chemistry journals in any case (trust is a problem across the discipline) but raw data in open projects solves this problem in as much as it can be solved.

    So what would I change next time?

    1) Fully Independent Contribution. The collaboration was set up because Stefan contacted me to ask if he could help out. That’s fine, but in an ideal world it would be clear to a lab director what was required without asking – that’s the aim of the Github To Do List that has since been introduced to OSM. But even there it’s sometimes not obvious what’s required and I think we can use Github more effectively. As much as possible in an open project one needs to promote independent contributions and an interlinked mentorship structure (the “Linus doesn’t scale” problem). Having said that, after the initial communications, Stefan ran the whole class independently, which is a testament to his achievement.

    The OSM Consortium has a public to do list

    The OSM Consortium has a public to do list

    2) Direct Data Deposition. The students did not deposit data into the lab notebook directly – Stefan himself aggregated the work and deposited the data for each compound himself. I think this arose because using the lab notebook presented a barrier to participation that was just slightly too large, and there was a concern that students might copy each other. I want to make sure the lab notebook is so easy to use that next time the students are happy to put the data up themselves as they are working – which is the standard practice in OSM. This means making sure that everyone understands that the data they are reading is like any data in any lab book and just because it’s on the internet doesn’t mean it’s correct or final.

    One of Stefan's ELN Entries

    One of Stefan’s ELN Entries

    3) Global Lab Buddies. Ideally we would have two teams in different places communicating with each other on a synthetic route and not via the central project hub. I have in mind something that ought to be of interest to funding agencies like Fogarty, USAID or Wellcome – a lab class in a developed country pursues a synthetic route and a lab class in a developing nation pursues the same or related experiments, with direct collaboration between students and with mentorship in both places. This has the potential to be an inexpensive way of creating a “lab buddy” scheme where students can share what they learn with each other directly (with only light guidance from a PI, so that the collaboration scales well) and there is no need to spend money moving people around or organizing bench fees; effective lab-based crowdsourcing is significant in terms of how we think about organizing “networks” between universities (e.g. the APRU or WUN) – you can do a lot more for a lot less money if you don’t have to buy airplane tickets.

    The experience makes me wonder about best practice:

    1) Mentorship. How many mentors are needed for a class? There needs to be a committed local champion like Stefan, and the class size can be left up to the lab director, who also manages local health/safety requirements. There needs to be a central mentor (me, in this case) to help with any snafus. I think there is real potential here for additional mentorship from pharma professionals who could ensure that the molecules being made are reasonable for a drug discovery/development project. Such mentorship could be provided directly pro bono, or organized through a PDP (e.g. MMV, DNDi) or learned organization (e.g. the RSC). Pharma experts in a given location could contribute to their community in this way – e.g. Merck could mentor students working in schools in New Jersey.

    2) Replication. It makes sense to me for two students to run each experiment, as a form of replication check. This is real research, so there should be controls, particularly if the students are not very experienced. It’s also probably a good idea for the students to make known compounds as part of the synthetic cluster. The need for positive controls of this kind is particularly keen in open projects since biological evaluation may well be performed in different labs where protocols will inevitably differ. A modest degree of replication makes everyone happier with the numbers ultimately obtained.

    3) End-to-End. The work the students do needs to be incorporated into the larger project (at least on a wiki or in a paper) which may require that the molecules are evaluated in some way. If this is needed, then it’s crucial that it happens, so that student effort is not wasted or merely archived. Never ask a crowd to do anything that is not then used. This needs to be factored in to the planning of project resources and means that before the synthesis starts, there needs to be a commitment from somewhere that the molecules will be taken on (in this case, to kill a nasty).

