Maybe you remember “the cell” from your high school biology book? A smooth, brownish blob, cut away to show the supposedly neat and orderly components, arranged just so.
It was an uncomplicated look inside the powerhouse of life itself. It was also not entirely accurate.
“That’s a caricature of what the cell really is,” said Eric Betzig, a group leader at the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Va. “The cell is this incredibly dynamic place where everything is moving — it’s all about kiss and run kind of stuff.”
Betzig, along with collaborators at six other institutions in the U.S. and Europe, has developed a new microscope that ditches the caricature, capturing the riotous action inside living cells. It does so in part by using a thin plane of laser light to illuminate cells within a subject — and a trick plucked from the stars to unscramble the light that comes back.
The result serves up visual treats, including:
White blood cells on a search, destroy, and tidying-up mission inside the inner ears of developing zebrafish embryos.
Human breast cancer cells, rolling like blood-borne tumbleweeds, commando-crawling through a tight vascular honeycomb, and jaggedly oozing though an opening in a vessel wall.
A cotton-candy-colored cavern of blooming neurons inside the developing spinal chord of a zebrafish. (You can glide through as neural projections, called axons, scuttle by your feet in both directions, and cell bodies bob and sway above your head like festive party balloons.)
Betzig’s research is outlined in a new study, published Thursday in the journal Science. An engineer by training, he said the research was inspired by a “very low attention span” for his own microscopes.
“Pretty much every microscope I do is in answer to my acknowledgement of the limitations and the frustrations that I had with the last microscope I did,” he said. (Betzig shared the Nobel Prize in chemistry in 2014 for a microscope he’s already mostly moved on from.)
The new microscope, called a lattice light sheet microscope with adaptive optics, has solved for most of those frustrations.
“It’s an amazing achievement and something that Eric has been targeting,” said Catherine Galbraith, an associate professor at Oregon Health and Science University, who was not involved in the research, but who has worked with Betzig in the past.
The thin plane of laser light is useful in illuminating living cells because concentrated light is fast and gentle enough to capture action without cooking cell innards, while also helping to preserve the fluorescent dyes used to label structures within the cell.
That lattice-light sheet alone can’t see very far beyond the very surface of a cell, however. “If you look at any depth inside of anything like the zebrafish or something like that, it’s too turbid to see,” said Betzig. “It’s just a mess.”
To deal with that inner mess, the researchers used a technique inspired by the distant stars. Astronomers use something called “adaptive optics” to cancel out the visual distortions of our turbulent atmosphere. They harness a “guide star” (a bright, nearby star or an artificial laser shot skyward) as a predictable reference point.
Scan laser guide stars into a specimen, and you have a way to track and de-mess the light’s bends and twists as it moves through living tissues.
Betzig described first seeing cells with only the lattice sheet technology in 2014 as “watching a lion in a zoo.” With the new, combined scope, he’s now “watching the lion on the savanna.”
Galbraith takes the metaphor even further: “You’re not just watching it on the savanna, you’re lying in wait on the savanna to see what actually happens.” She said that for microscopists, the fundamental challenge has always been to observe and not disturb, and that the new microscope goes a long way toward doing that.
The next step is making more than one working version of it.
“When you see these movies, you just say, ‘Oh my goodness, I want to study this,’” said Jennifer Lippincott-Schwartz, a senior group leader at Janelia and a colleague of Betzig’s. “But a key aspect of whether it will be embraced, is how quickly people can have access to these microscopes.” She added: “They’re not easy to build.”
Betzig is working to commercialize the technology in the coming years, but he fears that even if there was a version a scientific lab or a pharmaceutical company could buy, there would still be a big data problem. The microscope doesn’t just spit out pretty video ready for posting to your favorite science social media account. What you get out of the machine is an unholy pile of flat images that need to be laboriously re-stacked through space and time.
Once you get through the pain and anguish of doing that, the slow reveal, said Betzig, blows away the researchers he’s working with, without fail. But many are left “crying a month later when they don’t know how to deal with 10 terabytes of data.”
He’s trying to solve that data problem with his feet. This summer Betzig will move his lab to the University of California, Berkeley, in part to try to tap local tech expertise.
“I’m going everywhere through the Bay Area banging the drum, trying to marshal troops together to work on it because, face it, and I’m just too goddamned old to solve the problem myself.”
If he doesn’t succeed? Betzig is toying with the idea of harnessing his microscope to create salable art in his retirement. Think George W. Bush, the oil painter, just with lasers and tissue samples.
