Eshel Ben-Jacob is taking cues from the collective intelligence of bacteria to learn how to interrupt communication between cancer cells. The physicist tells Madhumita Venkataramanan how this strategy could even turn the disease against itself
As a physicist, why are you studying cancer?
I study pattern formation in natural systems and have been promoting the idea of for three decades now. That began because, philosophically, I wanted to find the special difference between a non-living particle and a single-celled organism. And what I found is that these organisms can sense the environment, measure it, process information and use stored data to make a decision. They behave as a community.
I had been working on this for 20 years when I learned of alarming discoveries about cancer. It dawned on me that like bacteria, cancer behaves as a networked society of smart cells. To my delight, I realised we could make use of what I had encountered in social bacteria to better understand cancer.
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Your research into bacteria included the discovery of two new species. What is special about them?
These bacteria, Paenibacillus dendritiformis and , live in colonies, each about 100 times the size of the human population on Earth. So it is like a big globe with very . The messages are elaborate: if they encounter antibiotics or some other threat, they send a message to the centre of the colony and stop moving; if they encounter something positive, like food, they send the bacteria best at ingesting and degrading food ahead, so they can feed the whole colony more efficiently.
The other interesting thing is that they distribute tasks just like multicellular organisms and even engage in collective decision-making. I created a scoring system for the social IQ of bacteria and found that these species were three standard deviations higher than the median. In human-speak, people like Einstein show the equivalent score.
How did all of this remind you of cancer and the way it spreads?
People used to think cells in bacterial colonies were almost identical, but we have since found that they distribute tasks and differentiate. Similarly, in cancer, people assumed the primary tumour was monoclonal – that all cells were the same. Now we know that’s not the case: tumours are multi-clonal and the cells show a similar differentiation of task and function. It’s a programmed venture, not random mutations.
Were there other similarities between social bacteria and tumours?
When I looked closer, I found more things. Cancer can induce genetic changes in the cells around them – to make surrounding cells feed them, just as bacteria do. Studies have also shown that cancer cells do not settle in just any human tissue, but instead carefully choose and prepare new sites by sending out spy cells, which again is similar to the behaviour displayed by bacteria.
So cancer is “smart” just like bacterial colonies. How does it use its smarts to survive?
Here’s a concrete example. When you have a blood clot, a factor called thrombin is released in the blood. Cancer cells have receptors that can detect the presence of thrombin. This gives them a hint that if there is a clot now, there is likely to be a situation of hypoxia – a shortage of oxygen – in the future because the blood supply will be limited. So even before hypoxia develops, they prepare for it. They increase their level of reactive oxygen species and get ready to use oxygen in a more effective way. This means cancer can prepare for the future.
Drawing on these social aspects of cancer, you developed a theory about a new way to fight the disease. Tell me about that.
If the success of cancer is because it is a society of smart and highly communicating cells, then we can fight it by using the methods of cyberwar. In other words, temper the control and communication, and even send signals to confuse them. With chemotherapy, cancers can escape, regrow or even become resistant. Our idea is instead to shock and disrupt channels of communication, making it harder for cancers to spread and evolve resistance.
“If cancer is a complex society, we can fight it using methods of cyberwar”
What’s an example of how you could disrupt cancer’s communication channels?
You can use a targeted molecule to trigger the thrombin receptor on a tumour so the cancer starts preparing for hypoxia. Then put the person in a hyperbaric chamber with high levels of oxygen. To prepare for the oxygen shortage, the cancer will increase its reactive oxygen species. But when there are high levels of oxygen in the environment, this is toxic to the cell. So the cancer cells will be dead because of their own preparation.
You might also compel the cancer cells to destroy each other. I’ve studied the cannibalism phenomenon used by bacteria in sibling colonies to kill each other, and even cracked the communication code that drives this behaviour. It turns out that cancers, too, use cannibalism – engulfing adjacent cancer cells when they run out of resources. So it is possible to take advantage of the mechanism and drive them to consume each other.
In particular you focused on the way cancer spreads through the body, or metastasises. How does this happen?
We focused on cancer metastasis because over 90 per cent of people who die from cancer die because of metastasis. In cancer, you have a primary tumour and at some point its cells switch from epithelial – the type that lines cavities of the body, but stay put – to mesenchymal cells, the type that can migrate to new locations. They then switch back to epithelial cells, which create new outposts for the cancer in the body.
What do we know about the way cancer cells switch between states, to spread in the body?
Robert Weinberg and his team at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, among others, that during the transition from epithelial to mesenchymal, some cells become a hybrid, a chimera that has characteristics of both types of cells. And Sendurai Mani’s group at the MD Anderson Cancer Center in Houston, Texas, found that in this hybrid state , in that they can reprogram or differentiate into a different cell type. That means they have a chance to develop resistance to drugs.
What we found is that the circuit controlling this switch between types of cancer cell is coupled to many other circuits. We are studying that genetic network.
So how do cancer cells switch from one state to another?
The switch circuit in cancers is made of two genes, each coupled to a type of molecule known as microRNA, which plays a role in regulating how RNA molecules are translated into proteins. One gene-microRNA pair acts as a decision-maker, the other as an integrator of information, combining incoming signals.
We discovered something unique in cancers: the switch from one type of cell to another – from epithelial to mesenchymal – is not two-way but three-way. It has a state that is in between – which is when the cells are in a hybrid state. We succeeded in breaking the cancer decision code. It’s a whole new logic.
How can this be used to thwart cancer?
When the cells switch from epithelial to mesenchymal, they go through the hybrid state that helps them develop resistance. But when they transition back to epithelial cells, they don’t become hybrids again – it’s a direct transition. Looking at the operating principle of the switch means you can trick it. In other words, you might be able to prevent the cells from switching back. If they stay in mesenchymal state, they cannot create outposts and form metastases. If they stay in the epithelial state, they cannot move to new organs.
So, using this switch, could you reprogram cancer cells to make them harmless?
One of the things you can do is play with factors of the immune system, such as TGF-beta (transforming growth factor beta), which regulates the epithelial-mesenchymal switch. If you manipulate the levels of TGF-beta – which can be done using the widely used anti-diabetic drug Metformin – you can toggle the switch.
But the dream I have is to reprogram the cancer cells into benign or less aggressive cells, similar to how people have taken skin cells, say, and turned them into stem cells.
Are there other ways that our understanding of bacteria can help to tackle cancer?
Another fascinating direction is trying to use bacteria themselves to fight cancer. A group at the European Institute of Oncology in Milan, Italy, demonstrated that can recognise and specifically destroy malignant lymphoma cells by infecting them with toxic cargo. I am interested in studying the nanotechnology systems that deliver that toxic cargo to kill cancers. The underlying foundation of the parallels with bacteria mean that the bacteria themselves should be powerful smart troops to fight cancer.
Profile
Eshel Ben-Jacob is a physicist at Tel Aviv University, Israel, and a senior investigator at the at Rice University in Houston, Texas. He investigates complex systems such as pattern formation in social bacteria and metastatic cancer
This article appeared in print under the headline “Breaking cancer’s social network”
