Meet the Scientists: Dr François-Xavier Weill

François-Xavier Weill is one of those rare truly interdisciplinary researchers: one part Microbiologist, one part Historian and one part Epidemiologist.

His work mainly focuses on the evolution, emergence and detection of new strains of enteric pathogens (which basically includes the nastier versions of Salmonella, Shigella, Vibrio and E. coli) around the different human populations on Earth…so that we can better understand how, when and why enteric diseases spread.

Of particular interest to our research, was François-Xavier’s focus for several years on the epidemiological mapping of large numbers of different Shigella species around the globe over the 100-odd years. This (currently) unpublished research specifically shows which Shigella species were prevalent during WWI and suggests how they might have moved around the globe during the war. We’ll link to the article highlighting this amazing body of work when it appears in late 2015!

Briony, Ailsa and I travelled out to Cambridge (UK) to meet with François-Xavier in his home...stopping to admire the punts along the river Cam.

In our highly caffeinated meeting, our discussions included:

• the role of nutrition in affecting the acidity of the stomach – lowering the defenses of soldiers and nurses to dysentery;
• the high similarity between E. coli and Shigella (something Kat Holt had also mentioned) – Shigella is essentially a weaponised E. coli, adapted to infect and rapidly multiply in humans;
• the change from Shigella dysenteriae to Shigella flexneri with improved hygiene, corresponding with the modern understanding of how S. dysenteriae wreaked havoc in the god-awful conditions in Gallipoli to the lesser incidence of S. flexneri in the much improved (and less tropical) trenches on the Western Front;
• how the identity of the dysentery-causing agents were strongly contested in the early 20th century – with many scientists insisting that amoebic dysentery (caused by the amoeba Entamoeba histolytica) was the only significant disease;
• how the high morbidity of bacillary dysentery (that is, dysentery caused by the Shigella bacillus) created such a high burden to the resourcing of the war, considering the need for intensive nursing of each infected soldier over a period of several days to weeks;
• the difficulty in studying dysentery, given that there are no animal models – that is, disease-causing Shigella only infect humans – and it’s never easy to experiment on humans…
• and finally what sensitive creatures Shigella really are, especially outside of their niche in the large intestine!

François-Xavier also made the interesting suggestion that we consider using Shigella dysenteriae type 1 as the anti-hero in our story, due to its ability to make the deadly Shiga toxin…although this presents other new difficulties to our current storyline!

Meet the Scientists: Dr. Laurent Debarbieux

The phage whisperer…

While in Paris, Ailsa, Briony and I travelled out to the Institut Pasteur to meet with Dr. Laurent Debarbieux – an expert on Bacteriophages – that is, viruses that infect bacteria. Laurent works at the forefront of research into using bacteriophages to attack and destroy particularly difficult bacterial infections, such as cystic fibrosis infections in the lungs. And while the results have been promising, there is still much work to be done to determine whether bacteriophages can be used reliably to treat clinical infections. At the same time, scientists like Laurent also need to convince our medical and public health authorities to consider the possibilities of using viruses as allies against particularly nasty bacteria! But with the current crisis in antibiotics, the stakes couldn’t be higher!

We had an amazing session discussing bacteriophages with Laurent, hearing his perspectives about how bacteriophages can adapt to infect new host bacteria. In particular, we picked his brains about the scientific creation of our story’s viral hero...

Meet the Scientists: Prof. Philippe Sansonetti

Pasteur-ising

How could a trip to Paris be complete without paying homage to Louis Pasteur?

First up, Briony and I visited the Museé Pasteur – a museum dedicated to the legacy of the man who discovered the role of microbes in fermentation, created vaccines for rabies and anthrax and much, much more.

Since the time of Aristotle, it was thought that many life forms spontaneously emerged from water, dust, rotting flesh or the aether. But Pasteur championed the idea of biogenesis (Omne vivum ex vivo "all life from life"), famously demonstrating that sterilised meat will not rot without exposure to microbes from the surrounding air (luckily, he didn’t try that experiment with a McDonalds burger).

Pasteur also famously showed that microbes were responsible for spoiling beverages such as milk, beer and wine – and invented the process of pasteurisation – where the heating of these liquids killed most bacteria and moulds, preventing the potential growth of spoiling or disease-causing microbes.

