Venter's Deep Linkage: Microbiome, Synbio, Genomics, and Computing

As usual, Craig Venter’s remarks on April 16, 2013 at UC Berkeley did not disappoint - they were inspirational, informative, and demonstrative of progress. Of note is the multidisciplinarity amongst different branches of his labs’ work, for example using synthetic DNA to perform genomic error correction in stem cell operations, genome transplantation between yeast and bacterial species, and linking microbiome activities to pathology and synthetic biology/biofuel synthesis. Some key points were:

• Microbiome – YASP (yet another sequencing problem) – While the human genome is currently thought to contain about 42,000 genes, the microbiome has 10 million genes across diverse phyla, taxa, and species 
• Biofuel – to obtain engineered algae with the desired phenotype that would be a viable alternative to oil, 300 parameters must be engineered 
• Gene function – even in the minimal genome for Mycoplasma genitalium, there are 50 genes whose function is unknown 
• New gene discovery – so far in general scientific discovery, 80 million genes have been found, 95% from ocean water sampling; again in these ‘design components for the future,’ function is unknown 
• ‘Digital phenotype’ is needed for health advance and big health data stream integration – an extended EMR with standardized transmittable digital data for all manner of phenotypic data, both phenotype 1.0 (e.g.; health history, prescriptions, lab results, etc.) and phenotype 2.0 (e.g.; digital omics profiles like proteomics and metabolomics).

Synbio in space

Many interesting applications of synthetic biology in space missions were discussed at the Synthetic Biology workshop held October 30-31, 2010 at NASA Ames in conjunction with the National Academies Keck Futures Initiative. Scientists from a variety of backgrounds came together to brainstorm solutions in an integrative approach. The most impressive aspect was how different areas of synthetic biology have been progressing enough to discuss ideas and techniques that could be applied to space missions in a robust way.

Environment enhancement
One of the most important areas that synthetic biology may be able to help with is in making space environments more manageable and habitable by humans. The regolith, the powdery blanket covering the moon and Mars, may likely need to be ameliorated into harder less dusty surfaces.

Biomining
Synthetic biology could be helpful in creating microbes to faster weather regolith/rock for an order of magnitude quicker release of bioessential elements such as Magnesium, Calcium, Potassium, and Iron. (related publications)

Biomaterials and self-building habitats
Synthetic biology could help to create microbes for use in building structures, both as scaffolds and by growing on scaffolds. Bacterially-generated alternatives to Portland cement (bricks made from bacteria, sand, calcium chloride, and urea) are currently being investigated, along with other plant-development inspired architectures.

New gene function
While the discovery of new mammalian genes has become saturated, the majority of newly sequenced ocean-based microbes continue to have novel gene functions. Some of these may be quite useful in space environments, for example, D. radiodurans, which can withstand significant radiation and rebuild its DNA when damaged.

Space economics – the Basalt Economy
The economics of space suggest that synthetic biological solutions might be developed more readily for space challenges, and later deployed on Earth as the technologies mature. The main constraint for space is developing in-situ solutions that are cheaper than lifting materials from Earth, as opposed to creating competitive products for Earth-based supply chains (e.g.; synthetic biofuel).

Tools
Whole human genome and metabiome sequencing, genome synthesis and assembly, and genetic design and proofing software (bioCAD) as shown in Figure 1 are all improving. A vast industry similar to that of semiconductor design and manufacture could likely develop for synthetic biology.

Figure 1: Example of SLIC/Gibson/CPEC gene sequence assembly (Source)

Personal genome: data analysis challenge

Five themes emerged from the material presented at the 3rd annual personal genomes meeting at Cold Spring Harbor Laboratory held September 10-12, 2010.

First was the trend of family sequencing becoming more of a norm; looking at genetic disease as it is represented in trios, quartets or other family groups.

Second was the trend of increasingly common multi-level analysis, investigating traditional genotype data together with structural variation, expression data, pathways, and cell lines.

