Interview between Andrew Lockley (AL) and Oxford Biodynamics CSO, Dr. Alexandre Akoulitchev (AA) about the role of OBD within the epigenetics sphere.

AL: Can you start of by recapping a bit about what genes are, and why it’s important to work on them?

AA: Genes are the functional units of our genome, and are responsible for our heredity. The entire human genome was finally mapped by 2003 – all 23,000 genes that we have. Activation of genes (gene expression) and deactivation (gene silencing) dictates everything in the body. When expression or silencing goes wrong it is the precursor to many diseases.

AL: What’s “junk DNA”, and why is it important?

AA: Genes make up less than 2% of our DNA. The other 98% was formerly referred to as “junk DNA”, because scientists didn’t know what it did. The very fact that the more sophisticated an organism, the more junk DNA it had, should probably have given them a clue that it wasn’t junk at all.

Nearly three metres of DNA is compressed into our cell nuclei. As you can imagine this is an incredibly complicated 3D arrangement.

In the 1990s it was discovered that this 3D structure led to different parts of our genetic material (including parts of the junk genome) interacting with other parts of our genetic material to form what are called chromatin conformation signatures (CCS). We learned that these CCS triggered gene expression or silencing. If you stretched out our DNA these sites looked miles apart – but in the 3D structure, they come together – and they have a monumental effect on our genes. Starting with a few hundred academic papers published in the early 90s, the scientific community has finally caught on. Last year alone nearly 20,000 papers were published on CCS.

AL: We hear the term epigenetics a lot these days; could you explain to me what epigenetics is?

AA: The Greek word “epi” means above. Epigenetics means “above genetics”. It is the study of the imposed changes to gene regulation, which occur during our life cycles. These changes are often due to external factors – such as diet, exercise pollution, stress, etc. This alteration of gene regulation occurs without changing the DNA sequence itself. The simplest demonstration of epigenetics at play is the differentiation of cells in our body. All our cells have the same DNA. The fact that some develop into muscle cells, rather than brain cells, is down to epigenetics.

AL: How significant are epigenetic influences in relation to human disease? I imagine that they are minor compared to those imposed by your genetic material.

AA: Far from it! It is now recognised that the stored information on your genome is responsible for approximately 30% of regulatory control of gene expression, whilst epigenetic factors are responsible for about 70% of regulatory control. This explains why the Human Genome Project fell short of answering all the questions on disease and heredity that it was supposed to address. Mapping the genome led to the discovery that less than 2% consisted of coding genes – with 23,000 in total. The other 98% was non-coding DNA – and that was thought to be “junk”. Epigenetics sees the regulation of gene expression in the context of the whole genome – recognising that junk DNA has an important regulatory role.

AL: Where does Oxford Biodynamics fit into this landscape?

AA:  We recognised that academic work done on the crystalline structure of yeast DNA, some 25 years ago, demonstrated that the 3D structure of yeast DNA led to long-range interactions occurring between areas of the genome that look totally unrelated when the DNA is stretched out. These long-range interactions were termed chromatin conformation signatures (CCS). The breakthrough came when we realised that – when the DNA is wrapped up in the chromosome – these regions are actually very close together and these CCS affect gene regulation if altered.

AL: I presume then that CCS are evident in human DNA? If so, has there been further research done on them?

AA: Humans have nearly three metres of DNA, compressed into the cell nuclei – which average just 10 microns in diameter. You can imagine how complex that 3D structure is. So, to answer your question, there are hundreds of thousands of CCS occurring in human DNA. If these are altered by external factors, it will affect gene expression. This is an epigenetic change – one that doesn’t change the genetic material itself. However, if this epigenome is altered, it can cause faulty gene expression – leading to disease, etc.

AL: What, in practical terms, has Oxford Biodynamics done – having had the early-mover advantage, by recognising the importance of CCS?

AA: The company was established in 2007 as a spin out from Oxford University. It established its intellectual property by getting granted a monopoly of patents: for using CCS in diagnosis of disease, and for use as biomarkers.

The first patent, for diagnosis of cancer using CCS, is licenced in perpetuity from Oxford University – whilst the rest of the patents are owned by the company itself. The next step was to produce an industrial platform. This had to be able to monitor CCS quickly, sensitively and reliably. Our EpiSwitch technology platform does this. Another proprietary aspect of the designs used in our technology is a package of bioinformatics software. This helps us predict positions of potential chromosome conformations of interest, with high accuracy. At our ISO-certified facility we have high-throughput screening, and robotic processing. Together, these technological advantages help us to come up with practical biomarker solutions – and to avoid getting lost, while looking for the “needle in the haystack” of large data sets.

AL: What is the business model, for applying this unique technology?

AA: As a company we wanted to become the ultimate “picks and shovels” play for a number of things – but most importantly pharma/biotech drug development. As you know, the industry spends fortunes on researching new drugs. If you can spot early on whether a drug lead is not working properly, it will save billions on development. As part of epigenetic regulation, a change in the CCS occurs very early – sometimes within hours of a drug being administered. That’s long before many other regulatory changes in the cascade of induced gene regulation. This is invaluable information for many of our partners.

As of today we have signed 23 contracts and have worked with six out of the ten top global pharma companies. These projects typically take six months to completion and generate good revenue (between $100k and $500k per contract). This revenue gives us a very low burn rate of some £2m pa. But the business model is that of license. Some of these contracts will eventually lead to a validated signature of biomarkers. These will help ensure, for the client, successful outcomes of clinical trials and regulatory approvals for their drug. Milestone payments, and royalties, will be paid to Oxford Biodynamics.

AL: Could you give an example of how my life might be affected by this?

AA: If you suffered from rheumatoid arthritis, the first line of treatment from the NHS would be a drug called methotrexate (MTX). The problem is that, although cheap, this drug only works on 40% of the patients. The potential failure of this treatment would be only assessed after six months. We have applied our technology, and can identify from the CCS profiles and how they change with 90% accuracy those who will or will not respond to MTX. This work has been done in collaboration with the Scottish Early Rheumatoid Arthritis (SERA) consortium. We presented the work at the American College of Rheumatology (ACR) Conference in San Francisco. If you were an RA sufferer it would mean that we can help the doctor make a clinical decision on the choice of the prescribed treatment – and save the non-responders to MTX from six months of suffering and damage.

In a similar way, we are helping identify patients who are likely to respond to the highly effective immune checkpoint therapies, in a plethora of cancer indications. Pembrolizumab (Keytruda) and Nivolumab have been now licenced in the UK. Readers might recognize Nivo as the immunotherapy refused to the late AA Gill by the NHS.

With very practical industrial solutions based on our biomarker technology, we consider ourselves at the forefront of personalised medicine – where we answer the question of whether certain patients  will respond to certain treatments.


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