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Bacteria are our unallied neighbors, which depending upon circumstances chooses to be our friend or foe. While bacteria such as E.coli have often been the workhorses for molecular biology studies, they have other uses as well. Surprisingly, they have enormous potential for cancer therapy. No, I am not talking about using bacteria as a factory to mass produce anticancer protein or DNA drugs (similar to how Insulin is produced today). Rather, I am going to discuss today how living bacteria can be engineered to develop cancer immunotherapies. This application is not a recent trend and its history dates the back to the late 1800s when a New York physician named Dr. Coley attempted to cure tumors using Streptococcus, a bacteria which is responsible for diseases like strep throat. However, his research with mixed results was lost to the rising prominence of other prominent anticancer treatment approaches like radiotherapy. In 1962, FDA removed bacterial therapy completely from approved medications due to lack of supporting evidence for bacterial therapy.
In recent years, there is a renewed excitement towards exploiting bacteria for cancer treatment. Various properties of bacteria make them very useful for this application. These properties such as the ability to move around relatively freely and migrate towards the tumor, and inherent potential to be toxic towards cancer cells when focused rightly can transform bacteria into cancer-killing machines. Allow me to elaborate it further.
Three key limitations of traditional chemotherapy are: being unspecific to cancer tissues, dependence on blood flow for delivery of the chemotherapy drug, and inability to penetrate the interior of solid tumors. Drugs are often packaged as capsules which are taken via the gastrointestinal route or they can be directly injected into the veins. However, the endpoint in both case is the bloodstream. With the flow of blood, the drugs circulate through the body and reach the target sites and affect the target tissues. However, there are two challenges with this “passive” approach. First, the cancer drug can quickly move away from the target without causing much damage. Second, they are unable to diffuse far inside the tumor tissue where a proper connection of blood vessels do not exist. Moreover, chemotherapy targets are seldomly unique. This means that they often have side-effects due to the interaction with non-cancerous tissues as well.
Bacterial therapy can navigate these inherent challenges of chemotherapy. Bacteria possess flagella, tiny lash like structures, which they use to drive their movement in a particular direction, often towards a nutrient source. This specific movement is called chemotaxis. However, they can be tuned to be attracted towards the tumor by following the concentration change of specific compounds only produced by cancer cells. Moreover, the intra-tumor environment is highly deprived of oxygen supply. This is because cancer cells grow very quickly, but blood circulation around them is often outpaced creating a shortage of oxygen. Bacteria that do not grow or live in presence of oxygen like Salmonella and Clostridium are attractive agents for anti-cancer therapy. They possess an additional natural capability to penetrate and inhabit inside the oxygen-deprived regions of the tumor. The bacteria can also be engineered to produce anti-tumor toxins. Many such toxins such as Cytolysin A, capable of disrupting cell membrane, and Tumor necrosis factor-alpha, a cell signaling protein involved in inflammation are inherently produced by bacteria. By using genetic engineering, we can design bacteria that can secrete desired drug molecules. This combined use of chemotactic guidance and anti-cancer toxin production is the basis for a targeted attack on cancer cells. By exploiting switches, a selective release of anti-cancer drug can be achieved within the tightly packed clusters of cancer cells. Thus, tumors can be bombed to death from inside.
Another way by which bacteria can aid in combating cancer is by helping in locating obscure tumors and metastases, tumor cells in secondary locations distant from the original site. Similar to the explanation above, bacteria can invade tumors tissues and colonize it. Instead of producing anti-toxins, bacteria can be used to illuminate cancers by the production of fluorescence proteins. Alternative strategies include detection using MRI and Positron Emission Tomography. These techniques can detect accumulation of bacteria by virtue of magnetic particle production and radio-labeled molecules. This detection can then assist in studying the development of cancer after the therapy and follow its migration to other parts of the body.
However, It has to be kept in mind that the original reason why bacterial therapy was shut down was due to the risks associated with it. These risks have not become irrelevant today either. Bio-engineering is complex and the evolution of bacteria in successive generations after release inside the body cannot be precisely determined in advance. Even the most well-understood bacteria E.coli, which is already found in human gut can cause medical ailments such as diarrhea and food poisoning. Also, bacteria can assist in tumor progression as well as by changing cell growth and triggering inflammation. Cancer is known to be driven by inflammation. To neutralize these threats, the advanced engineering of bacteria using synthetic biology is being explored to install a kill switch inside bacteria. These kill switches will activate alongside anti-tumor production and as soon as bacteria bomb the tumors and perform their role, they will self-destruct themselves.
The idea of developing these bio-bots is indeed enigmatic and perhaps will lead to better cancer treatment. This is a hallmark example of the “Age of Biology” where more and more unique biological systems are being built by infusing principles of engineering and design which have been tremendously useful in other areas of applied science. Whether these approaches will be effective and safe in human patients, and survive the test of modern regulatory standards, time will tell.
- Forbes, N. (2010). Engineering the perfect (bacterial) cancer therapy. Nature Reviews Cancer, 10(11), pp.785-794.
- Kramer, M., Masner, M., Ferreira, F. and Hoffman, R. (2018). Bacterial Therapy of Cancer: Promises, Limitations, and Insights for Future Directions. Frontiers in Microbiology
- Song, S., Vuai, M. and Zhong, M. (2018). The role of bacteria in cancer therapy – enemies in the past, but allies at present. Infectious Agents and Cancer, 13(1).