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Picking out the relevant needles from the haystack

Picking out the relevant needles from the haystack

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.


OMICS to the rescue

OMICS to the rescue

by Elise Wachspress

If you hang out with cutting edge scientists, you might hear or see the word (the suffix? a crossword puzzle answer?) “omics.” What are omics?

More than likely you‘ve heard of genomics, the study of the structure, function, evolution, and mapping of genomes, the collection of all the DNA in each organism.

And perhaps you’ve heard of transcriptomics, the study of all the ways an organism’s DNA is “transcribed,” or written into smaller molecules, the RNAs. While the DNA provides the basic, relatively unchangeable blueprints, environmental needs in the cell prompt the activation of specific genes. It’s like the highway engineer who, using her part of the blueprint, stages and directs the construction of one of the on-ramps. She’s working in concert with the larger plan, but somewhat separately from those directing other parts of the project.

Then there’s proteomics, the study of the structure and function of all the proteins that carry out the business in the cells. If the genome is a blueprint, and the engineering crew the RNA, the proteins are the molecular machines and building blocks—the backhoes, drills, and concrete—used to carry out the design.

The newest of the ‘omics fields is metabolomics: the study of all the chemical outputs of our cells and every microorganism that lives in and on us. These molecules, taken together, reflect the entire, functioning system, like how the cars and trucks using the highway are moving and thus creating new capital for society. Metabolomics is something like Here or Google maps, measuring important indicators of how the system is performing at both the street and system level. In a biological system, a genome can tell you what is possible, but the metabolome tells you what is actually happening.

But these readouts are more complex and critically useful: how a particular drug is working, how our immune system is responding, how microbes inside us are contributing to our health or modifying their environment to outcompete others, or even how our brains are prompting our bodies to act, and vice versa. New metabolomics technologies can help scientists non-invasively identify disease biomarkers, discover microbial products that can become new drugs, and identify the safest, most efficient ways to maintain health.

Among the many important resources the Duchossois Family Institute (DFI) is developing at UChicago is a facility that specializes in metabolomics. Led by Jean-Luc Chaubard, the DFI Host-Microbe Metabolomics Facility will feature state-of-the-art mass spectrometry, a powerful analytical technique that can be used to detail the profile of complex mixtures, whether solid, liquid, or gas. With this and other advanced instrumentation, DFI scientists will be able to understand the balance of molecules in blood, plasma, saliva, fecal, and even tissue samples, as well as in the waste products left behind when microbes are cultured (grown) outside the body.

Chaubard and his group will be looking at many things: from neurotransmitters and amino acids to bile acids and short-chain fatty acids, recently identified as critical to a healthy immune system. They will use large chemical libraries to create specialized “panels” that can profile multiple metabolites simultaneously. With these capabilities on campus, individual investigators will have ready access to new assays tailored specifically to their work.

The Metabolomics Facility will also help DFI investigators hone experimental design, decide when and how best to collect and store samples, and prepare those samples for testing. Importantly, they will also help in the data analysis that is critical in massive data-collection regimens like mass spec.

Chaubard, with a background both in academia (at Memorial Sloan Kettering and Caltech) and business (as founding director of the Molecular Discovery Lab at Modern Meadow, in New Jersey) is up for the challenge. An entrepreneur at heart, he is excited to be launching a resource that will set up UChicago as a leader in studying the convergence of immunology, the microbiome, and human health: “Here at UChicago, I get to work with some of the best scientists and doctors in the world, translating their work into practical applications that range from mechanistic understanding of human biology to early disease detection and discovery of novel drugs. It’s an honor to have this opportunity to improve the human condition.”

The Metabolomics Center is just one of the new platform resources made possible by a $100 million gift from The Duchossois Family Foundation and Craig and Janet Duchossois. We will bring you descriptions of several more in the weeks to come.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office.