Remember taking children’s cough syrup as a kid whenever you got sick? Some flavors were more palatable than others, but all have left most of us with distinct, visceral memories of dissolved plastic fruit. It comes as no surprise that the intended purpose of these flavors was to mask the taste of the medicine enough to take a full spoonful with only mild fuss. However, for one crucial drug called praziquantel, dealing with the horrible taste of medicine was under-funded and overlooked. Recently, scientists previously unknown to each other joined forces to tackle this issue and provided a look at how science can be done.
The Impact of a Fluke
According to the CDC, the microscopic parasites known as blood flukes are considered to have the second largest impact on human health after malaria, but are still considered a “Neglected Tropical Disease.” These parasitic worms (species of the Schistosoma genus) reside in fresh water and implant themselves in human skin and then migrate to the bloodstream where they can persist, sometimes for decades. Symptoms can be rather non-specific: fever, chills, muscle ache, and cough. These are caused by the body’s immune reaction to the flukes’ periodic release of eggs.
For most tourists and one Tour de France winner, the disease — schistosomiasis — can be cured with straightforward drug treatments. However, for those living in endemic areas (PDF), dealing with the disease is more difficult and can have more significant effects on their livelihood. In these regions, children are often repeatedly infected by the parasite. This chronic burden of parasite infections slows children’s physical and mental development. These sorts of effects and the lack of attention it gets have led schistosomiasis to be referred to as a “silent pandemic.”
Schistosomiasis in endemic regions is treated with periodic administrations of the drug praziquantel (PZQ). Depending on the severity of disease in these regions, the breadth of administrations ranges from just school children to entire communities. Regular treatments are particularly beneficial for children, as these treatments prevent the onset of chronic schistosomiasis and therefore enable them to develop at a more normal rate. However, getting children to take PZQ isn’t easy. First, the pills are large (600mg), making it difficult for children to swallow them. Second, they taste horrendous. When given to adult volunteers, PZQ was described as “an unpleasant chemical or metallic taste or a taste circumscribed best by old rubber.” Some children find the taste so disgusting that they end up gagging and vomiting. Furthermore, children often chew rather than swallow these pills, thereby releasing more of the taste over their palettes.
On the left, where the hydrogen atom is facing towards you (indicated by the solid triangle), is the active form of PZQ, the form that kills blood flukes. On the right, where the hydrogen atom is facing away from you (indicated by the dashed triangle), is the inactive, absolutely disgusting form of PZQ. Source: The Synaptic Leap
The Problem of Praziquantel
The awful taste of PZQ is attributed to exactly 50% of the pill. When PZQ is manufactured on an industrial scale, the most cost effective process produces an equal mixture of two forms (or enantiomers) of PZQ. This is called a racemic mixture. They have the same chemical makeup (C19H24N2O2), but differ structurally at a single hydrogen atom. One form is active and readily kills parasites. The other form is inactive and tastes terrible. In other words, half of the 600mg pill that children take is ineffective and, at best, tastes like old rubber. Therefore, the solution seems simple: tweak the chemical reactions and produce a pure drug of only the active form.
However, schistosomiasis is called a neglected tropical disease for a reason. Compared to HIV, malaria, and tuberculosis, organizations aren’t putting much money into finding better drugs for schistosomiasis, particularly if there is already one that is cheap to manufacture and predominantly gets the job done. Recognizing that there was no incentive for organizations to improve upon the large-scale production of PZQ, Dr. Matthew Todd in the School of Chemistry at the University of Sydney decided to take on the challenge. However, he chose to take an unconventional approach.
Resolving Praziquantel
According to the Internet, people fucking love science. However, many scientists would correct you and say you in fact love the data that science produces. Science itself—the process of obtaining that data—is not as pretty. Any scientist will tell you that our lab notebooks are filled with failure. The data we publish in scientific journals are often distillations of what worked, even if it’s not replicable. And progress is always slow: a lab may research a topic by themselves, publish their findings, gain funding, expand on their original work, publish these new findings, gain funding, and do this process ad nauseam. Brick by brick, this process will reveal new understandings into nature, but the pace is tedious.
