Human Microbiome: Futurist Augmentation Platform

The human microbiome is essential in working symbiotically with the human (and indeed all animals) for nutrient synthesis and pathology prevention. However, the large numbers of microbial populations are complicated and dynamic which makes it challenging to profile their activity and construct meaningful interventions. The 14th Annual Microbiology Student Symposium, held at UC Berkeley on April13, 2013 addressed some of these issues (conference program). 

There is tremendous microbiomic variation between individuals – a person’s gut microbiomic signature is perhaps as uniquely distinguishable as a fingerprint. There may be variability within the individual too, but there is a strong trend to persistent populations over time. The microbiome adjusts quickly to dietary and environmental change, within a day, and can shift back just as quickly. If certain populations are wiped out, other substitute species within the same taxa or phylum may emerge to (supposedly) fulfill a similar function. Pathology conditions like Crohn’s disease, colitis, and irritable bowel syndrome (IBS, IBD) are likely to mean the dysbiosis (e.g.; microbial imbalance) of the whole biosystem (not just are certain disease-related bacterial populations elevated, but mitigating populations may be much lower. Given the complexity of the microbiome with thousands of species across tax and phyla, machine learning techniques may be useful in combining a series of weak signals into a prognostication as the SLiME Project in the Eric Alm lab at MIT has done, claiming to predict IBD as accurately as other non-invasive methods.

In the longer term, the microbiome could be the perfect platform for many different less-invasive augmentations for the human - bringing on board micro-connectivity, memory, processing, and electronic storage (Google Gut Glass?), with applications such as real-time life-tracking and quantified-self monitoring and intervention.

Human augmentation substrate: the microbiome

The human microbiome, comprising 10x human cells, is interesting not only for its significant role in determining health, disease, drug response, and individuality, but also in possibly being a less-invasive human augmentation substrate, for example, bringing nanoscale connectivity and memory processing modules onboard via the microbiome.

New research has identified that only five microbial lineages exist on humans: firmicutes, bacteriodetes, actinobacteria, proteobacteria, and other phyla which is surprising compared to the diversity of microbial phyla on Earth. However, within the lineages, there are many strains and species, for example 1,600-2,000 distal gut species of microbial bacteria in each person, only 7% of which were known previously (paper). Gut bacteria is critical to human functioning, one activity is producing butyrate in colon epithelial cells to maintain energy homeostasis. (paper, article)

The microbiome is a complex adaptive system: resilience and vulnerability
Research extends beyond characterization - an investigation of perturbations to the human microbiome has shown resilience in recovery following a disturbance. However there is vulnerability with persistent perturbation. The human microbiome may not reassume its initial state unless the disturbance is at a frequency that the system has experienced before and for some time. In this case, the system may get stuck in an alternative state or local maximum. (paper).

Rational growth in consumer genomics

The overall tone of the Consumer Genetics Show, held June 2-4, 2010 in Boston MA, was a pragmatic focus on the issues at hand as compared with the enthusiasm and optimism that had marked the conference’s inaugural event last year. One of the biggest shifts was the new programs that some top-tier health service providers have been developing to include genetic testing and interpretation in their organizations. It also became clear that the few widely-agreed upon success stories for genomics in disease diagnosis and drug response (i.e.; warfarin dosing) have been costly to achieve and will not scale to all diseases and all drugs. Cancer continues to be a key killer app for genomics in diagnosis, treatment, prognosis, cancer tumor sequencing, and risk prediction. Appropriate approaches to multigenic risk assessment for health risk and drug response remain untackled. Greater state and federal regulation seems inevitable. Faster-than-Moore’s-law improvements in sequencing costs continue as Illumina dropped the price of whole human genome sequencing for the retail market from $48,000 to $19,500.

There was generally wide agreement that from a public health perspective, personalized genomics is scientifically valid, clinically useful, and reimbursable in specific situations, but not universally – at this time, better information should be obtained for some people, not more information for all people. The focus should be on medical genetics strongly linked to disease, and on pharmacogenomics in treatment. For example, genomic analysis is required for some drugs by the FDA (maraviroc, cetuximab, trastuzumab, and dasatinib), and recommended for several others (warfarin, rasburicase, carbamazepine, abacavir, azathiprine, and irinotecan). A key point is to integrate the drug test with the guidance for drug dosage.

Even when genomic tests are inexpensive enough to be routine, interpretation may be a bottleneck as each individual’s situation is different when taking into account family history, personal medical history, and environmental and other factors. One idea was that the 20,000 pathologists in the US could be a resource for genomic test interpretation; pathologists are already involved as they must certify genetic test data in CLIA labs. Genomic tests and their interpretation would likely need to be standardized and certified in order to be reimbursed in routine medical care. A challenge is that health service payers are not interested or able to drive genomic test product design.

Key science findings

1. The Regulome and Structural Variation

Michael Snyder presented important research that the regulome, the parts of the genome located around the exome (the 1-2% of the genome that codes for protein), may be critical in understanding disease genesis and biological processes. The complexities of RNA are just beginning to be understood. It is known that there is more than just the simple transcription of DNA to RNA involved in controlling gene expression. For example, there is also tight regulation in splicing newly synthesized RNA molecules into the final RNA molecule and in translating messenger RNA to ribosomes to create proteins. Research findings indicate a global/local model of gene regulation, that there are master regulators with universal reach and local regulators operating on a local range of 200 or so genes.

