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DNA Synthesis Markets

A few years back Sriram Kosuri & George M Church published an interesting article on the applications of large scale de novo synthesis. Recently, a number of companies have popped up exploring new approaches to DNA synthesis.

I thought it might be fun to imagine what the ultimate market for ultra-high throughput DNA synthesis could be. The applications here assume the ability to produce perfect reads, of any length, for almost no cost (to the vendor).

What existing markets could we capture, and what potential new markets exist. The numbers and justifications below are part of this thought experiment, and shouldn’t be taken too seriously.

The table below summarises the global markets for each application discussed:

Market Market/year Global (MUSD)
DNA Data Storage 1500
Research Apps 1500
Bacteriophage synthesis 20000
Higher Organism synthesis 10?
DNA Origami 10?
DNA Computing 1000

DNA Data Storage

One application of large scale DNA synthesis being mooted is as a data storage media. The most attractive data storage application is as an offline storage media.

Currently, Magnetic tape is used for offline storage. It’s something like 4 times cheaper to store data on tape than on hard drives. The disadvantages of course is that it’s not available for random access. Storing data on DNA would have a similar access profile, so we can imagine that their market sizes might be similar.

Current tapes store ~15Tb of data, and cost in the region of 150USD. If we can slash the cost by a factor of 5, it’s likely DNA storage based devices could capture this market.

There are currently two main players in large capacity tape storage LTO8 and TS1155. In 2013 LTO tapes were selling ~25 million tapes a year [1]. Tape sales are increasing year-on-year. Assuming 50 million is ballpark correct (both tapes types). We assume we can sell 15TB of storage for ~30USD (5x cheaper than existing solutions) and capture the entire tape market. This gives us a market of 1500MUSD per year in DNA storage.

This is potentially an underestimate, as the market for tape based storage is increasing indicating a healthy appetite for offline storage solutions.

Research Applications

Existing research applications for oligonucleotide synthesis are clear. If you can produce longer or higher accuracy oligos, it’s likely that you can capture this entire market. One report suggests that the global market for oligonucleotide synthesis is currently in the region of 1500MUSD, and is growing [2].

Whole-genome syntheses

De novo synthesis of bacteriophages

Here’s where things get even more speculative. We all know that resistance to existing antibiotics is increasing, and that new antibiotics are taking longer than we’d like to come online.

One possible solution that has been suggested is to start prescribing bacteriophages [3]. Rather fascinatingly there’s an institute in Georgia that has been doing this for some time as described in this 1997 BBC documentary.

There are a number of issues with making bacteriophages a practical therapeutic. A significant hurdle [4] is that a bacteriophage is specific to a narrow range of hosts.

One approach might be to prescribe a complex cocktail of phages. A better (and potentially more practical approach) might be to figure out exactly which bacterial infection a patient has (through point of care sequencing) and then prescribe a phage to target exactly that infection.

This might be one phage out of a library of tens of thousands [4]. So, rather than every pharmacy storing such a large stock of phages, why not just have a DNA synthesiser in every clinic creating/culturing phages for patients [8].

The current US outpatient market for antibiotics is 269 million prescriptions per year. If we replace all these prescriptions with point of care bacteriophage synthesis at 15USD we get ~4000MUSD. I assume the worldwide market is 5x the US market giving 20000MUSD.

We might also consider other therapeutics applications of DNA synthesis, for example aptamer therapeutics. It’s harder to make a case for point of care synthesis here however.

De novo synthesis of higher organisms

De novo synthesis of the genomes of higher organisms is a fascinating idea, but the commercial applications are less clear to me. You might want to synthesis one novel organism, but you would then duplicate it through other means. It therefore seems like more of a research tool.

DNA Origami

DNA Origami is another application where it seems like there should be novel applications of de novo synthesis on a commercial scale. However, it’s not clear to me what these might be.

DNA Computing

Another speculative application might be using DNA for computing. It’s currently unclear what the killer application of DNA computing might be. But as we’re just throwing ideas around, lets assume we can solve a complex computational problem using DNA computing. In particular lets assume we can solve hashing problem and use that as the proof of work function for a cryptocurrency.

Figures for bitcoin mining rigs are all over the place, but mostly in the billions. As we’re just throwing numbers around here, let’s assume it could be a market of 1000MUSD a year and use this as a proxy for the size of the DNA Computing market.

