Most bioengineers will likely tell you the basic goal of those in the field is to make new, useful stuff — yeast imbued with the power to produce medicines, synthetic tissue to help repair injuries or burns, furniture made from the fibers of fungi, that sort of thing. Drew Endy, PhD, a bioengineer at Stanford University, has a different goal:
“To create a planetary-scale civilization that harnesses bioengineering to flourish in partnership with nature,” he said. “That, and a renewal of liberal democracy for the 21st century.”
Mushroom furniture be damned.
The aim of Endy’s bioengineering specialty, synthetic biology, is to refine the underlying fundamentals of life — like the genetic code — so that it is possible for more biotechnologies to be made real, including things that nature itself wouldn’t dream of. Put simply, one of the main goals of synthetic biology is to “make the making of things” easier, said Endy.
“We tend to think of biology as something that happens to us,” said Endy. “But more and more, we are happening to biology. We’re in an era, scientifically, where we can express our intentions into the very kernel of life to allow for possibilities that are simply never going to exist otherwise.”
Maybe that’s an organism that glows in the presence of poison; crops that are suited for harsh conditions; or cells engineered to seek and destroy tumors, only to self-destruct when the cancer is cleared. The idea is to enable new solutions to our world’s biggest problems — medical crises, environmental threats, humanitarian conundrums — through a means that would be infeasible through nature or improbable through more traditional laboratory techniques.
He hopes that in a few decades, biotechnology will emerge as a core pillar of society — not only as an economic powerhouse for supplying food, materials and medicines but as an intrinsic aspect of our culture. “I’m talking about a civilization in which we don’t think of biotechnology products as distinct but just a normal part of life because they’re everywhere and they work reliably.”
Endy’s current work ventures into a field of biology that’s still under construction, and he’s leading the effort to build the foundation by creating bioengineering-friendly organisms and systems that, quite literally, cannot fail. Every bioengineer’s dream.
A partner in biology
An engineer by training, Endy began dabbling in biology in the early 1990s, before synthetic biology came into its own. At the Massachusetts Institute of Technology, where he began his career, he helped launch the biological engineering major. Since coming to Stanford, where he is an associate professor of bioengineering, he’s been recognized by the White House for his contributions to open-source biotechnology and has made a name for himself as a synthetic biology pioneer and leader. But it’s not just the science that drives Endy.
“Drew is incredibly socially conscious,” said George Church, PhD, professor of genetics at Harvard University and a longtime colleague of Endy’s. “There’s a fairly small subset of engineers in each field who are not only hacking physics, chemistry and biology but are also doing so with social structures in mind. That’s Drew.”
“My greatest wish is that the culture surrounding bioengineering is one of love,” said Endy. If this came true, “all the good things that could be done in partnership with biology become possible.” Because at its core, said Endy, love between two entities (yes, in this case, society and bioengineering) often relies on trust and partnership.
In his efforts to manifest this vision, Endy has served on the National Science Advisory Board for Biosecurity and the National Academies of Sciences, Engineering, and Medicine’s Committee on Science, Technology and Law; he currently serves on the World Health Organization Advisory Committee on Variola Virus (Smallpox) Research and the International Union for the Conservation of Nature’s Synthetic Biology Task Force. He and others also founded a public-benefit charity, the BioBricks Foundation, the mission of which is “building with biology to benefit all people and the planet.”
It’s big talk — especially because Endy admits that even he is unsure whether scientists know enough about biology, specifically genetics, to build entirely new organisms. Most every organism, including humans, contains some DNA that’s basically useless; it serves no life-supporting function. It may be residual, left over from our ancestors, redundant or just a random genetic scribble. So, which are the vital bits?
The core of Endy’s team’s research explores taking away the guess work. The basic premise is twofold: first, parse the genetic elements critical to an organism’s survival, then use that information to create organisms built only from their “essential” parts. For scientists manipulating biology to print organs from scratch or to engineer drought-resistant crops, for example, that total understanding of a living system is a be-all-end-all goal.
“If you want to build an organism, you want to definitively know what you’re working with, and right now part of what bioengineers are working with is ambiguity,” he said.
