April 24

Forgotten Cure Part 3

  1. As a scientist, describe the main experiment you would like to see performed before phage therapy is approved for human use. What are the risks involved with using phage therapy?

I would like to see tests done on the human response to therapy. Many phage therapies could evoke an allergic reaction as the immune system mounts an attack on these foreign bodies. Furthermore, how would the kidneys and liver function differ, especially in patients with conditions weakening these filtration systems, when trying to filter out the remains of the bacteria cells and phage particles. This includes the effects of endotoxins, in which people could enter septic shock causing much fatality. As with most therapies that could involve a toll on either the kidneys or the liver, enzymes would have  to be monitored closely during the entire time of clinical testing. In addition dosage of phage therapy would have to be taken in to account before it reaches the point that the immune system will start mounting  a defense against the foreign particles.

Category: Sriram Avirneni | 2 Comments on Forgotten Cure Part 3
April 24

Forgotten Cure Assignment Part 3 4/23/19

Forgotten Cure Assignment Part 3 4/23/19

2. One of the biggest problems in phage therapy has been in the approval process. Describe the trouble surrounding FDA approval and recommend some suggestions to improve the process of phage therapy approval.

One of the biggest issues that Sulakvelidze had was the FDA’s unrealistic expectations because phage do not work the same way antibiotics do, they cannot be tested or treated the same way during the approval process. Phage mutate and change so often that constantly sequencing every new phage in a cocktail is prohibitively expensive. Sulakvelidze and his company did not have the funding to do all of the necessary testings for FDA approval, so they had to put their VRE project on hold. A similar issue was faced by GangaGen so they, like Sulakvelidze, chose to focus on animal applications first. Many of these issues stem from an FDA approval system that does not understand bacteriophage and underfunded research.

I think that the easiest way to improve the process of phage therapy approval is to improve the basic research of phage first. When the author describes the conference held by GangaGen, Ry Young calls for a renaissance in phage research, and while this idea was initially not as well received at the conference, I think it would improve the process of phage therapy approval. I think if more were understood about phage in the first place it might make the FDA approval process easier because there would be less unanswered questions, and much of the research that small start-up companies do not have the funding to do could be done, at least conceptually, as part of the process of learning more about bacteriophage. In addition, I think that Sulakvelidze and GangaGen were smart to realize that it is easier to work with animals first. By focusing on making food products safe first, these companies were exposed to the approval process at less stringent standards and helped normalize phage. While this won’t directly improve the process of phage therapy approval in humans, I think that using phage in other industries first would help make phage product testing more uniform and easier to cross apply to people over time. I think that with a larger body of phage research, and phage usage in other industries the approval process would be improved and some of the concerns the FDA outlined when working with Sulakvelidze would be mitigated.

Category: Lucy FIsher | 1 Comment on Forgotten Cure Assignment Part 3 4/23/19
April 24

Forgotten Cure 3

Describe the differences between Intralytics and GangaGen. Can you locate their “best selling products”? What are the main struggles these companies have to deal with? Look at their current web page. What changes have taken place since the writing of The Forgotten Cure?

Although both of these companies deal with locating phages and creating remedies, the approach, purpose, and usage of the phages are on opposite sides of the spectrum. The greatest difference between the two companies is the location in which they were founded: the United States and India. This demonstrates that despite the large distance between centers or institutions, the building of knowledge within science is not an individual activity but rather a massive group project that requires the participation of many scientists all around the world. Along with location, the circumstances led Intralytix to stop the projects concerning human-resisting bacteriophages and to lean more towards phages resistant to contaminating-bacteria found in meat, poultry, fruits, and vegetables as these were suggestions made by the FDA. This led to the creation of a phage cocktail that is resistant to listeria monocytogenes. GangaGen, on the other hand, remained on their goal to find human bacteria-resistant phages which they did and produced StaphTame which became their “best-selling” product.

