Truly personal genomics – Clive Brown, Oxford Nanopore
At the moment, getting a genome sequenced is a length process. After purchasing a kit and providing a sample, the sequencing itself, the base calling, the analysis, are all managed by a third party. This works brilliantly for research and healthcare systems, but leaves genomic consumers with very little control over how their data is managed. For the vast majority of people, the technology and the expertise to take control of their data are out of reach.
This model could be about to change, with the open access publication of the ‘CliveOme’, the genome of Clive Brown, CTO of British biotech company Oxford Nanopore. The company may be best known for putting a DNA sequencer in space, but through his personal genome project, Clive is looking to impact the world of sequencing a little closer to home.
We spoke to Clive in some detail about the implications of DIY genome sequencing, and as only some of those comments made it into our main coverage we decided to share the full interview here.
One of your motivations for sequencing and publishing your personal genome was to “get the ball rolling on a new self-sequencing model” where individuals can create, access, store, and re-sequence their own genetic information at their own discretion. In the future, how do you see this approach fitting into existing models of genomic research, or even healthcare?
Right now the model is very much the opposite of this. There are several reasons for that, some of them prosaic, some of them structural that may need reform. The way that traditional DNA sequencing technology has developed has been all about laboratory research. The processes, reactions and the equipment have all been designed and priced with that in mind. Equipment is very expensive and highly technical. This tends to centralise its operation.
There are other reasons to centralise, the practicality and also politics of genomic and genetic research and healthcare tends to concentrate the capital and expertise in a small number of hands. A sort of ‘trickle up’ has occurred in genomic research where projects have gotten bigger, machines require more upfront capital, processing thousands of samples centrally requires large infrastructure, logistical, IT and organisational support, and so more money and power as moved to the top of the genomics pyramid.
There are some benefits of this approach too, around quality control for example. In the middle ground we have intermediate level sequencing operations where again, capital requirements are high, but machines are often idle, so frittering away money on depreciation. Money that could have been pointed at unfunded projects. The justifications for centralisation have merit, but without a competitive alternative a somewhat self-serving monster has been created. Only one company really makes money from this and it’s not currently us.
Part of our goal at Oxford Nanopore is to break this cycle by providing genomic tools that can be run by one person, anywhere to analyse anything. We have also tried to do this without the upfront capital requirements, focusing on what you might call a ‘pay as you go’ model. For some of our devices this means people who would otherwise miss out on funding, or who would be beholden to a central service, can now do it all for themselves, even outside of the laboratory. However, we also acknowledge that central service is key for some scenarios, and so we make versions of the technology that can supplant the existing big-box workflows at low or even no capital.
This applies to research and, once approved, medical sequencing. A central clinic, or a doctor should be able to run these assays. In our view also, the big-box model has left a lot of “developing countries” behind. It’s a rich country’s game as it stands. I heard a story about one such ‘developing’ country in Africa who had felt pressured to try to buy into the big-box centralised model, but for a whole host of practical reasons were unable to operate the entire workflow and had only done two machine runs (a machine should to hundreds per year to be cost effective), still their Californian supplier was also charging 10% (of capital cost) service fees. In my mind that is deplorable – it is Devil take the hindmost. We believe our devices can be used by any enterprising, bright scientist or medic, anywhere.
But let’s go further. The trajectory of the technology is to make it usable by anybody. Yes even non-scientists. Yes, there really is interest. I was inspired very much by the ground-breaking 23andMe who, offering a fairly weak and old fashioned genetic testing technology, were able to get over a million curious people to spit into a tube and pay a subscription to try to understand what is going on in their own DNA, at a fairly superficial level. I think that, when we can put a drop of spit into a cheaper version of our technology, all of which is being actively developed, people at home will be able to sequence their genomes and have access to analytics to help them understand it.
I once, on a platform, spoke about using a modified DNA sequencing toothbrush to do this, it would email you by the time you got to work with a report. I wasn’t joking! It is technologically feasible to do that given some effort. What might a person look for? Well in my view its entirely up to them. You’d get your genome, from white blood cells and cheek cells, you’d get bacteria and viruses, you’d probably get circulating DNA indicative of a whole variety of things (see literature). A particular interest is to track things over time, generating baselines. We could then look for meaningful perturbations from those baselines, both within individuals and also between groups (if they share their data) and also across geographical domains. All potentially very powerful with modern analytics and AI. We already have patient advocacy/activist groups wanting to map and monitor their status via their own blood borne DNA profiles, then take that to the clinicians.
