The Molecular Age:The Birth and Applications of Metagenomics

Considered by some as the founder of microbiology, Anton van Leeuwenhoek was one of the first people to note the presence of microbes, or 'animalcules' (as he called them) in the human body. Inspired by Robert Hooke and his book, Micrographia (1665) which discussed microscopes, their design and their applications, he continued to investigate these animalcules and constructed his own microscopy techniques to study the natural world. 

Fast-forward a few hundred years, we now know that the human body plays host to trillions of symbiotic microbes. These microbes play a significant role in human immunology, digestion, detoxification processes and even physical development, furthermore the production of metabolites by the microbiota is thought to have contributed to the evolutionary fitness of man. Similarly, the oceans, which cover around 70% of our planet are indoctrinated with microbes, however only a minute percentile has been studied. In order to discover these micro-organisms and their interactions, van Leeuwenhoek-style observations would not be suitable, nor (in many cases) would standard, modern day culture techniques. Therefore, how can we study them? 

In the 1990's researchers at Monterey Bay Aquarium Research Institute (MBARI) pioneered metagenomics. Metagenomics can be defined as the study of all the genetic material in an environment, without the necessity of lab isolation or cultivation. One of the main driving forces behind the development of metagenomics is the difficulty associated with culturing marine microbes - in fact many cannot be cultured, so alternative methods to study them were desperately sought after. The MBARI proceeded to isolate DNA from marine microbes directly from water samples, fragments of the isolate were then inserted into vectors and the sequence of these determined. They successfully identified a myriad of novel genes using this method, allowing inferences about the physiology of microbes to be made.

Recent advances and refinement of genomics and bioinformatic techniques now confer detailed and complex pre-assembly filtration, assembly and post-assembly analysis of the genomic data, revealing greater insights into the life of microbes. It is evident that metagenomics needs to be combined with more classical methods to effectively study microbes.That said, other modern techniques can also be used in conjunction with metagenomics to provide some definitive physiological information; metatranscriptomics and metaproteomics are examples. As with most genetic studies a vast amount of data is produced, but, is there such a thing as too much and is all of the data relevant? 

The Human Microbiome Project (HMP) conducted in 2007, was the first time metagenomics was used for biomedical application. The key aims of the Human Microbiome Project (2007) was to characterize the microbial inhabitants present both in and on the human body, whilst exploring the how this symbiotic relationship is affected during times of illness and disease. The information yielded from the HMP and other projects has been and continues to be instrumental in altering medical treatments/guidelines (e.g. prescription of statins; Kaddurah-Daouk et al. 2011), and our understanding of physiological processes and interactions (e.g. immune-inflammatory response; Cahenzli et al. 2013). The information produced could also pave the way to personalised medicine.

From a more ecological perspective, metagenomic techniques have been applied to coral bleaching. Akin to the HMP, researchers wanted to investigate how the microbial community changes during times of dysbiosis. Having used metagenomics, the importance of viruses and fungi in mediating/influencing the microflora during bleaching events was realised - a standard culturing method would not have brought this information to light. See Wegley et al. 2007 for more information.

To conclude, it is evident that the age of the 'omics' is bringing previously unknown information to light. That said, it is prudent to note that other, more traditional techniques are still vital in understanding microbes. Metagenomics has a diverse range of applications, from biomedical to ecological and reflects to some extent how much scientists can learn from other disciplines - more interdisciplinary interaction is needed to advance research fields. However, with these advances and great yields of data, do we have more data than time? 

References

• Cahenzli, J., Balmer, M.L. and  McCoy, K.D. Microbial–immune cross-talk and regulation of the immune system. Immunology, 2013, 138(1): 12–22. 
• Kaddurah-Daouk, R., Baillie,, R.A., Zhu, H., Zeng Z.B., Wiest, M.M., Nguyen, U.T., Wojnoonski, K., Watkins, S.M., Trupp, M. and Krauss, R.M., Enteric microbiome metabolites correlate with response to Simvastatin treatment. PLoS ONE, 2011, 6 (10).
• Wegley, L., Edwards, R., Rodriguez‐Brito, B., Liu, H., & Rohwer, F. Metagenomic analysis of the microbial community associated with the coral Porites astreoides. Environmental microbiology, 2007, 9(11), 2707-2719.
• Wooley, J.C., Godzik, A. and Friedberg, I. A primer on metagenomics.  PLoS Computational Biology 2010, 6. - Provides a detailed review of metagenomics.