Need a human organoid? DNA-guided 3D printing can now make you one

Researchers from the University of California, San Francisco (UCSF) have developed a new technique that allows them to precisely construct custom-designed miniature models of human tissues using what the school refers to as “the biological equivalent of Lego bricks.”

The method is known as DNA-programmed assembly of cells (DPAC), and as senior author Dr. Zev Gartner and his colleagues explained in Monday’s edition of the journal Nature Methods, it allows them to more precisely grow organoid-like tissues of pre-determined sizes, compositions, shapes, and spatial heterogeneity.

Thousands of custom-designed organoids can be produced using this technique, and they can be used as models of human mammary glands, each of which contain several hundred cells. These mini-tissues can be constructed in a manner of hours and enable scientists to study how specific structural features affect normal growth or are altered by cancer.

Furthermore, they could be used to test out potential new drugs or even enable scientists to create entirely new organs, the study authors said in a statement. Any type of cell can be used in DPAC, according to Dr. Gartner, and it will follow pre-determined cues to develop into tissues.

So how does this process work?

Researchers have at times struggled studying how the cells of complex tissues self-organize and make decisions as a unit, as well as how they break down due to disease, because it can be rather challenging to identify the specific cause of a certain cellular behavior. Cells grown in dishes, on the other hand, lack the realistic 3D structure of other cells, according to the authors.

By using DNA as part of their new technique, Dr. Gartner and his colleagues are able to produce simple tissue components that can be easily manipulated and studied. The DNA acts kind of like a Velcro-style fastener, bonding cells with complementary strands and making it possible for the scientists to use them like building blocks to create organoids for research.

“One of the key aspects of our approach to assembling tissues is using synthetic DNA strands to program physical interactions between cell,” Dr. Gartner explained to redOrbit via email. “Two complementary strands of DNA – one flavor on each cell surface – stick to one another” through Watson Crick base pairing, a process which involves hydrogen bonding patterns.

“We have multiple flavors of DNA that can direct multiple interactions between multiple cell types. The complementary DNA sequences are analogous to the male and female sides of a Lego brick,” he added. “However, unlike Legos, the cellular building blocks we use have a spherical shape and hundreds of thousands to millions of individual tiny DNA strands sticking out from its surface, much like the hairs on a tennis ball. Thus, the entire surface of the cell is sticky.”

This enables it to stick to the entire surface of another cell with a complementary DNA sequence on its surface, noted Dr. Gartner, a an associate professor of pharmaceutical chemistry at UCSF. The reason that this approach was selected, he said, was because it is “very mild, very specific and very rapid,” enabling them “keep our cells alive, position them with respect to one another with considerable accuracy, and do so quickly so that we can make complex tissues.”

Method could be used for drug screening, cancer research

As part of their research, the UCSF-led team used the technique to develop several different types of human tissues that served as proof-of-concept organoid arrays. In one experiment, they created arrays of mammary epithelial cells and investigated the impact of adding low levels of the cancer gene RasG12V to the cells around them.

They found that normal cells grew faster when an organoid with cells expressing RasG12V at a low level, but that more than one such cell was required to get this abnormal growth process to start. Furthermore, they learned that placing cells with low RasG12V expression at the end of a tube of normal cells allowed the mutant cells to branch and grow.

Dr. Gartner’s group plans to use the DPAC technique to study the cellular or structural changes in mammary glands that can cause tissues linked to tumors that metastasize to break down and spread to other parts of the body. They also plan to adapt what they discover from simple models to ultimately construct fully-functional human tissue, such as lung and kidney tissue.

“In the short term, we plan to explore the use of the arrays of organoid-like tissues we’re building for drug screening, cancer research, and basic science studies of development,” he told redOrbit. “Our long term goal is to figure out how tissues build themselves through the process of self-organization which is very different then the process that engineers use today to build non-living materials like cars, microchips, and buildings.”

“It is our strong feeling is that only when we understand how cells self-organize into tissues and organs will we truly be able to control those processes to engineer functional tissues and organs for transplant,” added Dr. Gartner added, whose team was also assisted by researchers from the Lawrence Berkeley National Laboratory.

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