Extraordinary Machines called Proteins

Dr. Doron Gerber’s eyes sparkle when discussing his favorite topic. “It’s all about proteins and DNA interactions - essential processes in any living organism”, explains Gerber. “Although there is so much we don’t know about proteins, one thing is for sure: They are truly amazing machines in the intricate ‘factory’ of the human cell”, he says.

Dr. Gerber is a faculty member at BIU's Mina and Everard Goodman Faculty of Life Sciences, and the BIU Institute for Nanotechnology and Advanced Materials (BINA) for 5 years now. After earning his post-doc at Stanford University, inspired by his mentor, he established a state-of-the-art research lab for applied microfluidics.

 “Recent knowledge from high-precision quantitative models offers a glimpse into this world of binding DNA and proteins”, he exclaims passionately, adding: “If we could only find out how proteins operate, we might be able to replicate their activity. This would require a bottom-up approach.”

“400 million people worldwide suffer from chronic Hepatitis B (HBV). Yet, after decades of searching for entry receptors of HBV pathogens, it’s still not clear to virologists how this virus enters liver cells,” says Gerber. “Other viruses as Ebola, Zika and SARS await new vaccines and therapies to be developed. Why do some viruses penetrate our body through the immune system, while others latch onto proteins and emerge later – this is still a mystery to us.”

Here’s something to think about the next time you get sick with a virus: We know that some viruses, such as the flu, infiltrate primarily by attacking healthy cells. Gerber explains that this could be related to binding affinities to certain proteins. “Once we understand how pathogens penetrate cells, and how they target host cell receptors,” he promises, “we could develop more drugs that will prevent cell entry. An example of such drugs that were already developed are drugs for treating HIV,” says Gerber. “They operate by inhibiting viral entry into a cell. The problem is that they take years to develop. If we had a tool that would make it easier to discover receptors and screen drugs, this could save a tremendous amount of time and money. That’s where micro-fluidics come in.”

“The micro-fluidic devices produced in our lab serve as highly-accurate research tools for studying proteins, gene regulation, and disease genetics,” says Gerber. “Scientists can perform thousands of experiments simultaneously and get results quickly”.

The devices, fabricated from polymeric organosilicon molds, each hosting a different experiment, look like miniature transparent plumbing systems. Quantities are controlled automatically through valves, feeding fluids to thousands of micron-sized channels. “We prime each channel with its own material, monitoring the production of proteins”, Gerber explains proudly. “A tiny chip in each device runs high-speed calculations of sequence and binding combinations.”

“Proteins that are located in biological environments are difficult to study. Protein arrays, also referred to as protein chips, are a fairly good solution, except that the proteins tend to dry up quickly, leaving only a small amount of active material to work with. Our devices generate functional protein arrays that accurately simulate complex protein interactions, requiring minimal amounts of fluid while eliminating ‘background noises’,” says Gerber.

“We use a DNA microarray that contains synthetic genes, to generate several thousands of human membrane proteins, which we place on a chip”, explains Gerber. “Next, we add a virus, and identify which host receptors – the protein elements in charge of binding to viruses - show high binding affinity to the virus.”

“As opposed to conventional methods which are tedious and inefficient, our technique enables the study of thousands of transmembrane proteins simultaneously. By doing so, we narrow dramatically the number of proteins that can potentially serve as cell receptors for a virus, reducing considerable time and costs involved”, he says.

His team recently designed a microfluidic chip containing a human membrane protein array (MPA). Adding two viruses - Simian virus 40, and hepatitis D virus - the objective was to search for host receptors that potentially bind with each of the two viruses. Pathogen interactions with the viruses, unknown previously, were observed and validated by conventional methods, confirming this powerful alternative in-vitro technique for studying receptors and pathogen growth, which will impact on future medicine.

Gerber hopes to advance personalized treatment of fatal diseases. “The problem is that tumors stop growing immediately when removed from the body,” he says. “My goal is to test tiny amounts of fluid taken from cancerous cells in a patient’s body, and within a few hours recommend the most suitable drug. This revolutionary approach is far cheaper than existing technologies, such as cell amplification and testing in immune-deficient mice”.

“We think that different binding speeds of proteins bare a certain significance, though we do not know for sure. The tools that are available are for researching fluids on a small scale. However, there are no tools for measuring binding paces of dozens of proteins in parallel, and running large scale comparisons. That’s why it has never been researched before,” says Dr. Gerber. “Our chip will be able to provide relevant binding information about proteins, using minimal quantities and applying the results to a larger scale,” he exclaims. Gerber is convinced that the more we advance our knowledge of proteins, the closer we get to reprogramming cells for treating future diseases.