I'm currently an Associate Research Scientist in the department of Ecology and Evolutionary Biology at Yale University. 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 succesfully (i.e. with the permission of the FDA) isolated, characterized, and used bacteriophage-based RTA's in human patients. And, while I realize that it is incredibly cliché to say, I like to believe that my research is multi-disciplinary (at least within the biological sciences) as it involves (in no particular order): molecular biology, bioinformatics, metagenomics, mathematical modeling, microbiology, pharmacology, evolutionary theory, and ecology.
Benjamin K. Chan, Ph.D.
165 Prospect St.
New Haven, CT 06511 USA
Bacteriophages (also known simply as '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 phagenomical (I keep trying to make this word an expression but people just aren't adopting its' use for some reason...I wonder why) number of phage -- and the corresponding genetic diversity associated with it -- has allowed us to utilize phages 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 work, perhaps unsurprisingly, 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.
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. Since bacteriophages kill bacteria in a way that differs from chemical antibiotics, the represent a different class of antibacterials that could potentially be implemented in clinical medicine and this is where V/RTA's come in.
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. The V/RTA approach uses 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 V/RTA's is 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 an RTA! (for more, see Chan et al. 2016 in publications). This result allowed us to demonstrate that the V/RTA approach can work and we are actively isolating, characterizing, and testing new bacteriophage every day (many of which have similarly interesting properties).
Doctor of Philosophy • 2008
My graduate work focused on the study of parental care behaviors in the neotropical poison frog Dendrobates auratus. These amphibians exhibit remarkable parental care behaviors and it was my hypothesis that these parental care behaviors provided a secondary benefit of improved resistance to the fungal parasite Batrachochytrium dendrobatidis (Bd) and other infectious diseases. At the time, few studies existed of the cutaneous microbial community of amphibians and because the fungus is contracted through the skin with infection being restricted to the skin, a thorough knowledge of this ecology could be essential for understanding the spread and virulence of this disease. I performed laboratory studies on a captive population which I collected from the invasive population on the Hawai’ian island of O’ahu which looked at conspecific transmission of cutaneous microbes as well as vertical transmission during nest attendance. Furthermore, a bacterium which I discovered on the skin of an American Bullfrog, Rana catesbeiana, which inhibited the growth of Bd in culture, was able to colonize the skin of captive D. auratus and be transferred between individuals resulting in greatly reduced mortality of frogs exposed to Bd.
B.S. in Biology • 2003
Associate Research Scientist • September 2013 - Present
As an associate research scientist in the department of Ecology and Evolutionary Biology at Yale University, I have focused my research on so-called Virulence/Resistance Targeted Antibiotics (V/RTA’s) with the objective of specifically targeting virulence and/or antibiotic resistance mechanisms of bacteria with bacteriophages. This approach utilizes the strong power of natural selection which has produced the diverse array of antibiotic resistance mechanisms we see today in the opposite direction, driving antibiotic resistant bacteria to an antibiotic susceptible state. The project which I was originally recruited to the University to work on consisted of using an adapted variant of bacteriophage PPO1 to infect Escherichia coli O157:H7 to selectively remove pathogenic forms of E. coli from cattle. However, my work involving multi-drug resistant Pseudomonas aeruginosa has become my recent focus and potentially most influential work. This work has resulted in FDA approval of a bacteriophage cocktail which is able to specifically target antibiotic resistance and virulence mechanisms of P. aeruginosa forcing an evolutionary trade-off between susceptibility to antibiotics and bacteriophage. When used in combination, we have observed synergistic effects in the clearance of bacteria both in a biofilm state and those in planktonic states and the restoration of an antiobiotic susceptible state in phage-resistant mutants. This potentially significant breakthrough in the antibiotic resistance problem could dramatically extend the lifetime of our current antibiotic library by reversing the rate at which antibiotic resistance occurs as well as improve the lives of those with conditions which predispose them to Pseudomonas infections (e.g. diabetics, HIV/AIDS patients, burn victims).