Snyder also presented updates on his lab’s ongoing research into the structural variation of the human genome. A high-resolution sequencing study has been conducted regarding the amount of structural variation in humans, finding that there are ~1,500 structural variations per person that are over 3 kilobases long and that the majority of the structural variations are 3-10 kilobases long with a few extending to 50-100 kilobases (application of this research: Kasowski M, Science, 2010 Apr 9).

2. Reaching beyond the genome to the diseasome, proteome, and microbiome

Several scientists addressed the ways in which science is quickly reaching beyond the single point mutations and structural variation of the genome to other layers of information. There is a need for the digital quantification of the epigenome, the methylome, the transcriptome, the proteome, the metabolome, and the dieaseome/VDJome. For example, the immune system is one of the best monitors of disease state and progression. The strength of individual immune systems can be evaluated through the VDJome (the repertoire of recombined V-D-J regions in immune cells; cumulative immunoglobulin and T-cell receptor antigen exposure)

There are many areas of interest in proteomics including protein profiling, protein-protein interactions, and post-translational modification. A large-scale digital approach to proteomics was presented by Michael Weiner of Affomix. A key focal area is post-translational modification. At least one hundred post-translational modifications have been found, and two are being investigated in particular: phosphorylation (the signal transduction can possibly indicate tumor formation) and glycosylation (possibly indicating tumor progression).

The microbiome (human microbial bacteria) and host-bacteria interactions are an important area for understanding human disease and drug response, and for Procter & Gamble in creating consumer products. The company has basic research and publications underlying products such as the ProX anti-wrinkle skin cream (Hillebrand, Brit Jrl Derm, 2010), rhinovirus, and gingivitis. The company has a substantial vested interest in understanding the microbiome with its variety of nasal, oral, scalp, respiratory, skin, and GI tract-related products.

Unified health data climate

The future of health management and biosecurity is having always-on access to the health data climate of individuals, families, communities, and countries. A whole new era of health awareness and self-management could be possible. Ideally, health data streams would be automatically captured and parsed into a comprehensive tableau of status monitoring and action-taking.

Key health data streams (Figure 1):

1. Genome - whole human genome sequence, abnormal tissue sequences (cancer, etc.)
2. Phenotype - current status of a wide range of biophysical markers including blood-based organ-secreted proteins prognosticating disease, cholesterol levels, blood pressure, and emotional state
3. Diseasome - catalog of cumulative immune system exposures and predicted response to toxins
4. Microbiome - microflora bacteria profile (gut, genital, skin, oral, etc.)
5. Environmentome - external environment measures including air and water quality, pollen/allergens count

Figure 1: Key health data streams.

Human microbiome and personalized medicine

In genomics, the eleventh annual meeting of Advances in Genome Biology and Technology (AGBT) was held February 24-27, 2010, and featured an eclectic mix of new research and bioinformatics tools. Genomic research was presented in a diversity of areas including human, animal, plant, and bacteria. Many research advances are coming from partnerships between one or more academic research teams together with commercial entities. The biggest buzz was around Pacific Biosciences, the 3rd generation sequencing darling, with their single-molecule real-time (SMRT) platform which is still on track for an estimated launch later this year. The platform could deliver a 30,000-fold improvement over current methods, and ultimately achieve sub-$100 whole human genome sequencing. Attendees were also wowed by 454 Roche’s bench top GS Junior System (initially announced in late 2009), making sequencing much quicker and easier, and priced at only $98,000 (a milestone for sequencing equipment which usually runs in the several hundreds of thousand dollars).

Sequencing data storage and transfer costs continue to increase with the computing industry still not cognizant of the whole new era of data processing and communications transfer that is necessary for Very Large Datasets. The NIH 1000 Genomes project, for example, is transferring many terabyte-sized files per day.

From a research standpoint, some of the most activity is in cancer genomics. A recent NIH study generated 100TB data sequencing a melanoma sample and a normal blood sample and has been refining the Most Probable Variant (MPV) Bayesian analysis method used to identify genetic mutations. Perhaps the most innovative new research activity is in RNA sequencing. Other specific findings of note are in the areas of the microbiome and genetic variation:

Human microbiome
The complex interactions between individual humans and their microbiomes could have a substantial impact on personalized medicine. In some cases of infectious disease in humans, the pathogenesis may be unknown 40-60% of the time (e.g.; respiratory disease, skin disease). Even rudimentary issues remain unsolved, for example, it may be undetectable from a simple blood draw showing staph infection whether the bacteria was on the skin surface or in the blood. Microbiome sequencing is allowing the identification of novel pathogens, and could also be useful at the human population level to assess the spread and mutation trajectory of pathogens.

Genetic variation: human and otherwise
The populations analyzed in human genome wide association studies are being expanded, with important findings for both ancestry reconstruction and medical genomics. Research was presented on African-American, Mexican-American, Bushmen, and Bantu genome studies. A deeper understanding of genetic variation is also being used to facilitate the selection of desirable qualities in agriculture and animal livestock. For example, a chicken sequencing project found 7 million unique SNPs, 5 million of which were novel, and several of which were useful in translational application.