"I am Large, I Contain Multitudes“ - Human Genome Project and the Realm of our Microbes

One of the most important scientific projects of the 21st century was the Human Genome Project (HGP), which identified all of the genes of the human genome [1].  We learned that a human organism possesses over 20,000 genes — no more than a mouse and much less than most laboratory plants [2]. How does such a complex and intelligent species exist with a relatively small number of genes? The answer to this question is brought to us by scientific reports saying that a human can no longer be considered an autonomous unit – because billions of microorganisms live in symbiosis inside each individual.

What will you learn from this article?

1. What is “microbiome” and how the term was introduced,
2. How the discovery of microbiome impacted modern medical landscape,
3. How the immunooncology therapy influenced scientific environment,
4. What is the corelation between the success rate of immunotherapy and the condition of patients’ gut microflora,
5. Conclusion

The History of Microbiome – the Synopsis

Bacteria appeared on Earth about 3.8 billion years ago as the first and most elementary form of life [3]. They colonized all environments, becoming indispensable elements for the proper functioning of higher organisms, including humans. This ensemble of microorganisms is called a microbiome. The term was introduced in 2001 by Joshua Lederberg, Nobel Prize laureate (the Nobel Prize in Physiology or Medicine 1958 “for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria“) [4–5]. By “a microbiome,” we define all microorganisms in a multicellular plant or animal organism.

The Weight of Microbiome Discovery in Modern Medicine

The number of cells in the microbiome of a human organism is approximately equal to the number of cells that build the body itself [6]. To better visualize this diversity, imagine that a human digestive tract contains more bacteria than stars in our galaxy [7]! In the gut alone, the genes of these microorganisms outnumber the human ones about 150 times (3.3 million unique genes of intestinal bacteria). The microbiome has thousands of different functions and is treated by many scientists almost as a new, separate organ or even our second genome [8–9]. Therefore, we witness a scientific revolution that completely changes modern medicine and the definition of “a human.”

The Promise of Immuno-Oncology in the Context of Cancer Therapy

One of the most vital and fastest-growing research areas on the microbiome is immunotherapy. Immunotherapy, used with great success in cancer treatment, is one of the most promising achievements of immuno-oncology in recent years. In 2013, the renowned “Science” magazine announced immunotherapy as the most crucial achievement both in medicine and science. Moreover, the American Society of Clinical Oncology (ASCO) recognized immunotherapy as the most vital oncological achievement in 2016 [10–11].

Unfortunately, not all patients respond well to the treatment. What is the reason behind that?

Immunotherapy and Intestinal Microflora – the Secret Behind Successful Cancer Treatment

The 2017 publications, describing studies conducted on animals as well as on humans, showed a direct correlation between the composition of intestinal microflora and the effectiveness of immunotherapy (immune response modulators, which are checkpoint inhibitors eg anti-CTLA-4, anti-PD1) [12–14]. Patients who responded positively to immunotherapy had a more diverse intestinal microflora than non-responders [15]. It is also possible to identify specific bacteria that differentiate these two groups [16–18].

The Birth of Next-Generation Probiotics Market

This discovery has opened a new segment of the Next Generation Probiotics (NGP) market belonging to the LBP (Live Biotherapeutic Products) product class [19]. Probiotics are defined as “live microorganisms that when given in appropriate amounts bring a health benefit to the host” [19]. Most of the microorganisms that are normally used in the production of probiotics belong to Lactobacillus and Bifidobacterium genus. New Generation Probiotics use bacteria that benefit patients with specific illnesses such as oncological and autoimmune diseases. Bacteria used in the new generation of probiotics may be based on non-standard species that have not been characterized yet. The literature indicates a few species that could be used as elements of the New Generation Probiotic, for example: Faecalibacterium prausnitzii, Akkermansia muciniphila, and Eubacterium hallii [19–20]. 

The strains used for the design of NGP often exhibit features similar to low-molecular or biological drugs. Progress in the development of NGP opens new possibilities for creating effective and safe therapies for patients [21]. One of them is a revolutionary approach, called “personalized next-generation probiotics” which uses the properties of live bacterial cultures isolated from donors. The concept of a New Generation Probiotic is already operating in the US market, approved by the Food and Drug Administration (FDA) as “a biological product containing living organisms such as bacteria that can be used to prevent or cure diseases, but which is not a vaccine” [19].

