The world's scientific and social network for malaria professionals
9268 malaria professionals are enjoying the free benefits of MalariaWorld today

The making of a PNAS paper...here's our story

September 3, 2015 - 20:35 -- Bart G.J. Knols

Once a scientific paper is published online and you can download a pdf of it, this addictive and magnificent feeling gets on to you. This is the fruit of all the hard work: first to get the funding to undertake the research, then the hard work to actually perform all the research, then the hard work to write up the manuscript, then the submission, the reviews, the rebuttal, and eventually acceptance followed by proof reading and then publication. The route from thinking up research to publishing about it is long, tedious, and really hard work. But why don't we ever talk about this route? Why do we publish our papers but don't tell our peers more about how we got there? The fun parts, the sweat and tears, or even the fights? This week we published an article in the Proceedings of the National Academy of Sciences USA (PNAS; attached below). And here's the story you don't know when you read the paper...

This PNAS paper started back in 2007. Yes, eight years ago. In June that year, a man called Anne Osinga entered my office. He had made an appointment but I didn't know him. Anne had just developed a special coating. A coating that had a positive charge that could be used on window screens to trap negatively charged pollen. He had not developed a coating for killing mosquitoes, but a coating to help hayfever patients. He knew nothing about mosquitoes but had wild ideas about bednets and his coating. This happens a lot (to me at least): People that have no clue about mosquitoes that think that they have the magic bullet for you. I know that many malariologists turn down requests for meetings with lay persons, but I never do. Because you never know... Well, Anne eventually became a shareholder in our company, is now the lead product developer, and co-authored the PNAS paper! This proves one simple thing: Sometimes great ideas do not come from fellow malariologists but from people working in completely different fields...

We got along well from the start. Together with the then PhD student Marit Farenhorst (the senior author on the article) we started work on coatings. For several years we tried, also in collaboration with the Belgian chemist Johan Deschietere (also on the paper and a co-developer of the coating), to develop a coating into which spores of the mosquito-killing fungus Metarhizium could be embedded in such way that the spores would 'sweat out' of the coating over time. Numerous coatings were made and tested by Marit. And with numerous I mean numerous - this was the sweat and tears part of the research. Frustration that we could not succeed in developing what we wanted, doubt that we ever could make it work kicked in. And we eventually gave up. Almost.

But then a new idea surfaced. Rather than developing a new coating, could it be possible to use the electrostatic coating developed for trapping pollen, but then replace the pollen with fungus spores? It was a wild idea, but hey, we were about to give up anyway, so one more shot at it couldn't do more harm. After years of frustration we finally hit the jackpot: This worked!

(Image: An Anopheles mosquito that was exposed to electrostatic netting that was treated with fluorescent bendiocarb. Under UV light, this bendiocarb lights up orange. This clearly shows the massive transfer of insecticidal particles from the coating to the mosquito, which is much higher than a mosquito that merely contacts an impregnated net with the tips of its legs. Image credit: Hans Smid).

Excited about this development we started to look around for funding. In2Care (our company) was only a year old and we were in desperate need of funding. Then we read about the upcoming call for proposals under the EU-FP7 framework. And decided to bring together a consortium of partners and submit a proposal. This was in January 2012. I remember this vividly as bad luck struck in my family. My 11 year old daughter didn't feel well and after three days it turned out that she had been walking around with a burst appendix for days. What seemed a minor surgical issue turned into a nightmare that lasted months and brought her on the brink of death twice. We were devastated and I could not concentrate on writing the EU proposal. Eventually Marit and colleague Remco Suer did all the hard work in bringing it all together and submit the proposal in time. Together with Matt Thomas (PSU), Patrick Hartmann (CTF2000), Ladslaus Mnyone (IHI) and Andreas Rose (Biogents), we submitted a good and solid set of ideas that led to the MCD project: The Mosquito Contamination Device project. Needless to say we were all thrilled when the good news reached us in June 2012 that our proposal would be funded.

Now work on the electrostatic coating could intensify and our focus was once again on using fungus on it. Our project has an External Advisory Board and during the first meeting with them (in Regensburg in September 2013) it was Dave Malone (from the IVCC) that made a strong and compelling case to start working with WHO-recommended insecticides and not just fungus. This, with hindsight, was excellent advice. Our focus shifted, and we started using insecticides on electrostatic coating. The results got better and better.