    4) How to Assess – or The Brown Oil Problem. I think the greatest power of crowdsourcing lab work lies in incorporating this into the undergraduate curriculum. Imagine that you’re planning a lab class, and you check online to find 38 different current project needs in open malaria, TB and Ebola projects. Let’s say the Open Source Pharma vision is made real and there is a repository of such projects that are known to be active that very day. This is not very far-fetched. You would, I think, be very keen to use one of these real research needs in your class, to fire up your students about how cool research is. If the syntheses were well-designed you could get started as soon as the starting materials were in. But the complication is: How to Assess the Project? What happens if a student fails to prepare a molecule that ought, in theory, to be preparable? How do we assess a project outcome if the outcome is novel, as part of a research project? I have no good answer to this, but feel that there are steps that can be taken:

    i) Clarity of Design. The designer of the synthetic route to be undertaken must provide as much detail as possible about the ease of the synthesis. This honesty is simple in open projects – in the NN synthesis undertaken by Stefan it was possible for him to see all of the mis-steps and failures that the OSM team had wrestled with previously, and it was therefore possible for us to provide a lot of advice about key steps. Students themselves can even cite previous attempts as mitigating circumstances (“Though the molecule could not be prepared it was noted that Mat Todd similarly failed to generate this key intermediate in experiment 34-6 (13th Oct 2012)…” etc)

    ii) Emphasis on Approach. The marking scheme used by the lab director needs to focus more on the approach used by the student and the quality of the scientific record produced than on the final outcome. This is in any case good academic practice. There remains an issue of plagiarism if students are posting items into the public domain, but one has to wonder about the value of having the students write reports that are vulnerable to this in the modern age.

    iii) Time-resistance. The marking scheme needs to be immune to later discoveries. If it is ultimately found that a particular compound is unstable, a student who has earlier made this compound and found the same phenomenon cannot have their efforts re-marked, just because this makes the assessment too conditional and complex.


    OSM is supported financially and scientifically by the Medicines for Malaria Venture and the Australian Government

    If people want to get involved in this kind of activity, and it’s not clear from the OSM To Do List or the wiki what is needed, then don’t hesitate to get in touch directly. It’d be great to generate some more synthetic schemes suitable for students. If you are planning a research project yourselves, and are writing a proposal, consider including some element of crowdsourcing+open source so we can have lots more students contributing to real research in the public domain.

  • mattoddchem 8:34 am on October 2, 2014 Permalink | Reply
    Tags: biomedical R&D, open source, , , private sector, The High Line   

    The High Line and the Public Good 

    The High Line is perhaps the most beautiful urban object I know. A former railroad track snaking through Manhattan, it has been repurposed as a garden and architectural haven, above the streets and passing within feet of the surrounding buildings, which are revealed, close up, like canyons to a fighter pilot.

    High Line in NYC

    The High Line in New York City

    The line started out as private enterprise. I wonder if the development was originally publicly subsidized. It any event the line failed, since trucking made it industrially obsolete. You can still pick out the original ironwork in amongst the grasses. More recently the line was saved by an initiative based on community action, seeded with public money, followed by private money. The funding that has made the High Line incredible is shown by plaques near the middle of the trail to be this mix of public and private influence. I’m in awe of those who had the original vision to see what the line would become.

    Public Leadership for the High Line

    Public Leadership for the High Line

    Private money for the High Line Development

    Private and Corporate Support for the High Line

    I first visited the High Line four years ago, then again a few weeks back. What a difference those years have made. So much new private industry has emerged along the sides of the tracks in the streets below – cafes, bars, shops where before there was little. Another example, should we need another, that public works can act as a seed for rapid private investment.

    The High Line is also free. It’s a marvel. I read that London is planning a garden bridge. To be great places, cities need inspirational works. We will rarely achieve that from public or private sector alone, but instead a combination without a predictable recipe.

    High Line - New Section

    Start of the Newer Section of the High Line

    I couldn’t help but extrapolate to pharma.

    Medicines sustain people – enabling them to do great things. A society profits enormously if its population is healthy. Effective medicines are a public good, produced by public and private enterprise. Yet we’re not currently producing the medicines we need, and we need to ask why. Perhaps we have become overly reliant on the private sector (which currently funds about 2/3 of all biomedical R&D). Probably no single system will work in producing what we need: every disease is different. The private sector needs the public sector to do what it can’t, and to do that it needs more R&D funds.