Postdoctoral Fellow • November 2011- September 2013
As a fellow in the division of Infectious Diseases at the University of Utah hospital, the focus of my work was the use of deep sequencing (also referred to as Next Generation Sequencing) to identify viral RNA signatures in frozen human brain specimens using bioinformatic techniques developed in house by myself as well as other laboratory members. This work was performed on a cohort of patients who died with progressive forms of Multiple Sclerosis (MS) and it was found that within these samples there was increased human endogenous retrovirus (HERV) expression when compared with our control populations (undiseased brain and encephalitic brain). These data suggested that the possibility of a cryptic retrovirus or a combination of endogenous viral elements may be contributing to the pathogenesis of MS, potentially reconciling the autoimmune and infectious nature of this disease
Research Assistant Professor • January 2010- September 2013
As a Research Assistant Professor in the department of biology, my research focused on Alzheimer’s disease (AD). AD is an incurable degenerative neurological disease that affects nearly 27 million people worldwide. This debilitating disease is characterized by neuronal and synaptic loss in the cerebral cortex, and is the most common form of dementia. Decades of research have yielded significant discoveries, however an etiological agent has yet to be described. Such a discovery could yield avenues of research toward treatments that differ from our current (and thus far, unsuccessful) attempts. I proposed that as a result of the well documented two-way exchange of cells during placental development, the immune system is forced to tolerate “non-self” microchimeric cells in order to both maintain pregnancy and benefit from subsequent tissue repair. Due to immunological changes associated with natural aging, these cells may no longer be recognized as “self,” culminating in an alloimmune response. Within most tissues, these cells can simply be removed and replaced by host cells without dramatically affecting organ function. However, within neural tissue, these cells may become integral components of the host tissue and, as a result, their removal could explain neurodegeneration in diseases such as AD. My central hypothesis was that examination of brain tissue recovered from patients with AD would contain microchimeric cells. My preliminary investigation into this possibility confirmed the presence of microchimeric cells within the hippocampus of a female with AD as well as four (of five) other brains from female’s with AD while failing to reveal the presence of these cells in five control brains. Thus, there is potential that neurodegenerative diseases such as AD may be explained by my alloimmune hypothesis.
Senior Laboratory Specialist • June 2009- November 2011
My work at the Fluorescence Microscopy Core Facility at the University of Utah School of Medicine involved training numerous faculty, postdocs, and graduate students in the proper use of confocal microscopes. I was also tasked with the development of software to analyze large image data sets as well as the creation of our web-based scheduling software.
Research Scientist• June 2008- June 2009
My research at OmniLytics, Inc. was focused on the development of bacteriophage-based products for the control of E. coli O157:H7 in livestock, the sterilization of hospital equipment to protect against colonization by Staphylococcus aureus and Pseudomonas aeruginosa, as well as the optimization of products designed to target the plant pathogens Pseudomonas syringae and Xanthomonas campestris. This brought my attention to phage therapy and its' potential to tackle some of the serious biological problems we face today.
My teaching philosophy is to inspire students to better understand the natural world by asking scientific questions and understanding the
process rather than presenting them with a list of biological facts to memorize. To me, understanding the concept is much more important
than the precise name of a pathway and providing students with the resources, tools, and guidance to explore the natural world independently
will produce a more enthusiastic, creative, and energized future generation of scientists. It is possibly due to this approach that I have been
able to easily recruit student researchers from my courses that have successfully gone on to pursue advanced degrees.
Yale University • Fall 2015
Wesleyan University • Spring 2015
Wesleyan University • Spring 2015
Yale University • Spring 2014
University of Utah
My training in academia and industry has resulted in a varied skillset spanning multiple fields. For example, my graduate work taught me basic animal husbandry techniques and how to conduct field studies involving animals and their behavior; my postdoctoral work in industry taught me numerous microbiological techniques as well as a better understanding of the industrial mindset and how to form profitable collaborations in industry; my work in the core facility, effectively a hybrid of industry and academia, allowed me to broaden my understanding of how ideas from seemingly divergent fields (e.g., physics, biology, chemistry) could be combined to understand scientific problems while improving my understanding of the benefits and limitations of laser scanning confocal microscopy and the corresponding techniques of sample preparation; my work in the University of Utah Hospital taught me relevant programming (python 2.7) skills, molecular techniques, and the need to bridge basic and translational/clinical research; More recently, my work at Yale University has allowed me to incorporate many of the evolutionary ideas that I learned during my graduate studies with my industrial and molecular approaches that I learned as a postdoc to conduct translational research with an evolutionary biology emphasis.