Intralytix struggled with a lack of funds and long-term partners as there were many cases in which this occurred. Intralytix were also losing their collaborations with other institutions thereby making it difficult for them to find revenue to fund the projects. In the spring of 2002, Intralytix began the process of gaining approval from the FDA to launch trials of phage therapy against VRE. In this process, they had help from their team of experts along with Marissa Miller, a program officer of the NIH’s National Institute for Allergies and Infectious Diseases. After some time, Sulakvelidze got a call from the FDA to set a conference call to report their decision. During the conference, the experts working with the FDA asked numerous questions to lay their confusion to rest. One of their main concerns was of lytic phages and that it may be used in the final products of Intralytix. Along with this, the government also recommended that Intralytix moves to another model which would more closely resemble the patients that would be candidates for phage therapy usage. Sulakvelidze took all their points and recommendations into consideration when writing another report for the FDA following the meeting. After the company was denied a much-needed grant, they decided to turn their focus away from human use and towards phages in agriculture, meat, and poultry. They received bad news such as their main partner, Ecolab, dropped out, they remained hopeful as they received news that a British company was interested in their product. However, they soon let go of the deal was they claimed that the economy was bad which led to other companies dropping their deals with Intralytix. GangaGen did not face as many struggles; however, they did face the problem of lack of funding along with an inability to receive timely approval from the FDA.

When Forgotten Cure was written, Intralytix were focused on creating phage resistant sprays and cocktails aimed to destroy bacteria that were found to contaminate meats and poultry. Now, on the company’s website, Intralytix announced its recent collaboration with Ferring Pharmaceuticals to design bacteriophages that treat inflammatory bowel diseases. The company’s products shifted from solely producing agricultural products to also include projects involving human pathogens. Also, on February 8 of this year, Intralytix announced that their study concerning bacteriophage targets within patients with Crohn’s diseases has entered a Phase 1/2a stage of clinical trials. GangaGen, on the other hand, remained on their focus of creating bacteriophages for human pathogens. Based on the publications posted on their website, the company began looking at looking and testing other factors that can affect endolysin efficiency within Staphylococcus aureus.  

 

Category: Sabin Patel | 1 Comment on Forgotten Cure 3
April 24

Forgotten Cure #3

As a scientist, describe the main experiment you would like to see performed before phage therapy is approved for human use. What are the risks involved with using phage therapy?

As a scientist, two factors must be considered with each experiment that is used to prove the effectiveness/usefulness of a new treatment. Firstly, the scientist should consider whether or not the treatment is safe and ethical before beginning an experiment. A good experiment that features the testing of a new treatment should be safe and should also provide evidence to the FDA and public that the treatment is usable without substantial harm (if it is to be made public). Secondly, the experiment should be designed to determine the effectiveness of the treatment without skewing results in a direction to support or disprove a hypothesis. This increases the credibility of the work from a scientific standpoint and would also make the case presented to the FDA more convincing. If I were a scientist trying to determine if phage therapy should be approved for human use, I would like to do a direct comparison study between antibiotics and bacteriophage therapy. This study would be accomplished by first obtaining a constant bacteria strain that was antibiotic resistant. Next, a phage cocktail would be cultured (similar to those created at Phage Therapy Centers, such as those referenced by Kuchment in the text) to attack that specific strain of bacteria. This phage cocktail would be tested in conjunction with a control group with no treatment, an antibiotic treatment that contained a cocktail probable to have success against that particular resistant strain, and a general antibiotic such as penicillin. Results would include the success of the elimination of the resistant bacteria and the levels of endotoxins released by the bacteria that had died. This study would examine not only the effectiveness of phage therapy in relation to other modern treatments, but also the safety in relation to other modern treatments. If the results from this experiment returned favorably, they would play a large role in changing public perception of phage therapy (Kuchment discusses how western medicine has traditionally favored antibiotics while eastern medicine has traditionally favored phage therapy, which followed the political lines leading up to and during the Cold War) and could play a crucial role in getting the approval of the FDA.

A risk factor that would also be addressed by this experiment would be the release of endotoxins upon lysis of bacteria. This is a problem that is shared between bacteriophages and certain classes of antibiotics, so this experiment would be very useful in discerning the extent at which phages cause endotoxins to be released compared with the extent that antibiotics do. However, phages may have a unique property that could limit this risk factor. In addition to Kuchment’s description, Doss, Culbertson, Hahn, Camacho, and Barekzi describe a method that involves genetic engineering of bacteriophages to eliminate their major lysis proteins; these new phages kill bacteria by creating a hole in the inner membrane via the holin. The release of endotoxins could go from a potential problem with phage therapy to a very big advantage, as eliminating the risk of endotoxin release would reduce the worries of additional problems in the future with endotoxins causing more severe problems upon the death of bacteria. A second risk factor that would be addressed by this experiment would be the risk that the public would not have faith in the treatment. An approved treatment would remain relatively useless if the public did not trust it, so having evidence to substantiate the claims made by proponents of phage therapy before the treatment was approved could encourage the FDA to be more confident in approval of the topic, swaying public opinion in a favorable way. To summarize, this would eliminate the risk as a scientist of investing many resources into a treatment and experiments that would not be widely used. A final risk with phages is that the phage cocktails used in treatment that are designed for more breadth rather than one phage is that they can also cause bacterial resistance. Therefore, it would be important to use phages carefully and in a focused manner to ensure that bacterial resistance would be minimized.