    But the public sector can do something genuinely radical that it’s not currently doing and which the private sector cannot – embrace an open source approach where all data and ideas are freely shared, anyone may participate and there are no patents. This is the idea behind Open Source Pharma. Such an open, meritocratic arena achieves something quite astonishing: it promotes competition and collaboration at the same time.

    Scaffolding at the End of the Line

    Scaffolding at the End of the Line

    The effect of going open source in the development of new therapeutics might simply be to de-risk some avenues of enquiry – to take discovery far enough that the private sector can accommodate the risk. The effect might be to enable genuinely new medicines to be discovered, developed and marketed completely from scratch. And the effect might be to provide a shocking and competing business model, if it’s done right. My money is on all three of these.

    The High Line opens up new spaces

    The High Line Opens New Spaces

    But let’s not be lazy and assume that public R&D needs to operate just like private R&D. It would be a serious mistake to spend public money like we’re spending private, pretending that we need to use the same research model. If we’re funding it differently, we can do it differently. So why not play to the strengths of what entrepreneurial public financing can do – and open it up.

  • mattoddchem 10:31 pm on June 25, 2014 Permalink | Reply  

    Sabbatical Day 1 

    Today I’m starting a 6-month sabbatical. Sabbaticals are a perk of academia (though every profession should have them) allowing the sabbaticalee to learn something new, start up a new project or mull over a large problem, freed of administrative and teaching responsibilities. It also provides time to finish papers, write grant proposals etc. Some people, for pragmatic reasons, take sabbaticals at their home institution, a staybattical if you will, but nothing beats the disruption of a move, and talking to new people, for thinking about tough problems in a new way.

    So what am I doing? I’m in Boston till September then in Oxford till January.

    The focus is on open source drug discovery. My lab ran an open science project in drug synthesis in tropical diseases with WHO, and is now at the centre of a fascinating experiment in open source drug discovery known as Open Source Malaria (OSM), with MMV. The first malaria papers will be written up in the coming months. There is a huge amount to do in OSM, but the project has achieved some key objectives already, in terms of demonstrating how open drug discovery can function efficiently, leveraging the power of a nimble and distributed group and identifying new, potent anti-malarial drug candidates. More on OSM in future posts. One of my main objectives during the sabbatical is to look at how we can scale-up OSM in the next 3 years, since it needs to be made larger if it is to compete effectively with established, large, closed projects operating elsewhere.

    University of Sydney contributors to OSM - me, Tom MacDonald, Jo Ubels and Alice Williamson

    University of Sydney contributors to OSM – me, Tom MacDonald, Jo Ubels and Alice Williamson

    My lab is starting up a project in Open Source Tuberculosis, with GSK Tres Cantos. This is exciting for lots of reasons, and I’ll be writing more on this project soon too, but with TB we move slightly closer to a disease area where drugs have a positive net present value, jargon for the idea that there is a profit incentive to TB drug discovery that makes an open approach more difficult to conceptualize end-to-end: how can an open source approach compete with commercial or academia/industry projects where future profits (guaranteed through patents) are used to off-set up-front funding of the research?

    So here are the two questions I’ll be looking at:

    1) How can we scale-up open source drug discovery precedents like OSM to become part of a new pharma industry?

    2) Could we use open source drug discovery in areas normally associated with a profit, such as cancer, Alzheimer’s or diabetes?

    These are great questions because it’s not clear how to answer them. My expertise is organic chemistry, and that is the important technical discipline I bring to such questions. The experience of previous open science projects has I think taught us a lot about how to run them. But I don’t want to contribute anything to a research effort that is either sub-par, or which is not maximally efficient. I don’t think we’re doing drug discovery (or, indeed, organic chemistry) efficiently. Indeed I think we’re hemorrhaging resources in the way we’re currently doing science. It is, to be frank, toe-curling. So I want to look at the two questions above so that I and my students can contribute only to the very best projects with the best structure and the most likelihood of finding a new medicine.

