Benjamin K. Chan, Ph.D.
Welcome to my [semi-, but mostly not] professional website! Here, you'll find a little bit about me, bacteriophages, phage therapy and the work I currently do at Yale University.
I'm currently an Associate Research Scientist in the department of Ecology and Evolutionary Biology at Yale University in the
Laboratory of Professor (and all-around awesome dude) Paul Turner. My research inovlves the development and creation of Virulence
Targeting Antibiotics (VTA's) and Resistance Targeting Antibiotics (RTA's) for the treatment of bacterial infections refractory to
traditional antibiotic therapy. I am incredibly fortunate in that my work spans the entire 'bench to bedside' spectrum and we've
successfully isolated, characterized, and used bacteriophage-based V/RTA's to treat several infections (with the permission of the FDA).
When I'm not yanking my hair out in frustration at the lab bench, I can occasionally be found playing outside and/or sampling for phage with my two little ones. Interested in talking about phage (or really, anything within reason...)? Send me an email or text (details below) and I'd be happy to chat!
Benjamin K. Chan, Ph.D.
165 Prospect St.
New Haven, CT 06511 USA
Bacteriophages (also called 'phage') are the viruses of bacteria. They are believed to be the most common lifeform on the
planet with an estimated 10,000,000,000,000,000,000,000,000,000,000 phage existing at any given moment -- ten million times
more than there are stars in the universe!! This crazy high number of phage -- and the corresponding genetic diversity
associated with it -- has allowed the use of phage for numerous applications ranging from use in electronic devices to
biocontrol in agriculture to treatment of human infections!
Recently, there has been a lot of interest in using phages to combat the increasing prevalence of antibiotic resistant bacteria. A significant portion of my research falls into this category. Since the discovery of bacteriophages over 100 years ago, there have been numerous attempts at using them in the clinic to treat bacterial infections. A lot of this work took place in the former Soviet Union and was largely ignored by the West as we developed and depoloyed highly effective (at the time) broad spectrum antibiotics. However, as the effectiveness of these antibiotics decreases, we are once again considering phages as a potential therapeutic.
Bacteriophage replication is generally described in one of two cycles -- Lytic and Lysogenic -- though other types of
replication exist (Google filamentous phage, for example). The figure below illustrates a simplified lytic lifecycle as
phages that we've treated infections with undergo this reproductive cycle.
Phages have notoriously narrow host range. That is, they can often only infect one to a few strains of a particular species of bacteria. This specificity has been both a blessing and a curse as it greatly reduces impacts on 'non target' bacteria (e.g., the microbiome) but also requires testing to ensure that a particular phage can attack and kill a particular bacterium of interest (e.g. one causing an infection). While the latter has historically been considered a significant disadvantage of phage therapy, we consider it a significant advantage as it allows us to selectively kill specific bacteria within the population of bacteria. For example, not all strains of E. coli cause disease in humans. In fact, most strains do not, and some can even be protective against other infections. So, a phage cocktail targeting E. coli would not only kill the potentially pathogenic strains, but the neutral (or protective) ones as well. Therefore, we should try to use phages that specifically target only problematic variants of these species.
There are many [,many, many] ways that bacteria can become resistant to antibiotics. Given the large (and genetically diverse)
pool of pathogenic bacteria, their propensity to exchange genetic information, and the rather strong effects of natural selection
(in the form of mis- and over use of chemical antibiotics), it's not surprising to see that antibiotic resistance has become the
problem that it is today. Bacteriophages kill bacteria in a way that differs from existing chemical antibiotics and represent a
different class of antibacterials that could potentially be implemented in clinical medicine as ultra-precise bacteria killing machines!
One major objective of our approach to phage therapy is to try and maximize the likelihood of clinical improvement when phage infect and kill bacteria, but also when bacteria evolve resistance to the phages that we deploy. We hope to achieve this by using phage that specifically infect and kill bacteria that have a particular virulence factor (or antibiotic resistance factor). When bacteria are exposed to phages of this type, there is strong selection for the bacteria to alter/down-regulate/eliminate the particular virulence factor in order to avoid infection. Thus, the use of these phage can be effective when phages are able to infect and kill the pathogenic strains of bacteria but is also effective if the bacteria evolve resistance to the phage as they are no longer posses the virulence factor. We tested this approach with a bacteriophage that appears to target a protein on the surface the multi-drug resistant pathogen Pseudomonas aeruginosa that allows for antibiotic efflux. Bacteria that became resistant to this phage suffered a trade-off and were once again susceptible to antibiotic therapy! In other words, we were able to reverse antibiotic resistance in a multi-drug resistant bacteria with the use of this phage!
Using phage to treat bacterial infections is known as, 'phage therapy' and has been practiced for over 100 years. A lot has changed and science has advanced significantly since their initial discovery allowing us to better understand bacteria-phage interactions which should allow us to deploy them more succesfully. For example, we now have the tools to identify what surface expressed proteins or sugars particular phage are using to adsorb to their bacterial hosts. This is a critical piece of information that's essential (in my opinion) when designing a treatment plan. We can also characterize, at the molecular level, the ways in which bacteria evolve resistance to phage infection, allowing us to predict (and capitalize upon) what will happen during the course of therapy.
We're constantly expanding our phage library with emphasis on bacteria of clinical importance. As our list of targets grows and we isolate, characterize, and develop new phage for them, I'll try to add them to the list. At the very least, however, we have libraries of characterized phage able to kill the following bacteria:
With permission from the FDA, we've treated several cases of multi-drug resistant bacterial infections in humans (and other animals!). The majority of these cases are still in the process of being described for the scientific literature and so I can't mention much about them until they're published reports but a few of our cases have been covered in the media and I thought that I'd mention them below:
In January 2016 we treated an individual with a longstanding graft infection. This infection, located on a Dacron graft that was part
of an aortic arch replacement was present for 4 years prior to our intervention and did not respond to multiple surgial interventions and
aggressive antibiotic therapy. As a result of this infection, a draining fistula formed and it was through this fistula that we applied phage
OMKO1 and ceftazidime. Following a single application of phage, this infection completely completely resolved. Our strategy for treatment
in this case was based upon our previous work that demonstrated
antibiotic re-sensitization following phage selection.
Read the published case report here.
In December 2017, we treated an individual with cystic fibrosis (CF) and a lung infection resistant to all available antibiotics. We treated this case by providing phage via a nebulizer. Following phage therapy, this young woman saw a total reversion in antibiotic sensitivities and dramatically improved lung funtion which has remained stable since! To read (and watch!) more about this case, check out the Media section below!
We treated another individual with CF and an antibiotic resistant lung infection recently. This individual had low pulmonary function and we were approached about using phage. In this case, we designed a phage treatment plan around first re-sensitizing the strains to chemical antibiotics and then reducing inflammation. Our lab assays with the infectious strains showed complete re-sensitization to multiple antibiotics following phage selection. Following phage therapy, these antibiotics were deployed and a notable improvement was observed coupled with a significant reduction in bacterial burden. Learn more about this case in the Media section below!
Our research has been featured in various places online. The gallery below contains links to some of these stories...