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by Elise Wachspress

Have you ever tried to follow a friend during a major marathon, like the one in Chicago?

This is only possible if you create a visible marker for either the runner, or—even better—the spectator, making it possible to identify each other in the huge crowds involved.

A red bandana is not going to cut it. You need something distinctive, highly visible and unusual, like maybe a giant letter “Q” balloon aloft above the throng!

Now imagine that you are trying to identify bacteria in the huge community of microbes nestled in your gut. Perhaps you want to find the particular ones involved in causing your illness or helping your body fight cancer. How do you identify these? Not only are there millions of “runners” in there, but they are reproducing hourly, which means the next generation might mutate and change the very “markers” you are using to follow them.

Nearly fifty years ago, Carl Woese, along with his graduate student Mitch Sogin, now a distinguished senior scientist at UChicago’s Marine Biological Laboratory in Woods Hole, Massachusetts, pioneered the use of a particular gene, called 16S ribosomal RNA, as a marker for microbes. Not only was the gene specific enough to identify types of bacteria; it was so “conserved,” or reliably unchanged over generations, that it became important as a “molecular clock” that could distinguish how closely bacteria might have been related over evolutionary history.

Woese used 16SrRNA to identify the archaea, a formerly unrecognized branch on the tree of life (and a great detective story!) Microbiologists now use the marker as a rapid, inexpensive shortcut to microbial identification. It’s just one of the arrows in the quiver of Sayantoni (Sam) Mukhopadhyay and her team as they study bacterial samples at the Duchossois Family Institute’s Microbiome Metagenomics Platform.

Mukhopadhyay’s team also helps researchers and clinicians sort out components of the microbiome with a newer, much more sensitive technique known as “shotgun metagenomics,” so called because of the somewhat scattershot way it targets pieces of the many genomes within a heterogeneous mixture. In this more complicated approach, the DNA from all the microbes in a sample is broken up into small segments and sequenced individually. After several rounds of fragmentation and sequencing, computer programs then identify the overlapping sections and reconstruct the sequences of the entire DNA strands from each bacterium.

This technique works especially well when some or all of the bacteria in the community have previously been grown in separate, pure colonies and fully sequenced by themselves. (Scientists and technicians have already laboriously sequenced the DNA of thousands of different bacteria and share these libraries.) These known bacteria become like the runners in a particular club who can always be identified by their specific combination of red bandana, white T-shirt, green shorts, and orange running shoes. Once these recognized sequences are accounted for, it’s easier to start homing in “new” bacteria DNA sequences not previously captured.

Not only can shotgun metagenomics provide an overview of complex communities of bacteria. It can also identify other DNA or RNA strands in a microbiome, like those in viruses—a benefit that seems clearer than ever in the time of coronavirus. Because shotgun metagenomics is so sensitive, the technique requires very careful preparation and handling of samples, so tiny DNA contaminants don’t skew the picture of what is actually going on in the microbial marathon.

And, as you might guess, the massive amounts of data involved require a lot of pretty sophisticated computational analysis. Eric Littman and Huaiying (Eddy) Lin are the seasoned bioinformaticians whose mathematical skills make sense of the endless combination of As, Cs, Gs, and Ts our internal athletes carry.

The new DFI Metagenomics Platform is a powerful tool for helping researchers and clinicians understand how microbial communities interact with each other and the human organism—information they are using here to understand how to resolve illness and, more importantly, promote health.