UOA08-05: Oxford Nanopore Technologies: a successful company built on innovative DNA sequencing
Submitting InstitutionUniversity of Oxford
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology, Genetics
Summary of the impact
Hagan Bayley's research on nanopore sensing for DNA sequencing at the
University of Oxford led to the formation of the spin-out company Oxford
Nanopore Technologies Ltd (ONT) in 2005. Since 2008, ONT has raised £
97.8M to support research and product development. This level of
investment arises as a direct result of the pioneering technology ONT has
developed, based on research in the UOA, which has the potential to
revolutionise DNA sequencing and other single molecule analyses. ONT
currently employs 145 people, nearly six times as many as in 2008, and was
recently valued at $ 2 billion. Evidence from ONT was used in a 2009 House
of Lords report on genomic medicine, demonstrating ONT's position at the
forefront of this new technology.
Nucleic acid sequencing is likely to become a core part of personalised
medicine and has many additional applications including in agriculture and
crop science, food safety and security, and defence. However, it is
currently an expensive and time-consuming enterprise. In 2004, the US
National Human Genome Research Institute (NHGRI) announced a series of
grants to support research with the aim of sequencing a human genome for
the cost of $ 1000 or less. At this cost, the technology should become
affordable enough to enable routine use in personalised medicine. The
speed and reliability of sequencing is also important for use in the
clinic. Conventional high-throughput sequencing technologies are
relatively slow; most require DNA samples to be amplified, cut to an
appropriate length, attached to a bead or surface and labelled with a
fluorescent tag which is read with expensive optical imaging equipment.
There is thus a need for `new generation sequencing' technologies which
use different approaches to sequencing and can therefore transform the
speed and reliability of genome sequencing, and hence the utility of
`personal' genome sequencing.
Hagan Bayley joined the Department of Chemistry in 2003 to carry out
fundamental research on membrane proteins. His research led to
breakthrough developments in the area of `new generation DNA sequencing';
specifically, his group worked on perfecting techniques to permit the
sensing of individual molecules using engineered membrane protein pores.
Bayley established that staphylococcal alpha-haemolysin, a bacterial
pore-forming toxin, could be modified by protein engineering to bind a
wide variety of partial blockers and that these pores might be used to
detect many different analytes at the single-molecule level. For example,
a paper published in 2005 (with researchers at Texas A&M University)
demonstrated how an engineered pore could be used to detect binding events
to monitor the concentration of a critical cell signalling enzyme,
cAMP-dependent protein kinase . This research built on previous work by
Bayley at Texas A&M on the assembly, structure and functional
properties of the alpha-haemolysin protein pore, and made use of the
technique of `stochastic sensing', in which the modulation by an analyte
of the ionic current flowing through a single protein pore produces a
signal that reveals both the concentration of the analyte and its
identity. Bayley has also used stochastic sensing to distinguish between
enantiomeric drug molecules. In 2005, Oxford Nanopore Technologies Ltd
(ONT) was formed to support and further translate his research to
applications in sequencing and sensing.
The work on engineered pores suggested that DNA and RNA might be
sequenced by pulling single DNA strands through a nanopore and detecting
nucleobases (including non-canonical bases) through their different
effects on the ion current passing through the channel pore. In 2006, a
breakthrough paper from the Bayley group demonstrated for the first time
that the four bases of DNA could be distinguished using an
alpha-haemolysin pore equipped with a cyclodextrin adapter . Following
this result, in 2009 -10 his group addressed one of the key issues in
strand sequencing: the need to be able to sense several different DNA
bases within the nanopore at once. The group showed for the first time
that an alpha-haemolysin pore could be engineered to contain more than one
recognition site, and thus identify groups of different nucleobases
simultaneously in an immobilised DNA strand [3, 4]. This marked a
critically important step towards continuous strand sequencing.
In 2010, the Bayley group demonstrated that it was possible to create
solid-state nanopores suitable for integration into wafer-scale devices,
by attaching a double strand of DNA to a single alpha-haemolysin pore and
threading it into a solid-state nanopore by electrophoretic translocation.
This research, in collaboration with Delft University of Technology,
showed that the hybrid nanopore remained functional in terms of ability to
sense individual DNA molecules . It formed the foundation for the
development of ONT's GridION and MinION devices for electronic single
molecule sensing and DNA and RNA sequencing. In parallel with the
DNA-focused research, the Bayley group has worked on similar methods to
enable nanopore sensing of protein molecules .