Chan, B.K., Narayan, D., Turner, P.E. Bacteriophage therapy results for a multi-drug resistant Pseudomonas aeruginosa infection. (in prep )
Chan, B.K., Sistrom, M.S., Wertz, J.W., Kortright, K.E., Narayan, D., Turner, P.E. 2016. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Scientific Reports 6, Article number: 26717
Akusobi, C., B. Chan, J. Wertz, and P.E. Turner. 2015. Convergent evolution of host-attachment proteins in phage PP01 populations adapting to Escherichia coli O157:H7. Applied and Environmental Microbiology (in revision)
Chan, B.K., Abedon, S.T. 2015. Bacteriophages and their Enzymes in Biocontrol. Current Pharmaceutical Design. Curr Pharm Des. 21(1):85-99.
Chan, B.K., Wilson, T.W., Fischer, K.F., Kriesel, J.D. 2014. Deep Sequencing to Identify the Causes of Viral Encephalitis. PLoS ONE 9(4): e93993
Chan, B. K., Abedon, S. T., Loc-Carrillo, C. 2013. Phage Cocktails and the Future of Phage Therapy. Future Microbiology 8:769-783
Chan, B.K., Abedon, S.T. 2011. Phage Therapy Pharmacology: Phage Cocktails. Adv Appl Microbiol. 2012;78:1-23.
Chan, B.K., Abedon, S.T. 2011. Bacteriophage Adaptation, With Particular Attention to Issues of Phage Host Range. In: Bacteriophages in Dairy Processing. Quiberoni, A., Reinheimer, J.(eds), Nova Science Publishers, Hauppauge, New York
Chen, L.L., Chen, X., Choi, H., Chen, L.C., Gouw, L., Andtbacka, R.H., Zhang, H., Jimenez, A., Rodesch, C.K., Chan, B.K., Jones, K.A., Martins, ., Hill, H.R., Schumacher, J., Willmore, C., Scaife, C., Ward, J.H., Morton, K., Randall, R.L., Lazar, A.J., Trent, J.C., Patel, S., Frazier, M.L., Jensen, P., Benjamin, R.S. 2011. Imatinib plus Peginterferon α-2b Induce IFN-γ–Producing Lymphocytes in Blood and Tumor Sites and Correlate with Improved Clinical Outcome of Gastrointestinal Stromal Tumor. Cancer Research.
Chan, B.K., Mirabello, M., Ferguson, J.W., Farmer, C.G. 2011. Fluctuating Pattern Asymmetry of the Neotropical Poison Frog, Dendrobates auratus as an Indicator of Habitat Quality. Conservation Biology
Chan, B. K., A. L. Peterson and C. G. Farmer. 2007. Dendrobates auratus (Green and Black Poison Dart Frog) Larval Predation. Herpetological Review 38(3): 321-322
Chan, B.K. 2010. Offspring Begging, Larval Relocation and Parental Care in Dendrobates auratus. Leaf Litter 3(1):4-5
Chan, B.K. 2009. Dendrobates auratus (green and Black Dartpoison Frog). Diel Activity. Herpetological Review. 40(2):202
Zala S.M., Chan B.K., Bilbo S.D., Potts W.K., Nelson R.J., Penn D.J. (2007). Genetic resistance to infection influences a male’s sexual attractiveness and modulation of testosterone. Brain Behav Immun. 22(3): 381-387.
In addition to traditional academic/researcher work, I have also acted as a scientific consultant (client list, when not covered by an NDA, available upon request) and public lecturer on various scientific topics. I am also a co-founder of ubiota, a personal metagenomics company which was established (in part) to provide the public with the technology and scientific know-how to examine their microbiome.