A milestone in cell biology! A database of 200,000 cell images to understand our cellular building blocks

A division of the Allen Institute, the Allen Institute for Cell Science, produced a digital description of the internal organization of human cells by processing hundreds of thousands of high-resolution images — a biological concept
that has so far been very difficult to quantify.
Through this work, the scientists also captured the details of rich changes in cell shape, even in genetically identical cells
grown under the same conditions.
The team describes their work
in a paper published today in the journal Nature.

"The way cells are organized tells us what they behave and who they are," said Susanne Rafelski, Ph.
D.
, associate director of the Allen Institute for Cell Science, who led the study with senior scientist Matheus Viana, PhD.
"While we're all trying to understand how cells change in health and disease, what is missing in this field is a rigorous approach to dealing with that tissue
.
" We have not yet exploited this information
.
"This study provides a roadmap
for biologists to understand the organization of different types of cells in a measurable, quantitative way.
It also sheds light on some key organizational principles of the cells studied by the Allen Institute team, known as human induced pluripotent stem cells
.

Understanding how cells organize themselves under healthy conditions — and the various variants contained under "normal" conditions — could help scientists better understand the problems
that arise in disease.
The image datasets, genetically engineered stem cells, and code involved in the study are all publicly available for use by other scientists in the community
.

"Part of what makes cell biology seem difficult to deal with is that every cell looks different, even if they're the same type of cell
.
This study from the Allen Institute shows that this variability that has long plagued the field is actually an opportunity to study the rules of cell combination," said
Dr.
Wallace Marshall, professor of biochemistry and biophysics at UCSF and member of the Allen Cell Science Scientific Advisory Board.
"This method can be generalized to almost any cell, and I expect many other cells to follow the same approach
.
"

Calculate the pear shape of the cell

In a work that began more than seven years ago, the Allen Institute team first constructed a group of genetically engineered stem cells that could illuminate different internal structures
under a fluorescence microscope.
The scientists mastered cell lines that labeled 25 individual structures and then captured high-resolution 3D images
of more than 200,000 different cells.

All to ask a deceptively simple question: How do our cells organize their interiors?

It turns out that getting answers is really complicated
.
Imagine having hundreds of different pieces of furniture in your office, all of which need to be easily accessible, and many of them need to move or interact
freely according to their respective tasks.
Now imagine that your office is a liquid capsule wrapped in a layer of film, and many of those hundreds of pieces of furniture are even smaller liquid bags
.
It's an interior design nightmare
.

Scientists wonder: How do all these tiny cellular structures line up with each other? For example, is "Structure A" always in the same place, or is it random?

The team encountered challenges
in comparing the same structure of two different cells.
Although the cells studied were genetically identical and cultured in the same laboratory environment, their shapes differed
considerably.
The scientists realized that if one cell was short and spotted and the other was long and pear-shaped, it would be impossible to compare the location of
structure A in two different cells.
So they marked the numbers
on those short and stubby spots and slender pears.

Through computational analysis, the team developed what they call "shape space," which objectively describes the external shape
of each stem cell.
This shape space includes shape variations in eight different dimensions, such as height, volume, elongation, and aptly described "pear-shaped" and "bean-shaped"
.
Scientists can then compare pears to pears (or beans and beans) to observe the structural organization
of cells within all similarly shaped cells.

"We know that in biology, shape and function are interconnected, and understanding the shape of cells is important
to understand the function of cells," Viana said.
We came up with a framework that allows us to measure the shape of cells, and when you do that, you can find cells that are similar in shape, and then you can look inside those cells and see how everything is arranged
.
”

Strict organization

When they looked at the locations of these 25 highlighted structures, comparing them in groups of similarly shaped cells, they found that all of the cells opened shop
in very similar ways.
Despite the huge differences in cell shape, their internal tissues are surprisingly consistent
.
If you look at how thousands of white-collar workers in high-rise office buildings are furnished, it's as if everyone has their desk right in the center of the office and the filing cabinet right in the leftmost corner, regardless of the size or shape of the office
.
Now suppose you find an office with filing cabinets thrown on the floor and documents scattered all over the floor – this might tell you something about
that particular office and its owner.

The same goes for
cells.
Spotting deviations from the normal state could provide scientists with important information about how cells change when they go from quiescence to movement, ready to divide, or what went wrong
with a disease at the microscopic level.
The researchers looked at two changes in their dataset — cells at the edge of cell colonies, and cells that were dividing to produce new daughter cells, a process known as mitosis
.
In both states, scientists were able to spot changes
in internal tissues associated with different environments or activities of cells.

Dr Ru Gunawardane, Executive Director of the Allen Institute for Cell Science, said: "This study brings together everything
we have done at the Allen Institute for Cell Science since the Institute's inception.
We built all of this from scratch, including metrics
to measure and compare different aspects of how cells are organized.
I'm really excited that we and others in the community can now build on that to ask questions
about cell biology that we've never asked before.
”