The creation of the anthrax and rabies vaccines brought great wealth to Pasteur, and led to the creation of the Institut Pasteur  - dedicated to the study of microbes. Still to this day, the Pasteur Institute is a world leader in the research of microbes, particularly their role in disease. And it was here at the Institut Pasteur, that we were to encounter Professor Philippe Sansonetti.

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Sansonetti vs Shigella

The anti-hero in our upcoming book The Invisible War is Shigella flexneri, the bacterium responsible for most of the dysentery (severe diarrhoea) in the trenches during WWI.

While S. flexneri still causes millions of cases of dysentery in the poorest societies on Earth each year, we now understand a lot more about how it causes dysentery – in no small part due to Professor Sansonetti.

The thing that makes all Shigella bacteria so pathogenic (that is, able to cause disease) in humans, is the ability for a very small number of Shigella cells to invade our intestinal epithelium (the wall of our gut). And once inside, these Shigella can take over our epithelial cells – stealing our energy and assimilating our building blocks to make billions more…causing continuous eruptions from our gut wall to invade new regions of our intestine. This process releases lots of blood, which mixes with the eruptions of our intestinal mucus (trying to flush them away), to create bloody, mucous stools – characteristic of dysentery!

Working on Shigella for over 30 years, Prof. Sansonetti has provided the most complete and unified view of any bacterial-controlled disease process. Perhaps not surprisingly, these discoveries are now being employed to develop a vaccine against different types of Shigella still causing illnesses and deaths around the world every day.

We sat down with Philippe to learn more about his discoveries into how Shigella cells invade the human gut epithelium and how they take over once inside – so that we were best able to describe this process in our story. Probably the most interesting thing we learned about was how Shigella bacteria can trigger the ruffling of an adjacent intestinal cell (see above image), a process of engulfing which essentially ‘tricks’ our intestine into swallowing and internalising the Shigella…after which, all hell breaks loose!

Meet the Scientists: Dr. Kathryn Holt

We began our research into the dysentery-causing bacteria Shigella with local expert Kat Holt.

The Holt group at the University of Melbourne are the next generation of microbiologists – a laboratory full of computer nerds, who sequence whole genomes of different disease-causing bacteria. But unlike traditional genome-sequencing approaches, their approach is to sequence and compare whole populations of clinical isolates from different locations, focusing on differences in the genetic differences in their transmission, antibiotic resistance, detection and more.

In our meeting, Kat told us about how so few Shigella can cause an infection and the important role of nutrition in preventing Shigella from infecting and causing dysentery. She also described the Shigella invasion plasmid (a plasmid is a mobile set of genes in circular form, separate from the genome), and the role this massive set of genes play in gaining entry through our defenses and into our intestinal epithelium (the cells lining our gut), and how they take advantage of our immune system to spread throughout our large intestine in a dysentery infection.

Kat also told us about her amazing work in discovering the changing infections of different Shigella species (such as Shigella sonnei) around Earth over the last century and implications this has for the millions of people still infected by Shigella each year and the role that clean water supplies can have in preventing dysentery.

Kat also rightly emphasised that the endogenous (native) human intestinal biota (particularly our resident bacteria) would play a large role in trying to fight off any Shigella bacteria in our gut…something we will surely work into our story!

Meet the Scientists: Dr. Jeremy Barr

The main stimulus for The Invisible War came from an article by Jeremy Barr “Bacteriophage adhering to mucus provide a non–host-derived immunity”, published in the prestigious US journal PNAS in June 2013.

Here, Jeremy, along with group leader Forest Rohwer, writer Merry Youle and other co-authors described a mutual symbiosis between mucus-producing (animal) “host” with their phage partners – where the virus partner limits mucosal bacteria, while the animal host presents new bacterial hosts in the mucus for the phage to reproduce.

The enemy of my enemy is a phage

Widely hailed as the discovery of a new immune system, we knew we had to speak to Jeremy Barr about the potential to describe this newly symbiotic relationship as a story in our series. We were overwhelmed by Jeremy’s enthusiasm about collaborating to communicate this discovery as widely as possible.

Jeremy also had an implicit understanding about the power of using narrative to engage people in a topic, something at the heart of our mission. One of our extra incentives for creating this particular story was the challenge of writing a story with a virus as a hero…something we hadn’t anticipated at the start of our process of creating Small Friends stories!