Matthew Todd, Phd. Source: The University of Sydney
In order to solve the PZQ problem, Matthew Todd wanted to circumvent the normally slow and sometimes opaque process of scientific research by opening up his project to anyone who could help. This sort of collaborative work, called open source science, is nothing new. If you’ve used things like Firefox, Wikipedia, or practically any form of modern technology, you have benefitted in some way from open source software. Open source work is open, collaborative, and free for the public to use without the threat of a lawsuit. The people who build these tools can be anyone with an internet connection and useful knowledge and ability. The end result is often an essentially altruistic contribution to technology.
In 2006, Todd posted on the open source biomedical research website The Synaptic Leap a project proposal whose aims were to find an inexpensive way to produce large quantities of only the active form of PZQ. His hopes were to work on the chemistry in his lab while being able to get help from any interested chemist around the world, not just the ones in his professional network. As a result, rather than publish his work bit by bit, struggling at each step, he would be able to significantly expedite the discovery process by fueling it with the collective knowledge of chemists around the world.
In order for this open source project to work, anyone and everyone must be able to see every single piece of data from every single experiment and be able to comment on these data. Therefore lab notebooks in the Todd lab were digital, meticulously kept, and posted online daily. This is a frightening idea for many researchers today. Worse than the fear of showing your inevitable daily mistakes to the scientific community, many of us would fear someone stealing our ideas and beating us to publication.
However, that didn’t happen. Initial interest in the project was minimal, but nevertheless valuable. Chemists, sometimes anonymously, followed the progression, commented in the lab notebooks, and offered advice on troubleshooting and future directions. From this, Todd decided (with the help of the online community) to take the existing racemic mixture of PZQ and figure out a way to remove the inactive, bitter form (rather than go the academically interesting route and try to synthesize just the desired form of PZQ).
To do this, Todd posted in a chemistry forum on LinkedIn in April 2010 asking for suggestions on what else his lab could do. Forum members, most of whom were complete strangers, suggested he work with Syncom, a Dutch chemical contract research company. In mid-May, they began a collaboration (for which Syncom was not paid). Progress was swift, and in just seven months the collaboration yielded a process to purify the active form of PZQ from the racemic mixture with simple, cost-effective steps.
An Opening
Previously unbeknownst to Todd, a separate private research company was contracted by the WHO to solve the PZQ problem at the exact same time. It too produced a simple, cost-effective way to make a better drug to treat schistosomiasis. The difference, however, is how the scientific community and the world at large benefited from the way the science was done.
Source: Michael Nielsen Blog
We know that this company found a successful way to purify the active form of PZQ, just like the Todd lab did. But we don’t know about any of their mistakes, their failures, or their thought processes. In contrast, the Todd lab kept their notebooks online for anyone to read, search, comment on, and learn from. We can see if they’re allocating grant money appropriately. We can see if they’ve fabricated data. We know all of their mistakes, successes, and everything in between.
And if their lab were suddenly forced to shut down due to lack of grants, natural disaster, and so on, we would still have their diligent notes because they are stored on off-site servers and backed up. Their work wouldn’t have to come to an abrupt end as others would be able to pick up where they left off.
More important than the availability of potentially useful knowledge hidden in all of our lab notebooks is the pace at which science can be done. By opening up their data to everyone, the Todd lab was able to find experts (or have experts come to them) and solve their problem quickly. There are thousands of scientists around the world that are stuck on problems without access to the resources (e.g. financial) offered by a private company, and asking one’s peers is only so helpful and limited by network size. Therefore, opening up science and encouraging more honest dialogue among scientists around the world could give researchers the opportunity to overcome hurdles that would normally take years of unnecessary struggle to surmount.
Many scientists may find this model of how science is done utterly unpalatable. They may exalt the benefits of the current academic system; they may cite issues with intellectual property; or they may be simply uncomfortable with increased transparency. But they may also be missing the point. Matthew Todd, who is now taking his open science approach to malaria drug discovery, explained in an interview with the University of Sydney, “I want a drug to be found for malaria as quickly as possible, and I don’t really care who does that. The work is important, not who does it. It’s like when you edit a Wikipedia article, you don’t do it because you want money. You do it because you want to do good work, and for that to be of the widest possible use to humanity.”
