Morbidostat

Here at Harvard University, scientists are investigating why some of our antibiotics are failing. It’s an experiment that happens in Prof Roy Kishony’s lab. Here they are deliberately trying to create superbugs. Roy Kishony “This is a new device we’ve developed – we call it the morbidostat.”

Antibiotic Morbidostat Bacteria
Dripping Antibiotic

Using the morbidostat, they are going to produce a highly resistant version of a harmless strain of the bacteria we all have in our gut. E. coli.

Roy Kishony “At the beginning you have bacteria just growing happily in the tubes, they have enough food, they are growing fast.”

The morbidostat is a continuous-culture device that automatically tunes drug concentration to maintain constant growth inhibition.

They start by trying to kill the E. coli by dripping in a low concentration of antibiotic. But as the millions of bacteria have been multiplying in the tubes, some, by chance, will have developed mutations that allow them to be resistant to the antibiotic.

Professor Roy Kishony

Professor Roy Kishony Morbidostat
Professor Roy Kishony

Roy Kishony “This mutant which start replicating faster than everyone else, ultimately it would take over the whole population.”

So now they tried to kill this new mutant strain. They up the strength of the antibiotic. Again, most of them die. But a new mutation appears, that can survive the even stronger antibiotic.

Professor Roy Kishony “And then we see another step, now they can grow in even higher drug concentrations, so we keep iterating this process over and over and over.”

This experiment shows that bacteria become resistant by being exposed to low levels of the very thing they are used to protect us from, antibiotics.

Now the team have created a new experiment to find out exactly what is happening in these mutant bacteria to allow them to be resistant. It starts with what is in effect a giant Petri dish.

Bacteria Petri Dish Morbidoststat
Giant Petri Dish

Professor Roy Kishony “We are setting an experiment really for the first time in which we’re going to let bacteria swim against ever-increasing concentration of an antibiotic, and see what happens.”

The jelly contains food for the bacteria to grow, but each slab is infused with an increasing concentration of antibiotic, which should act as a barrier, killing the bacteria.

Roy Kishony “The first slab has no drug, then about the amount needed to kill the bacteria, then 10 times more, 100 times more, and 1000 times more.”

The experiment begins with a tiny drop of E. coli.

Roy Kishony “They’re certainly going to spread when there is no drug but what we want to see Can they actually go to the place where there is an antibiotic?”

A time-lapse camera captures the spread of the bacteria. As the experiment begins, it’s easy for the bacteria to grow in the first section, with no antibiotic.

Bacterial Culture Morbidostat
Jelly Mould

Roy Kishony “Where there is no drug, it’s very easy for them, there’s food but no stress. Then they hit the boundary where the drug concentration increases.”

At the barrier where the antibiotic starts at the first concentration, the spread is halted.

Roy Kishony “They get stuck there for a while, they tried to go into this area because there is food, but every time you try to go into it they get killed by the drug.”

But that doesn’t last long. Very soon, the mutant appears that can break through the barrier. Whole new colonies grow that can live happily in this concentration of antibiotic. And it doesn’t stop there, this happens again and again, even up to 1,000 times concentration.

Roy Kishony “At the end of the experiment we’re at the maximum level of solubility of the drug, we just cannot add more drug, it doesn’t dissolve any more.”

Resistance Limit Morbidostat
Bacteria Spread

This carefully controlled epidemic all happens in the space of just one week. The team is beginning to pick apart these mutant bacteria to see exactly how this is happening in the presence of antibiotics, by peering inside the bacteria, at their genes.

Roy Kishony “What actually happens under the hood when we open and look at the genomes of this bacteria. We can do now, we can sequence a whole genome of these bacteria and see what are the exact changes that happen. Typically, what genes changed and allowed them to mutate in such a way it can grow in this higher drug concentration.”

External Links

The Morbidostat – Nature Genetics

Scientific breakthrough by Sabancı University – gazeteSU

Morbidostat | Professor Roy Kishony | Bacteria Resistance

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