 

Doss, J., Culbertson, K., Hahn, D., Camacho, J., & Barekzi, N. (2017). A Review of Phage Therapy against Bacterial Pathogens of Aquatic and Terrestrial Organisms. Viruses, 9(3), 50. doi:10.3390/v9030050

Category: Henry Burns | 1 Comment on Forgotten Cure #3
April 23

Forgotten Cure #3

As a scientist, describe the main experiment you would like to see performed before phage therapy is approved for human use. What are the risks involved with using phage therapy? 

The Forgotten Cure discusses about many experiments that have been conducted by GangaGen and Intralytix to test the effectiveness of phages. One of such experiment pertains about salmonella which was tested using chicks by Perdue, a large poultry producer, and Intralytix. To ensure that the food was free of bacteria, antibiotics were registered to the chickens, but the FDA banned the production of many antibiotics such as fluoroquinolones and Baytril. To test if bacteriophages would serve as a better alternative to antibiotics, Perdue decided to test salmonella in chickens, since it produced a greater effect on humans compared to chickens. The procedure was conducted by spraying and injecting phages onto and into the chick eggs on the 17th day, when the immune system is developed and working. At the same time medicine was injected into the chick’s egg. Vaccinations were also provided to the chicks after they were born and sprayed with phages one more time. As a scientist, I would like to see the results of this experiment, but also, I would like to see phage therapy used in treating Staphylococcus aureus. As mentioned in The Forgotten Cure, “staph aureus is highly virulent, and can infect patients who are completely healthy,” (89). Staph aureus is known to cause infections, and boils, but if it enters the bloodstream can even cause an infection to the heart- valve. Maybe a concoction of phages or phages and vaccines, as used in the experiment about salmonella, could help treat staph aureus.  

Even though phage therapy seems to be a possible alternative, there are many risks that come with it. Phage therapy could potentially be harmful if the bacteria releases toxins into the body which could lead to septic shock. Phages can switch from being lytic to lysogenic and cause a potential risk to the body. If the phage turns to be lysogenic, it can alter the bacteria’s genes and can possibly create a pathogenic bacterium. Also, there could be some doubts from the public and there could be various reactions knowing that they are being injected with phages. When viruses were added onto food, people tend to be scared about the thought of viruses in the food they eat , since people would usually avoid viruses and bacteria. The FDA could also provide risks for phage therapy especially humans, since the process to attain anything is very long, and requires a lot of clinical work. Many tests must be done on animals then humans and then shown to the FDA for approval. Even if approval is achieved, sufficient funding is required to be able to proceed and implement phage therapy, experienced by Intralytix after the British Company stopped funding them.  

Category: Sona Subramanian | 1 Comment on Forgotten Cure #3
April 23

The Forgotten Cure 3

  1. As a scientist, describe the main experiment you would like to see performed before phage therapy is approved for human use. What are the risks involved with using phage therapy?

As a scientist, I would like to see an experiment looking at the effect of endotoxins released from bacteria as a result of phage therapy usage and as a result the potential for septic shock to occur in a patient. As The Forgotten Cure states that phage therapy can act rapidly, something that was described by d’Herelle when he saw the rapid curing of dysentery patients during the first world war. Ramachandran additionally stated that this endotoxin release is a perceived limitation of phage therapy, as the threat of septic shock is not one to be trifled with.  In addition to endotoxins, allergic reactions to the phages and other aspects of the lysate solution would also have to be looked at in order to ensure its safety. But overall the threat of endotoxins and septic from the rapidly killed bacteria is what concerns me most as a scientist, thus I believe there should be several trials in order to ascertain the effect of relatively mass endotoxin release, of various types, on the body. This could potentially be done by injecting endotoxins into animals at an expected level of what would be released, or by infecting animals with bacterial diseases and then curing them with phage therapy and observing the effect of endotoxins that way. However, there is a way to mitigate, maybe even eliminate, the threat of septic shock as a result of phage therapy use. As Ramachandran determined that by blocking the endolysin gene in bacteria, toxins could not be released from the bacteria since it would not have the ability to lyse. The blocking of the endolysin gene also has the added bonus of limiting horizontal gene transfer between phages and bacteria as well as certain commercial benefits. Overall there is always a risk when foreign contaminants enter the body, either from the phage therapy itself or the byproduct of the phage therapy fulfilling its purpose. However, with appropriate testing and the blocking of the endolysin gene the threat of septic shock should be mitigated, making phage therapy much safer humans, thus encouraging its approval by governing bodies like the FDA.