Most sequencing is currently done for you by a service. People can interpose themselves into that process. With self-sequencing you are in control. Part of that means asserting your right to understand your own biology, and, in this case taking ownership of your own genetic profiles. I am attempting to assert these rights via Copyright.
I think both models will co-exist perhaps with some tension. Some people, like me, would like a sort of DNA electronic wallet, where they store and control the access and exploitation of their own data – I might even charge a fee to have it used in a medical trial. Some people have argued all medical records could also be de-centralised to patients this way. I would say, that’s good, if they opt in. The default, in a way, is the current direction of travel, where people are seeking to offer everything as a service, control the data, control the interpretation of the data, through authority. There is a definite move in some quarters towards empowered patients having more active involvement in their healthcare. Equally there is also resistance to this in the medical profession in some, not all, quarters.
Did you find anything in your sequence that surprised you, or that you weren’t expecting?
Not yet. I had a collection of tests for nasties before I embarked on this. Nothing major showed up but the tests and genetic profiles are not comprehensive. People seem to divide into two camps. People who want to know what might be coming, who want to wrestle with it, manage it, and perhaps make changes. Then there are people, who I fully respect, who don’t want to know. They want to live in peace until the bad news comes, and deal with it then. You can argue the merits of both. It seems to me people should be allowed to choose.
But also, most people don’t realise that genomic information is very very very weakly predictive against lifestyle information in most cases. There are a small number of very nasty Mendelian or sporadic mutations that give high certainty of the, generally degenerative, diseases most people fear. Even those mutations don’t give accurate onset information. If you have one of those you are going to find out sooner or later anyway. In my view it just depends whether you’d like some forewarning, or prefer to live in ignorance. By the way, if the diseases in question are Mendelian then your family history, which you probably already know, is a strong indicator of your risk.
I may have a rare disease that resembles the mild form of Familial Mediterranean Fever. My father also had it. We never had it formally diagnosed and I do not have the well know mutational profile that is associated with that phenotype, so I’m quite keen to see if I can track that down. If it is an FMF disease it’s rare in my ethnicity. Maybe I can add to the knowledge of sporadic fevers with an n-of-one analysis.
You have an extensive background and expertise in genomic sequencing, and in the MinION device. How simple would the self-sequencing process be for someone without a molecular biology background?
For now, they’d struggle. But if you look at our upcoming technology developments a lot of our efforts are on enabling anybody to this. Those developments are months away, and we also have developments to increase the amount of data produced by the technology and at a much lower cost.
Beyond a simple interest in the contents of our own genomes, what do you see as some of the most exciting future applications for the DIY approach to personal genomics?
There are a very large number of applications. Probably the biggest impact may come from large numbers of people inventorying what is whizzing about their blood stream on a regular basis. Even better of it can be annotated with other information. What a dataset if we can get millions of people doing it over many years! I think it would supplant all of these centralised human genome uber-projects very quickly.
I have a hunch that sequencing the parts of the genome (yes we can focus down too) that control the immune response, say antibody diversity, regularly also over time – might be a particularly rich source of information. The dream is that we can see problems via circulating DNA before they become problems, and intervene to head them off. Pick your disease for that! It’s probably the most exciting experiment in human healthcare since vaccination was invented. Some people don’t like this model at all.
But I’m reminded of the 70s/80s; if you owned a car back then, it would break and then you’d go to a garage. They’d hit you with a bill, fix only the thing that broke and send you on your way until the next thing breaks. Often one thing breaking weakens other thing. Modern cars now have real time monitoring and management systems built in. They can pre-emptively detect things that are likely to cause a breakage (such as low oil, faulty brakes etc.) and warn you long before you break down. It is a much better system. Of course some people still just ignore the warnings, but that is their choice.
There’s huge potential in people choosing to open their personal DNA wallets up to academic researchers, under reasonable rights. This will catalyse many advances, and my bet is some of those people will want to participate in that research. The public understanding of DNA can be improved, and many of the fears and taboos that have been created can be substantially defused. That is in everybody’s interests.