What bioengineering really needs, according to Endy, is certainty as to which genes are needed for a particular organism to survive along with what each gene is doing. So, he’s working on that, aiming to establish a bare-bones version of a genome, which he’s dubbed a “cleanome.”
Establishing a cleanome for key organisms would allow bioengineers to build and create with more certainty and safety, he said. It could even support the adoption of bioengineering as common practice throughout society, but that’s a vision of a more-distant future.
To advance his ambitious idea, Endy started small — with a simple, well-studied, bacteria-infecting virus called phi-X174.
Scientists can tell where genes start and stop by looking at patterns in DNA sequences. But determining which genes are essential can be difficult. Strategies include looking across related species to spot conserved genes; searching for mutant (but still viable) versions of the organism to see how their gene patterns differ; and identifying evidence that the critical genes are making proteins.
The next step is to turn off those genes one by one, monitoring how the organism fares. If it can’t survive without the gene, the researchers deem the gene essential and mark it on the organism’s genomic annotation — the map charting significant elements along its DNA sequence.
“After that, most research moves on to asking what the obviously important genes do. But we’re saying, ‘Are we sure we’ve found and labeled everything that’s functional in the first place?’” Endy said. In 2017, the researchers in his lab took it upon themselves to answer that question for phi-X174 and found that its genome encodes up to 315 potential genes.
Gabrielle Dotson, an undergraduate researcher in Endy’s lab at the time, helped lead that effort. Their experiment involved building a new virus with only the 11 genes scientists had thought were functional. The idea was, if 11 genes are all phi-X174 needs, the cleaned-up virus should grow at the same rate as a normal phi-X174.
It did not: The cleaned-up phi-X174 grew at half the rate of the normal variant. So, something was missing from the annotation. The researchers discovered that “something” wasn’t a gene but a genetic modifier — a stretch of DNA that influences a gene’s activity. Without that modifier, the gene’s function was stunted. In variants that contained the modifier, the organism grew normally.
The team published a study in the Proceedings of the National Academy of Sciences in 2019 providing all the DNA details that make phi-X174 tick, creating what Endy believes is the first truly validated annotation of a genome.
“With our phi-X paper, we were trying to set up a new way of thinking, showing how the genetics of natural living systems can be formally completed by building the thing from scratch,” said Endy.
For years, living systems big and small have been repurposed for commercial use, like bacteria engineered to produce biofuels, said Dotson, who is pursuing her PhD at the University of Michigan, Ann Arbor.
“Applying this approach to get a complete genome annotation for organisms of interest could allow us to more rigorously redesign genomes for a new beneficial purpose,” she said. “This simple virus is a proof of principle that we can build off of as we start thinking about other more complex systems.”
Putting up (genetic) guard rails
The cleanome could provide bioengineers with the materials to more easily build new “synthetic friends,” as Endy puts it. But for every gas pedal, there must be brakes, so Endy and graduate student Jonathan Calles are pushing on yet another aspect of life’s foundations — evolution — but from an engineer’s perspective.
Conceptually, a fail-safe system could be a self-destruct button triggered when something goes wrong. Think of a rocket headed for the moon. If halfway into the stratosphere the rocket takes a sharp turn toward a big city, that’s a problem. The fail-safe system in the rocket flags the dangerous reroute and explodes the rocket midair, saving the town.
That’s what Endy and Calles want to do for synthetic organisms. This would be a crucial feature for say, cells engineered to seek out and attack tumor cells. You certainly wouldn’t want those cells to evolve inside a patient to have new cell-killing abilities.
“If we want to be practical and moral bioengineers, which we do, and we anticipate needing to deploy bioengineering to help solve the world’s problems, we need something that actively preserves whatever biological solution we’ve devised,” said Calles. In other words, you want whatever you’ve engineered to do exactly what you’ve built it to do and nothing more.
In all organisms, DNA serves as the instructive template for proteins; any changes to those instructions, or mutations, can change the resulting proteins. In nature, mutations are common, and some help organisms evolve with new adaptations to survive.
Other mutations reduce the organism’s fitness, and while one mutation might not bring down the whole organism, as more pile up, the organism is less likely to survive and pass on the changes it acquired. Because evolution depends on the passing on of newly acquired mutations, a fail-safe system would significantly slow evolution down.
