Various scientists around the world are trying to build cells from scratch. Marileen Dogterom has been piecing together a cytoskeleton in the Netherlands. Kate Adamala is attaching receptors to a lipid bilayer in Minnesota. And Tetsuya Yomo built RNA that can evolve like the real thing in Japan.
But by and large they’ve been working independently on different cell parts. Now, a growing number of collaborations are melding these efforts together and speeding progress toward an audacious goal: building a living cell out of non-living molecules.
It’s an idea that’s been bandied about for decades, but scientists say recent technological advances have rendered viable what was once a pipe dream. A cell constructed from the ground up would let researchers better test drugs, enable bioengineers to build the next generation of cellular machines, and help biologists answer the fundamental question: What does it mean to be alive?
And funders and university administrators are increasingly backing such a goal. A 25 million euro Dutch project across six universities to work on building a synthetic cell is kicking off in September. A second collaboration, this one spanning multiple European universities, met in July at a German castle and is thinking about applying for a 1 billion euro grant toward the same purpose. And in the U.S., a motley crew of undergrads and legendary genetic engineers met this week at Caltech to jumpstart a project they call “Build-A-Cell.”
These efforts are all driving toward a common purpose: constructing organisms that have some properties of cells, such as the ability to divide and pass on information to their offspring. Scientists can also customize these new creations, building cells to do things that might not occur in nature.
But perhaps most interestingly, they might build something that meets our definition of “alive” but looks nothing like existing cells — perhaps it has a different information storage molecule than DNA, or it is enclosed not by lipids but by proteins. Creating and studying such a thing might help answer the basic question of what it means for something to be alive.
Top-down and bottom-up
Earlier this year, researchers at the J. Craig Venter Institute announced that they had created a minimal bacterial cell — a Mycoplasma bacteria that contained just enough genes to stay alive. That number is 473. Snip one more gene off, and the bacteria won’t work properly. Add an extra gene, and now the bacteria is carrying unnecessary baggage. But, at the time of the study’s publication, the scientists only knew the function that 324 those genes actually served. The remaining 149 did something to keep the cell chugging along, but scientists don’t know what.
This “top-down” approach — starting with an object in nature and shaving off bits and pieces until you arrive at what is fundamental to that form of life — has gotten scientists pretty far, but has left them with a handful of genes they know are necessary but whose specific functions are unclear. A complementary method would be to construct a cell “bottom up” from constituent parts — a mitochondrion here, some ribosomes there — ensuring that you know exactly what you were putting into the cell and what purpose it serves.
Those efforts are still in their early days. Individual research teams are making progress on the components, but, up until a few weeks ago, there weren’t large collaborations to put those parts together or direct the research efforts. But recent advances in genome synthesis technologies make a large-scale project more feasible now than ever before, scientists say.
Dogterom is taking on the cytoskeleton, a project that started 20 years ago while she was a postdoctoral researcher at Bell Labs in Murray Hill, New Jersey. Back then, it was just basic science. But over the past ten years, she became more interested in the idea of her cytoskeleton fitting into a complete synthetic cell. And now, as a professor of bionanoscience at TU Delft in the Netherlands, Dogterom is one of the lead scientists on the 25 million euro collaboration.
The cytoskeleton is a cell’s scaffold, arranging elements and keeping them in the right place. And when cells divide, the cytoskeleton plays a fundamental role, grabbing onto the DNA and pulling half into one of the new cells and half into another.
Dogterom is focusing on a specific part of the cytoskeleton: the microtubules, which are tiny, hollow tubes formed by proteins called tubulin. Dogterom constructed bundles of microtubules and is making them mimic real-life cellular structures that arrange DNA in a cell during the process of cell division.
To do this, she put these tubulin bundles inside of lipid-encased water droplets — basic compartments that model cells — and coaxed them to position themselves on opposite ends of the droplet, as if they were lining up DNA in preparation for a cell to divide.
Dogterom said that her next step is to move the microtubule bundles into a formation that mimics what happens in real cells when the cytoskeleton pulls apart the DNA.
So far, Dogterom’s microtubules don’t really come from scratch — they’re formed from tubulin proteins derived from pig brains. Tubulin proteins assemble themselves into 13-sided prisms — the microtubule structure — when left unattended.
