The anatomy of an unusual infection – African Trypanosomiasis

Meet Trypanosoma brucei. They are those delicate wisps of blue you see among the red blood cells in the picture. T. brucei are a species of microscopic parasites called Trypanosomes that cause a disease called African sleeping sickness in humans and Nagana (Zulu for ‘depressed in spirits’) in livestock. Seen mainly across rural sub-Saharan Africa, it is spread by the bite of the infected tse-tse fly.

In humans, the infection is not immediately recognisable as sleeping sickness. Patients always experience recurrent fever but other initial symptoms are vague and range from headaches to serious organ damage. In the second stage, when the trypanosomes cross into the brain, they show sudden changes in behaviour, problems with co-ordination and the disturbed sleeping patterns. Left untreated it leads to coma and death.

Host vs Parasite

Our first line of defence, the ‘innate’ immune system, recognises generic structures of invading microorganisms and attacks them. It also alerts our more specialised ‘adaptive’ immune system, which mounts a response directed against specific structures. To counter these responses, parasites employ various strategies ranging from aggressive attack on the immune system to more subtle subversion.

To start with however, many of them just hide. For instance, when Plasmodium, which causes Malaria, enters the blood, it slips into red blood cells. Leishmania parasites live more dangerously having adapted to survive inside macrophages, the cells that usually swallow and digest foreign bodies. An American trypanosome species, T. cruzi that causes Chagas’ disease across Latin America has also evolved to enter human cells.

On the contrary, African Trypanosomes remain in the bloodstream where they are most vulnerable to the host’s defences. Even here, their surface remains covered with a dense layer of a molecule called “variant surface glycoprotein” (VSG) which practically screams ‘I’m foreign and dangerous, kill me!’

Left: Parasite surface with VSG coat (purple) and Antibodies (yellow). Right: A closer look at the VSG molecule.

Our immune system responds by producing thousands antibodies which are proteins that can specifically bind a particular structure (such as the VSG) on the parasite surface. This allows immune cells to easily find and eliminate them. Such an efficient response is possible because our immune cells can mutate. Yes, you read that right; they mutate by randomly rearranging bits of genes such as those that make antibodies. This means that from about the 10,000 or so genes they have to detect invaders, they can make over a hundred billion variations. A clever trick indeed.

Unfortunately, it’s an old one. Like our adaptive immune cells, trypanosomes have also learnt to mutate on demand. They use this ability to change their surface coat proteins and thus become invisible to the highly specific response. The ‘mutants’ can then happily multiply while our immune system needs to start from scratch. By the time a response against the new coat is established, the parasites switch coats again. The resulting cycle of rising and falling parasite numbers is the reason for recurrent fever in the initial stage of the disease. Depending on the species, this cat and mouse game can last between a few weeks to many years. It tires the immune system out and the trypanosomes eventually invade the brain to cause further havoc.

Disease burden

Sleeping sickness is a major public health burden: it is a debilitating disease that kills about 30,000 people every year. Nagana adversely affects farmers who are dependent on cattle for milk, meat and labour intensive tasks such as ploughing the field. Moreover, vast tracts of fertile land in sub-Saharan Africa still remain unused due to tse-tse infestation. All this feeds in to the endless cycles of poverty, hunger and lack of development that plagues this region of the world.

Recent efforts in controlling the tse-tse fly population have brought down the number of reported human cases to fewer than 10,000 for the first time in 50 years, according to the World Health Organisation (WHO). However, current drugs especially for the second stage of the disease suffer many limitations – they are ineffective, difficult to administer and can have severe, and sometimes fatal side effects. Combining known drugs has improved treatment somewhat but better drugs have not been forthcoming.

But are they?

… to be continued.

Next focus:

Review of research efforts

The evolutionary story of Trypanosomes

 

Image sources: 1- http://www.parasitemuseum.com/trypanosome/, 2-http://dx.doi.org/10.1016/j.cell.2007.08.046

Matters of the Heart

I study heart development – how genes control the formation of our four-chambered pump from from a simple tube-like structure. OK, to the two or three people who have seen this before, I do feel bad about recycling this picture time and again. But this poster captures what I currently do so well!