In a fail-safe organism, the idea is to rejigger life’s underpinnings so that any and all mutations are inherently detrimental and thus leave the organism more susceptible to death.
“I have to qualify this by saying it’s kind of a crazy idea,” Endy said. “We’re quite literally exploring reconstructing biology’s central dogma to limit evolution.”
What’s in a fail-safe?
To understand how this fail-safe system should work — and why it could impede evolution — it may be helpful to put yourself in the shoes of a ribosome, a tiny machine that operates inside cells to make proteins.
As a ribosome, your job is to gobble up the amino acid molecules specified in your genetic instructions, link them together in the prescribed order and spit out the result: one of the organism’s many proteins. But you don’t work alone. You have a helper, and its name is transfer RNA. Transfer RNAs hunt down amino acids and hand them to you so that you can turn them into proteins.
Transfer RNAs pair with specific segments of your genetic instructions, called codons, which code for a given amino acid.
And just to make things nice and complicated, several codons can represent one amino acid — and there are almost as many types of transfer RNAs as there are codons. That’s how the natural biological system works.
In the fail-safe system, the team weeds out the transfer RNA genes so there’s only one transfer RNA per amino acid.
As a result, there’s only one viable instruction code per amino acid, and if a mutation occurs, it’s more than likely that no transfer RNA will be available to keep the protein-making process rolling. When that happens, the ribosome is stalled and can’t contribute to the cell’s life.
The idea is, the more mutations that accumulate, the more ribosomes will stall and the less likely the mutant cell will persist in a survival-of-the-fittest competition.
Endy’s team’s first fail-safe model was an engineered version of E. coli protein synthesis. Now, they’ve turned to the trusty phi-X174 to show how a fail-safe system would play out with a genome that has some complexities not found in other lab models — like genes that overlap.
Now, after two years, Calles and Endy are about halfway to making a fail-safe version of phi-X174. But if there’s one thing they know, it’s that there’s more than one way that evolution could evade a system meant to stall it.
“There’s this famous quip from evolutionary biologist Leslie Orgel: ‘Evolution is cleverer than you are,’” said Calles. “It keeps me up at night.”
The big picture
While the researchers spend most of their time mulling over molecules and toying with transfer RNAs, Endy keeps the grand vision: to empower the public to engineer biology in the same way they’re empowered to read and write.
To what end? It all comes back to partnership with nature, democracy and helping humanity flourish in synergy with biology and the planet. The key to a synthetic biology-fueled democracy, Endy said, is having the option to change biology yourself.
He draws on history to exemplify the idea. In the early 1800s, Thomas Jefferson wrote John Adams a letter about access to land ownership for citizens.
“They could have land to labor, from which they could derive a satisfactory livelihood and eventually retire,” said Endy. “This kind of option and access to a means of production is often a defense against political oppression — if the government or someone else is going to oppress me, but I can provide for myself elsewhere, I’ll just leave.”
Endy ponders what it means to have those sorts of options in the 21st century. The idea isn’t to create an upheaval of the global economy, where everyone engineers their own food and medicine.
“I still think the power of the market should be in full play. But I also think the option to access bioengineering capacities can be a safeguard against being exploited. Another way to think of this is as an intrinsic defense against monopolies.” It’s also a never-ending source of problem solving.
Endy hopes for a future for society that’s rooted in building a new kind of infrastructure in which it’s possible to “parts kit” genomes. As in, you could buy sets of genes or the cleanome version of organisms to build your own synthetic organisms.
In concrete terms, Endy sees bioengineering as a necessary staple of any society. So, it should be possible to design and make things like food, drugs and other bio-based solutions anywhere.
“That implies we’re going to have to implement a fully disaggregated workflow, where the DNA designs you come up with in one place operate reliably in another,” he said. “It also implies we’re going to need to fundamentally understand how biology works, through efforts like the cleanome, so that we’re not doing endless tinkering and testing but designing and deploying.”
It’s an ambitious, unwieldy vision. But he’s determined. Every email he sends ends in the same way. In place of a signature is a promise: “Our victory inevitable, our timing uncertain.”