Private sequencing in a public world: the disruptive reality of nanopore sequencing

[talk script from the conference]

Introduction

Tēnā koutou i tēnei ahiahi. Kia ora.

Guten tag liebe Humboldtianerinen und Humboldtianer.

Es ist eine Ehre hier sprechen zu dürfen.

Good afternoon everyone. I'm grateful to have been given the opportunity to talk here today.

My name is David Eccles. I work with other researchers at the Malaghan Institute of Medical Research, trying to understand the basic science behind Cancer and the Immune System.

Today, I'm going to talk to you about something made from the basic building blocks of the living world. I'm going to talk to you about Deoxyribose Nucleic Acid, more commonly known as D-N-A.

I love DNA. How can I not love it? After all, it's in our blood.

DNA From a Tomato Source / 1

I call DNA the recipe book of the living world. Every living thing has DNA in it; it codes for the things our bodies make, and tells the cells in our bodies what to do and where to go.

To extract DNA from many things, you can grind them up in a mortar and pestle, add a bit of water, let it drip through a filter, then add a bit of alcohol.

This here is not just DNA, because there are some tomato-ey proteins that stuck to it as it was drained through the tea strainer, but it gives you an idea of what DNA looks like: long, stringy white stuff that has an amazing ability to clump together with itself.

DNA From a Tomato Source / 2

When DNA is represented at an atomic level, we see that it is composed of four different nitrogenous bases: double and single carbon rings that are supported by a sugar/phosphate backbone.

Each of these bases can be represented symbolically as one of 4 letters: A, C, G and T. When combined into a string of sequential letters, we call it a DNA sequence.

The process of converting from the physical thing of DNA into a model on a computer is called DNA sequencing.

Sequencing DNA by Shape

But how do we get from the physical thing to the sequence?

Imagine there is a device that can scan across an image of DNA, like a photocopier, and work out how much black there is in each line of the image. What you end up with is a squashed down representation of the DNA, showing how much stuff there is at a particular place in the DNA.

If our line detector were sensitive enough, then we would be able to distinguish the four different bases just on this profile alone. A and G look similar, as do C and T. Similar, but a well-trained eye would be able to tell the difference.

TEDxWellington2016 - Trust

In March last year, I was a speaker at the TEDxWellington conference, and the organisers did something a little different: trying to embed a theme of "Trust" into the conference.

As speakers, we didn't find out until our dress rehearsal the day before where the conference venue would be. The attendees didn't know where they were going until they were inside Peter Jackson's private cinema at Park Road in Miramar.

We were asked to keep our attendance a secret: no one at my work knew I would be talking at TEDx that year. I told my wife (after asking for permission), but one of the other speakers even kept it a secret from her partner. He didn't know she would be a speaker until she got up on stage and started talking.

In the context of this, I had to find a way to do my own rehearsals of DNA sequencing. I challenged myself to demonstrate DNA sequencing and analysis of a tomato on stage, with the added complication of trying to hide that preparation from my work colleagues.

All this secrecy was possible thanks to a company in England called Oxford Nanopore Technologies, and thanks to a cheap sequencing device that they designed called a MinION. Its commercial price is less than a plane ticket from Germany to New Zealand, and it was sitting next to my laptop while I was giving the talk, occupying a couple of pixels in the video feed from the conference.

Sequencing DNA by Nanopore

The MinION contains a consumable flow cell, which has thousands of small sequencing pools, each which has a waterproof cover over the top. This cover is pierced by protein tunnels, which we call nanopores.

An electric current is hooked up to the flow cell, which encourages DNA to move through the nanopores. Similar to the picture I showed previously, the shape of the DNA changes along its length, and this changes the electrical resistance. The change in resistance is recorded by the sequencer and sent to a computer over a USB cable.

This sequencer is very portable: all it needs is some prepared DNA, and a little bit of electricity.

Nanoscopes and Wide-angle Lenses

Because the MinION sequences DNA by looking at it, it can show you things that fuction at a higher and lower level than the one-dimensional A/C/G/T sequence. Some features of prepared DNA can only be seen by looking at the electrical signal created by the MinION: chemical changes on the scale of a few nanometres.

And yet, at the other end of the scale, the MinION doesn't limit the length of the DNA that is put into it. You can look at repetitive structures, and maybe they're not exactly repetitive after all, having more complex patterns, only visible when looking at the big picture.

When I use this device, I get glimpses like these about what might be missing in our knowledge of DNA, and I get really excited by that.

The Audacity of Roasted Coffee

The next time I demonstrated the MinION in a public setting, my need for secrecy was gone.

We arranged to have a demonstration table set up during the Australasian Genomic Technologies Association conference in Auckland last year. A request was put out for DNA samples before the conference began, and I carried out sample preparation and DNA sequencing during the breaks in the conference. I showed people the electrical signals generated by DNA from a virus, I looked at DNA from a mouse parasite, and I even had a shot of espresso.

It was a wonderful experience. I could get something out of pretty much everything I put in, and I felt like I had full control over what went in and what was done with what came out of the sequencer.

Privacy is not Black & White

More than a few years ago, I was attending a small symposium in Geneva on Genomics, Ethics, Law and Society. I learnt a great deal about the opportunities presented by releasing information about DNA to the world, but also a lot about how it worked best when that release was done in a careful, controlled way.

One of the speakers at that conference was Helen Nissenbaum, who was talking about the challenges of privacy in todays society. She explained that privacy was different from secrecy; privacy is about control, or more specifically about the control of the flow of information. We can imagine a spectrum of privacy, stretching from a situation where someone wants to keep everything secret, to a situation where everything is laid out in the open, warts and all.

The Costs and Benefits of Privacy

Katharine Reynolds mentioned in her Honours thesis that New Zealand law prohibits discrimination in terms of the provision of insurance on the grounds of disability. She argued that this probably also applied to DNA variants that predicted a disability in the future. However, insurers are able to adjust terms or pricing, as long as there is sufficient statistical data, or reasonable professional opinion, to do that.

So, should we not be doing any research on DNA, for fear of it being used as the grounds for discrimination, either by insurance companies, or by anyone else?

This year, we can now see that knowledge of the DNA inside us can lead to huge benefits. In the last month or so, there have been three demonstrations of DNA modification that have lead to miraculous results in people: blind people got their sight back; babies that needed assistance to breathe can now sit, eat, and speak; and a child that was running out of skin is now running out of the house and around the playground.

These people were cured of a disability because scientists were able to look at their DNA, see how it could be changed, and then change it. But some people don't want to know, and some people don't want to be changed. Change is disruptive, and change can have long-term consequences beyond anything that we could ever think of at the time.

Knowing about our DNA is a personal thing. Everyone should have the right to control that knowledge, or even to not find out about it at all.

Māori Genetic Research

Especially for indigenous research, it's very important that the participants of research have control over what is done with their property: their body, their DNA, their data. I think that this sequencer gives communities this control over their property.

The control of DNA research can be placed in the hands and arms that provide the DNA. Sample preparation is simple enough that someone can use this sequencer, and get results from it, with a couple of hours of training. By keeping the preparation, generation, and analysis of results within the community, they are free to ask their own questions and have ultimate control over what is done with their property.

A Change in a Resistance

In conclusion, by looking at the change in a resistance, we can explore the mysteries of the genetic recipe of life. This sequencer gives us the control to make that exploration in our own time, and in our own place. Given the low cost and accessibility of the MinION, it seems to me that the only thing holding us back from that control is a social resistance: in other words, a resistance to change.

I hope that I've helped today to lead you to that path to change.

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