TL;DR we have a job opportunity working at the interface of genomics and disease modelling for malaria vector control. Anyone with a strong background in science and/or computing is welcome to apply. See the job description for details of how to apply. Read on for more background and information on the post.
Current challenges in malaria control
Malaria is still a massive global health problem, particularly in Africa. The best way to control malaria in Africa is to target the mosquitoes (a.k.a. vectors) that transmit the disease from one person to another. You can protect a household from malaria by giving everyone an insecticide-treated bed net to sleep under, or by spraying the walls with insecticides. Both of these measures have been very effective, but there are challenges.
The first challenge is cost. To have an impact, literally millions of bed nets have to be produced and distributed, and have to reach everyone who needs them, even in remote regions. Nets last up to three years at best, so new nets have to be distributed regularly. Spraying is also a major logistical challenge. Hundreds of thousands of households need to be sprayed, and spraying needs to be repeated every 6 months or so. Teams of people need to be trained and provided with equipment and insecticide. A lot of money is spent on malaria control each year, but it is a some way short of what would be required to eliminate malaria within any reasonable time frame, and sustaining funding over a long period is a big ask.
The second challenge is resistance. Mosquitoes evolve insecticide resistance, which means that genetic changes occur that alter the mosquitoes’ physiology and/or internal chemistry, rendering insecticides ineffective. Those genetic changes are spreading throughout mosquito populations across the African continent. There is a broad consensus that something needs to be done, but there are no easy answers, and the global health community is struggling to mount a coordinated response.
Advances in malaria vector control
Broadly speaking, there are two ways of responding to these challenges. One is to use existing insecticide-based mosquito control tools more wisely, to avoid or delay the spread of insecticide resistance. The other is to develop new tools for mosquito control.
Insecticide resistance does not appear in a mosquito population instantaneously. It is a process, whereby resistance mutations occur, increase in frequency over a number of generations, recombine with other mutations, and spread via the movement and mating of mosquitoes from different locations. If a single insecticide is used continuously year after year over a broad geographical area, then resistance will emerge and spread quickly. But if more than one insecticide is available, there are options for how these can be used. One option is to rotate insecticides, switching after a period of one or two years. Another is to use different insecticides in different areas, in a mosaic pattern. A third option is to use more than one insecticide at the same time. The good news is that there are a number of different insecticides now available for spraying, and new nets are also available that combine an insecticide with a “synergist” that counteracts resistance. So these are practical options, and serious efforts are underway to plan and implement a coordinated strategy for insecticide resistance management.
With careful management we might be able to delay the spread of insecticide resistance, but that doesn’t change the fact that bed nets and spraying campaigns are expensive and logistically challenging. For these reasons, serious investments are being made in the development of alternative technologies for mosquito control. In particular, new tools based on genome editing are in development that can be used to introduce a genetic modification into a mosquito population. The modification can be designed to crash the population, or to change its ability to transmit malaria parasites. The trick is to engineer the modifications so they are able to selfishly propagate themselves through a mosquito population, a process known as gene drive. This is not science fiction, the technology exists and has been proven in the lab. There are still many hurdles to overcome before this technology could be deployed in the field, but the potential value is enormous, because these modifications are self-spreading, meaning that they are carried from one place to another by mosquitoes themselves. The logistics required to deploy them are therefore simpler, and they could reach remote areas which are difficult to access for net distribution or spraying.
If we want to manage insecticide resistance, how do we know if rotations, mosaics or mixtures are best? Which will maximise the time for resistance to emerge and spread? On what time frame should rotations be done? On what geographical scale should mosaics be implemented? Is it better to do both rotations and mosaics at the same time? Which insecticide and/or synergist combinations are best? Should we combine nets and spraying? If we want to deploy a gene drive construct, how many mosquitoes do we need to release? Where do we need to release them? How often do we need to release them? How far will the gene drive spread? By how much will the mosquito population size be reduced? What impact will this have on the rate of malaria?
These are not simple questions, and cannot be answered by simple analysis. Instead, we have to build computer models of mosquito populations, which capture all relevant aspects of climate, geography, ecology, behaviour, epidemiology and evolution. These models are a way to synthesize everything we know about mosquitoes, and allow us to try out different vector control strategies in the virtual world of a computer simulation, investigate the likely outcomes, and then make informed decisions about how to proceed in the real world. For example, models are now available that can be used to explore and compare the impact of rotations, mosaics and mixtures of insecticide-based interventions. Models have also been developed that help us to understand how effective gene drive constructs have to be before they will spread throughout a mosquito population in a self-sustaining way. Models like these are a vital bridge between theory and practice, and need to be as complete and accurate as we can make them.
