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Revision as of 08:18, 15 October 2012

Penn 2012 iGEM Wiki

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Overview of Bacterial Therapeutics

Currently, in the field of medicine, groundbreaking approaches to therapeutics are constantly being developed. With the advent of synthetic biology, bacterial therapy is rapidly emerging as a promising source of therapeutic potential for many diseases, especially cancer. Consequently, bacteria can actually be seen as the ideal vector for the production and delivery of drugs for many diseases.

Why Bacteria are Ideal

One reason bacterial therapies have been proven to be better than many existing therapies is due to the fact that many bacteria already exist in a commensal or even mutualistic relationship with the human body. The reason this serves as an important advantage over other options is that it lessens the chance of a harmful response from the immune system. Introducing foreign entities into the body reduces the chance that the therapy would continue to work after a long period of time since the body’s defense mechanisms would kick in. This is exactly why working with or engineering strains that are part of the various microbiomes of the human body would be ideal. Escherichia coli is an example of a commensal bacteria in the gut that has been engineered to treat cholera. Scientists have managed to program E. coli to express cholera autoinducer 2 (CAI-2), inhabit the gut, and effectively block the quorum sensing that cholera use to propagate disease in the gut [1]. Another example of this has been through engineering Lactobacillus L. jensenii, a vaginal strain to produce anti-HIV proteins to serve as a preventive measure again HIV [2].

Another feature that makes bacteria optimal is that they already contain compounds and metabolic pathways that can release or produce drugs. As a result, this helps reduce costs for extra materials by utilizing natural processes. Complete chemical synthesis is very costly so any efforts that can harness the biosynthetic processes are greatly preferred. However, using a purely biosynthetic pathway leads to low yields. This is where synthetic biology techniques come into play where low prices and high yields can become a reality. A case where synthetic processes have been utilized effectively is in the case of the anti-malarial drug Artemisinin. Scientists have successfully managed to engineer E. coli to produce a precursor of Artemisinin by altering some pathways that can purified in a cost-effective manner [3]. Another great bacterium to engineer is Lactobacillus, due to the fact that it is part of pathway of fermenting milk in to yogurt. Using this strategy, in 2008, MIT’s iGEM team attempted to manipulate Lactobacillus bulgaricus to produce an antimicrobial peptide that would inhibit the binding of Streptococcus mutans. This would eventually prevent the formation of cavities. Moreover, this method effectively creates a cheaper, sustainable way to keep the therapy functional since small amounts of the bacteria are required to re-ferment milk and keep producing this antimicrobial yogurt for one’s teeth [4].

In addition, a large proportion of diseases are bacterial. This allows one to consider the possible interplay between different bacteria. One way in which this interaction has been embraced is in the earlier cholera therapeutic with E. coli. Here we have two bacteria, engineered E. coli Nissle 1917 and Vibrio cholera, of which both have the ability to quorum sense or communicate with other cells. However, the latter is pathogenic and the former is not. As a result, since bacteria only have the ability to communicate with other bacteria that produce the specific CAI-2 it allows the E. coli to trick the Vibrio cholera to believe that the they have already inhabited that part of the gut and prevent the formation of the cholera biofilm [1]. These types of bacterial interactions are an interesting consideration to make when creating therapeutics where other non-pathogenic bacteria can beat pathogenic bacteria at their own game by emulating their behaviour.

Many bacteria are also facultative or obligate anaerobes. This is incredibly relevant for many diseases where hypoxic areas need to be targeted, the most obvious one being cancer. Initial attempts were done with facultative anaerobes (although considered to be an aerobe at the time) such as Listeria monocytogenes because they are noninvasive and are easy to control through antibiotics. However although they did cause some tumors to regress, ultimately they preferred aerobic environments [5]. Then they tried Salmonella which was another facultative anaerobe, but thought to favor anaerobic environments more. Due to this preference they were predicted to accumulate around the necrotic centers of cancerous tumors, and especially after modifications made to amino acid machinery [6]. Nevertheless, it remained flawed due to the fact that it was invasive and the safety and viability of the option in the long-term remained unpredictable. Finally, more recently, an attempt was made with Clostridium, an obligate anaerobe. This was a great candidate since it would only target oxygen-depleted areas of tumors, and thus not be able to cause any systemic disease. In addition, Clostridium are sporulating bacteria which enable them to be metabolically active only in areas of necrotic tissue. As a result, the Clostridium would be inert everywhere else and thus unlikely to cause an immune response [7]. When this was tried out in practice the localization of Clostridium tetani turned out to be highly concentrated in hypoxic areas and therefore made it a suitable target for cancer therapies [8]. Clostridium was eventually tried out years later as a vector and proved to have sustained anti-tumor effects [9].

Bacteria are also advantageous by the fact that they motile due to their flagella. This is especially useful in diseases where the area of infection is large and deep. The bacterial flagellum is useful in these situations because they have the ability to penetrate tissues [10]. Moreover, this also illustrates the point that bacteria will not be entropically limited, unlike passive molecules, and can thus acquire energy to reach areas that are not as easily accessible. This results in allowing the bacterial density to be higher in areas away from the vascular source from which they arrived. Once again this sort of advantage primes bacterial therapies well for areas of tumors that are quite large and deep. Furthermore, the flagella allow bacteria to exhibit chemotaxis which is once again beneficial for cancer therapies. Several bacteria have shown to accumulate preferentially in tumorous regions due to the nutrients provided from dying cells [11].

Additional points can be made to show why bacterial therapeutics are just plain convenient. First of all, bacterial genetics are very well-understood. This makes them easy to manipulate and build circuits in, similar to electrical engineering. In addition, bacteria are responsive to their environment which enables the potential to create “smarter” therapeutics that would enable precise controls even after delivery, and eventually ensure long-term success of the treatment. These controls can be achieved through creating circuits that are responsive to their environment using various promoter strategies. Finally, bacteria are very easily externally detectable through various techniques that include the use of light, magnetic resonance imaging, and positron emission tomography. This will enable scientists to measure the state of the tumor and therefore the success and efficacy of treatment.