Chapter 2. Open Source Biotech Consumables

Introduction

Let’s face it, biotech startups are expensive. And they’re not just expensive, they’re also hard. Not just scientifically hard, but also unnecessarily, bureaucratically hard. Even if you’re somehow independently wealthy and can afford to plunk down $100k to get your own lab started (and you don’t mind getting looked at funny by your friends, “What? You can’t do biotech on$100k!”), it still takes a long time to find a seller of biological materials that’s willing to do business with an individual or newly formed startup company operating out of a basement. Both of these problems, cost and inaccessibility, are preventing the biotech revolution from taking off in the way the computer tech revolution took off when people started doing things in garages. We need to fix this.

First, I want to point out that there has been great progress on the lab equipment front. Access to a basic molecular lab is now obtainable and affordable both through hardware makers (e.g., OpenPCR) and through community equipment pools (Biocurious, Berkeley Biolabs). The most comprehensive list of these resources is probably Quitterie Largeteau’s biotech/hackerspace list. Getting access to higher-end cell culture and regenerative medicine gear still requires more creativity. But I can see the momentum now that will take us there with time.

In this article, I will highlight another front where there has been much less progress until now—the need for access to inexpensive biological consumable reagents, outside the confines of academia and industry and absent of limited-use restrictions.

Price Versus Cost

A poorly kept secret that we biotech overlords have is that biotechnology reagents don’t have a cost. They have a price. Big difference.

Frankly speaking, after all these years in the industry, I still have no idea how people can get away with charging several thousand dollars for a milligram of recombinant protein. That’s an amount that you can see with the naked eye, if your eyesight is really good, but even then, you can see it only just barely. If you had to make a recombinant protein in your undergraduate biology class, then you know that the cost of doing this is essentially the cost of highly refined sugar water (= culture media) plus the cost of highly refined salt water (= chromatography buffers). Using sophisticated 1970s hardware like a shaking incubator and an Akta purification pump, any undergaduate biotech student can make many milligrams of protein in a single day, for each liter of culture medium and chromatography buffers consumed. The sales price of these things is tens of thousands of times their production cost, including highly skilled labor. If this doesn’t make sense to you, then that’s because it doesn’t make sense period. I would simply refuse to believe the facts of nature described in this paragraph if I hadn’t made numerous recombinant proteins with my own hands at virtually zero cost and if I hadn’t spent some \$500,000 of other people’s money purchasing them. There is no reason these things should be happening at the same time on the same planet. But they do happen. On our planet.

Inaccessibility

People in the field have a lot of different views on what’s causing the price of biotech to be so much higher than its cost. And they’re all correct. High knowledge barriers—yes. Up-front capital investments required—absolutely. An enormous government funding program bidding up prices—totally. And many more. But one of them is most interesting. One is the master barrier. One barrier is protecting all the others from falling to the onslaught of human ingenuity. It’s what I like to summarize as inaccessibility.

Large companies and governments have the ability to keep biotechnology profitably inaccessible by exploiting a fundamental principle that has become known as the “Central Dogma of Molecular Biology.” The Central Dogma governs which biological resources can by nature be reproduced, and which cannot. Most functional biologics undergo something like the life cycle in Figure 2-1.

DNA is the most upstream source of biological information. It harbors the genes, which are the “blueprints” for making functional biological entities. Uniquely, DNA has the gift of self-renewal, as it gets replicated during cell division. The nonfunctional “blueprints” written in the DNA get translated into protein (through an RNA intermediate, which we will neglect for the purpose of this article). Proteins are the functional agents that make biology go, and they are also functional tools that scientists need to do biological research. In a way, this is analogous to “compiling” a software program. The important difference to software, however, is that once “compiled,” proteins are a dead end. If you have only a protein, but you’re denied access to the DNA coding for it, then there is no known way to make more of it, and there is no known way to turn it back into DNA.

What the Central Dogma allows is the sale of functional proteins that scientists can never make more of. By physical law, they’re required to come back for more, guaranteeing a steady stream of profits whenever someone wants to test a new idea. For good measure, a material transfer agreement is slapped onto these purchases, making sure that the scientist can never enter into commercial competition, even if she should ever get a hold of the DNA. Meanwhile the government keeps printing money and funnels it to the scientists by various routes to ensure they can afford the ongoing extortion. It’s an MBA’s paradise. A government-approved establishment scientist wouldn’t mind enough to cause real trouble either. But it’s killing the ability of self-funded individuals and startups to access biological resources that would be free, if they weren’t restricted.

