I still remember the moment. That's something that I will never forget. The hair on my hands
just stood up. It's a microscopic universe within each cell. This is an unprecedented
view of the cellular world, where we can actually see immune cells scooping up sugars in the
ear of a zebrafish in real time. Focusing only on the crawling immune cells, we've noticed
two classes of them. One, it seems was not hungry at all, but it was very active in terms
of trying to figure out what the environment is. But there was another one that was slouching
around with a lot of food in its belly. We can actually conceptualize, visualize, and
analyze the contents of each of these cellular compartments in this crawling immune cell
as it's scooping up its environment. That is a level of detail no one's ever seen before.
We’re living in a new era of cell biology, where microscopy advancements are
giving biologists the opportunity to reveal the hidden patterns of cells. What we expect
to learn from here on out will transform our understanding of human health and rewrite
the textbooks on the fundamental unit of life.
For centuries, microscopes have illuminated
previously invisible worlds. We’ve learned how cells divide and even discovered the existence
of bacteria and microorganisms. These historical breakthroughs are often found in your typical
high school textbook. I fell in love with the cell and wanting to understand the cell
when I saw textbook images. I learned as I started studying the cell, that those are
vast simplifications of what those structures actually do and what's inside the cell. They
don't allow us to embrace the messiness and complexity in the cell. At research organizations like
the Allen Institute for Cell Science, biologists are taking a more integrated view to better
understand this complexity. So we at the Institute are trying to think of all the structures
of the cells in a holistic manner. If we don't understand which parts of the cell interact
with which other ones we won't ever be able to understand the true mode of action of a
drug, or perhaps where the side effects come from. It's that integrated knowledge of how
when you pull here, you move there, that allows us to understand the cell or the tissue or
the organism properly. And if you don't do that you're going to miss really important things.
In order to see the patterns that are actually happening in the cell in space
and time, we have to be able to image the cell well in space and time. New microscopy
is what's allowing us to image a cell in three dimensions, in their native context without
killing and hurting the cells, which is just absolutely needed
for us to just study the cell as it is. But seeing biological processes inside living
samples without harming them is easier said than done. One of the ways scientists image
these dynamics is with fluorescence microscopy. However, harsh light from this technique can
cause phototoxicity, meaning the cell can get sick during the imaging session. Lattice
light-sheet microscopy was invented a few years ago to correct for that challenge.
So it's a non-diffracting beam, meaning that as the beam is traversing through the sample,
it's not converging or diverging. We put several of these at very specific positions
such that you interfere every beam with itself and then create a very thin sheet of light.
This fine sheet of light repeatedly sweeps over a sample in order to avoid the damage
that’s typically associated with other microscopy techniques. The result builds a high resolution
3D movie depicting relatively undisturbed living cells functioning over time.
But tissues and other biological structures surrounding cells tend to scramble the light from the
microscope, resulting in blurriness. To compensate for this, the same team behind the lattice
light-sheet microscope borrowed a trick astronomers use to get clear views of distant stars - adaptive optics.
Just like how astronomers use lasers as “guide stars” to course correct blurriness
in telescopes, the process for looking at the infinitesimally small world of cells through
thick tissues and in living samples works in the same way. Using a laser guide, aberrations
that distort the light’s path are revealed and corrected by the microscope. There's
several examples where we've worked with some of the biologists, and showed them a few of
our samples. Their reactions have typically been, "Even though I've been studying this
for a decade, it's as if I'm looking at this for the first time." And that is always inspiring.
Even just talking about this is giving me goosebumps.
With such promising feedback from
biologists, Gokul and his team of instrumentation scientists and computational
experts are taking that technology one step further in a newly created imaging center
in Berkeley. This is unlike any microscope you may have seen in high school. Its purpose
is to shed light on molecular mechanisms that are either poorly understood or not understood
at all. MOSAIC is the Swiss army knife microscope, as we have called it during development. And
the reason we've called it the Swiss army knife is because when we were trying to miniaturize
the adaptive optics with lattice light sheet, we realized that all of the components that
go into building that microscope can be repurposed to build a completely different microscope.
MOSAIC combines about seven to 10 different imaging modalities into one microscope. You
can reconfigure or transform the microscope from one mode into another mode. Such that
you can interrogate your sample using different modalities.
We've imaged everything from live imaging, also everything that's dead as well.
Cells didn't evolve in isolation. Cells didn't evolve on a cover slip. The goal of this whole
project was to see, hey, can we create a tool that will allow biologists to be able to look
at their particular processes in a more physiological, more natural environment.
For you to have an effect in medicine and other fields, you need to understand to be able to perturb,
mitigate and or intervene, right? And that's basically what this is doing. This instrument
is going to be laying the groundwork in order to help understand
how a virus enters a cell. For instance, if you can understand
the mechanism by which it's fusing to the plasma membrane and then injecting
its contents into the cell, you now have the ability to intervene.
The team behind MOSAIC
has already built one instrument, and is in the process of bringing a second one online.
The next step will be opening up the instrument to biologists. Because the thing is we can
only get so far by ourselves. The goal is to make sure folks that have the ability to
have the impact, we want to make sure we break the barriers down. Whether it's access to
instrument time, whether it's access to computational resources or working with the computational biologists.
With tools like these soon coming online, biologists like Susanne are excited
about the next decade of cell biology. We basically have a little alien world that none
of us can wrap our minds around, and it's all of these technologies that are allowing
us to start to do that more intuitively. Imagine a world where you could look at a cell and
you know what it's doing, what it has done and what it will do. That means that you could
collect a pathological specimen, and without too much perturbation or staining collect
a whole bunch of information and features just from the image, that let a pathologist
know something about the prognosis of the disease and the mechanism of why that's the case.
There will of course be more and more innovation. That's always how it works, but
this set of innovation is going to get translated into useful results for everyone.
There's literally trillions of inanimate molecules inside of cells that work together somehow
to create life. That's basically what thousands of scientists around the world are trying
to understand is how life works. We want to watch the dynamics, the interplay between
these molecules in order to really understand the complexity, understand the beauty of what
is happening within the cells. Biology is probably one of the last human forefronts. It's
the age of exploration again, but instead of looking out at the galaxies, we're looking
at the galaxies inside of the cells.