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 This (currently) unpublished research specifically shows which Shigella species were prevalent during WWI and suggests how they might have moved around the globe during the war.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: 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!

Researching "The Invisible War" - Meeting the computational biologist

Cycled down through a blustery Melbourne afternoon (no gloves, cold fingers) to meet Kathryn Holt at the Bio 21 Institute. She found us a spot on Flemington Road to have coffee and Gregory asked, “So, do you know why we asked to meet you?”

She shook her head, smiling quietly and I wondered if she thought we were a bit crazy. Gregory pulled out copies of Squid Vibrio and Zobi and launched into a description of Mission Symbiosis Storytelling.

Kathryn explained to me that she’s a computational biologist – which I had never heard of. There’s something kind of amazing and on the edge of humiliating about being the absolute novice thrown into these conversations. Kathryn talked me through it.

She’s working with samples of the Shigella bacteria, which causes dysentery (some of which are over a 100 years old, from WW1. Think of them sampling soldiers’ stools and keeping those samples intact for so long). Kathryn does genetic analysis and uses that information to trace where Shigella bacteria have travelled in the world. She told us about a guy from the Pasteur institute, who’s obsessively using genetic data to exactly track the movement of Shigella bacteria from trench to trench during the war. I love the stories I get to hear of humans dedicated to drilling down such specific details.

Kathryn talked about the Shigella bacteria’s “type three secretion system”. The they have 40 or 50 genes which can form the shape of a needle used to puncture a human gut wall. Then they manipulate our cells so they can live inside them. Her descriptions were so graphic. I was already seeing scenes of our story forming.

She talked about the microbiome, the thousands of species of bacteria in our gut, some of which would compete with Shigella, helping us to beat the dysentery.

I sat there, cold hands gripping my coffee, listening with a kind of gleeful astonishment.

The last thing I wrote in my notebook for that meeting was, “macrophages patrolling your gut”.

Researching "The Invisible War": The Official History of the Australian Army Medical Services Vol II

It’s a great, fat blue tome, which is exactly as you’d imagine from the title. I am drawn into the disease prevention chapter: diagrams of different shit-pits used in different locations. Statistics on the various illnesses suffered at any one time (trench fever, typhoid, mumps, VD.) The view of sanitation as a core army discipline. Procedures from diagnosis to reporting to quarantine. Information that I find hard to retain – but which it will be necessary to get right.

It doesn’t seem like the kind of chaos war stories often depict. It seems efficient. I’m astonished that in “that mad world of blood, death and fire” they managed to keep such detailed records. There is a great sense of achievement in the text. It tells a success story – a pride that the rolling war bureaucracies across several nations’ armies kept illness to a minimum. I’m struck by the paradoxical efficiency of keeping men healthy so they can continue to kill. I wonder if the nurses were? I find this paragraph:

It will be carried out as follows: Diagnosed cases of the above diseases will be notified by telegram to this office immediately a diagnosis has been arrive at. The notification will be sent by the officer commanding Casualty Clearing Station…Suspected cases of Dysentery will also be notified…the ADMS of the Division who will at once take steps in direct communication with the Officer in charge of the Mobile Laboratory concerned for the investigation of the carrier condition of the contacts in order that those found free from infection may be returned to duty without unnecessary delays and that the carrier contacts may be suitably dealt with.

Order dated 14th June 1916, quoted in The Official History.

I read it over and over again. The Mobile Laboratory! What did it look like?

I search the index for dysentery. There is one page here, two pages there. I start to find references to the bacteriology. They know how many cases were caused by the Shigella bacteria and how many by the Flexner. Which means, I assume, that someone was looking at soldiers shit under a microscope? Or would the bacteria be present in a mouth swab? I’ll have to check with Gregory. The bacteriology sections reference the notes of an Australian, Leiut. JC Martin and I wonder where he was working and what his days looked like?

And then, surprisingly, it references the notes of a woman: Miss F. E. Williams. She seems to have worked alongside Martin. Many of the references are to notes shared between them. A woman. I’m suddenly excited. Can I make her my central character? Who was she? Where was she from? (Fingers crossed she was from Victoria, because our main character needs to be.) What was her relationship to Martin? Did they ever meet D’herelle? I’m going to spend some time trying to track her down.