Next Big Thing: Peeling back the layers of the microbiome

Next Big Thing: Peeling back the layers of the microbiome

I first peered down a microscope at the microbial world when I was an undergraduate at the University of Queensland. I had been debating whether to go on to medicine or do an honours project, but as soon as I took in the sight of this unexplored universe I felt utter amazement.

I was astounded at the diversity of cellular morphology in this seemingly simple microbial community.

At the time, we were using a technique that allowed us to fluorescently label different lineages of bacteria and archaea, so we could see their incredible structural diversity and the way they organise themselves in very discrete ways – this told us that there was so much more complexity there than the morphology alone was telling us.

The craziest thing was that we knew so very little at the time. But we could see the emerging technologies that would allow us to better understand them, and that’s when I decided I was going to focus on research.

This allowed me to play a part in the genomic revolution in microbiology that took off around the early 2000s.

Professor Jill Banfield asked if I was interested in moving to Berkeley in California to try a crazy idea. She proposed that we could go into an environmental sample and basically extract all the DNA from all of the microorganisms, then reconstruct them to get a picture of who was in that sample and what they were doing. I said “sure”.

I was astounded at the diversity of cellular morphology in this seemingly simple microbial community.

This was the beginning of what we now call “metagenomics”.

Up until then, researchers mainly identified microorganisms in an environmental sample using the 16S rRNA gene, which was something like a barcode based on this short, single gene sequence.

This would give us some taxonomic information and allowed us to say that one microbe was phylogenetically related to another.

But what we really wanted to do was reconstruct the genomes of all the microorganisms in an environment. This is what we now do with metagenomics.

One of the reasons that we need do this is because we haven’t been able to grow the vast majority of these microorganisms in the lab before, which is one of the big bottlenecks of microbiology.

The only way we could identify these uncultured microorganisms was from their DNA sequences. But in metagenomics, we started to move into sequencing the entire genomes of these microorganisms.

We would take that bulk DNA, randomly cut it up into small fragments, sequence it, and then try to put together the genomes of all the microorganisms that are in there.

I like to think of it this way: if you have a single microorganism, and a single genome, you have a single puzzle that you’re trying to put together.

But when you’re going into an environmental or clinical sample, you’ve got thousands of puzzles where you’ve mixed up all the pieces, and you’re trying to bioinformatically put those pieces back together to reconstruct the genome of each individual microorganism in that sample.

A man in a lab coat sits in a lab.
Gene Tyson. Credit: Supplied

This way we were getting our first insight into not only what microorganisms are there, but what functions they are able to perform in their environment. That was very exciting at the time.

The astounding advances in technology have made this possible at a larger scale. When I was working on my PhD just two decades ago, for example, we might work on a very simple microbial community, and spend around hundreds of thousands of dollars to generate 100 million base pairs of data.

Today, you could generate that same amount of data for a few cents.

This is all to do with the improvements in sequencing technology coupled with improvements in the bioinformatics tools that help make sense of this vast amount of data, and of course the computing infrastructure that sits behind it.

In parallel with what’s happening in metagenomics, we’ve also been able to do this with metatranscriptomics, looking at the mRNA expression of entire microbial communities; the proteins they produce through metaproteomics; and then the resulting metabolites through metabolomics.

When you integrate these different layers of biological information, you can really learn what is happening within a microbial community.

While I do a lot of work with environmental microbiomes, my recent ARC Fellowship is focused on the human microbiome. This is an exciting area of research with huge potential in human health and medicine.

The gut microbiome is linked to a wide variety of diseases – from immune and metabolic diseases to cardiovascular and neurological diseases.

The aim of the field now is to move beyond association data and into causality so we can show that there is a direct link and a mechanism of action driving these associations.

The aim of the field now is to move beyond association data and into causality

As we learn more about the role of the human microbiome in health and disease, a lot of next-generation probiotics are likely to come on the market.

These are called live biotherapeutics, where you basically deliver these microorganisms as a treatment. There’s a lot of exciting work going on to develop new live biotherapeutics for various diseases like inflammatory bowel disease.

And in the neurological space – the gut microbiome is very important in the production of neurotransmitters and the regulation of communication between the gut and the brain. There are links between the gut microbiome and anxiety, depression, and stress.

You might even be able to turn someone who’s a non-responder to a specific drug into a responder.

This can be particularly important in the cancer space – studies have shown that there are very big differences in the gut microbiome of someone who will respond to immunotherapy compared to someone who doesn’t.

The development of therapies across these areas is going to be particularly exciting.

As told to Graem Sims

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