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DNA synthesis: new process, new prospects

Traditional methods of DNA synthesis are slow and costly. Twist Bioscience's novel method uses a silicon platform, which enables the volume of reagents to be reduced while increasing the reaction efficiency. They are able to produce DNA at a much lower cost than their competitors, which gives researchers in many fields — pharma industry, industrial-chemical companies, agricultural biology, synthetic biology, etc. — access to more high-quality DNA. The company also explores the potential for DNA to be a storage solution in the future. They notably collaborated with the university of Washington and Microsoft to store two pieces of music (Deep Purple’s “Smoke on the Water” and Miles Davis’ “Tutu”) into DNA for the UNESCO’s Memory of the World programme.

November 2017
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lire en français
Executive Summary

The phosphoramidite chemistry, published in 1982 by Professor Caruthers from the University of Colorado, is still used nowadays to synthesize DNA. Twist Bioscience has moved this chemistry to silicon, which allows to shrink the volume of reagents so much that they can make one million oligos at the same time. Dr. Leproust and her team are therefore two to three times cheaper than the competition. Their goal is to continue to drive that price down. For example, they have shown that DNA is a great media for storing data in the long term. It is much better than magnetic tape in many ways — extremely permanent, extremely dense, universal format — but it is still more expensive. DNA is such a fascinating molecule and something that will transform people’s live for the better. Through its many applications, we will be able to make the world more sustainable and more healthy.

Paris Innovation Review — What is Twist Bioscience’s novel method of DNA synthesis?

Emily Leproust — DNA is made of four nucleotides, adenine (A), cytosine (C), thymine (T), and guanine (G). The chemistry of making DNA has a very long history starting in the 1950s, when researchers first tried to chemically synthesise DNA. They had a bottle of A, a bottle of C, a bottle of T and a bottle of G and they tried to stitch those nucleotides together. That research cumulated in a chemistry called phosphoramidite, published in 1982 by Professor Caruthers, from the University of Colorado. This chemistry, which is still used nowadays by everybody to synthesize DNA, is at the same time very stable and convenient — bottles of A, C, T and G are stable for weeks, even months — and enable very fast and efficient creation of strands of DNA.

The next step in the commercialization of DNA synthesis has been to develop hardware and software to control that chemistry to make DNA sequences on demand for customers, because there are a lot of applications of DNA. In 1982, when the chemistry was published, only one oligonucleotide (oligo) at a time could be made. Then a company came up with a new instrument with which four oligos could be made. In the late 1980s, a machine was then able to make 96 oligos at a time. It was a big deal because then people stopped making their own oligos and started outsourcing the DNA synthesis to what is called oligos houses.

Let’s now fast forward to Twist Bioscience. We have taken the same chemistry but we have ported it onto silicon. We were the first one to do it. Moving the phosphoramidite chemistry to silicon allows us to shrink the volume of reagents so much that we can make one million oligos at the same time, and not only 96. Those oligos produced on silicon chips can be turned into a number of higher-value DNA sequences for pharmaceutical, industrial-chemical and research applications. For instance, we can turn them into guide RNA which are very useful for gene editing using CRISPR-Cas9, into targets for drug discovery and drug development and also use them for data storage.

Is it revolutionary ? Would you say you are democratizing DNA synthesis?

The idea of making a lot more oligos at the same time has been around for a while. I did my PhD in the late 1990s in that field. However most of those technologies were using glass. As far as we know, we are the only company to have done two things : first bring this phosphoramidite chemistry to silicon and second, perfect it to push the quality to a new level. Right now, when we synthesise our oligos, we have one error in a thousand bases. Our previous record was one in 500 bases. We are really pushing the bar of quality further.

You can get DNA without Twist Bioscience. However, with Twist you get DNA at a much higher throughput, at a lower cost and at a perfect quality. We are not necessarily putting DNA into more hands. But for the hands that already exist, we are giving them access to more DNA. We are improving the productivity of our users : they can do more experiments, they can find what they are looking for faster and more efficiently.

Our goal is to develop our business in such a way that cloning becomes obsolete.

If you buy a gene now from our competitors, it will be about 25 cents per base pair. When you buy it from Twist, it costs 9 cents per base pair. We are two to three times cheaper than the competition which allows our clients to buy two to three times more DNA for the same budget. The goal is to continue to drive that price down. For example, we have shown that DNA is a great media for storing data in the long term. It is much better than magnetic tape in many ways but it is still more expensive. So our goal is to push the technology to lower the cost of DNA by 5,000 times, 10,000 times, even 1,000,000 times, so that DNA can be competitive against magnetic tape.

Why is DNA such an ideal data storage solution?

There are a number of advantages. First of all, DNA is what nature has been using to store information for millions of years. Our DNA is our hard drive. Through billions of years of evolution, this is what nature has chosen. The data stored in DNA has the same benefit as DNA itself, which is extreme permanence. It is a molecule that will stay stable for thousands of years. You can find readable DNA in 20,000 years old bones of mammoths...

