How to make DNA affordable


Everyone should have the opportunity to make beautiful things with biology, and that means we need to get better at giving people the opportunity to work with DNA tools. There are two methods that are typically used to get interesting DNA right now: people email their buddies, or they get the DNA from plasmid repositories. Those plasmid repositories have a big problem: they are exclusive to academics, both in property rights and in price.

How did this happen and how/why should we make it so more people have access to DNA tools?

Current repositories have historical baggage

In the early 90s, advancements in DNA technology got people thinking about ownership of biological materials. This led to several long-lasting agreements on the handling such materials, such as the Nagoya Protocol and the Uniform Biological Material Transfer Agreement (or UBMTA). The UBMTA gave academics a standard way to share biological materials that was legally recognized by their institutions (in the form of a co-signed contract), which made the annoying lawyers go away. With the NIH behind the UBMTA, it quickly became the status-quo of sharing materials. Oddly, the UBMTA disallowed commercial use and redistribution of any materials shared under it.

Those restrictions don't really make much practical sense, and they were largely ignored by scientists (there has never been a suit based only on a MTA), but since it made the legal departments at universities happy, it stayed in place. In the 2000s, the two current large plasmid repositories, Addgene and iGEM, were founded. However, the UBMTA was the status quo - which forbade redistribution (such as through plasmid repositories). Early on, it would have been way too hard for these organizations to build up their repositories without fitting into the current MTA landscape, so they did some interesting hacks. iGEM simply ignored MTAs (which they could do because they only shipped to academics), while Addgene decided to be an intermediary between two organization's tech transfer offices.

In essence, in order to fit into the current legal landscape, these plasmid repositories limited who they could share with. In both cases, this meant giving up ownership to the materials that

they supply. Individual labs may ignore MTAs, but both Addgene and iGEM are now large enough targets that they cannot ignore MTAs and the restrictions against commercial use.

DNA synthesis opened new possibilities

It is important to note that the harsh UBMTA restrictions can only be applied to physical materials. The DNA sequence information itself had none of these restrictions, and could be resynthesized freely (previously at great cost). You could have two tubes of DNA, one synthetic and one derived from UBMTA material, which are atomically indistinguishable but have completely different material rights.

High throughput DNA synthesis first emerged in the early 2010s with Gen9, and nowadays is done with Twist Biosciences. For the first time ever, DNA synthesis was a practical alternative for getting hard-to-get plasmids. This observation prompted the BioBricks Foundation to create a new material transfer agreement called the OpenMTA, which removed the restrictions on commerical use and redistribution, and create a project called the FreeGenes Project, which resynthesized useful DNA materials under this new agreement. Though those materials would have the same sequence as materials under the UBMTA, by synthesizing the sequence from scratch it would be freed from those material right restrictions.

Since Addgene is an intermediary between organizations, it can't change the MTA that materials are shipped under. Resynthesizing popular material would also be competing with their depositor

base, which they aren't willing to do. iGEM, on the other hand, has the opportunity to resynthesize materials from scratch, but so far hasn't focused much on this idea. However, there are other reasons why iGEM can't make widespread DNA distribution happen.

We need continuous distribution

Addgene ships materials to researchers year-round, but iGEM does something very different - it ships all materials once a year. By shipping all materials at once, they can scale their operations to get a much lower per-gene cost than Addgene could hope to get. This works since all the teams that participate in the iGEM competition are supposed to start their projects at approximately the same time. For real research, though, this isn't good enough - people need continuous access to DNA in order to do research quickly and efficiently. iGEM is in no position to change their distribution cycle, since it gives nearly zero benefit to their organization. In order for more people to get access to DNA technology, we need an continuous distribution cycle, where materials are constantly shipped when needed.

Continuously sending materials also gives the added benefit of being able to improve over time, and can respond to consumer demand more effectively.

DNA should be cheaper

There are 3 important metrics when considering the unit costs of shipping DNA:

1. Ease/Cost of production

2. Ease of use

3. Ease/Cost of shipment

iGEM ships DNA materials as dried plasmid DNA in plates, while Addgene mostly ships DNA as individual agar stabs. iGEM's production is fairly difficult, but is very easy to ship, and use is easy if you have a little experience in bioengineering. Addgene's production is easy, but can't be automated or scaled well. It's easy to ship and to use, but has a short shelf life, which means there needs to be a constant supply of human labor.

In both cases, the production costs are rather high - in iGEM's case, this is because the DNA has to be purified and prepared on plates. In Addgene's case, this is because of the physical processing necessary to produce the agar stabs.

A single strain from Addgene costs $65, while creating an iGEM team (for the distribution) costs $5000. Labs only order the strains strictly necessary from Addgene, while iGEM mostly only serves undergrad teams. These costs are easy to justify with the amount of value delivered, so why would we want to reduce the price of getting DNA if a perfectly stable non-profit or for-profit business can be created without dropping prices? Network effects are why.

Synthetic biology as a field is based on standard parts and standard composition of those parts. However, getting things to work is still pretty iffy, and so most scientists tend to reuse plasmids and parts that they already know work. This conservatism is passed down from PI to graduate student to undergrad, cycling as each rise in the ranks or retire. The more people you can convince to use a part kit, the more people will want to use it (since it worked for friend and colleague X, it should work for me!)

In the end, if you can make great genetic engineering toolkits for a low price, you can effectively capture more of the market than if you had a "high but justified" price which many can't afford. Building the best genetic engineering toolkits in the world is an envious position - the amount of opportunity afforded by that status is where real income could come from.

|                         | Low Unit Cost | High Unit Cost |
| High Shipping Frequency |        ?      | Addgene        |
| Low Shipping Frequency  |      iGem     |    Email       |

In conclusion

To review:

Back to the original question: How do we make it so more people have access to DNA tools?

I believe the answer is to create an organization which can:

1. Leverage DNA synthesis capabilities to serve under-served non-academic markets for DNA

2. Dramatically reduce the cost of producing and shipping of that DNA (high shipping frequency at low cost)

- Keoni Gandall 2020-08-24