New “biological computer” targets cancer while sparing healthy cells

The holy grail of cancer drug targets is akin to a unicorn horn: a marker that only cancer cells have, clearly distinguishing them from healthy cells. In fact, almost all of the targets for cancer drugs are also found on many healthy cells, resulting in severe non-tumor toxicity which, in extreme scenarios, can be fatal.

Synthetic biologist Kobi Benenson might have a way around this. Inside a modified virus, he and his colleagues at ETH Zurich have packaged a programmable genetic circuitry that uses multiple targets to create the profile of a cancer cell. Detailed in a mouse study recently published in Science, it is a nanoscopic biological computer that travels around the body, running a program that seeks to recognize and kill cells that match this cancer profile, but spares the cells. healthy ones that do not meet all the criteria.

“[Simple drugs] it’s like trying to catch a criminal by saying ‘anyone who wears loose pants is a criminal’ or something, ”Benenson explained. “With this broad criterion, we will catch like 99% innocent. You really really have to be refined by combining several pieces of information. So it is the same with disease.

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The biological computer is a genetic circuit with designed molecular switches that can perform simple calculations, much like the silicon transistors in the heart of smartphones and laptops perform calculations. The Benenson circuit has two main components – an “AND” function and a “NOT” function – so the computer looks for cells that have a profile of two common molecules in cancer cells, but not a third that does not. is common only in healthy cells. This makes the computer more likely to accurately distinguish cancer cells from healthy cells.

“So we have this type of decision if A and B but not C,” Benenson said. “This ultimately results in the activation or absence of a therapy that can kill the cancer cell.”

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The “AND” function is made up of two molecular switches on the computer’s genetic circuitry that bind to designated cancer targets. For these targets, Benenson’s team used a protein common in liver cancer cells and another common protein in liver cells in general. If the first switch binds to its protein, it sends a molecular signal to the second switch. If the second switch also binds to its protein, the circuit forces the cell to create a new protein called HSV-TK. This combines with another compound, which must be injected separately, to kill the cell.

But healthy cells also carry these targets. So the team had a third molecular switch on the circuit recognize a compound known as let-7c, which is common in healthy cells but not cancer cells. If this switch binds to let-7c, it triggers a process that stops the computer’s kill command, thus preventing the cell from running.

Scientists have been working on biomolecular computers for years, said Wilson Wong, a biomedical engineer at Boston University who was not involved in the research. He called Benenson’s new genetic circuit a tour de force.

“It’s pretty well done – the culmination of at least 10 years of work,” Wong said.

The first feat was to compress the entire biological computer into the small engineered virus that delivers the circuitry into cells. “Putting everything within the virus size limit is no small feat,” Wong said. “You have to write a fancy program, but it only fits 2 megabytes of space. It’s like that.

This system opens up a whole new world of possible drug targets, Wong said. Most other cancer therapies only recognize targets that exist on the outer membranes of cells, but now microRNAs, proteins, and other intracellular molecules are available for engineering.

“The intracellular pathways were not drug-induced,” Wong said. “And now they are. It’s enormous.”

The other feat was to make the “NOT” function work, Wong said. Typically, cancer drugs only attack a cell when a target is present. This means that besides allowing biological computers like this to build safety switches, it still opens up a whole new way for drugs to recognize cancer cells.

“This ‘NO’ logic that they do is very, very unique thing, ”Wong said. “This means that when something is missing in a cancer cell, it attacks. No other drug can do it. If a cancer cell does not have a gene or a target, it is usually not drug-free. It’s in the trash right away, even if you know it makes cancer super unique. “

Once the team designed the biomolecular computer, they tested it in mice with liver cancer. In a group of mice, they injected the whole computer with both “AND” and “NOT” functions. Another group of mice received a partial genetic circuit that only had the “AND” function. These mice suffered toxic side effects, but the mice that received the full computer both saw their tumors disappear and were spared the toxicity.

“It was very nice to watch,” said Benenson.

This does not necessarily mean that the therapy will be safe and effective in humans, Wong warned.

“Sometimes a lot of targets are not expressed the same way in mouse models as they are in humans,” he said. “This is where things kind of fall apart. The question will be: “Do humans have the same profile as the tissues of mice?” We do not know.

The next step will be to refine the biomolecular targeting computer and possibly test it in humans. Benenson and his colleagues at ETH Zurich created a biotechnology called Pattern BioSciences to do this with this therapy and to develop other drugs.

“It makes sense to do this in a business,” Wong said. “If that was my job, I would also be doing a business. “