Personalized Probiotic Treatment – Possible Future of Cancer Treatment

Perhaps personalized probiotics will become a procedure normally used in the treatment of oncological patients in the coming years and research on the microbiome will provide us with new tools to understand what it means to be human. To quote Ed Young, the author of the book “I Contain Multitudes: The Microbes Within Us and a Grander View of Life”:

‘When Orson Welles said “We’re born alone, we live alone, we die alone”, he was mistaken. Even when we are alone, we are never alone. We exist in symbiosis (…) None of those lives is lived in isolation; they always exist in a microbial context (…) we see individuals, working their way through life as a bunch of cells in a single body, driven by a single brain, and operating with a single genome. This is a pleasant fiction. In fact, we are legion, each and every one of us. Always a “we” and never a “me”. Forget Orson Welles, and heed Walt Whitman: “I am large, I contain multitudes.” ‘

Works Cited:

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[2] “Home – Genome – NCBI.” Advances in Pediatrics., U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/genome.

[3] Delong, Edward F., and Norman R. Pace. “Environmental Diversity of Bacteria and Archaea.” Systematic Biology, vol. 50, no. 4, Jan. 2001, pp. 470–478., doi:10.1080/10635150118513.

[4] “’Ome Sweet ‘Omics– A Genealogical Treasury of Words.” The Scientist, www.the-scientist.com/commentary/ome-sweet-omics—a-genealogical-treasury-of-words-54889.

[5] “The Nobel Prize in Physiology or Medicine 1958.” Nobelprize.org, www.nobelprize.org/nobel_prizes/medicine/laureates/1958/.

[6] Sender, Ron, et al. “Revised Estimates for the Number of Human and Bacteria Cells in the Body.” PLOS Biology, vol. 14, no. 8, 2016, doi:10.1371/journal.pbio.1002533.

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[11] “ASCO Names Advance of the Year: Cancer Immunotherapy.” ASCO, 15 Apr. 2017, www.asco.org/about-asco/press-center/news-releases/asco-names-advance-year-cancer-immunotherapy.

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[13] Roy, Soumen, and Giorgio Trinchieri. “Microbiota: a Key Orchestrator of Cancer Therapy.” Nature Reviews Cancer, vol. 17, no. 5, 2017, pp. 271–285., doi:10.1038/nrc.2017.13.

[14] Burki, Talha Khan. “Gut Microbiome and Immunotherapy Response.” The Lancet Oncology, vol. 18, no. 12, 2017, doi:10.1016/s1470-2045(17)30841-0.

[15] Matson, Vyara, et al. “The Commensal Microbiome Is Associated with Anti–PD-1 Efficacy in Metastatic Melanoma Patients.” Science, vol. 359, no. 6371, Apr. 2018, pp. 104–108., doi:10.1126/science.aao3290.

[16] Routy, Bertrand, et al. “Gut Microbiome Influences Efficacy of PD-1–Based Immunotherapy against Epithelial Tumors.” Science, vol. 359, no. 6371, Feb. 2017, pp. 91–97., doi:10.1126/science.aan3706.

[17] Patel, Jaymin, and Jason M. Crawford. “Microbiota-Regulated Outcomes of Human Cancer Immunotherapy via the PD-1/PD-L1 Axis.” Biochemistry, vol. 57, no. 6, 2018, pp. 901–903., doi:10.1021/acs.biochem.7b01249.

[18] Gopalakrishnan, Vancheswaran, et al. “The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy.” Cancer Cell, vol. 33, no. 4, 2018, pp. 570–580., doi:10.1016/j.ccell.2018.03.015.

[19] O’Toole, Paul W., et al. “Next-Generation Probiotics: the Spectrum from Probiotics to Live Biotherapeutics.” Nature Microbiology, vol. 2, no. 5, 2017, doi:10.1038/nmicrobiol.2017.57.

[20] Cani, Patrice D, and Matthias Van Hul. “Novel Opportunities for Next-Generation Probiotics Targeting Metabolic Syndrome.” Current Opinion in Biotechnology, vol. 32, 2015, pp. 21–27., doi:10.1016/j.copbio.2014.10.006.

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