Exclusive: A New Way To Study The Miracle Of Life

Becoming speaks for the first time about growing a placenta

It’s one of those “only in San Francisco” moments.

You’re in the China Basin neighborhood and walk into an office building. You go past a door belonging to a moving company and another belonging to a finance company. You edge down a couple of hallways and walk past more offices of other sedate enterprises. Then, you get to the entrance of Becoming, open the door, and things go from bog-standard to bizarre and wonderful in an instant.

Becoming has desks where people work on laptops . . . sort of. Really, it has tables that have fought for their right to exist among an ever-encroaching morass of lab equipment and homemade scientific contraptions. There are soldering stations next to incubators next to gene sequencers next to optics setups on crates next to metal shelving racks packed full of centrifuge tubes and cell culture plates. The person most familiar with the nature of the chaos is the researcher sitting by the entrance who must lean back every time someone comes through the front door to avoid being compressed.

“We’re sticking into every little nook we can,” says Jack Cohen, the co-founder of Becoming. “Literally, every space.”

Becoming is bursting at the seams because it has been busy trying to build something groundbreaking - a new type of metabolic exchange system. Those words could apply to a lot of things, but, in this case, Becoming has found a way to grow and sustain a placenta outside of a body. Becoming uses this lab-grown placenta to nurture a mouse embryo, and it can observe what takes place as the embryo’s cells divide and grow. In other words, Becoming has engineered a new means of supporting the developmental process outside of the body and analyzing it in excruciating detail. In other, other words, Becoming can watch life unfold and perhaps do so for very long periods of time, and this could alter our understanding of the body in profound ways.

“No one has done this before,” says Cohen. “It’s not in the scientific literature.”

Scientists have, of course, been able to observe the development of mammalian embryos outside of the body for decades. We have simple devices like roller culture rotators that swirl around tubes full of living cells in a bid to keep the cells bathed in nutrients and oxygen as they try to grow. Such techniques have allowed researchers to keep mice embryos going for a few days.

Jack and Divya at their lab. The couple met at a startup accelerator because of course they did.

The trick, though, is that these systems then break down as they’re not able to provide the embryo with enough of what it needs in terms of nutrients and waste removal to keep growing. We can only watch how the miracle of life occurs up to a point.

About three years ago, Cohen and Divya Dhar Cohen – the co-founder and CEO of Becoming and Jack’s spouse – sensed an opportunity to advance the state-of-the-art with these developmental systems. Divya, a Kiwi medical doctor with a background in bio-tech start-ups, had been reading papers related to stem cell technology and saw researchers forming ever more complex cell models. They were taking single cells and growing them into clumps and coaxing them toward being full organs. Divya fixated on the placenta as being one of the most interesting organs to work on because of its role in supporting life and decided to see if it might be possible to create a full, functioning placenta outside of a body.

As luck and love would have it, Divya had married Jack, who has a PhD in physics from Oxford and happens to be quite adept at building complex scientific contraptions by hand. The couple raised money (they won’t disclose how much or from whom yet), hired some employees, found their office and set to work. They’re speaking about their company and technology for the first time here.

A MOUSE’S gestation period runs about 20 days. The placenta begins to form about midway through this process, as the embryo starts to search for more fuel.

“Most people think the placenta comes from the mum,” says Divya. “But it doesn’t. It comes from the embryo.

“The egg gets fertilized, and it has all the cells that it needs to maintain itself, including the placenta cells and the yolk sac cells, and obviously itself. Eventually, the placenta becomes the pathway to get more nutrients. So, the placenta attaches to the maternal environment to create this exchange of nutrients and gases.”

Becoming has, in effect, developed a way to replicate the maternal environment with a machine, or rather, a series of interlinked machines. On a metal rack in its office, Becoming has connected pumps, oxygenators, dialysis systems and containers full of liquids to each other via a series of tubes. Together, these mechanisms serve as lab-made replicas of human organs like the heart, lungs and kidneys. Their goal is to provide nutrients and expel waste. A series of sensors and computational models watch over what’s happening to make sure the chemical balance, temperature and other factors are at the right equilibrium to support ongoing development. The rack of gear then connects into a nearby incubator so that it can feed the embryo inside.