    To start to answer question 1, I’m helping run this unique meeting. The outcomes will be written up and extensively disseminated. It’s very exciting to get this group of people together, all of whom are in touch with an even wider network of talented people who are interested in trying something new. We’ll be discussing prizes, for example – the idea that if you award large sums for research performed you can separate out the costs of research from the price of a medicine. I’m very excited to see what comes out of the meeting.

    To answer question 2 I am visiting two institutes, both leading the field in data sharing for drug discovery in areas such as epigenetics. So from late June to mid-September I’ll be in Boston working with Brian Hubbard’s team at the Harvard/MIT Broad Institute – this is a great fit because Brian and his colleagues have extensive industry experience, but have moved to the Broad to try out something genuinely new.

    Boston, on the morning of Day 1

    Boston, on the morning of Day 1

    Then from late September to early January I’ll be at the Structural Genomics Consortium at the University of Oxford, working with Chas Bountra. (The chief medicinal chemist there, Paul Brennan, is a buddy of mine from postdoc days at Berkeley). Chas has been a leader in open science for some time, securing extensive funds for the SGC’s activities and working effectively with the pharma industry to share data that underpins much of the structural biology that fuels rational drug design. The aim in both places: to collect together a group of people willing and able to try a project in open source drug discovery in an area such as cancer. i.e. to define a target, a hit compound, a scientific project structure and a governance/financial plan for how something like this might work. Both the Broad and the SGC lead the world in sharing data related to biomedicine, but neither have an open source project currently operating – i.e. one where anyone from outside those institutes may contribute, and it is clear what the project will do tomorrow. Collecting such a group together is really tough, and I don’t know how to do this, which is why I need a sabbatical. The aim is a project that is properly federated – labs in several countries working on the same project, using local funds, acting as a kernel, to which anyone else may contribute should they have the expertise. How?

    So I’m in Boston till September, then Oxford till the end of the year. Ping me if you want to talk about open drug discovery or organic chemistry. Even better, if you’re interested in trying out something in open drug discovery, by contributing to a consortium of loosely affiliated scientists who share what they do each day, please get in touch.

  • mattoddchem 2:34 pm on May 13, 2014 Permalink | Reply  

    Open Source Pharma and Prizes 

    I’m involved in a meeting happening next month in Italy that is asking “Can we develop a new open source pharmaceutical industry?” We’ll be talking amongst other things about incentives (such as prizes) and new ideas for the structure of pharma (legal and economic) and trying to come up with some pilot projects. This post serves as an announcement of the meeting and a description of the agenda – true to the philosophy underlying the idea, the agenda is open to input from anyone (please just comment below). This page may therefore change in response to input from people, so any changes will be tracked.

    Context: A while back, when my lab first started working on open source research for neglected tropical diseases, I was contacted by Jaykumar Menon, formerly of the X-Prize and now professor of practice at McGill University. He was interested in whether we’d considered prizes to stimulate activity. This got me to thinking about ways we might be able to combine prizes and completely open ways of working. Jay has now managed to secure funding from the Rockefeller Foundation to host a meeting to start looking at these ideas in detail. It’s taking place at the Rockefeller Bellagio resort on Lake Como, July 2014. Only 23 people can come, and we’re trying to create a diverse mix of attendees from across research, policy and philanthropy. Besides generating the funding and momentum for the meeting, Jay has driven the gathering together of a diverse set of people, and I’ve chipped in where I’m able, since we’ve learned a lot in recent years about how open source drug discovery works as part of Open Source Malaria (including how we’re operating the consortium) and in previous work with WHO on open source drug synthesis. I also gathered a group at WHO last year to ask “Is Open Source Drug Discovery Practical?” and though I’ve not yet uploaded the recordings of the session, and though there are many issues to work through, the answer to that question looked to be “yes”.

    Below is the current status of the blurb about the meeting and a draft agenda, derived from Jay’s original concept note. Please feel free to comment/criticise below. We’d love to hear about anything we might be missing, or relevant literature or people we should be talking to. An objective of the meeting is to discuss but also to create viable project proposals that we could take to possible funders for formal comment.