Category: Nathan Newton | LEAVE A COMMENT
April 23

Forgotten Cure 3

Question: Describe the differences between Intralytix and GangaGen. Can you locate their “best selling products”? What are the main struggles these companies have to deal with? Look at their current web page. What changes have taken place since the writing of The Forgotten Cure?

Alexander Sulakvelidze was the co-founder of Intralytix, a company that initially focused on the use of phages to combat human diseases and bacteria found in produce and poultry. Vancomycin-Resistant Enterococci (VRE) was Intralytix’s main target during their starting days in the world of bacteriophage therapy. Intralytix faced some expected challenges that surrounded bacteriophage therapy in human diseases. The Food and Drug Administration was an obstacle that was proven tough to get around when it came to initiating clinical trials. Intralytix’s bacteriophage concoction to combat VRE was rejected by the FDA, and as a result, the company switched gears to focusing on bacteriophage therapy of meat and poultry.

Dr. Janakiraman Ramachandrian was the primary founder of GangaGen and “leader” of a Scientific Advisory Board that was composed of many notable figures. GangaGen appeared to have not have battled the same amount of financial troubles that Intralytix had in their time, due to donors and investors in the company. GangaGen centered their focus around E. coli 0,157, with the ultimate goal of passing clinical trials and placing itself on the market. After a large investment from Otsuka, a Japanese pharmaceutical company, GangaGen was highly encouraged by Otsuka to concentrate on human diseases in comparison to Intralyix.

Perhaps the largest struggle that Intralytix and GangaGen encountered was the FDA and gaining approval to move forward to clinical trials. There was a large amount of skepticism surrounding bacteriophage therapy. Companies were also hesitant with investing and utilizing bacteriophage therapy. Nevertheless, Intralytix was able to secure a distributor, manufacturer, and producer of their products, all without the product receiving approval from the FDA. However, in 2006, strides were made from the FDA approving the use of phages in prepared foods.

The Intralytix website displays its list of products, all of which food safety, pet food safety, or harvest of animals. None of the featured products on the Intralytix website directly combats human diseases. This indicates that after Intralytix switched over to meat and poultry bacteriophage therapy as seen in The Forgotten Cure, they did not switch their focus back to human diseases. Notable products include SalmoFresh and EcoShield. The GangaGen website puts emphasis on Ecto-Lysin (P128), which presents strong evidence that it is the “signature GangaGen gene” that was inserted in the place of the lysin gene as described in The Forgotten Cure. The GangaGen website cites research that seems to focus on the Ecto-Lysin as their main recombinant protein. MRSA was also on the radar of GangaGen during The Forgotten Cure. The GangaGen website indicates that MRSA is still a focus of the company.

 

Category: Emily Gaw | 2 Comments on Forgotten Cure 3
April 23

Forgotten Cure 3

One of the biggest problems in phage therapy has been in the approval process. Describe the trouble surrounding FDA approval and recommend some suggestions to improve the process of phage therapy approval.

To begin, it appears that any process that appears in front of the FDA must be simplified before doing so. For example, Intralytix’s phage cocktail wasn’t projected to make it through simply because it had multiple ingredients. Instead, they focused on a small market topical treatment, which would open up a corridor for more development within the field that would be expanded. In general, it is very difficult to make it through FDA approval due to the thoroughness it requires to be approved. Not only do research and results have to be thorough, but funding and personnel have to be thorough as well. If a company doesn’t have the necessary expertise or funds to complete an experiment to the extent at which the FDA requires, the company stands very little chance of passing through. However, pertaining specifically to phage therapy, the field is underserved. As we have learned, the attention given to phage research has dropped off again, and although it is beginning to pick back up it still hasn’t blossomed to its full potential. As a result, not as many people have done research on phages, nor has a significant amount of funding been directed towards discovering a way to effectively incorporate phage therapy into modern medicine. Perhaps making the public and the FDA more aware of the process and efficiency of phage therapy, would our country then more readily accept this changing form of medical treatment.