But is this really happening? A casual observer of the field might be confused for a minute: at first glance, the Internet appears to be full of nonprofits purporting to “share biological resources” with names like ATCC or Addgene. They have DNA for sale, or cells containing DNA, and it’s not for a terrible amount of money. That’s true, until you try to order something from them. If you don’t have a university affilitation, you’re not even going to get an email back from these folks. And those readers who do have a university affiliation will remember getting inundated with 20 pages of material transfer agreements that have to be signed in blue ink and mailed around physically, because they’re just too important to leave to email. This is where you have to promise to never share the DNA with anyone and do everything in your power to prevent it from being used commercially. It is ironic, although perhaps unsurprising, that these nonprofit “resource sharing” entities have made themselves into the stalwart guardians of the closed-source reagent vending industry (see Figure 2-2).

The proprietary biologics vending industry protects its astronomical markups by guarding its self-renewing source of DNA by physical possession and through restrictive contracts with those willing to sign them.

The next wave of life-saving, economy-saving, and planet-saving biotechnologies is going to come from small teams of startup entrepreneurs with no access to any variety of “other people’s money,” as it always has. These fine folks need to be given unbureaucratic access to the basic tools to do their work.

Pricking the Bubble

The protections of the closed-source biologics vending industry are actually thin as paper and brittle as glass. For most of this stuff, they have no patents, no copyright, no government regulations, hardly a lobby to speak of, and no monopolies of any kind. They manage to lock biotechnology away from new entrants and to keep the cost of doing science in the stratosphere for establishment professionals, solely through the physical possession of the source DNA and by imposing contractual restrictions on those willing to sign them.

What if there was an alternative? What if there was a source of DNA, tested and certified for the production of high-value biological reagents, that does not impose any restrictions on how the DNA gets used? If this alternative was available, the existing closed-source system would become obsolete overnight. Different reagent production companies could snap up these DNA constructs and start competing on efficiency of gene expression and reagent production, rather than on efficiency in keeping secrets. The prices of biological reagents would collapse, and the quality would improve, as these characteristics take the place of corporate secrets as the main criteria for competitive success. The power of free-market capitalism (meaning the nonsecretive, noncrony kind) would finally be unleashed to tear down the barriers to biotechnology-based scientific wealth, as it has done with so many barriers before it (Figure 2-3).

Today I am delighted to announce that the pricking process has begun. I have synthesized, manufactured, tested, and fully validated a collection of open source plasmids coding for some of the very basic building blocks of biotechnology. I do charge an initial purchase price to pay for storage, ongoing quality control, and the provision of a reliable source of these molecules. But there is no proprietary barrier of any type on their use. You may grow them on your own, modify them, give them to others, sell them, sell products derived from them, and do whatever you (legally) want to do with them. I offer the following constructs today, and as of this writing am still the only one in the world offering for unlimited use:

• Expression plasmids for Taq polymerase, Pfu polymerase, and DNA ligase
• Plasmids for producing DNA ladders (size standards) for 100 bp, 1 kb, and mass standards
• Mammalian resistance plasmids (neo, hygro, puro, and blasti)

And this is only the beginning. I am first creating a basic suite of molecular tools. These tools are already supporting the creation of a second tier of tools with direct applications in regenerative medicine and industrial biotechnology. As more patents in these fields expire, open source stands ready to make all these wonderful tools available and accessible to anyone willing to use them.

I create the open source plasmids with with my private corporation Gene And Cell Technologies, of which I am the majority shareholder. There is no contract assigning the open source plasmids to the company. I have no corporate investors (although I do gratefully acknowledge a number of true “angel” investors, who all support my charitable open source mission; none of them required any restrictive paperwork). I do not know of any patents covering these plasmids or any of their elements, and do not believe them to be restricted by any form of intellectual property. My material transfer agreement (MTA) consists of a single line: “These plasmids may be used for any legal purpose.”

The first open source DNA construct was pOpenTaq, containing the DNA for Taq polymerase protein. Taq is the workhorse driving polymerase chain reaction (PCR), the “DNA copy machine,” which is an essential component of virtually every molecular laboratory. pOpenTaq is already enjoying great popularity throughout the world, as can be seen in Figure 2-4.

pOpenTaq is my open source Taq polymerase production plasmid, available for unrestricted use. It appears that people around the world are now using my first open source DNA construct and are talking about it in all kinds of languages. I have no idea what they’re saying, and I didn’t get paid for much of this, because they gave it to each other. But it cost me little to make it, and it makes me very happy to see that my first open source gift to the world is being appreciated and used.

I must acknowledge that not all of Gene And Cell Technologies is open source. The main purpose of the company is to support my own personal regenerative medicine research through supply chain integration. If and when I can afford to share one of the tools I create, then I will continue to offer it to the public on open source terms that combine doing good with doing well.

I would like to thank Dr. Justin Rebo for his valuable insights into the mechanics of the biotechnology industry and for working with me during the earliest stages of my adventures in open source biotechnology.