    On a personal level, despite my finding this general concept immensely exciting, there are so many questions one can ask and discuss specifically on prizes – how would prizes be awarded? For what? Who might fund a prize, and why? How would a prize be governed so that it is compatible with open ways of working? What is the role of the private sector in prize-driven, open projects? How would a prize alter the motivations for people to participate? I’ve also become increasingly interested in an important feature of open source I have noticed over the last two years in operation: an open arena is a way to combine competition and collaboration. I hope we can explore this at the meeting and beyond.

    The purpose of the meeting is to nurture the growing but powerful field of open source pharma. Items for discussion:

    1) What does “open” mean, for example the difference between open source and open innovation? My view on this is that open source means something very specific – that all data and ideas are shared openly, that anyone may participate in a project at any level. Open innovation refers to a competition in which there is no requirement for competitors to share anything. These two approaches are therefore polar opposites in terms of workflow).

    2) The relevance and prospects of open source for pharma, at each stage of the pipeline and including the role of generics manufacture or commercial pharma as partners/contractors.

    3) Open source pharma in the context of other approaches already being discussed or developed, including push mechanisms (traditional grants + Product Development Partnerships) vs pull mechanisms (Advance Market Commitments, priority review vouchers). Also patent pooling. The focus of the meeting needs to be distinguished from other initiatives that are attempting to find new drugs but which are not adopting open models.

    4) A possible global incentive prize for an open source, patent-free drug candidate (initial target: probably TB (the TB bacillus resides in nearly 1/3 of humanity), but the ideas are more generally applicable to e.g. malaria, antibiotics. Open source is a way of doing research, but prizes could incentivise it.

    5) Consider forming a light touch network/consortium for the largely on-line and nationally-based open source pharma communities

    6) Work jointly to draft a project for taking the field forward, to be finalized with inputs from funders in the 4 months post-meeting

    7) Jointly author a paper to be published in a journal on the contours, promise, and a way forward for open source pharma

    Taking these points, we can draft an agenda for the 2.5 days:

    Session 1: Setting the scene- what’s wrong in the kingdom of drug R&D

    • Current needs and gaps
    • Whether and why the current system fails
    • Illustration: peculiarities of TB (possibly also malaria, antibiotics)

    Session 2: Other existing incentives and enabling mechanisms

    • Incentives: Push and pull mechanisms
    • Models: PDPs, pharma spin offs and initiatives (e.g. Lilly Chorus model)
    • Example: Piero Olliaro to speak about current initiatives in TB drug discovery/development. What have they delivered? What are they promising to deliver? Are such initiatives solutions, or partial solutions?

    Session 3: Open source research: what does it really mean?

    • Examples of Open Source (OS) drug dIscovery/development
    • Strengths and weaknesses of OS research
    • Can we develop minimum criteria for what counts as OS?
    • What would OS Pharma look like?

    Session 4: New ideas for incentives & mechanisms

    • Prizes: example of past experiences; proposals that have been made
    • Innovative management of IP: patent pooling to facilitate research (examples from other areas)
    • Combining these ideas (e.g. the MSF 3 P proposal)

    Session 5: Exploring an end to end system based on incentives and enabling mechanisms

    • Can push, pull and pooling work with open source research?
    • What would be the business model? Can this work in TB? can this work beyond TB?
    • Proposal for a light touch consortium
    • Proposal for a draft project