In 2005, the Bayley laboratory was awarded an NHGRI `$ 1,000 Genome'
grant, which was renewed in 2010 — the only such grant outside the USA.
The total award has been in the region of US$ 10M. In 2009, Bayley was
awarded the Royal Society of Chemistry World Entrepreneur of the Year
Award in recognition of his contribution to the commercialisation of
References to the research
Asterisked outputs denote best indicators of quality; University of
Oxford authors are underlined.
1. * Xie, H., Braha, O.
, Gu, L.-Q., Cheley, S.,
stochastic sensing can be used in an engineered pore to detect binding
events at the single-molecule level.
Single-molecule observation of the catalytic subunit of cAMP-dependent
protein kinase binding to an inhibitor peptide. Chemistry and Biology 12,
109-210 (2005). DOI: 10.1016/j.chembiol.2004.11.013
2. Astier, Y., Braha, O. and Bayley, H. Toward single
molecule DNA sequencing: direct identification of ribonucleoside and
deoxyribonucleoside 5f0a2-monophosphates by using an engineered protein
nanopore equipped with a molecular adapter. J. Am. Chem. Soc. 128,
1705-1710 (2006). DOI: 10.1021/ja057123+.
3. * Stoddart, D., Heron, A., Mikhailova, E., Maglia,
G. and Bayley, H. Single nucleotide discrimination in
immobilized DNA oligonucleotides with a biological nanopore. Proc. Natl.
Acad. Sci. USA 106, 7702-7707 (2009). DOI: 10.1073/pnas.0901054106 Paper
describing how an engineered αHL pore containing 3 recognition sites can
be used to identify all 4 DNA bases in an immobilized single-stranded
4. Stoddart, D., Maglia, G., Mikhailova, E., Heron,
A. and Bayley, H. Multiple base-recognition sites in a
biological nanopore: two heads are better than one. Angew. Chem. Int. Ed.
49, 556-559 (2010). DOI: 10.1002/anie.200905483.
5. * Hall, A.R., Scott, A., Rotem, D., Mehta, K.K., Bayley,
H. and Dekker, C. Hybrid pore formation by directed insertion of
alpha hemolysin into solid-state nanopores. Nature Nanotechnology 5,
874-877 (2010). DOI: 10.1038/nnano.2010.237 Paper describing the
creation of hybrid nanopores suitable for integration into wafer-scale
Details of the impact
The research described above has underpinned the formation of a very
successful company, Oxford Nanopore Technology (ONT), which has attracted
more than £ 105M investment, £ 97.8M of this since 1st January 2008. This
very high level of investment arises as a direct result of ONT's
pioneering technology, which has the potential to revolutionise the fields
of DNA sequencing and single-molecule analysis.
ONT was spun-out of the Department of Chemistry in 2005, founded on
intellectual property from the University of Oxford, to exploit the
technology developed by the Bayley laboratory and develop it into a
robust, commercial product. From the outset the company aimed to create
`disruptive technology' (one that establishes an entirely new market or
new behaviours in an existing market, thus disrupting the old one). From
2008 onwards, ONT forged collaborations with leading nanopore researchers
at other institutions including Harvard University, the University of
California Santa Cruz and Boston University, in addition to the company's
existing relationship with the University of Oxford. This work has
generated an IP portfolio for the company comprising >300 issued
patents and patent applications in >80 patent families, including 12
key patents arising from Bayley's work at Oxford . A new agreement in
2010, renewed in 2012, strengthened ONT's collaboration with the
University of Oxford through funding (>£ 2M) for the Bayley laboratory.
The deliberate decision to engage multiple institutions with relevant IP
has given ONT a world-leading position in nanopore sensing and ensured
that a UK-based company stands to profit from the enormous potential of
this technology, with associated benefits to the UK economy.
In February 2012, ONT revealed the GridION system at the Advances in
Genome Biology and Technology conference in Florida. GridION is a
nanopore-based platform that utilises key elements of Bayley's research,
in addition to research from other ONT partners. The primary emphasis of
GridION is efficient DNA/RNA strand sequencing (efficient both in time and
cost), but it can also be adapted for the direct electronic analysis of
target proteins, with applications in the discovery and validation of
disease biomarkers and the development of subsequent diagnostics (e.g. in
relation to drug response or status of a disease). ONT has revealed that
the technology within the GridION platform can be miniaturised into
MinION, a portable device for electronic single-molecule sensing that
plugs into a PC and is the size of a USB memory stick. These devices
measure single molecules directly, without the need for amplification of
the target molecule, fluorescent or chemical labelling, or optical
instrumentation; in addition analysis of data can be performed in real
time, and multiple nanopore measurements can be made in parallel, making
it both cheaper and faster than current sequencing technologies .