Notes

[1]
~25 Million tapes sold per year
~150USD
https://en.wikipedia.org/wiki/Linear_Tape-Open

[2]
“The global oligonucleotide synthesis market generated $1.5 billion revenue in 2017 and is projected to advance at a CAGR of 10.8% during 2018–2023. The market is mainly driven by increasing research activities in synthetic biology, rising prevalence of cancer and infectious diseases, advancements in oligonucleotide synthesis technologies, and favorable government regulations.”
https://www.psmarketresearch.com/market-analysis/oligonucleotide-synthesis-market

[3]
www.bioprocessintl.com/manufacturing/nonantibody-therapeutics/bacteriophages-an-alternative-to-antibiotics-challenges-and-possible-solutions-for-bringing-them-to-market/

[4]
“However, from the biotechnological point of view the specificity of bacteriophages is a challenge; it means that the industry should be prepared to provide a tailored therapeutic phage or phage cocktail for each individual pathogenic bacterium. The challenge is vast since there are hundreds of pathogenic bacterial species, i.e. potential targets for phage therapy, and most of the species may contain dozens of sero- or genotypes that each may be susceptible to different phages. Therefore, to cover the whole field of infectious diseases there would be a need for a bank of thousands or tens of thousands of phages with different specificities.”
https://link.springer.com/article/10.1007/s10529-007-9346-1

[5] “In 2015 alone, approximately 269 million antibiotic prescriptions were dispensed from outpatient pharmacies”
https://www.cdc.gov/antibiotic-use/stewardship-report/outpatient.html

[6]
btcmanager.com/bitcoin-mining-industry-set-to-bring-in-4-bln-2017/
http://fortune.com/2018/02/24/bitcoin-mining-bitmain-profits/
https://www.businesswire.com/news/home/20180503005882/en/Top-Insights-Cryptocurrency-Mining-Hardware-Market-Technavio

[7] http://arep.med.harvard.edu/pdf/Kosuri_Church_2014.pdf

[8]
“Cross-genus rebooting of custom-made, synthetic bacteriophage genomes in L-form bacteria”
http://www.pnas.org/content/115/3/567

DNA Synthesis Research Groups

I’ve been looking for research groups actively investigating new approaches to DNA synthesis (published since 2014). While there are some interesting approaches, I’m surprised I’ve not been able to come up with more groups.

If you know of any, let me know!

Lab name Website Recent Publication
Keasling Lab Group Page De novo DNA synthesis using polymerase-nucleotide conjugates
Ingenuity Lab (closed)
Photo-cleavable nucleotides for primer free enzyme mediated DNA synthesis
Duhee Bang’s Lab Group Page Toward a new paradigm of DNA writing using a massively parallel sequencing platform and degenerate oligonucleotide
Tom Brown Group Group Page Gene assembly via one-pot chemical ligation of DNA promoted by DNA nanostructures
Church Group Group Page Large-scale de novo DNA synthesis: technologies and applications

Notes…

Primer-Independent DNA Synthesis by a Family B DNA Polymerase from Self-Replicating Mobile Genetic Elements
https://www.sciencedirect.com/science/article/pii/S2211124717314869

Template-Independent Enzymatic Oligonucleotide Synthesis (TiEOS): Its History, Prospects, and Challenges
https://cdn-pubs.acs.org/doi/abs/10.1021/acs.biochem.7b00937?journalCode=bichaw

Click to access KR101785074B1.pdf

The history and advances of reversible terminators used in new
generations of sequencing technology.

Large-scale de novo DNA synthesis: technologies and applications.

Nanopore DNA Sequencing Research Groups (August 2018)

This is a draft list of research groups engaged in research on the use of nanopores for DNA sequencing. It’s based on this list. I went through this and searched for groups that had published research on DNA sensing using nanopores since 2015. I also added a couple of groups. The list is likely incomplete, and I plan on tidying it up over the next couple of days.

