Wednesday, June 24, 2015

Metagenomics and "A feeling for the organism"

Evelyn Keller's biography of Barbara McClintock is entitled "A feeling for the organism". A few paragraphs in this last chapter sum up quite nicely how McClintock viewed the scientific enterprise and discoveries:

"Over and over again, she tells us one must have the time to look, the patience to "hear what the material has to say to you," the openness to "let it come to you." Above all, one must have "a feeling for the organism." One must understand "how it grows, understand its parts, understand when something is going wrong with it. [An organism] isn't just a piece of plastic, it's something that is constantly being affected by the environment, constantly showing attributes or disabilities in its growth. You have to be aware of all of that.... You need to know those plants well enough so that if anything changes, ... you [can] look at the plant and right away you know what this damage you see is from-something that scraped across it or something that bit it or something that the wind did." You need to have a feeling for every individual plant. "No two plants are exactly alike. They're all different, and as a consequence, you have to know that difference," she explains. "I start with the seedling, and I don't want to leave it. I don't feel I really know the story ifI don't watch the plant all the way along. So I know every plant in the field. I know them intimately, and I find it a great pleasure to know them." This intimate knowledge, made possible by years of close association with the organism she studies, is a prerequisite for her extraordinary perspicacity. "I have learned so much about the com plant that when I see things, I can interpret [them] right away." Both literally and figuratively, her "feeling for the organism"

I agree wholeheartedly. Others may science differently, but I make my living by looking and studying everything about the bacteria I work with. Going into each experiment I have an idea of what to expect (even if these "experiments" simply involve streaking out cultures from frozen). If you give me a genome of Pseudomonas syringae, I can tell you the main components you'll find . I can tell you how certain strains will grow (or won't), what the colonies will look like, how long they'll take to pop up, what color they'll be. It took me a few years to gather this intuition, but now that it's engrained I like to think I have an innate sense when something is "off". I liken this to a scientific Spidey-sense. The challenging part is truly knowing when to follow up on these odd results, when to store away for the future, and when to disregard them as uninteresting.

I was reminded of McClintock's "feeling for the organism" by a couple of stories from metagenomics that have popped up across my feeds. Before I say anything else, I don't intend to denigrate the quality of the science or data underlying these stories by any means. The work is solid, I just think we're starting to find some limitations in the power of "big science" and these holes usually pop up in the discussion sections of papers and press releases. The first of these stories was a tour de force looking at metagenomics of the NYC subway system. The authors reported a variety of interesting results, but the tag line that a lot of news outlets seemed to focus on were the presence of Yersinia pestis (plague) and Bacillus anthracis (anthrax) within the subway system. The limitations of these methods have been hashed out already (here and here), but I want to focus on the inherent lack of "a feeling for the organism" when dealing with metagenomic data. Studies of any open microbial ecosystems are going to find a diversity of taxa. Unless you bring in specialists, there is simply no way to know the ins and outs of each organism. In the case of the NYC subway metagenome, from my interpretation at least, the authors looked at only bits and pieces of the Yersinia and Bacillus genomes without capturing the whole picture. They had to do this because the story was so inherently large that you couldn't possibly investigate everything in depth. However, specialists with "a feeling" for either Yersinia or Bacillus could have provided a viewpoint on which directions (other genes to look at, levels of nucleotide diversity which seem a bit too high) to follow up on to truly demonstrate presence of these bugs within the subway.

Likewise, one part of the story on urban microbes in this piece caught my eye:

"Rodents are under study, too. White-footed mice (Peromyscus leucopus) in New York City carry more Helicobacter and Atopobium bacteria — associated with stomach ulcers and bacterial vaginosis in humans — than their suburban counterparts"

I worked and slaved over Helicobacter pylori cultures all through grad school. I simultaneously loved and hated that bug. It's finicky growth patterns are the reason I moved over to study the reliably growing Pseudomonas after grad school. Unless something has dramatically changed since I've been in the literature (which is completely possible), rodents are terrible hosts for H. pylori strains that cause stomach ulcers (general overview here). You can get a subset of H. pylori strains to grow in mice, but there are often a variety of genetic changes that take place that allow them to adapt (see here).  I wouldn't be surprised if there were multiple Helicobacter strains within mice in NYC, but my money is on the fact that they aren't Helicobacter pylori that could cause stomach ulcers.

These are the tradeoffs that are made when dealing with immense data sets, and I'm not quite sure how to fix this. No one has a feeling for ALL THE MICROBZ. If you have a fun/interesting story on microbiomes that focuses on a couple of taxa in bold, at least try to run your data and ideas past someone that truly has a feeling for these organisms before publishing the paper. If it holds up after that, more power to you.

2 comments:

  1. If only psychologists and psychiatrists could view the subjects of their work in this way.

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  2. David, I could not agree more. The whole organism is the Object of Study, not its DNA. The same applies for ecology: ecology happens in individuals, populations and communities. You will never get the whole picture just by looking at individuals' DNA and working with OTUs.

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