 

Category: Cooper Johnson | 2 Comments on Forgotten Cure 3
April 23

Forgotten Cure 3

The global rise of multi-drug resistant bacteria has resulted many concerns for this antibiotic resistance is fast approaching. This had led many scientists to review the forgotten cure that was forgotten in the west but not the east. The long clinical history of phage therapy in Eastern Europe, combined with more recent in vitro and in vivo success, shows potential for phage based antibacterial agents. Despite the fact that phage therapy is not yet approved by FDA, phages have already been used to save lives in experimental treatments. A patient who suffered from antibiotic-resistant bacteria was reported in San Diego. Tom Patterson was infected by a multidrug-resistent Acinetobacter baumannii. He was quickly flown back to California and treated with antibiotics, but he near got better. He was saved by a cocktail of phages purified from sewage in Texas. In the near future, as antibiotics lose their effectiveness, we might see more stories like this one. One day, phage might move from our last resort against antibiotic-resistant bacteria to our first line of defense, bringing the “forgotten cure” back to life.

With the multiple lives saved from phage therapy, phage therapy should be tested on humans for other diseases and not AIDS first. I see phage one day becoming a big help to save lives, but not as a first resort, but definitely not last. Once FDA approves phage therapy for a disease on humans, I see more and more experiments run to test these forgotten cures, but only when hard data supports this, phage therapy will just be a “last resort”. Once experimenters have enough data to show that researchers have found a cure for a particular cure, then human trails can start, which will then have to convince the public that “hey this is actually good”. Animal trials would be done first before the start of any human trials. Even with growing antibiotic-resistance, researchers are still producing new antibiotics that work, but only for a short period of time, making the bacteria stronger. Even if phage therapy were to be “the go-to cure”, I see that one day the bacteria to grow an immunity and would research go back to antibiotics? Possibly an endless loop of resistance.

Phages are not used since in the discovery of penicillin in 1928 that shifted modern medicine in the west. To produce phage, scientists have to grow large quantity of bacteria that is the natural host of the phage. Bacteria is then infected with phage, but the problem lies with the isolation of live phages. I would look at other ways of isolating phages and not from multitude of dead bacteria corpses, since this could lead to a deadly immune response. Phage also take a lot of time, time that patients do not have – especially when phages are used as a last resort. Last, other concerns about phage therapy are centered on its safety and efficacy. Since the western world abandoned phage therapy, little data is available. However, institutes like Phage Therapy, Phage Biotics, GangaGen, Exponential Biotherapies continue to provide research on the forgotten cure, and from their studies, phage therapy does not exhibit major safety concerns.

Category: Michael Lum | LEAVE A COMMENT
April 23

Forgotten Cure 3

  1. One of the biggest problems in phage therapy has been in the approval process.   Describe the trouble surrounding FDA approval and recommend some suggestions to improve the process of phage therapy approval.

Part of the issue surrounding FDA approval was the stigma associated with phage therapy–because the use of bacteriophages for medicinal purposes was relatively uncommon to doctors in the United States, the standards for approving any phage cocktail were relatively unclear. There was no clear set of guidelines for what boxes needed to be checked for the treatment to be cleared by the FDA, so the leadership was able to come up with unrealistic questions to vet the doctors involved in Intralytix. Perhaps another decade or so of analysis of bacteriophages and their life cycles, habits, and safety in humans will allow researchers to get FDA approval for phage therapy. Knowing the answers to any possible question that the FDA could fire at them could streamline the approval process. Doctors and researchers understand antibiotics to a great extent, but they don’t know a great deal about phages and people tend to be afraid of things they do not understand.

Additionally, Kuchment writes, “‘We used to look for phages in sewers on the street,’ he said, by removing manhole lids or drain covers. But passersby would stop to ask what they were looking for, and when Roy replied “viruses,” they looked alarmed” (109). The public would need to be unbothered by this because there is no use fighting for the approval of a drug that people refuse to use because it is so ‘strange.’ This mindset is likely widespread and can veil the FDA in their vetting of phage therapy as well as potential phage therapy patients. Again, further research can allow people to understand the many benefits and overall value of phage therapy and allow it to be welcomed into the United States.

 

Category: Lily Goodman | 2 Comments on Forgotten Cure 3