    Status of Invitees
    1. Jaykumar Menon, McGill
    2. Matthew Todd, University of Sydney and Open Source Malaria
    3. Manica Balasegaram, MSF
    4. Els Torreele, OSF
    5. Piero Olliaro, WHO/TDR
    6. Zakir Thomas, OSDD
    7. Tanjore Balganesh, OSDD
    8. UC Jaleel, OSDD
    9. R. Venkat, TATA Trusts, Dorabji Trust
    10. Arun Pandhi, TATA Trusts
    11. Peter Kolb, University of Marburg
    12. John Wilbanks, Sage Bionetworks
    13. Bernard Munos, Innothink/Faster Cures
    14. Tomasz Sablinski, Transparency Life Sciences
    15. Sherwood Neiss, Crowdfund Capital Advisors
    16. John McKew, NIH/NCATS
    17. [MMV]
    18. Melinda Richter, head of Janssen Labs
    19. Samir Brahmachari, Chief Mentor, OSDD
    20. Rob Don, DNDi
    21. [Free]
    22. [Journalist]
    23. Sarah Dennis, McGill University (logistics)

    Collection of Relevant Links/Ideas:
    MSF summary of alternative financing/research models, includes: “When DNDi developed ASAQ in partnership with sanofi-aventis they insisted that the newly developed medicine not be patented. In doing so they have now been able to start work on transferring technology to an additional African industrial partner to produce and sell the medicine.” and “As these prizes only take the research so far, it is important that adequate measures are put in place to make sure that when a final product relying on this innovation is developed, access for the populations in need is secured.

    Impact of patents, and the new Trans Pacific Partnership

    Guardian Global Dev article on advice on how to develop drugs

    Patent Pooling


    The EU PreDiCT-TB Consortium (not open as far as I know).

    The Critical Path to TB Drug Regimens (also not open as far as I know).

    The Stop TB Partnership

    Guardian letter from MSF on “Big Pharma’s Ransom for New Drugs”

    Toll-access review on “Curing TB with Open Science

    Guardian article (9th May 2014) on problem of antibiotic resistance

    Kauffman Foundation report on economic incentives that might help in repurposing efforts by pharma (May 2014)

    The Accelerating Medicines Partnership (relevant to non-infectious diseases)

    WHO/TDR’s ongoing interest in alternative financing mechanisms. May 2014

    DNDi’s views on the advantage of the PDP model. May 2014

    State of play on NCEs for NTDs, with shared data from DNDi. Feb 2014

    (Updated 21/5/14 with input by email from Manica Balasegaram from MSF, including the first draft agenda)

    The Original Concept Note Description:

    Overview: A small gathering of a maximum of 23 people on the shores of Lake Como at the Rockefeller Foundation Center in Bellagio, Italy on July 16-18, 2014, on the subject of open source pharmaceuticals.

    Where: The Rockefeller Bellagio Center is a renowned spectacular site – the former villas of a princess, literally on the shore of Lake Como.

    Rockefeller Bellagio Center

    Who: A diverse and meaningful set of parties. Convening organizations include the Rockefeller Foundation, the Open Society (Soros) Foundations, and McGill University. Other attendees include representatives from the Tata Trusts (India’s largest philanthropic organization), the World Health Organization, Cipla (the global pharmaceutical manufacturer and generics giant), Medicins Sans Frontieres (Doctors Without Borders), Open Source Malaria, OSDD (the Open Source Drug Discovery initiative, an India-based consortium of 50+ universities, software giant Infosys, and the national supercomputer system of India; OSDD has already sequenced for the first time the TB genome), private sector entrepreneurs, and a crowdfunding pioneer.

    When: The meeting is Wednesday through Friday, July 16-18, 2014; participants are encouraged to attend all three days. Most participants will arrive the evening of Tuesday July 15, and leave Saturday morning, July 19.

    Logistics: Milan airports (LIN or MXP) are closest. Local transportation, food (all meals), and lodging (in the villas) will be provided.

    What’s It All About: Truly radical innovation to meet health needs. An inspiration: “Linux for drugs.” Specifically, a move away from closed-door, market based systems, towards an open source (meaning crowdsourced, and patent free) pharmaceutical industry, an emerging avenue drawing from extreme advances in computational technologies, collaborative methodologies, and Linux-type approaches to IP.

