You’ve undoubtedly seen this plot before: a cast of characters gets slowly whittled down over the course of a quest, in which increasingly difficult challenges compels the protagonists to acquire new skills. A familiar story, but you’ve never seen it play out in a movie quite like this.
The cast members are bacteria. Their set is a large acrylic dish, four feet wide and two across. It is filled with a nutritious agar jelly that contains varying amounts of an antibiotic. The outermost sections are free of the drug—a safe zone in which microbes can easily grow. But as they move towards the dish’s centre, the concentration of antibiotic goes up in 10-fold increments, and conditions become increasingly deadly. To survive in these toxic zones, they need to evolve resistance.
And that’s what they do. At the start of the video, bacteria are dropped into the edges of the dish and soon colonise the outer safe zones. Then they hit their first antibiotic wall, which halts their progress. After a few moments, bright spots appear at this frontier and start spreading outwards. These are resistant bacteria that have picked up mutations that allow them to shrug off the drug. They advance until they hit the next antibiotic zone. Another pause, until even more resistant strains evolve and invade further into the dish. By the end of the movie, even the centre-most stripe—the zone with the highest levels of killer chemicals—is colonised.
What you’re seeing in the movie is a vivid depiction of a very real problem. Disease-causing bacteria and other microbes are increasingly evolving to resist our drugs; by 2050, these impervious infections could potentially kill ten million people a year. The problem of drug-resistant infections is terrifying but also abstract; by their nature, microbes are invisible to the naked eye, and the process by which they defy our drugs is even harder to visualise.
But now you can: just watch that video again. You’re seeing evolution in action. You’re watching living things facing down new challenges, dying, competing, thriving, invading, and adapting—all in a two-minute movie.
Michael Baym, part of Roy Kishony’s team at Harvard, is the director of these videos. He’s also their producer, casting director, stage manager, and lighting technician. He used to call the dish the Observatory of Microbial Growth (OMG) but more conservative peers forced him to change the name to the Microbial Evolution and Growth Arena plate (MEGA-plate).
The original name is perhaps more appropriate: when Baym showed the videos at an evolutionary biology conference in Washington DC last month, many attendees were awed and slack-jawed. “It’s exciting, creative and, game-changing,” says Shelly Copley from the University of Colorado, one of the organisers. Baym himself, who has seen the movies hundreds of times, is still blown away by them. “You can actually see mutations happening,” he says, before shaking his head and smiling.
The MEGA-plate began as a side project. Baym was inspired by a colleague who had created a “morbidostat”, a set-up in which bacteria are grown in a flask and challenged with antibiotics. The better they grow, the more drugs are added to their midst. Their environment constantly changes, making it increasingly difficult for them to survive, and forcing them to continuously evolve. “It’s like a game of bacterial whack-a-mole,” says Baym. “We hit them with bigger and bigger hammers, and they wear better and better hats.”
But bacteria floating in a flask can only tell you so much. In the real world, evolution doesn’t happen in a swirling, uniform vat of liquid. Microbes have to grow over surfaces, invade new territory, compete with neighbours. Space matters. That’s why Baym created the MEGA-plate.
“I then got an email saying: You need to stop everything you’re doing and focus on this.”
Setting it up was easy: Baym just ordered “the largest piece of plastic we could that would still roll through a door.” Shooting the videos was the hard bit. Most agar is yellow which makes for terrible video, so Baym and his colleague Tami Lieberman used ink to dye it black. They’d get reflections from the ceiling, which they solved with a lot of black paint and gaffer tape. Water would condense on the lid of the plate, so they rigged by space-heaters to dry it out. Other microbes would contaminate the jelly, so they deployed copious amounts of bleach.
Baym and Lieberman worked evenings and weekends. “It was a secret side project and then suddenly we realised there was something to it,” he recalls. “At a department retreat, we showed the first movie where we saw clear patterns of evolution. I then got an email saying: You need to stop everything you’re doing and focus on this.”
The MEGA-plate shows just how easily and readily bacteria can flout our medicines. On its first try, the common gut microbe E. coli evolved to be 1,000 times more resistant to seven very different antibiotics. It became 10,000 times more resistant to trimethoprim, and 100,000 times more resistant to ciprofloxacin. Some strains could even yank the ciprofloxacin out of solution, wearing crystals of the supposedly lethal chemical like little hats.
Other scientists have shown this before, albeit not quite in such a beautiful and intuitive way. But the MEGA-plate isn’t just a fancy visual aide. It’s also a valuable research tool. Baym and his colleagues can collect microbes from different places on the plate and sequence their DNA. They can then reconstruct the gradual accumulation of mutations that allowed some bacteria to make it all the way from the safe periphery to the deadly centre. They can work out which mutations matter.
“We’re visual creatures. Seeing is believing.”
Most importantly, they can look at how bacteria evolve in realistic three-dimensional spaces. “It is very exciting and takes us much closer to the real thing,” says Pamela Yeh from the University of California, Los Angeles.
Here’s an example. Resistance doesn’t come for free, and the same mutations that make bacteria invincible tend to slow their growth. You can see that in the movie below: at the 0:30 mark, the bacteria have advanced into the first antibiotic zone, but their colonies are faint and sparse.
But as the movie continues, bright spots start appearing within the faint areas. These are bacteria that have picked up “compensatory mutations”, which allow them to grow quickly and resist antibiotics. They ought to have been the fittest microbes on the plate, able to colonise new areas more effectively than their slower-growing peers. But more often than not, they became trapped. Weaker strains at the front of the expanding wave of microbes were already gobbling up all the nutrients, leaving their faster-growing peers with nowhere to grow. “You don’t have to be better than everyone else around you; you just have to be the first in a new area,” says Baym.
It shows the importance of randomness in evolution “in a really beautiful way, a way that is easy to visualize and thus hard to deny,” adds Yeh. “It’s not just that mutations need to arise, it matters very much where those mutation pops up.”
It is increasingly clear that location matters in infectious diseases. For example, people with cystic fibrosis often develop chronic bacterial infections in their lungs. Those microbes don’t grow as a single uniform population; instead, they form isolated clusters that stick to separate parts of the lung, evolve independently, and often vary in important traits like antibiotic resistance. “There are some really interesting parallels between those infections and the multiple coexisting wavefronts [on the MEGA-plate,” says Michael Brockhurst from the University of York. The latter might be very useful for studying the former.
Beyond any applications in research and medicine, the MEGA-plate also makes for a wonderful teaching tool. It makes the abstract concrete. It vividly brings the process of evolution to life—and to view. “We’re visual creatures,” says Baym. “Seeing is believing.”