Third was the trend of greater breadth and sophistication in cancer genome analysis; the fledgling field of a few years ago now including dozens of sequenced cancer tumor genomes, the first cancer methylome, and cancer transcriptome analysis.

Fourth was the trend of the oft-heard challenge of scaling personal genome interpretation, making it automated, affordable, and actionable.

The fifth theme was the continued improvement in genome sequencing technology through new approaches such as quantum dot nanocrystal sequencing and strobe sequencing.

Status of cancer detection

The Canary Foundation’s annual symposium held May 4-6, 2009 indicated progress in two dimensions of a systemic approach to cancer detection: blood biomarker identification and molecular imaging analysis.

Systems approach to cancer detection
A systems approach is required for effective cancer detection as assays show that many proteins, miRNAs, gene variants and other biomarkers found in cancer are also present in healthy organisms. The two current methods are one, looking comprehensively at the full suite of genes and proteins, checking for over-expression, under-expression, mutation, quantity, proximity and other factors in a tapestry of biological interactions and two, seeking to identify biomarkers that are truly unique to cancer, for example resulting from post-translational modifications like glycosylation and phosphorylation. Establishing mathematical simulation models has also been an important step in identifying baseline normal variation, treatment windows and cost trade-offs.

Blood biomarker analysis
There are several innovative approaches to blood biomarker analysis including blood-based protein-assays (identifying and quantifying novel proteins related to cancer), methylation analysis (looking at abnormal methylation as a cancer biomarker) and miRNA biomarker studies (distinguishing miRNAs which originated from tumors). Creating antibodies and assays for better discovery is also advancing particularly protein detection approaches using zero, one and two antibodies.

Molecular Imaging
The techniques for imaging have been improving to molecular level resolution. It is becoming possible to dial-in to any set of 3D coordinates in the body with high-frequency, increase the temperature and destroy only that area of tissue. Three molecular imaging technologies appear especially promising: targeted microbubble ultrasound imaging (where targeted proteins attach to cancer cells and microbubbles are attached to the proteins which make the cancerous cells visible via ultrasound; a 10-20x cheaper technology than the CT scan alternative), Raman spectroscopy (adding light-based imaging to endoscopes) and a new imaging strategy using photoacoustics (light in/sound out).

Tools: Cancer Genome Atlas and nextgen sequencing
As with other high-growth science and technology areas, tools and research findings evolve in lockstep. The next generation of tools for cancer detection includes a vast cataloging of baseline and abnormal data and a more detailed level of assaying and sequencing. In the U.S., the NIH’s Cancer Genome Atlas is completing a pilot phase and being expanded to include 50 tumor types (vs. the pilot phase’s three types: glioblastoma, ovarian and lung) and abnormalities in 25,000 tumors. The project performs a whole genomic scan of cancer tumors, analyzing mutations, methylation, coordination, pathways, copy number, miRNAs and expression. A key tool is sequencing technology itself which is starting to broaden out from basic genomic scanning to targeted sequencing, whole RNA sequencing, methylome sequencing, histone modification sequencing, DNA methylation by arrays and RNA analysis by arrays. The next level would be including another layer of detail, areas such as acetylation and phosphorylation.

Future paradigm shifts: prevention, omnisequencing, nanoscience and synthetic biology
Only small percentages of annual cancer research budgets are spent on detection vs. treatment, but it is possible that the focus will be further upstreamed to prevention and health maintenance as more is understood about the disease mechanisms of cancer. Life sciences technology is not just moving at Moore’s Law paces but there are probably also some paradigm shifts coming.

The three most suggestive areas for coming life science discontinuities are genomic sequencing, nanoscience and synthetic biology.

Genomic sequencing contemplates the routine scanning of each individual and tumor at multiple levels: genomic, proteomic, methylomic, etc. Nanoscience is the ability to design, construct and render mobile a large variety of molecular [biological] devices. Synthetic biology is designing new or modifying existing biological pathways in order to produce systems with superior or different properties, exercised by both traditional practitioners (recent conferences: Advances in Synthetic Biology, Synthetic Biology 4.0) and diybio’ers.