If you’re modelling a mosquito population, there are certain things you need to know. For example, there are some basic questions about mosquito biology, such as how long does a mosquito live, how many times will a female lay eggs, how many eggs will she lay each time, how many offspring will survive, etc. There are also questions about the environment in which mosquitoes live, like where are the breeding sites, where are people to feed on, are breeding sites there all year round or only during the wet season, if so when is the wet season, and so on.
Many of these questions can be answered with careful field and/or lab work. However, other parameters are harder to determine directly. For example, how big are mosquito populations? How far do mosquitoes fly on average? Do some mosquitoes use aestivation (a kind of hibernation) to sit out the dry season? Previous wisdom was that mosquitoes don’t move very far, up to around 5 km in their lifetime. But recent studies have shown that many insect species engage in purposeful, wind-assisted migration, travelling hundreds of kilometres. There have also been studies suggesting that different mosquito species use different strategies to cope with the dry season, with some aestivating and others migrating. These are important parameters when it comes to modelling insecticide resistance or gene drive, because they have a big impact on how fast and far these could spread.
Mosquito genome sequencing
An alternate way to resolve some of these unknowns is via genome sequencing. If you’re not a population geneticist then this may seem like a knight’s move, but stick with me. You are probably familiar with the idea that DNA contains genes which encode proteins, and thus a genome (the total DNA sequence of an individual organism) provides a blueprint for growth and function. You may also have heard that a genome contains a lot of “junk” DNA, which doesn’t encode any functional proteins and is silently passed down from one generation to the next, mostly hidden from the buffeting forces of natural selection. In fact this junk DNA is a treasure trove, because the processes of random mutation and recombination that occur with each cycle of mating and reproduction create a living record within this DNA of each organism’s ancestry. By comparing these DNA sequences between lots of individual mosquitoes, it is possible to reconstruct a surprisingly detailed account of the major events that occurred to the ancestors of those individuals, stretching from the previous generation back an astonishingly long way into the past. This is because events and processes like an increase or decrease in population size, or migration between populations, affect the patterns of mating between individuals, which in turn affect the patterns of genetic diversity and relatedness observed in DNA sequences from present day individuals.
This process of inferring the demographic history of a population from genome sequence data is a major field of statistical and computational research. There are a wealth of papers, methods and software packages available (e.g., dadi, Stairway Plot, MSMC, ABC, to name a few). The major drivers behind this research have largely been human history, where genomic analysis has been used to reconstruct major migration events or infer interbreeding between modern humans and neanderthals; and conservation biology, where genetic estimates of population size are used to determine whether a species is endangered, and if so, what action is needed. However, this is still a young field, wrestling to make best use of the data deluge becoming available thanks to recent developments in high-throughout, whole-genome sequencing technology. Another complication is that mosquitoes are quite unlike many of the species that have been studied in this way, because of their large population sizes and high levels of genetic diversity. This means that there are no well-calibrated, off-the-shelf solutions for inferring mosquito population size or migration rates from genome sequence data. Substantial work is needed to understand, adapt, improve and tune methods for demographic inference from genomic data before we can get the answers we need.
We are looking for someone to work at the intersection between genome sequence data analysis, statistical methods for population demographic inference, and computational modelling and simulation of mosquito populations and control. That probably sounds like an intense place to be, requiring a lot of specialist knowledge, but that’s not the case. If you do have experience in one or more of these areas then that will undoubtedly help. But this is fundamentally a cross-disciplinary role, and so the most important requirement is a willingness to step into an unfamiliar field, and to dive in without losing sight of the bigger picture or the connections between different areas. That’s why we’re open to applications from anyone with a strong track record in any scientific or computational area.
Our team’s strength is in the analysis of genome sequence data, and so a major part of the role will involve exploring, visualizing, summarizing and understanding the genomic data being generated by MalariaGEN (more on that below). But an important component will be to work with and improve statistical methods and tools for inferring demographic features of mosquito populations. And although we are not a modelling group, some time spent gaining an intuition for infectious disease modelling, and in particular, current approaches to modelling of vector-borne diseases and vector populations, will be beneficial.