    The need of course is dire. Despite the efforts of the philanthropic, government, and private sectors, the health needs of billions globally are still going unmet, and research is still incommensurate with the scale of the problem. For example, only 1% of new approved drugs are for diseases of the developing world. And in high income countries, research into high impact but low-revenue drug classes such as antibiotics is too sparse, and overall drug development costs are extremely high, resulting in a lack of affordability. A variety of alternative approaches exist – we will focus here on the emerging open source movement. Imagine a new crowdsourced patent free drug candidates, going through publicly funded preclinical and clinical trials (funding interest has already been expressed), then being taken up by generics manufacturers on a market basis to create affordable cures for billions. Questions: How real is open source pharma? What are its prospects? And what is the path forward?

  • mattoddchem 12:24 pm on July 15, 2013 Permalink | Reply
    Tags: , , , , Open Source Research   

    An Example of Open Source Drug Discovery 

    “Open Source Drug Discovery? How does that work?” I am asked this quite a lot. There are some principles and core practices that are involved, embodied in the Six Laws, but those are quite hifalutin. Let me give a practical example.

    The main point is that everything is open, so anyone can come along, make molecules, do biology, do informatics, contribute data to the lab notebooks, coordinate the research and generally contribute in any number of ways for which there are simple technological solutions. All sorts of inputs are possible, including experimental ones.

    Earlier this year there was a need to make a bunch of molecules as part of the first medicinal chemistry campaign in the open source malaria project. The hit molecule that was the starting point had an ester in it, and initial results had shown that the ester was a problem. There were several ester replacements that needed to be synthesized. Many of these had been made. A few had either not been tackled or were proving difficult to make. Alice Williamson made up a “Wanted” poster to highlight that anyone could have a go at making them (see below, and in these nice images of the process of collaboration that Alice also made).



    Because these difficulties were being tackled in real time, other scientists could read about them and suggest solutions. Patrick Thomson, an Edinburgh PhD student, was reading this and decided to join in. He got going in the lab on the sulfonamide sE, started posting his data to the same lab notebook the Sydney team were using (to make it easier to compare and share data) and started his own blog to help marshall and summarize results. He corresponded with a student in my lab in Sydney to overcome synthetic hurdles. Several of us worked together to ensure quality control of the data – simple in the digital age.


    And Patrick nailed it. He made the compound. He then mailed it off for biological evaluation. Not to Sydney, which would be a waste of good funds for freight charges, but to a local lab at The University of Dundee. With the appropriate controls and sharing of all data, testing of compounds in different labs can be trusted to deliver a consistent picture.


    In the event, Patrick’s molecules (he tested 3) were inactive. This is a shame, but at the same time the ester/sulfonamide replacement is an obvious one to make and the data enhance the paper where these results will go, on which Patrick will be an author.

    Patrick showed great initiative here, and philosophical agility – he got involved with something unfamiliar where he had not met the people he’d be working with. Maybe it’s because he agreed with the principles of openness, or maybe it was because he saw that all project data were being shared so trust wasn’t an issue – he could see the project involved quality science. Either way, Patrick has provided an excellent example of how open source experimental lab-based research can work on a practical level.

    Which makes one think of all sorts of added benefits of working in a genuinely open manner. One is that open source research provides a low-tech infrastructure for researchers from developing (endemic) countries to get involved in collaborative projects with their peers in the developed world. There are no expensive online tools, no subscription fees for software. Researchers carry out their work in local labs, and share all the data online using existing technology solutions. Crucially the mechanism scales because researchers interact directly, rather than having to pass everything by a bottleneck professor. There is no monolithic “aid” program needed, just the means for people to work together effectively and efficiently. The involvement of endemic labs remains to my mind a top priority target for open research – the barrier is identifying the labs with the right level of chemical facilities (if anyone has any ideas…).

    Today the Open Source Malaria landing page is launched – the project used to be called Open Source Drug Discovery for Malaria, but the name was changed partly to highlight more the real essence of the project – open source. Much of the research is about basic synthetic chemistry, or biology and yes it’s aimed at finding new medicines for malaria, but at the same time the power of the approach lies in how it changes the way we do basic science. The new website highlights the most productive tools used thus far – the lab notebooks, the Github To Do list, the Twitter account, the wiki.