I will soon be leaving to start a PhD in an entirely different field. I am VERY excited about that, but there are a few moments of over-stretched heartstrings and pangs of leaving this stuff behind. So here’s the whats and whys of my research answered:

Bugs – a missing definite article, a not water-tight allusion.

How to chat up a Nobel laureate 101

So we had a celebrity in our midst recently – Sir Paul Nurse was here to give this year’s Baddiley lecture, billed the highlight of our academic calendar. Nurse is one of today’s most eminent scientists, a 2001 Nobel Prize winner (among a number of other awards) and the new President of the Royal Society. I remembered him from a  BBC Horizon episode, that set out to understand why Science seemed to be under attack so much these days. It turned out to be a bit of a controversy for the perceived unfair presentation of climate change skeptics and HIV-deniers (I didn’t know there was such a thing!) etc and it’s been wrangled enough here and here and much elsewhere, so can’t be arsed to go into it here. Anyway, I was very excited about getting to see him talk about his own work.

We had to walk over to the medical school on the main campus some half hour away. Good – outside was lovely and sunny and amazingly, less windy than usual. He wound together three stories from his current work on the regulation of cell cycle – which are interesting enough to warrant a separate post later. And then there was the drinks reception…

So what do you do when you’re about 5 feet from a Nobel laureate for about 40 minutes in the same room? You should go say hi right? right? I almost did. About 20 times. But chickened out each time. There were middle-aged men in suits, they throw me off. Even when there weren’t any I thought – what have I possibly got to say? What do I want to ask him? So I pretended to just want a photo with him (which I didn’t) but thought it was too crass to actually get one.

There was a post-doc who attended the talk with me however who had absolutely no qualms about going up to people and talking to them -so she did. I dawdled around and drank free wine in the warm evening, and joked about pick-up lines one can use in a situation like this. She asked him – if any of his post-docs had left science, and what it was about the ones that stayed that gave them the edge. Particularly pertinent to her because she’s a postdoc trying to make the transition into PI-hood and finding it difficult – not surprising in these uncertain times.

So what makes a successful scientist today? It’s probably been said before but it’s worth re-remembering, especially coming from someone who is a successful scientist (to say the least). You need to:

• enjoy the lab work, the experiments (check!)
• not necessarily be particularly intelligent (I take heart), it’s not as important as…
• …having the nose – being able to pick out what is most likely to yield a discovery (…uhm)
• knowing when to stop a line of inquiry – to be able to step back and (and not be so attached to your work that you can’t) see that it’s futile (can be learnt, no?) 
• getting a really really good post-doc experience – famous lab/papers ( n/a, don’t have a PhD yet)

So now it seems really obvious what to ask – advice! Duh moment.

Read up about their work in advance and think of a good question about their talk – even if it’s something you didn’t understand. If you sound stupid, they are more likely to be generous about it and they probably won’t remember so it doesn’t matter. If you’ve been pondering something even tangentially relevant to science, perhaps a latest discovery, you could tell them what you think and ask them for their opinion on it. Have they written a book? Getting it signed is a great excuse to speak to them. Have you seen them on TV -  did you enjoy it, was is controversial? I’m not so sure about this as a starting point but suppose you could ask them about their take on it and try not to sound like a tabloid journalist? Hmmm.

If nothing – introduce yourself, say you enjoyed their talk (you obviously did if you want to go speak to them) and if they don’t show any more interest, say it was nice to meet you and slink go away. Enjoy the free wine :) More often than not, in a drinks reception type leisurely setting, I think they’d actually be interested in talking to people other than men in suits, such as yourself.

Besides, this is not only a utilitarian exercise – these are people who have consistently gone beyond doing Good Science. So while it may be ‘useful for your career’, you never know – it might just be a fascinating conversation and that would be worth it in itself.

There she goes again..

This time, for real!

Whatever catches my eye on the internet and real-life (probably in that order). And a little bit about forays into Science outside the Lab. And maybe some about the agony and ecstasy of a PhD application process.