Drew Endy's lab at Stanford develops engineered DNA systems capable of storing data and computing inside living cells. He's also a co-founder of the BioBricks Foundation, an organization working to advance biological engineering openly so as to benefit all people and the planet. For his many efforts in open science, Endy was recognized earlier this year by the White House as a Champion of Change, a program created as part of President Barack Obama's Winning the Future Initiative.
Endy's team made news in March with a publication in Science describing the development of “transcriptors,” transistor-like digital genetic switches that enable cellular computing. These logic gates built from transcriptors are now available at Addgene through the Biobrick Public Agreement (BPA) Plasmid Collection along with a BIOFAB kit comprised of well-characterized bacterial transcription and translation initiation elements.
Open Science with BioBricks
The BioBrick Foundation's Linda Kahl explains the Addgene collaboration this way: "Addgene is one of the leaders in distributing plasmids amongst the academic community. On the BioBricks Foundation site, we have a collection of promises to not assert property rights for particular engineered genetic sequences; but it’s only the promises and associated sequence information. Addgene has partnered with the BioBricks Foundation to distribute the physical DNA samples, for when that's the preferred mode of receiving parts."
"We have found an amazing and valued partner in Addgene," Endy added. "The phrase we like to use is 'the parts must flow.' People must be able to use genetically encoded functions - the words in our language for programming life - and they should be free to use and used for good. It's wonderful to have Addgene as a professional public-benefit partner who shares our core values."
Addgene spoke with Endy more about the BIOFAB and BIL gates plasmid kits, the Biobricks Public Agreement, and the future of the bioeconomy.
Addgene: What do these BIOFAB and BIL gates kits – the first to be made available via Addgene and the BPA Plasmid Collection - enable?
Endy: The BIOFAB collection is the beginnings of what we think of as an operating system for engineering an entire cell. Typically when people use plasmids, they are trying to do one thing at a time. What the BioBricks Foundation is seeking to accomplish is to make the engineering of biology much easier. So you could imagine engineering the entirety of a cell. That's a big long-term technical challenge. We have a strategy that organizes how we start the work, and it begins with the central dogma - replication of DNA, transcription of DNA to make RNA, translation of RNA to make proteins. That's central to everything that goes on inside a cell. Until we get a handle on precise, forward engineering of the central dogma at the genome scale, it's going to be tricky to tame the rest of a cell.
The BIOFAB plasmids represent the first systematic collection of genetic parts for precisely forward-engineering the central dogma across many genes simultaneously. These parts have been carefully engineered to support reliable functional composition. In other words, these parts can be used over and over again in combination with novel genes to get very precise expression levels. The BIOFAB project is seeding the beginnings of an operating system for programming life, starting with the central dogma.
Addgene: And the BIL gates collection?
Endy: The Boolean Integrase Logic (BIL) gates collection of parts implements the basic logical functions, which we know and love. Boolean is in reference to George Boole who in 1854 was thinking about logic and analyzing human language and observed that we humans find it useful to describe and interact with the world using words like OR and AND. These logical operators are so useful they are implemented in most materials that have been engineered. For example, Boole’s logic shows up in mechanical systems, plumbing, computers, and now through BIL gates we've implemented them in DNA. We thought these were so much fun and so incredibly useful that we wanted to make them free to use by everybody. (For more on these tools and how they work, watch Endy's 10-minute YouTube primer on BIL gates.)
Addgene: Why is it so important to you that these parts be made freely available?
Endy: When we start thinking about languages, humans have two types of languages: one to communicate amongst each other, like this conversation we are having now is in English, and then there are languages to communicate with other things. These are programming languages like Java or Python. The question is who owns languages? Who owns English? Well, everybody does; it's free to use and that tends to be true about most successful human-to-human languages. Who owns computer-programming languages? That's trickier. Sometimes it's the developers. But, it turns out over time that the most successful computer languages are free to use. Of the 15 most popular computer programming languages, 12 out of 15 are free. Now, the BioBricks Foundation wants to develop a language for programming life. We can work backwards and say for this to be successful in the long term, if it's going to communicate between humans (i.e., our dreams and intentions) and the genetics and chemistry of life, then this new language needs to be free.
The Future of Synthetic Biology
Addgene: You've described the pieces in these kits as the beginnings of an operating system or language for programming life. Which pieces are still missing?
Endy: That's a great question. You can see that we have the beginning of control around the central dogma. We have the beginnings of computational logic and data storage. What we don't have are the keyboards and displays. We don't have good ways of converting typically invisible information into actionable signals. Let's say I wanted to detect every primary metabolite in a cell. The only way to do that at scale right now is to grow up a bunch of cells, sacrifice them all, blow them up, and slam that onto a mass spec. That's very time intensive and expensive. There's the promise that we could instead have things like peptide or RNA aptamers that act as genetically encoded sensors. Those sensors could transduce otherwise invisible molecules into regulation of gene expression including growth or fluorescence. There are a few examples of engineered RNA switches, but we've not yet seen the development of enough sensor domains. Ultimately, we'll need a couple thousand or so sensor domains for everything you could imagine. That I think is the next priority; we need the keyboards and displays for control and visualization.
Addgene: What do you envision for the future as this programming language is put into practice?
Endy: I think it's important to understand that these platforms, or pieces of a platform, that are now available exist within the context of the larger bioeconomy, and that it’s been 40 years since the invention of genetic engineering. What's incredible is the bioeconomy is already pretty substantial. It's estimated that genetic engineering as applied to products on the domestic market generates $300 billion dollars every year. That's two percent of the U.S. gross domestic product – equal to mining. There is an absolutely incredible hidden story here. The parts we are releasing simply plug into this existing economic activity. People are using BioBrick parts to make more materials: to make more fuel, to make more chemicals, to make more medicine. The parts we have right now are well adapted to work in prokaryotic bacteria, not in fungal systems or plants. We are really plugging into the "stuff sector" if you will, making chemicals and materials, and we anticipate plugging into the probiotic and cellular therapeutic space. If you were to look forward to the future of the bioeconomy it's less clear, but the way I'd leave it is mostly to the imagination. The question is: what can you use biology to make?
If you think about the BIOFAB collection and really dig into its engineering qualities, what these parts allow is for someone to forward engineer a system of 10 genes. You can now forward engineer a 10-gene system to do something. We know from our testing of these parts that the chance your genes will be expressed at the level you want is 93 percent. All of a sudden, for the first time, you've got a collection of reusable, off-the-shelf genetic elements that allow you to begin to imagine designing 10-gene systems with quantitative precision. There are few designers of biological systems today who are building 10-gene systems from scratch. (They may be building genomes, but that's just rebuilding existing genomes.) BIOFAB is laying down a challenge to its users and to the design community: If you can begin to reliably put together 10-gene systems, what do you want to make?
So, tell us readers, what do you want to make?
Jerome Bonnet et al. "Amplifying genetic logic gates." Science. 340, 599-603 (3 May 2013).
Vivek Mutalik et al. "Precise and reliable gene expression via standard transcription and translation initiation." Nature Methods. 10, 354-360 (10 March 2013).