Lab name Website Recent Publication
Nanopore Group – UC Santa Cruz Group Page Mapping DNA methylation with high-throughput nanopore sequencing
The Aksimentiev Group Group Page DNA sequence-dependent ionic currents in ultra-small solid-state nanopores
The Albrecht Group Group Page Low Noise Nanopore Platforms Optimised for the Synchronised Optical and Electrical Detection of Biomolecules
Anselmetti lab Group Page Controlled translocation of DNA through nanopores in carbon nano-, silicon-nitride- and lipid-coated membranes
Bayley Group Group Page Nucleobase Recognition by Truncated α-Hemolysin Pores
Behrends Laboratory Group Page Length- and Species-Selective Detection of Short Oligonucleotides using a Microelectrode Cavity Array of Biological Nanopores
Cees Dekker Lab Group Page
Chen Research Group Group Page
DRNDIĆ Lab Group Page Monolayer WS2 Nanopores for DNA Translocation with Light-Adjustable Sizes
Edel Group Group Page Double Barrel Nanopores as a New Tool for Controlling Single-Molecule Transport
The Nanopore Group at Harvard Group Page
UW Nanopore Biophysics Group Page
The Hall Lab Group Page
Keyser Lab Group Page
Jiali Li Lab Group Page A tip-attached tuning fork sensor for the control of DNA translocation through a nanopore
Xinsheng Ling Group Page Rapid fabrication of solid-state nanopores with high reproducibility over a large area using a helium ion microscope
Maglia Lab Group Page Alpha‐Helical Fragaceatoxin C Nanopore Engineered for Double‐Stranded and Single‐Stranded Nucleic Acid Analysis
Meller Group Group Page
McGrath Lab Group Page DNA Translocations through Nanopores under Nanoscale Preconfinement
Muthukumar Lab Group Page Temperature effect on ionic current and ssDNA transport through nanopores
Laboratory of Nanoscale Biology (Aleksandra Radenovic) Group Page Identification of single nucleotides in MoS2 nanopores
Rosenstein Laboratory Group Page In Situ Nanopore Fabrication and Single-Molecule Sensing with Microscale Liquid Contacts
Stein Lab Group Page Nanopore Sequencing: Forcing Improved Resolution
Stuart Lindsay Group Page Universal Readers Based on Hydrogen Bonding or π–π Stacking for Identification of DNA Nucleotides in Electron Tunnel Junctions
Taniguchi Lab Group Page Quantitative analysis of DNA with single-molecule sequencing
The T.-Cossa LAB Group Page DNA Translocations through Nanopores under Nanoscale Preconfinement
Wanunu Lab Group Page Length-independent DNA packing into nanopore zero-mode waveguides for low-input DNA sequencing
Yitao Long Group Page Construction of an aerolysin nanopore in a lipid bilayer for single-oligonucleotide analysis

Need to add:
Zero-mode waveguide detection of DNA translocation through FIB-organised arrays of engineered nanopores

Virtual Nanopores and DNA Synthesis

The Genapsys concept of virtual wells, defined by fields and use of nanopores by Iridia to selectively expose a template under synthesis to a polymerase had me pondering over the concept of a virtual nanopore. That is to say, a nanopore that is defined by fields rather than physically.

My initial thoughts were that a larger pore (>1nm, perhaps as large as 10 to 100s) could have embedded negatively charged electrodes. The field generated by these electrodes might be used to further restrict the area though which a strand can translocate the pore.

It seems unlikely (though not impossible?) that this would produce a pore that could be used for sequencing (the height of the pore, and construction point being difficult to control precisely).

However, in the Iridia concept the construction point doesn’t need to be thin, the diameter of the pore just needs to be small enough that the polymerase (also negatively charged?) can not translocate through the pore. So such a pore could be valuable for synthesis if it could be made to work.

In addition to this, because the size of the nanopore is adjustable, it might be possible to completely close the pore. This could be valuable in some designs.

Googling around for virtual nanopores, I came across a paper describing a related concept [1].

The paper “Tunable Aqueous Virtual Micropore” describes the application of a quadrupole trap to the translocation of biomolecules. The concept is demonstrated using a planar micron scale system using beads.

The quadrupole approach is used in mass spectrometers to direct ionised particles. In this system they’re used to direct the motion of a particle based on its mass/charge ratio.

To me this system seems more complex than required to confine the strand, but there’s quite likely something I’m missing. In a nanopore system, I assume electrodes would be embedded in the side of the pore. This would allow the strand to be confined as it translocates. Unfortunately the paper was published in 2012 and there doesn’t appear to have been a follow up.

I’m curious to see if some kind of field based confinement ever gets applied to synthesis systems. It also seems possible that the virtual well concept could be of value here.

[1] https://onlinelibrary.wiley.com/doi/abs/10.1002/smll.201101739