If we were to photograph your living room every day at 7 pm, we would probably learn some interesting things about you. And what if we were to photograph the contents of your garbage can? What else might we learn? Prof. Yifat Merbl of the Weizmann Institute of Science does research into the garbage cans of human cells, and in the past few years she has found treasures there.
In an article published in "Nature," she and her research team describe an entire immune system that was previously unknown and is located in that part of the cell. Besides the innate immune system and the acquired immune system as we know them, there’s another arm.
Alongside the researchers in Prof. Merbl’s lab, research teams of Prof. Zvi Hayouka of the Hebrew University Faculty of Agriculture, Food and Environment; Prof. Nissan Yissachar of the Faculty of Life Sciences at Bar-Ilan University; and Prof. James Lowe of the University of Illinois in the US, participated in the research.
What Merbl calls "the cell’s garbage can" is the proteasome, a protein complex found in abundance in the cells of most organisms. For several years, Merbl and researchers in her lab have been studying it and its products, by methods that they developed and that have yielded many new discoveries.
"Originally, I didn’t research microbiology or microbes," Merbl told "Globes". "We researched how the products of the breakdown process in the proteasome changes in the case of a cancerous or auto-immune disease." The first surprise emerged a few years ago. "We discovered that not only are the products of the breakdown within the proteasome different from what they are in healthy tissue, but that the proteasome, the garbage can itself, is what changes."
How does that work?
"Here’s a garbage can, proteasome," she shows a magnified example of a molecule. "Aaron Ciechanover and Avram Hershko, researchers at the Technion who won the Nobel Prize, discovered that it has a kind of ‘cap’, a regulatory sub-unit that breaks down proteins that have stopped working.
"The breakdown of the proteins in the body has two functions: one is to turn the proteins back into usable building blocks; the other is to present the components to the immune system. When this change occurs, the second function doesn’t take place.
"We discovered that during a disease, another cap is formed for the proteasome, which causes them not to present the breakdown products to the immune system. That is in effect cancer’s escape mechanism from the immune system." This in itself was an exciting discovery that brought the team prestigious articles and awards.
How did you get from there to anti-microbial activity?
"We continued to research the breakdown products of the proteasome, and we identified products of the chopping up that appear time and again. We typed their sequences into scientific search engines, and suddenly discovered that these were sequences that had been identified by other researchers as having anti-microbial properties. At first we found one like this, two, three, 273!" These were substances that had been identified in the past, not all of them in human beings. Some were found to kill off microbes in lab samples, or to deal with microbes in flies, for example.
"Some of these substances had already been marked out in the past by scientists as options for the development of new antibiotics, but no-one knew that they were part of an orderly system within the proteasome that worked all the time to produce them for that purpose."
They were in the garbage can. Nobody looked there.
"We discovered that they were buried deeply within the protein, and could be released only if the protein was being broken down. So we looked among the products of the breakdown of proteins for more substances that were suitable in their structures for being anti-microbial, but were yet unknown to science. And we found lots of those as well. Hundreds of thousands."
A new mechanism for science
In the current research, a new, third cap was discovered for the proteasome. "When this cap appears on the proteasome, it cuts out from the proteins more pieces that look anti-microbial," Merbl says.
This cap appears when there’s an infection?
"That’s what we found. When we infected cells with a microbe, we saw a crazy change in the chopping process, such that many more sequences that seem to have anti-microbial properties appear. After that, we disabled the anti-microbial cap, and then infected the cell with microbes. We saw that when the cap isn’t available, there’s less ability to make the cuts that yield the anti-microbial sequences, and the microbes thrive. That part of the project was led by Karin Goldberg, a research student in the lab.
"After that, we put the microbes in a Petri dish with our chopped up proteins, and we saw that the sequences damage the microbe to a degree similar to known antibiotics. But if we put the whole protein together with the microbe, nothing happened. This is a mechanism that happens only through the mediation of the proteasome."
By now it’s clear that this is not coincidental. We seem to be looking at an immunity mechanism that is new to science, but very old in nature.
When Merbl and her team produced the sequences from the proteins and gave them to mice with a bacterial disease, they found that they could halt the reproduction of several kinds of bacteria, including hospital bacteria that are considered very problematic.
"So far, we have not succeeded in predicting exactly which sequence will kill which bacterium," says Merbl. That is a question for further research.
The tip of the research iceberg
Merbl is excited at the idea of these substances becoming antibiotics. "Combinations of several such substances could be very strong. And these are substances that the body recognizes. There’s a chance that they will be less damaging to healthy bodies."
Do these substances also damage desirable microbes in the body, as antibiotics do?
"We still don’t know for sure, but it would appear that there are microbes whose development in human beings over the years has caused them to raise a sort of flag that prevents these pieces of protein from dismembering them. It may be that, when a person nevertheless contracts a bacterial infection, it happens because bad bacteria imitate this escape mechanism."
It really does sometimes happen that we are ill with a bacterial infection, despite the fact that we have this amazing mechanism in our bodies.
"It’s possible that when an infection nevertheless arises, it happens because the dose of bacteria crosses a certain threshold beyond which we can’t cope with it, and then if we also add these substances from outside, or locally at the site of the infection, we’ll be able to help. It could also be that a person who suffers from immune system failure will benefit from the addition of substances from outside.
"We’re curious about the fact that not all the sequences attack the same bacteria. The next stage is mapping the substances and their efficacy against infections. We’d be glad to hear from research students who want to do this." There are more questions, says Merbl: "Perhaps there’s a similar mechanism for dealing with viruses and fungi as well? We are at the tip of the iceberg of understanding the function of proteasome in diseases."
Even before the publication of the "Nature" article, Merbl’s discoveries caused excitement in the biomed industry, and there even those who are betting on her for a Nobel Prize.
Published by Globes, Israel business news – en.globes.co.il – on March 9, 2025.
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