Can bacteria be a cure?

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The applications of genetically modified bacteria can be countless including industrial processes, environmental remediation, and new drugs and therapies. This last application seems particularly paradoxical: Are bacteria able to cure diseases? How is that possible?

Bacteria are one of the smallest living organisms. They are ubiquitous and appear in enormous quantities. It is estimated that the mass of bacteria on Earth is at least five thousand times higher than the mass of all Homo sapiens! Over 90% of bacteria live in soil or in oceanic sediments.

For most of us, bacteria do not carry any positive connotations. We associate them, quite correctly, with such contagious diseases as the plague, tetanus, and tuberculosis. On the other hand, without bacteria, there would be no cheese, yogurt, wine, vinegar, or other products of the fermentation process that humans have used for thousands of years. Their practical importance and relatively simple structure make many species of bacteria the best and most fully known organisms. This knowledge includes the lifestyle, adaptations, and metabolic capabilities (such as the ability to produce antibiotics), as well as the genetic material of bacteria, which has already been fully catalogued for hundreds of species. Our understanding of the functioning of bacteria is extremely useful as it reveals new opportunities for the application of these microorganisms. It allows us to intentionally modify the genetics of bacteria through the introduction of beneficial properties and the elimination of unfavorable features.

Smart drug

Cancer is a type of disease in which bacteria may prove particularly useful. Although doctors have a wide range of treatment methods at their disposal, mainly based on chemo- and radiation therapy, the options still remain insufficient in too many cases.

The main task of the physician is to select a form of therapy that will vigorously attack cancer cells but do the least harm to the body's healthy cells. The problem is that these two types of cells do not differ in any clear way. While most therapies destroy tumors, they also damage other, healthy tissues. Another limitation of current treatments is their limited efficacy, or their inability to completely eliminate cancer cells. Even a small number of surviving cancer cells can initiate a recurrence of the disease. This is why oncology requires actions which are both powerful and precise. The explanation for the limited efficacy of "conventional" chemical drugs is complicated. One reason for their inability to completely eliminate cancer cells is that cancer is actually a complex and heterogeneous tissue which is difficult for drug molecules to penetrate; the therapeutic is passively distributed within the body, carried to tissues through the bloodstream, and then diffused into cells.

This is where bacteria can be of help. Their mobility is extremely useful as it overcomes the limitations related to the passive distribution of drugs within organisms. Bacteria can actively migrate from the bloodstream to tissues and penetrate into cells, thereby overcoming biological barriers on the way to the tumor. This property can be used for the transport of therapeutic proteins and genes into cancer cells. Thus, after penetrating a tumor, bacteria can play the role of a special agent or saboteur, destroying cancer from the inside or calling on the body's healthy cells for help.

The bacterial ability of chemotaxis, or to respond to chemical signals from the environment, is equally important. Appropriately selected strains move to the cancer tissue on their own, and their invasive capabilities (which make them so dangerous in contagious diseases) allow them to enter inside. Animal studies indicate that certain bacterial strains of the genus Salmonella are at least a thousand times more likely to accumulate in tumors than in healthy tissues. These strains were intentionally modified so that they would not produce the enzymes necessary for the synthesis of specific nutrients. This is why, after being introduced into the organism, bacteria prefer sites with rich sources of metabolites, such as cancer tissue. This is also where the bacteria find suitable living conditions. The combination of bacteria and cancer cells may stimulate the immune system to act, inducing an anti-cancer response. Moreover, the bacteria can multiply inside the tumor, thus increasing the power and efficiency of their activity.

fot. © Matej Kastelic |


How to make only the cancer "fall ill"

The unique environment that is formed inside the tumor may be another way of guiding the bacteria towards cancer cells. One of the important factors is the low concentration of oxygen resulting from the insufficient development of blood vessels inside a growing tumor. Spores of some bacteria of the genus Clostridium may grow only in anaerobic conditions. Thus, after administering them to a cancer patient, the bacteria will grow only deep inside the cancer tissue and it is only there where their pathogenic potential will develop.

What can be done if this potential turns out to be too strong? Fortunately, in such cases our knowledge about the genetics of bacteria and their predisposition to genetic modifications also proves useful. Appropriate modifications may result in the decreased virulence or limited pathogenic capability of bacterial strains so that these harmful attributes are directed only towards cancer cells. This process is called the attenuation of pathogenic strains and it enables us to create organisms that may be safely administered to patients without the risk of causing a general infection, as it is only the cancer that should "fall ill." However, should the therapeutic bacteria spread across the organism and become a threat, we may refer to the solution which has been known for almost a century — antibiotics. Susceptibility to antibiotics is an important advantage of bacterial therapies, as it allows us to control the "drug" even after administering it.

Bacterial cancer therapies are currently being developed by a number of research groups throughout the world, including a team of scientists at the Faculty of Biochemistry, Biophysics, and Biotechnology at the Jagiellonian University in Krakow. These studies are based on a Salmonella strain called VNP20009, which in mice has the ability to localize selectively in tumors and, at the same time, is safe for other tissues. Unfortunately, the hopes that the VNP20009 strain will act similarly in humans have not been confirmed. Clinical studies on patients carried out more than ten years ago proved that although the bacteria, even when administered intravenously, are harmless for people, their accumulation inside tumors is insufficient. "We believe that it can be changed. Our strategy is focusedon such modifications of the bacteria that force them to produce an antibody fragment on their surface, which, like a bombsight, will help the bacteria to hit the cancer cells," explains Dominik Czaplicki, PhD, a member of the research team. Targeting the tumor is not everything. Salmonella, as an intracellular parasite, is naturally capable of infecting and entering cells. Then, as a result of further genetic modifications, the bacteria can act like a Trojan horse, destroying the cancer cell with the use of its own mechanism of programmed cell death (so-called apoptosis). This is caused by a certain type of protein which is produced by the bacteria only after entering the infected cell. The protein brings a signal which releases a cascade of reactions leading to the self-destruction of the cell.

It is worth noting here that the aim of the treatment is not to completely remove tumors with bacteria, but rather to alarm the immune system and to stimulate it to produce a strong anticancer response. The danger signal, which is necessary to cause the alarm, results from the mere presence of bacteria, and the debris of the dying cancer cells provides additional information about the nature of the enemy. This is how the defense mechanisms of the human body are supposed to lead to the destruction of cancer, and the appropriate stimulation may make their response more effective than chemotherapy. It can be compared to the application of a vaccine into the tumor itself, where the vaccination can be the most effective.

Sixty years after the discovery of the DNA structure, scientists know quite a lot about the genes and genetics of humans, but they know even more about the genetics of microorganisms. Practical benefits are already noticeable in many aspects of life, including the food and pharmaceutical industries, and we are getting closer and closer to the application of this knowledge in hospitals.

Does GMO mean mutant vegetables and dangerous attempts to play God? Nothing could be more wrong — all strains of bacteria that may be used for future treatments are genetically modified organisms!

Research team: Joanna Bereta, PhD; Paulina Chorobik, PhD; Dominik Czaplicki, PhD; Monika Bzowska, PhD; Krystyna Stalińska, PhD; Anshu Rastogi, PhD; Karolina Ossysek, MSc; Marta Obacz, MSc; Lucyna Potempa, MSc