    With these simple tools, Patrick was able to make an important, material contribution to an experimental research project without ever leaving his Wimbledon-winning home country. Anyone else can do the same if the inviolable principles of open source are agreed upon – No Need to Ask.


  • mattoddchem 10:50 pm on June 7, 2013 Permalink | Reply  

    Open Source Competitions and Prizes #1 

    I recently read Future Perfect by Steven Johnson. The book articulates what is meant by a person being a “Peer Progressive” – someone with a set of values based on the power of distributed networks to solve problems (a “Baran Web”) as opposed to a more regulated, centralized mechanism (a “Legrand Star”). It’s an interesting read that gets better as the book progresses. Lots of stories, but there is one particular gem.

    There has been recent talk about prizes being used to alter the way drugs are found, such as Bernie Sanders‘ proposals for ways of funding the prize pot. I’ve written before about the idea of a teamless competition for open projects. We planned this, but have not yet deployed it – more about that later.

    What I find interesting is Johnson’s description of the use of prizes (“premiums”) in mid-18th century England to find a way to produce a deep “Turkey Red” dye derived from madder plants. The organization administering this prize, and others, would become the Royal Society of Arts (RSA); the competitions were very successful. The thing that struck me most about the story was the mechanism of promoting innovation – no patents in a competition with a significant prize where the aim is something of commercial significance. As Johnson quotes from the Rules and Orders published by the Society in 1765: “No person will be admitted a candidate for any premium offered by the Society who has obtained a patent for the exclusive right of making or performing anything for which such premium is offered.” As Johnson says “Prohibiting patents meant that solutions could circulate more quickly through society, and could be easily improved upon by subsequent inventors or scientists. The RSA wanted you to profit from your idea. They just didn’t want you to own it.”

    This, to me, is a crucial aspect of whether patents are harmful for drug discovery or whether they promote innovation. This also goes to the heart of how to run prizes for drug discovery. If we want the best ideas and for those to flow freely, we shouldn’t have a secretive research process. Jamie Love’s suggestion was to de-link the research process and the process of reclaiming costs. The deal is: make me a drug for cancer and I will give you a billion dollars, but you don’t have any say in how much the medicine will cost. Will that work? I don’t know, but it’s a possible solution that would allow the free sharing of information during the discovery process, which is why it’s interesting. I predict in the near future we’re going to see more government/NGO money going to support contract drug discovery in big pharma – that is part-way to the same goal of removing the need for excluding people from the process.

    The open competition structure was applied in the Matlab programming competition – an open process, with a prize, where everyone can see the previously-submitted solutions. Yes, this means you are able to tweak someone else’s solution a little and submit it as your own, but this is surely the way to get to a good solution most quickly.

    The open source drug discovery project I’m part of has a completely open structure (without the prize) as spelled out in the six laws. It’s crucial the structure is a Baran map (a redundant network), not a Legrand Star where everything goes through a central point (Linus doesn’t scale). The needs of the project need to be clear, and the structure must be such that anyone can take part. The network also needs to have redundancies and be robust. Changes to the structure have to be easily accommodated. So can such an open arena be combined with a prize? There are lots of things to think about here, and one of the reasons we haven’t deployed a prize yet is because we want to get it right. We don’t want to set something up that is too small, or with the wrong structure. How do we ensure that participants contribute everything into the public domain? Will the money pervert the incentives, possibly irreversibly in the sense that when the competition is over there will be a serious drop off in participation (as in Deci’s classic study on intrinsic/extrinsic motivation (PDF)).

    I’ve been talking a lot about this with a talented guy I know, Jaykumar Menon. Jay secured resources from the Rockefeller Foundation to host a meeting to address this issue for a few days in 2014 at their Bellagio Centre, and now we’re setting it up and organising who’s going. I’m starting to talk about it now to garner insights people might have in advance. It’s very exciting. I’m optimistic that in those few days we can thrash out a good way to do this – make a competition long-term useful and actually effective.

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