Discover - USA (2020-01 & 2020-02)

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A Microscope That Sees DNA

BY KAREN WEINTRAUB

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Joshua Weinstein spent hours in

graduate school pulverizing zebrafish

in a blender. That was a normal first

step toward sequencing the fish’s genes, but

it had a high “ick” factor — and he felt like

it wasn’t very good science. Although his

results would tell him about the fish’s overall

genetic activity, they couldn’t reveal which

genes were present and active in different

places: like inside the fish’s immune tissue or

its nerves, or within a cancerous tumor. And

he wanted to know.

So Weinstein co-developed, and this year

unveiled, what he calls a DNA microscope.

It’s actually not a physical piece of lab equip-

ment, but a technique that allows research-

ers to examine precisely what genetic

activity is happening where. Although some

colleagues quibble with calling the devel-

opment a microscope, several agree that it

could offer profound new insights into how

cells function.

Je Lee, an assistant professor at Cold

Spring Harbor Laboratory on New York’s

Long Island, compares traditional gene

sequencing techniques to looking at the

ground from a satellite. You can see a lot

of detail, but you can’t see what’s going on

inside a shopping mall. Metaphorically, the

DNA microscope can, Lee says.

The “coolest thing” about the new

technique is that it allows scientists to see

gene activity deep within cells because

it doesn’t depend on the bright lights of a

traditional microscope, says Justin Crocker,

a synthetic developmental biologist at the

European Molecular Biology Laboratory

in Heidelberg, Germany. “This is the first

group to pull it off in a way that seems like

it actually worked.”

Theoretically, the approach could be

used to understand exactly what’s going on

inside a tumor — such as how many cells are

cancerous and how many more are likely to

turn dangerous. “That’s a real strength of the

technique,” Crocker says.

The technique works by assigning a

unique tag to every copy of a given active

gene across a tissue sample. These tagged

segments of DNA, keeping their spatial ori-

entation in the sample, are multiplied —

doubling every minute. The molecules

become so numerous that they spill out from

their origin points and bump into the tagged

bits of DNA overflowing from neighboring

cells. The tags grab onto one another, so the

DNA molecules pair up — creating a record

of which genes originated near each other.

Researchers then process this informa-

tion using a combination of DNA sequenc-

ing and artificial intelligence to generate

3D maps of which genes were active in the

sample, and where. This view could reveal

previously unseen spatial relationships

between genes across cells. CE

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With the new technology,

researchers can see gene activity

across a tissue sample at a

much higher resolution (B) than

was possible with old, optical

techniques (A).

Joshua

Weinstein

DNA microscopy

allows scientists

to look inside a

tissue sample

and map active

genes, color-

coded and in 3D.