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01.28.20 - Transformational Tools

The test tube on the left holds a mouse brain before tissue cleaning.
On the right, after the process is complete, the tissue is nearly invisible.

 

When an ambitious UC Irvine graduate student decided on a doctoral research project, he and his adviser realized the necessary instrumentation wasn’t available on campus. So they built it themselves – or at least part of it.  Their efforts resulted in Translucence Biosystems, one of the newest tenants in CALIT2’s TechPortal incubator.

Translucence seeks to transform the study of cellular structures in animal tissue – a field known as molecular histology – by offering tools, software, assays and data processing services that open the door a little wider to a cutting-edge methodology.

The company’s premier product is a novel chamber that attaches to a Zeiss lightsheet microscope. The chamber allows researchers to view intact, large tissue samples at the cellular level at high resolution, something they could not do before.  Manufacturing and selling the chambers is just one aspect of the new company’s business, however. Translucence offers its clients a complete package of specimen analysis, including tissue clearing, 3D imaging and data processing.
To understand the company, one has to understand its origins. In 2016, Ricardo Azevedo entered UCI’s  M.D./Ph.D. program. He and his adviser, neurology and behavior Associate Professor Sunil Gandhi, were discussing research projects involving tissue-clearing, a chemical technique that allows biological tissue to be examined at the cellular level using a light microscope.

Fat in tissue does not allow light to pass through, so samples must be treated first. The tissue-clearing process chemically removes fat while leaving the proteins intact in order to homogenize the refractive index – how light bends as it enters the tissue. These steps render the tissue optically transparent, allowing researchers to view an entire sample in a specialized tool called a lightsheet microscope.

The process is groundbreaking. For centuries, scientists who wanted to examine tissue at the cellular level had to shave it into thin slices, affix those slices to slides, stain or otherwise treat each sample, then reconstruct the images into a three-dimensional model for analysis. The method is laborious and expensive, and severely limits the amount of information available. Until several years ago, it was the only way to examine tissue at the cellular level.

Azevedo had experience with tissue clearing, having helped to develop the technology as a research assistant at Rockefeller University in New York City. But UCI didn’t have the right microscope, so Azevedo and Gandhi traveled to Caltech in Pasadena to use its Zeiss lightsheet microscope. When they returned, Gandhi proposed that UCI purchase a lightsheet microscope of its own.
That led to a dilemma. There were two competing brands available, each with distinct advantages and disadvantages. The Zeiss brand, which could easily image very small organisms like fruit fly embryos and tiny fish, had higher resolution and better optics than its competitor, which could accommodate larger tissue samples but at lower resolution.

“In theory, the Zeiss microscope is a better microscope,” says Translucence CEO Damian Wheeler. “But it doesn’t work very well as it comes out of the box for large tissue samples.”

So Azevedo and Gandhi decided to design an adjustable chamber, which attaches to Zeiss’ Lightsheet Z.1 microscope and can hold larger tissue samples, like biopsies or mouse brains. They succeeded, and along with CEO Wheeler, incorporated Translucence in August 2018.

Says Azevedo: “That back and forth between size and resolution kept coming up. And the best solution was the Zeiss microscope and creating the attachment.”

The company moved into TechPortal last January. “TechPortal has been invaluable for us,” says Wheeler. “We’re largely self-funded, so this opportunity to have a space that helps us and is affordable has been amazing. It’s much better than my kitchen nook,” he adds, laughing.

In addition to its self-funding, the company has earned two SBIR grants totaling nearly $675,000 from the National Institute of Health’s Brain Initiative. Those funds enable continued research into cellular-level brain activity.
The company’s founders are all neuroscientists. So current research focuses on analyzing brain tissue, including neuroinflammation and neuronal activity. But brains are just the beginning for Translucence, which has four employees and is hiring more. Potential applications for its technologies include biopsies for cancer, kidney disease and other conditions, or for improving assays used to gauge clinical trials or aid in drug development. “We often talk about brains simply because we are neuroscientists but these techniques can be used on any tissue in the body,” Wheeler says.
 
With large pieces of tissue, the tissue-clearing approach to histology is orders-of-magnitude faster than slicing. “We can take a mouse brain that, using state-of-the-art technology from a couple of years ago, would take about a week to image, and we can image it now in as quickly as 20 minutes,” says Gandhi.

The real advantage, though, lies in the technology’s ability to image a tissue sample in its entirety, as opposed to one slice at a time. “It opens the ability to ask different questions,” Wheeler explains. “Because with the same effort you would have spent looking at two different areas, you can now look at 1200 different regions of the brain in parallel and find things you would never have seen before.”
The technique also allows for easy comparisons with living tissue. “This technology lets us link between the three-dimensional view we can get through live-imaging of animals and humans to the underlying cellular view,” Gandhi says.

Zeiss, an optical and optoelectronics company, initially balked at the idea of partnering with the startup. Before long though, the multinational conglomerate became an ardent supporter, helping Translucence promote its chamber to their lightsheet microscope customers.

“A growing group of researchers all over the world have chosen the Zeiss Lightsheet Z.1 system for its sensitivity, speed, ease of use and flexibility. We are happy that group will be able to further expand the flexibility of sample handling towards even larger and/or organic solvent-based cleared samples,” says Sven Terclavers, head of regional product and applications sales for Zeiss Research Microscopy Solutions. “The company always aims for scientists to be able to advance their research, and as this chamber extends the Lightsheet Z.1 system’s flexibility even more, I’m sure it will positively influence their research.”

That is proving true in UCI’s Optical Biology Core facility, which is using the new instrumentation. “Translucence’s technology adds a valuable component to the higher resolution and faster imaging of the Zeiss Lightsheet,” says Adeela Syed, developmental and cell biology associate project scientist and director of the facility. “The community within and out of UCI are very excited about the new chamber. We have more and more researchers wanting to try clearing and imaging because of images seen from Dr. Gandhi’s lab.”
More importantly, perhaps, the company is developing software, computational models and statistical methods that can extract important information from the reams of data – gigabytes to terabytes – that result from tissue analysis. “Our clients are thrilled about the data: it’s beautiful and very exciting,” Gandhi says of the 3D images their techniques capture. “But the big question is, how do we analyze it and make it into something that’s useful?”

Wheeler, Gandhi and Azevedo see Translucence leading a histology revolution. “Because whether it’s five or 10 or 20 years from now, someday there will be only 3D histology. No one will be slicing things to image them. We’re right at the forefront of that,” summarizes Wheeler.

-- Anna Lynn Spitzer