It’s this machine that has helped Becoming start to progress beyond the less sophisticated roller culture rotators that researchers have relied on for the last half century. (For the moment, Becoming is keeping the exact details of the fluids and other parts of its machine secret and declined to let us publish photos of the device.)

“The hardest thing is the homeostasis,” Divya says. “When something is growing, it’s very dynamic. It’s consuming things and producing waste. It’s taken us a couple of years, but we can now get that balance right. This has all become possible because of the plethora of cheap sensors available, advances in microfluidics and advances in artificial intelligence. Suddenly, you can combine these things and build homeostatic controls.”

Becoming still has much work ahead of it, but today, it’s revealing the most promising results from its tests with a mouse embryo. The company has produced images showing early placental cells growing and behaving normally outside of the body over the period of a few days. The cells move and fuse with the surrounding tissue just as they would during early stages of pregnancy. And this is a big deal.

Up to this point, scientists have learned how to keep embryos alive outside the body for short periods, and they’ve learned how to grow placental cells in isolation. What they haven’t been able to do is reliably watch the first steps of placental development unfold as part of a living embryo, under controlled laboratory conditions. In Becoming’s system, the cells that would typically form the placenta have started pushing outward and organizing themselves, while the rest of the embryo continues its work. It’s not a full placenta yet, but it does appear to be a biotech first that should help us watch how things become multicellular, complex organisms much longer than ever before.¹

“Development is the craziest process,” says Jack. “Every animal pretty much starts from one cell and is a ball of chemicals that then divides and divides and goes through this radical change in morphology and shape. And it does this pretty reliably every time. And we don’t know how that works.

“We don’t understand that process. We’ve been limited to a point where the placenta takes over. Now, we’re pushing beyond that point with this technology and can understand development further.”

The Becoming founders think they might have unlocked a host of major advances with their system. As Jack notes, they can learn more about one of life’s most amazing and crucial processes. In the bigger picture, the company has also now built a system that unites robotics, software and optics in a way that could be used to nurture and study all sorts of complex tissue. This, on the extreme end, could help with growing organ systems or, more simply, with watching how medicines interact with tissue over long periods of time.

Because its machine is so packed full of sensors and cameras and does things other developmental machines can’t, Becoming argues that it’s collecting new types of scientific data. It has built an AI model fed by data on how its machine works and how the cells develop, and the company believes that this model could, in turn, reveal fresh insights about how the human body developers and operates.

“If we think about current techniques like single cell genetic sequencing, scientists are measuring, say, a liver cell’s genetic state and then measuring it again a few hours to a few days later,” Jack says. “That’s cool, and you can see the effects of certain perturbations.

“But you’d also really like to understand development from a single cell all the way to a complex organism over a long time horizon – over days, weeks and months.”

The data and the model could get so good (again with the caveats that it’s very early days here) that Becoming might be able to create virtual versions of cells growing and dividing that allow for new forms of experiments based on much deeper knowledge of how the fundamental nature of life works. Becoming’s technology could perhaps be used to replace part of the animal testing process, follow disease progression in new ways and help with creating tissues for transplantation or developing longevity drugs. “We think we’re creating some really foundational technology,” Divya says.

In the months ahead, Becoming hopes to keep pushing the limits of its machine and to see if the placenta and embryo it’s supporting can grow for longer periods of time. The Cohens are convinced that they’ve already solved the major technical hurdles to pull this off, and that the rest is a matter of engineering.

“Our goal is to figure out what’s required to extend development beyond a single cell to a complex organism,” Divya says. “People have been trying to push this as far as possible for the last 50 years, but there’s been a limit. We’re saying now that we might be past that limit.”

1. It should be noted that Jacob Hanna's lab has done particularly impressive work here and pushed the limits of what’s possible with the roller culture methods. Becoming will also have to deal with immune and endrocrine system complexities in the months ahead.