The genomic data you’ll be working with come from the Malaria Genomic Epidemiology Network (MalariaGEN), which is a multi-centre collaboration generating the world’s largest resources of genome sequence data on malaria parasites and mosquitoes. Last year we published the largest ever genetic study of mosquitoes (or in fact any arthropod), in which we sequenced the genomes of 765 mosquitoes collected from 8 African countries. That paper is just the beginning of a much larger programme of mosquito genome sequencing. Data from the second project phase are already curated and available online, comprising genomes of 1,142 mosquitoes from 13 African countries. We have already sequenced all ~3,000 mosquitoes from the third project phase and are curating those data now. And we have launched a follow-on project which will aim to sequence ~10,000 mosquito genomes per year. All of this is made possible by our close partnership with the Wellcome Sanger Institute, a world-leading centre for genomic research.
This is both a scientific and a computational role, so hopefully you will already have some programming ability, and will be keen to develop new skills. I expect you’ll have to work with existing software written in a variety of languages, so some flexibility and open-mindedness will be needed. People in our group code in a number of different languages so there is a diverse set of experiences to draw on, but we are converging on Python and making heavy use of the scientific Python / PyData ecosystem of packages for our day-to-day genomic data analysis. We are big fans of open source software, everything we create goes up on GitHub, and we try to align our code with other packages and best practices in the scientific Python ecosystem as much as possible. In recent years we’ve created a couple of open source Python packages, including scikit-allel and Zarr, and it’s been a great pleasure to interact and collaborate with others working in the scientific Python community. The culture of professionalism, collaboration and high quality software engineering is so strong now in the open source community, and we are benefiting a lot from bringing that culture into our own work as a team. I encourage everyone in our team to get involved in open source software, it is an invaluable learning experience.
Professor Dominic Kwiatkowski is the head of our group at the Big Data Institute (BDI) in Oxford where this role is based, and also heads our sister group at the Sanger Institute. The work in our group spans human, parasite and mosquito genomics, and I lead the mosquito (vector) programme. This role will also involve working in close collaboration with the Target Malaria project led by Austin Burt at Imperial College, London. Target Malaria is leading the development of gene drive technologies for malaria vector control, and is making great strides. Our groups in Oxford and Sanger also include teams working on the genomics of malaria parasites, and there are many parallels, so we keep in close touch. We are also very fortunate to be supported by amazing lab, informatics, data, admin and communications teams, and there is a great ethos and spirit of cooperation across the piece. They are genuinely a great bunch of people to work with.
The job is based at the newly built Big Data Institute (BDI), which is part of the Li Ka Shing Centre for Health Information and Discovery at the University of Oxford. The director of the BDI is professor Gil McVean, one of the most respected people in the field of statistical genetics. Our group at the BDI is part of the infectious disease programme, which also includes the Malaria Atlas Project led by Pete Gething, and Christophe Fraser’s group who work on HIV, as well as Gil’s research group who work on a variety of problems in statistical genetics. The building is only a year old and still not full, but it is a great environment to work in. There is a weekly infections seminar where you can hear anything from me talking about the history of insecticide resistance, to Gil or Christophe giving a whiteboard talk on coalescent theory, to the head of the HIV programme at the Gates Foundation talking about the plan for HIV control in Africa, to how Bayesian geostatistics can be used to model the spread of terrorism.
And the social areas and all of the seminar rooms have been painted with whiteboard paint, so you can write on the walls. That’s probably all you needed to know.
This is an academic position, which means that we cannot compete with the commercial sector on salary. There has to be some compensation, and apart from all of the above, there is a lot of flexibility around working hours. We all make an effort to be at the office between 10 am and 4pm at least 4 days a week, but otherwise as long as the work is getting done you are free to work where and when suits best. I have three children aged 7, 2 and 9 months, and I usually stay at home in the morning long enough to help get everybody ready and out the door in time for school/pre-school. At the other end of the day, I always leave in time to get home for bath and bedtime. I do sometimes work in the evening, but the weekends are sacred. I work from home one day a week, and I also travel over to the Sanger Institute one day a week, so there is plenty of variety and opportunity to get focused work done, as well as catching up with colleagues and collaborators, without missing out on family time.
How to apply
See the official job description for details of how to apply. Don’t forget to include a tailored cover letter and a CV tailored to address the requirements listed in the job description. If you can, try to back up the claims you make in your CV with some evidence. E.g., if you say you are a fluent Python programmer, give a brief description of a non-trivial program you have implemented, or even better, a link to a GitHub repository with code you wrote.
If you have read this far, thank you for taking an interest. If you have any further questions, please feel free to get in touch.