Racing amoeba across a microscopic maze is no doubt fun, but the reason scientists around the world are spending time and effort to breed the perfect contestants is because of its implications for disease and healing.
Research groups around the world working on cell-movement have been invited to participate in the second edition of the Dicty World Race, a microscopic Pac-Man of sorts where the contestants are cells, the race is a silicone maze, and the destination is a pool of a tasty chemical.
The challenge for the scientists is to create the line of cells that will be the quickest to traverse this maze. Unlike in typical athletic competitions, the organisers joke, genetic engineering and chemical “doping” are not only allowed but highly encouraged. This chemical-directed movement, called chemotaxis, is a crucial feature of immune cells in the body called neutrophils.
When a pathogen invades our body, these are the first to rush to the scene and defend against infection. Neutrophils navigate from the bloodstream by following the scent of specific chemical signals emitted by the enemy microbe. How well the neutrophil can exhibit this targeted movement determines how well the body can fight infection. On the other hand, overzealous neutrophils cause problems in diseases such as arthritis, where they enter joint tissues and cause damage and pain.
As much as we now understand the molecules that allow neutrophils to exhibit chemotaxis, we’re still unclear about how the different molecules work together. Hence, we have not been able to develop ways to enhance or inhibit neutrophil migration for therapeutic purposes. This is what led to the genesis of the first Dicty World Race, which took place at a lab at Harvard Medical School belonging to one of the organisers, Daniel Irimia, in 2014.
The first time around, participants were allowed to use either of two types of cells, Dictyostelium ‘Dicty’ amoeba (commonly known as slime mould) or a line of human cancer cells called HL60. These two types of cells are established models for human neutrophil cells, which themselves are difficult to study using typical lab tools. Dicty cells and HL60 have the added advantage of being relatively easy to genetically meddle with.
Many ways to win
For a cell to complete the maze and emerge victorious, its speed is not the only thing that matters. In fact, the winners of 2014’s race weren’t the ones that were the fastest but the ones that were willing to sacrifice speed for precision. The winning Dicty cells, from Team 12, were engineered to have an over-active ric8 gene, which enabled them to be more intelligent in navigating by sniffing out and moving toward regions of higher concentrations of the chemical bait. Though this slowed them down somewhat, Team 12’s slow but steady cells dominated, comprising 48 of the first 100 cells to cross the finish line.
Second in place were the HL60 cells from Team 4 which employed a contrasting strategy. Engineered to be more flexible and contract more easily, these cells were among the fastest cells to participate. However, their technique was much cruder and less directed, likely costing them the top rank. Team 4’s cells comprised 19 of the top 100.
Other strategies employed included minimising the stickiness of the cell to the surface of the maze, reducing the number of lateral pseudopods (arm-like extensions of amoeba) that distract the cell from moving forward, isolating new wild Dicty strains, etc.
In general, the results of the race, published along with detailed analyses in the journal PLOS One on June 22, revealed several differences between the chemotactic behaviour of HL60 and Dicty cells. The average HL60 was found to be more than twice as fast (18 µm/min) as Dicty cells (8 µm/minute), whereas the latter were shown to use the shortest routes and make fewer mistakes.
Consequently, Dicty cells were able to locate the entrance of the maze much sooner than HL60 cells, but HL60 cells were much faster in traversing the maze once inside. Their respective weaknesses are significant as they reflect those of neutrophils in burn victims who are, as a result, highly prone to fatal infections.
The mazes were designed keeping in mind the features seen in human tissues, including mechanical confinement, chemical gradients and various other obstacles. “Neutrophils, for example, encounter similar conditions when they squeeze between other cells when moving through tissues or moving towards a site of inflammation,” pointed out Irimia.
“The tools we have now to measure human neutrophils are significantly better than the traditional tools that everyone else is using, and we want researchers and clinicians to start using them,” said Irimia. This event is a playfully meaningful way that they hope to get the word out.
This year it’s better and bigger
The first event was not without hurdles. Some cells got contaminated before the day of the race; some cells from a European team did not make it across the Atlantic Ocean; some had problems adhering to the surface of the maze. This year’s race, which will take place on October 26, is being prepared to overcome last year’s difficulties. More importantly, there is an added category. “The race we are organising this year in October, we will have a category for human neutrophils,” revealed Irimia in an email interview.
While the 14 teams of 2014 came from the US and Europe, the organisers are hoping for larger and more widespread participation this time. “All scientists who are curious about how cells move are welcome,” said Irimia. Their website allows people to sign up for news about the race, and participants to register. “Hopefully, more scientists will start thinking about the challenges related to human neutrophils and become involved.”
Monica Skoge from Princeton University, the lead author of the paper said via email that Dicty researchers are a relatively small but international community. “They’re united by a fascination with Dicty’s unique life cycle and an appreciation that Dicty can teach us a lot about fundamental biological processes and signalling systems that are relevant to human health. The website DictyBase serves as the central hub and promotes the sharing of resources and information,” she added.
Indian labs do make an appearance on DictyBase. One of the labs is that of Baskar R. in IIT Madras. He pointed out that right now his work does not deal with chemotaxis but said that even if it did, his lab’s participation would depend on the time available, resources and students who are willing to spare time to get involved in this work. “In the present circumstances, I will not go for it,” he admits, but he said there might be other labs in India who might be interested.