MinION will be made available to selected researchers to use, assess and
evaluate from late November 2013 .
Currently, ONT's nanopore-sensing technology is the only near-market
method which looks set to break the $ 1,000 barrier (it is expected that
MinION will be marketed at around $ 900), and importantly it will provide
extremely fast and robust sequencing, differentiating it from other
sequencing technologies . ONT calculates that if 20 of its
second-generation GridION nodes were used together, a human genome could
be sequenced in 15 minutes at a highly competitive cost (since the
single-molecule techniques developed at ONT do not require the cyclic
addition of reagents) . Application of this technology will not just be
in human health and personalised medicine but also in agriculture and crop
science, environmental science (e.g. detection of toxins in water), energy
and defence (e.g. detection of explosives). The potential global market
for `next generation sequencing' is significant: in 2012 it stood at $
232M and is expected by market researchers such as BCC Research to be
approximately $ 7.6bn by 2018. The announcement of GridION and MinION
attracted considerable worldwide media attention from national and
international newspapers including the New York Times, Guardian, Sunday
Times and Financial Times, as well as from scientific journals including
Science. These reports highlighted the low cost and high speed of ONT's
devices, and the two sequencers were described as `impressive, credible,
possibly amazing' and as a potential `game-changer' [10, 11].
The enormous potential of ONT's new technology, coupled with its wide
intellectual property portfolio and product pipeline, has generated a very
high level of investment during the impact period. Seed funding that
enabled ONT to be established was obtained in two rounds from IP Group in
2005, and in June 2006 the company raised £ 7.75M. Since 1st January 2008,
ONT has raised a further £ 97.8M (representing 92% of total investment
since company start-up) from a range of sources in the UK and the US. Over
a third of this (£ 34.1M) was raised in May 2012 almost entirely from
existing investors in the company — a clear indication of the extent to
which investors see the potential for GridION and MinION to become highly
successful. ONT is currently well funded for the next phase of corporate
The success of ONT is also reflected in its workforce. During the impact
period the number of people ONT employed increased nearly 6-fold, from 25
in 2008 to 145 in July 2013. The vast majority of current staff are
employed in research and development; they have backgrounds in multiple
disciplines including nanopore science, molecular biology and
applications, informatics, engineering, electronics, manufacturing and
commercialisation. ONT has UK offices in Oxford and Cambridge and US
offices in Boston and New York, and is building a commercial team in
advance of the launch of the products. Since 2008, ONT has also benefited
from the transfer of 3 highly-skilled staff from the Bayley laboratory.
Two of these bring academic research expertise to an industrial R&D
setting and work in application development and advanced research, and the
third works for ONT's IP team . The company was valued at $ 2bn by a
Numis Securities analyst in November 2012 .
ONT made an important contribution to the 2008 - 09 House of Lords
Science and Technology Committee session on Genomic Medicine. ONT provided
evidence to the effect that the new technologies were advancing so rapidly
that the government needed to take action. This evidence helped to shape
the recommendations in the 2009 final report , which are now being
taken forward by the Government (for example, via the Human Genomics
Strategy Group, established by the government to address questions raised
by the report ). This influence further reflects ONT as a pioneering
leader in the field of new generation sequencing.
Sources to corroborate the impact
The first Bayley patent to be licensed to ONT, US 7939270 B2, granted May
2011: `Delivery of molecules to a lipid bilayer', part of the technology
underpinning GridION and MinION.
ONT webpage confirming details of the GridION and MinION technology and
what it can do.
- The Corporate and Communications Director at ONT can corroborate details
of the `15 minute genome', the projected cost of MinION, its availability
to researchers from late 2013, details of company employees, and the role
of staff who have joined ONT from the Bayley laboratory.
February 2012 article in the New York Times, announcing the release of
MinION and corroborating the descriptions of the device quoted here.
May 2012 article in Science News, announcing the release of MinION and
corroborating the descriptions of the device quoted here.
ONT webpage, confirming investments in the company.
BioIT World report corroborating the $ 2 billion valuation of ONT.
Reports from the House of Lords Science and Technology Committee session
on Genomic Medicine, confirming the evidence provided by ONT to the
Human Genomics Strategy Group report, January 2012, confirming actions as
a result of the report cited at .