Secondly, DNA is extremely dense. To give an idea of the magnitude, let’s imagine we get a hard drive that has the size of a phone, where you can store one terabyte of data. One thousand of these, which would take quite a lot of physical space, will allow one to store one petabyte of data. If we were to store a petabyte of data in DNA, that would fit in the size of a grain of salt !

Another benefit of DNA is its universal format. With electronic media, it is not possible to read a VHS tape on a CD reader, or a CD on a USB driver, etc. With most electronic media, the writer and the reader are the same, whereas DNA is universal and can today be read by no less than five technologies. DNA is also very easy to copy. With a molecular biology technology called PCR (polymerase chain reaction), a dollar and an hour are sufficient to amplify that petabyte of DNA millions of times. It would cost a lot of money and take a lot of time to copy a thousand hard drives. So DNA has a lot of benefits and we believe it will be a great media in the future.

Would you say that it is the ultimate technology for data storage?

DNA will never replace hard drive. One disadvantage of DNA is that it does take a little bit of time to read the data back. It is called latency. For some applications, fast responses are needed so hard drives will still be used. DNA will be used for applications where a few hours of latency will not be a problem. So it will be a replacement for tape but not for hard drive.

For example, we collaborated with the university of Washington and Microsoft to demonstrate that we could store some pieces of music into DNA. The Montreux Jazz Festival identified two pieces, Deep Purple’s “Smoke on the Water” and Miles Davis’ “Tutu”, the university of Washington and Microsoft then encoded the data in DNA on a computer and we synthesized this DNA. We read it back to make sure it was 100% correct and it was ! Now that DNA will be stored forever as part of the UNESCO’s Memory of the World programme. As music composer Quincy Jones told us, it is quite remarkable that a piece of human imagination will never be lost and will be accessible to future generations.

Do you plan to store some more important archives into DNA?

Right now our main effort is around the technology development, to push further the performance of our synthesis technology and mostly around price reduction at this point. Of course there will be some milestones along the line.

Why is the decrease in the cost of DNA synthesis so important, especially for synthetic biology?

The goal of synthetic biology is to engineer biology. It is an approach to practice biology at a very high throughput. It means getting a lot of data points from which it is possible to learn about the system that is studied and engineer it in the direction you want it to go. Part of that learning is to follow the engineering principles of the design-build-test cycle. To conduct experiments as part of that process, researchers need a lot of genes. Because our synthesis costs are much lower, we enable people to design more DNA, so they can build more and test more. And the more they test, the faster they get to their answer of engineering the system the way they want. We therefore think we are having a big impact in this field. We want to keep enabling that field and be the company that people rely on to advance their research.

Read our article: Synthetic biology: what industrial prospects?

What are main industries you are working with?

We serve four industries and we have about 200 customers. The first one is the pharma industry, which is using our technology to discover and develop new therapies and new treatments such as immuno-oncology, DNA vaccines, biological drugs, etc. They can potentially use our CRISPR tool to do target discovery, our genes to do hit discovery and development, our next-generation sequencing products (NSP) to do patient stratification for clinical trials... On the pharma side, we truly serve the full spectrum.

We also serve industrial-chemical companies that are developing new organisms to make chemicals through fermentation of sugar. It is widely known that sugar can be fermented to produce alcohol and CO2 — in France you call it champagne. The gene of the yeast can be changed so that instead of making alcohol, it can produced any sort of chemical. There is a rush right now to move the production of those high-value specialty chemicals away from oil, as a source of carbon, towards fermentation.

We also have clients amongst companies in the field of agricultural biology, that are developing new ways to produce fertilizers, to protect plants from new diseases or weather, even to produce more yield. Bayer and Ginkgo have just started a $100 million joint-venture to look for fertilizer that is not based on ammonia production, which uses a lot of natural gas, but instead to do fertilization through a bacteria. That will be a huge advancement for the production of more sustainable and cheaper food. Let me give you another example to illustrate what agricultural biology can achieve: in Hawaii, 100% of the papayas have been genetically modified to be resistant to fungi. Without this genetic tweak, papayas would have disappeared. The same thing is currently happening with bananas. There is a fungi that is wiping out all the banana farms and if a genetic fix is not found, very soon there will no more bananas.

The fourth industry we are working for is academic research. They are using DNA to do their research in understanding how biology works.

Where do you want Twist Bioscience to be in five years?

Our goal is to develop our business in such a way that cloning becomes obsolete. Right now, a lot of people clone DNA. It is a very tedious process, that takes a lot of time and does not add a lot of value. That way, we will further advance all the work of pharmaceutical companies and the development of novel therapies to fight cancer and chronic diseases.

We would also love to extend to other markets, data storage is one of them. Hopefully, we will have a data storage solution available in five years. We need to lower the cost to be very competitive and to offer a better solution than tape, something that is permanent, very dense, easy to process and to access. When that happens, a number of current users of tape will switch to a DNA-based solution because it will be better.

DNA is such a fascinating molecule and something that will transform people’s live for the better. It is the blueprint of life. Everything in our body that enable us to live is contained in our DNA. And through the many applications of synthetic DNA, we will be able to make the world more sustainable and more healthy.

Emily Leproust
Chief Executive Officer, Twist Bioscience