Thursday, 2 February 2017

Moving in a straight line - sounds simple, right?

One hundred years ago Asa Schaeffer blindfolded his friend and challenged him to walk in a straight line. He did three loops of a spiral, before tripping over a tree stump. This wasn't a cruel prank, it was an experiment, and all people are surprisingly bad at this simple challenge.




More modern experiments showed it is lack of external reference points that trips people up. Blindfolded in a desert? You walk in circles. Not blindfolded in a desert? Straight lines. Forest on a sunny day? Straight lines. Forest on an overcast day? Circles. Current Biology, DOI: 10.1016/j.cub.2009.07.053

People need some external reference point, a distant hill, the sun, or even the direction of shadows, to manage a straight line. Why they drift into circles without a reference isn't clear. Is it asymmetric leg strength? A handedness bias? Or some psychological miss-correction? What is clear is that it is a universal problem.

Navigation without reference points is always difficult. This is why spin stabilisation is widely used to stop flying objects, from bullets to rugby balls, curving off course in the air. Even advanced tools like inertial navigation systems, which use dead reckoning from measuring acceleration, always drift off course. 

So how about swimming cells? Many swimming cells and microorganisms have the ability to swim in a straight line. Most have no ability to look at a reference point, they can only perceive the liquid they are in immediate contact with. They are also typically top small to be affected by gravity, so have no way of using up or down for reference. They are essentially blind.

The trick for straight line swimming in cells seems to be some kind of spin stabilisation. Way back in 1901, H.S. Jennings noted that many microorganisms spin as they swim, and thought this could be a spin stabilisation somewhat like a spinning bullet. The problem is it can't be. Rugby balls, bullets and spacecraft use spin stabilisation which depends on rotational inertia to keep them spinning and stable, similar to a spinning top. If you made a top that was the size of a cell, and span it in water, it would stop spinning immediately; there is too much friction. The American Naturalist, 35(413):369-379


It turns out the mechanism is just geometry. A person walking is a back-forward/left-right, a 2D, situation. If you curve the walking path it makes it into a looping circle. For a cell swimming there is another direction to think about; in 3D there are two ways to curve the swimming path. The first which curls the path into a circle, and a second which twists the circle to elongate it into a helix-shaped path. Elongate the helix far enough and it turns into a straight line, with the cell rotating as it swims.


The interesting property of the helical swimming paths is their stability. If a cell deliberately twists its swimming path into a helix then small asymmetries (the cellular equivalent of having one leg stronger than the other) won't bend the swimming path into a circle. Instead it just slightly alters the shape of the helix. It can ensure the cell swims in a dead straight line.

My latest paper is all about how cells manage straight line swimming, looking at trypanosome and Leishmania human parasites. Each aspect of swimming has been looked at before, but I believe has never previously been put together as a full story: from mutants with altered cell shape (to add more or less twist), measuring the effect on swimming, and matching this to simulation of how cells achieve their straight line swimming. PLOS Computational Biology, DOI: 10.1371/journal.pcbi.1005353

There are still big unanswered questions though: Why do parasites need to swim in a straight line? And what are they swimming towards? This is an area of active research, with several major trypanosome research groups (especially Kent Hill and Markus Engstler) interested in addressing these questions.

Saturday, 28 January 2017

Molecular Cell Biology of Protozoan Parasites - Ghana 2017

Things change fast in Ghana! Three years ago, I helped teach a course for young African scientists in the University of Ghana in Accra. This January I got the chance to do the same again, and it has been fantastic. The University of Ghana is becoming a centre of great science in West Africa, with huge contributions by Gordon Awandare and his West African Centre for Cell Biology of Infectious Pathogens (WACCBIP) course, funded by the World Bank.


This time around, our teaching course was made possible by our TrypTag project, funded by the Wellcome Trust. We applied for extra funds so we could transfer the genetic engineering technologies we developed for TrypTag into the hands of African researchers; to get the research techniques to the parts of the world that really suffer from parasitic diseases.

Our course focused on tools for analysing parasites and what makes them tick, particularly using genetic tools. We mostly looked at Plasmodium (malaria), Trypanosoma (sleeping sickness) and Leishmania (leishmaniasis). To teach the malaria side of the course we had the excellent Kirk Deitsch (Cornell University, New York) and Oliver Billker (Sanger Institute, Cambridge). On the trypanosome and Leishmania side we had Keith Gull (University of Oxford) and Sue Vaughan (Oxford Brookes University), along with the TrypTag team: Jack Sunter, Sam Dean and me!

So what was the course all about?

We focused on the tools to help young African scientists (starting their Master's or PhDs) take control of their research - from learning about free genome data and bioinformatics experiments, to computational and genetic tools to make discoveries about parasite biology.

A major part of the course was tools for handling DNA: PCR for detecting genes in a sample, amplifying DNA to clone it into a plasmid, and working with software (ApE) to design cloning strategies for gene tagging, deletion and RNA interference/siRNA knockdown. Teaching how to design a PCR or cloning experiment, rather than just teaching how to do the experimental technique, was very popular.



We also taught how to use the sequence resources you need for working with DNA: How to get the most from genome databases, like PlasmoDB for malaria and TriTrypDB for trypanosomes and Leishmania. The course also covered bioinformatics experiments, thinking how to test a biological hypothesis using existing data from genome data. The students quickly recognised the power of this approach, particularly given genome sequence resources are free! Many were immediately applying these ideas to their areas of research.



We made sure there was a big push towards critical thinking. The student's loved critical reading of articles in the journal clubs, and thinking about how to apply this critical assessment to their own experiments to make them as good as possible.


We also tried, for the first time ever, using the TrypTag.org website as the start point for a bioinformatics experiment. The students were challenged to start with a protein localisation patterns to identify protiens likely involved in particular aspects of parasite energy metabolism, then test whether any of these were unique to trypanosomes making them a potential drug target.



This was the perfect stress test for the new TrypTag.org website and server. It coped with up to a page view per second, and downloads of 10 images per second, with no problems. All over a slightly unreliable internet connection in Ghana! Many thanks to the scientific computing at the Sir William Dunn School of Pathology in Oxford for helping make this happen.


Overall the course was a great success, with very positive feedback from the students and local research staff. The students were smart, engaged and hard-working. It will be exciting to see what these young people can achieve over the next few years.