Eventually, she’d like an artificial cell to be able to create these proteins on its own. That’s one of the major challenges and future directions for the field, she said — building DNA systems that print out proteins like tubulin, but also the other components of a cell, so that the artificial cells will build themselves from the bottom up.
Life from outer space?
Trying to make cells from their basic building blocks, without limiting oneself to how those blocks happen to be arranged on Earth, might also help scientists identify extraterrestrial life, said Adamala, an assistant biology professor at the University of Minnesota.
“When we go out to different bodies in the solar system, we are going to find something,” Adamala said. “We need to know, what are the criteria that define life? If we find something on Europa — [has this] been alive or not?”
Of course, NASA has a working definition for life — “a self-sustaining chemical system capable of Darwinian evolution” — but that only describes the life we happen to have on Earth. Some scientists would add to that definition that living organisms must be able to maintain a stable internal environment that is different from the external environment, for instance in temperature or concentrations of chemicals. But not everyone agrees, Adamala said.
“We need to know, what are the criteria that define life? If we find something on Europa — [has this] been alive or not?”
Kate Adamala, University of Minnesota assistant biology professor
Adamala said she thought this would be a big topic of discussion at the Build-A-Cell meeting she attended earlier this week at Caltech.
“I would love to come out with a consensus definition of life, but that’s not going to happen,” Adamala chuckled. But, she said, the participants agreed that they don’t need to answer this age-old question before moving forward. The engineering will progress while the existential questions run as background processes, because scientists who disagree about whether the synthetic cells are alive still need the same tools to build them.
Yomo, a professor at East China Normal University, echoed a similar sentiment: “[To] synthesize the life is more easier than understanding it.”
Biohackers of the world, unite!
There are definite dead ends on the road ahead. For instance, scientists might run into a similar challenge as the necessary genes with unknown functions: necessary functions that don’t have a clear genetic cause. Scientists might put everything they think is necessary into a cell, only to watch it sit there like the blob that it is.
“You think you’ve added everything you need to make a cell, but it doesn’t work, and you don’t know what to add,” Endy said. “It’s a foreseeable showstopper, basically.”
However it could also be a learning moment — figuring out why a stunted synthetic cell doesn’t divide like a real one, for instance, would tell us more about how the real one does its magic.
One motivation for the European group, said Dogterom, who was one was one of about 40 scientists and policymakers who gathered at a castle near Munich this month to discuss the efforts, is to “get a much better fundamental understanding of what is the difference between a collection of molecules and something we would call a life.”
Drew Endy, a Stanford bioengineering professor who convened the Build-A-Cell meeting, has a slightly grander vision. The ability to build cells, he said, could transform the fabric of society by democratizing the means of production. Cells are tiny factories that can produce goods, but can also make copies of themselves. They can exist anywhere on the planet that supports life. Properly engineered, they could rearrange matter in a myriad of ways, potentially replacing heavy manufacturing and factory-based production that currently concentrates power in the hands of the rich few.
“What are the means of production that are relevant to the 21st century, and what does it mean to apply [those] so that people can be citizens of the future as opposed to oppressed consumers?” Endy asked.
Endy is keeping this broader goal in mind from the beginning, setting up open structures that facilitate open discussion — a publicly available Slack channel and freely accessible Google documents. Endy is also forming partnerships with companies that produce synthetic DNA to allow researchers to acquire genetic material for free for any purpose, not just building new cells.
The BioBricks Foundation, a nonprofit of which Endy was one of the founders, announced last month an agreement with Twist Bioscience (TWST), a gene synthesis company, to give away copies of 10,000 different genes, the selection of which will be determined by online voting.
Synthesized genes can be subject to restrictive usage agreements — it might be forbidden to sell them, or to give them away. Not so for these 10,000 genes.
Endy said that the genes will be free — “free as a beer (i.e., no cost)” and also “free as in freedom (i.e., no encumbrance).”
The hope: that the burgeoning field of biological engineering proceeds in a free, open, and collaborative manner, available to the general public, and maybe, just maybe, restructuring society in the process.
Correction: A previous version of this story misstated the location of the Build-A-Cell meeting.