Exploring Malaria Treatment and Open Source Drug Discovery on Reddit

On October 4, ACS Publications hosted a Reddit AMA with researchers Matthew Todd and Alice E. Williamson of the Open Source Malaria Consortium. Mat and Alice recently published a paper in ACS Central Science on open source drug discovery and its impact on a new treatment for malaria. Their research could have a major impact on how we develop treatments for all kinds of diseases, and their commitment to open source research is more than fitting in an open access journal. Reddit users were intensely curious about the subject, and as always asked a variety of thoughtful questions. Below are some highlights:

/u/mandragara: What do you think about using rational drug discovery over traditional methods? Would you consider collaboration with Biophysicists within your university?

Mat Todd: Good replies in this mini-thread. I think [Reddit user] kevtree has it – the point is that you want a mixture of approaches. There has been a big shift in anti-infectives towards “phenotypic” drug discovery since there you start with a useful fact: This molecule kills this pathogen. That’s got to be good, right? Then you start to try to improve it. You could take such a molecule all the way to market without knowing what it does, amazingly. Yet there are very good approaches that use more rational approaches. The Structural Genomics Consortium, for example, do many projects this way: find a small molecule that binds, validate the binding with X-ray cryst, improve it in silico and do the synthesis. It really depends on the pathogen and the molecular target. I’d always want to be open to different approaches, therefore. I do think that, for infectious, phenotypic screening is a very good starting point. Incidentally OSM’s Series 4 is at the point where we know the compounds work, but have a poor idea of how they work. If you want to help, here’s the live competition.

/u/twiddlingbits: I’m more interested in the concept of Open Source Drugs. Writing software in your spare time requires a home computer or laptop versus needing a lab to do chemistry. Lab research is expensive so how do you fund your work without whomever provides the funding owning the results? Typically any discovery belongs in majority or even 100% to the funding organization (industry, VC, Government or your University). If your work does discover a better malaria treatment do you plan to patent it then sell the rights or make it available for free?

Mat Todd: Yes, you need a lab to make molecules. There are other things you can do that also only require a computer (e.g. our currently-live competition). I don’t think there is that much difference between the two industries: open source software development requires significant investment at the core, just like OSM does. In our case the core of the consortium, my lab, has investment from the Aussie government and the NGO Medicines for Malaria Venture in Geneva. This supports 1-2 people (so quite small). The rest comes from other places either supported by MMV or other institutions, and volunteers. We describe some of this in the conclusions section of the paper. Money will always be needed – but the efficiency of the investment in open source should be quite high (nothing ever lost or needlessly repeated). Patents? No. Check out the Six Laws in the paper!

/u/cabintom: Hi! So I live in eastern DR Congo, and instead of working, I am at home redditing right now because I’m actually sick with malaria. Yay. Anyways, I’ve been taking a dose of doxycycline everyday in a bid to prevent the very circumstance I now find myself in (I believe I must have missed a dose). Now, I’m quite privileged to be able to afford prophylaxis… my Congolese friends, on the other hand, can only dream of preventing the illness and usually just seek treatment at a hospital when a malaria flair up gets really bad. My question is, will open drug discovery lead to affordable medicine for the folks living in impoverished areas such as this one?

Mat Todd: Hi there Cabintom – yes, you’re right. The end result of open sourcing the process is that you have a drug at the end that is inexpensive. That seems to me to be a good solution. Anyone should be able to make and sell it – as currently happens with the generics industry. Low-cost medicines are an aim of many people, with one specific strategy (“delinkage”) being recommended by the recent UN High Level Panel on Access to Medicines but open source is (we think) the best way to get there.

/u/donkzwonkz: Hi! I have a few questions for you today:

1. Being someone with an interest in science, but (somewhat) far away from Sydney, are you planning to expand the undergraduate courses to the other universities in the region and further away? (e.g. Singapore)
2. Why do you pick Malaria rather than the plethora of other diseases out there?

Alice Williamson: Hello!

We’d love to expand the undergraduate collaborations to any institutions that would like to participate, so certainly. If you are interested in taking part then perhaps you could have a chat to some of your professors to see if they’d like to work with Open Source Malaria. The open source approach is well-suited to crowdsourcing in student labs, since all the students can see what all the others are doing and students can get involved in real research problems. If a lab PI takes on the responsibility of running the lab and managing safety, and if mentors can be arranged (e.g. through OSM generally) then the whole thing should scale. Stefan Debbert at Lawrence University did this as part of Series 1, and Patrick Thomson, a student at Edinburgh who worked on Series 1, did this with a smaller number of more advanced students in Series 4. Some other links that might be of interest can be found in the summary of some of the work that I’ve done with first years at The University of Sydney who synthesised 8 new antimalarial compounds over the last couple of years.

Right now a group of students at Haverford College are working on several OSM targets in the lab and so are some students at MCPHS and I have several other universities (U.S., U.K. and N.Z.) signed up to participate in the coming months, which is very exciting! This is something that will be a major part of OSM in the future and will be enormously powerful for synthesis and education.

In answer to your second question, why malaria? Well, firstly we chose a disease with a low market incentive as this seemed to make sense in the ‘first test’ of an open model. Also, we think that universities are the right places to investigate medicines for diseases that mainly affect developing countries. Mat chatted to MMV very early on and they were very receptive to the idea of an open source project and there was also a large set of compounds to choose as starting points thanks to the groundbreaking GSK Nature Paper that was published just before OSM was launched.

/u/mdhe: Question for Alice: As an organic chemist, what do you think about conventional synthetic organic drugs vs. rapidly advancing large biologics, both generally and in regards to Malaria?

Alice Williamson: I think both are very important. In the case of malaria for example, GSK have developed the first vaccine for malaria. It’s a fantastic achievement that has taken about 30 years, because the parasite is so good at ‘adapting to the host and evading its immune responses.’ The vaccine has been designed for plasmodium falciparum (the deadliest form of malaria) but for other types of the parasite, such as vivax, synthetic organic drugs are the only form of treatment. Human trials of the vaccine (in >15000 patients) showed that a treatment program of 4 injections reduced the cases of malaria by 36% in young children and 26% in infants (RTS,S Clinical Trials Partnership. Lancet 386, 31–45, 2015). These figures are really important but are much lower than typical vaccine outcomes so we’re not at a stage where we can prioritise biologics for malaria just yet. In fact, lots has been written about how tackling malaria requires a multi-pronged attack: nets, insecticide, vaccines, drugs.

More generally, I don’t think it is a case of ‘drugs vs biologics’. There is a necessity for both types of medicine and sometimes combinations of both in treatment programs.

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