Then, during the Vector Control Working Group meeting of RBM in Geneva in February 2014 I sat down with Hilary Ranson, of the Liverpool School of Tropical Medicine, with a request. We were hoping to test our coating against her resistant lines of Anopheles. I was excited when she agreed and we started planning a trip to Liverpool. This time Marit and lead author Rob Andriessen prepared for a 2-day trip to Liverpool, which was a long shot. Would it all work out well in such a short visit? It did. Rob and Marit came back with amazing results. Using Hilary's Tiassale strain from Ivory Coast, of which she said 'normally nothing kills that strain', we succeeded in killing it with deltamethrin. Yes - a pyrethroid against which this mosquito is highly resistant. Better still, we could reduce the concentration of insecticide on the coating 15-fold and still kill it. This was a eureka moment. What seemed almost impossible worked: Killing a highly pyrethroid-resistant mosquito with a pyrethroid with a concentration 15 times lower than used on commercially available bednets. Beers and cake during our lab meeting followed of course!

But was this a one-off? A lucky shot? We then wanted to test the coating against more resistant strains from across Africa. That would require much travel but then our long-term collaborators from Johannesburg helped out. In the lab of Maureen Coetzee, Lizette Koekemoer and Basil Brooke, many different (resistant) lines are maintained, so a trip to South Africa could make it work. It was Marit who travelled to Johannesburg and worked day and night (with the excellent support from Basil) to expose the different lines to the electrostatic coating. Again the results were spectacular.

Armed with data collected at the Liverpool School and in Johannesburg we started to realise the full impact of what we had developed: A novel method to kill pyrethroid-resistant mosquitoes with...pyrethroids. The first drafts of a manuscript were then prepared by Rob and Janneke Snetselaar (who performed much of the lab exposures in our lab), and a discussion then followed where we would send it to. The results were spectacular, the impact possibly massive: Could this be material for Science or Nature? We thought about Nature communications for a while, but eventually decided to take another route: PNAS. In 2009 it was former ICIPE (Kenya) director Hans Herren who had served as editor for our PNAS paper on fungi, so maybe we could try to see if he would be willing to undertake this task once more?

Hans responded highly positive after seeing the manuscript and suggested we submit the paper through the direct route to PNAS. That was last June. After hitting the 'submit' button a period of anxiety started. Would the PNAS editor consider this work of sufficient merit to send it out for review? Well, he published an editorial himself shortly after our submission titled 'Impact, not impact factor'. A marvellous piece. This generated hope on our side. It went out for review...

Weeks later, in the middle of a meeting (with an outside guest!), Marit quickly checked email on her mobile and couldn't help her excitement and shouted a loud 'Yes!'. We were in, and received three glorious reviews of the manuscript. One reviewer actually wrote 'frankly, it's a game changer'. More beers folowed, as you can imagine!

After submitting the rebuttal, a few weeks passed before the final word of acceptance reached us. This was such an exciting time! And finally, this week, the paper came out (its attached below - we paid the high price for making it 'open access').

The electrostatic coating is already used in a novel autodissemination ovitrap for dengue/chikungunya vectors and over the last 12 months, some 35 thousand pieces of this trap were sold. In Tanzania, the electrostatic coating is in use in so-called eave tubes in more than 1800 houses, providing additional protection against malaria for some 10 thousand Tanzanians. Much more is in the pipeline and plans for additional vector control options using this coating are on the drawing table.

Never, ever, dismiss an idea, no matter how wild it is, that is brought to you by a 'stranger'...it can generate great new ideas, products, and a paper in PNAS!

More information about In2Care, see: www.in2care.org

More information about the EU-FP7 funded 'MCD Project', see: www.mcdproject.eu

AttachmentSize
PDF icon Andriessen et al. 2015_PNAS.pdf1.03 MB

Comments

Clive Shiff's picture
Submitted by Clive Shiff on

What a great story Bart, you do have the gift of the "gab" and present stories in an exciting manner. I heard you on this subject in Jerusalem, and it is great to see it in print,
Congratulations, it is a game changer. But you also involved an impressive group of colleagues, which is an example to most of us. Truly international

Clive Shiff

Submitted by Ricardo Ataide on

Hi Bart, it is always great to know how papers come to life, and many of them have such great personal stories behind them. This was a great read! And it makes us think that publishing together with your team must be great: we always get beer and cakes!
Cheers!

Ricardo Ataíde