Consistently Pursuing Maximum Therapeutic Potential

Throughout my research career I have had the privilege to work on extremely varied projects with amazing scientists including two Nobel Laureates. The unifying theme of these projects has been therapeutic potential. From epigenetics,  to aptamers, and bacterial engineering, I seek out projects that promise to relieve suffering, and benefit the most patients.

I am currently the Lead Scientist for the Lead Program at Synlogic Therapeutics. At Synlogic we are merging the advancements made in the fields of synthetic biology and host/microbiome interactions to engineer bacteria with specific pharmacological functions to treat metabolic disease from within the human gut. Previously, I was a postdoctoral fellow in the Silver Lab split between the Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering. I have included examples to some of my published research below. .


   
  
 
  
    
  
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     Gut microbes interact closely with the mammalian host, impacting disease and metabolism. Changes in the microbiota can lead to Crohn’s disease, inflammatory bowel disease (IBD), colorectal cancer and pathogenic infections such as  Clostridium difficile . Current techniques for studying microbe/host interactions are limited to evaluating population-level changes through sequencing, but cannot sense localized or low-level chronic inflammation or the early-stages of a pathogenic infection.   We have genetically engineered E. coli to monitor, sense, and report on the gastrointestinal (GI) environment.   These engineered bacteria are ideal for sensing changes to the gut environment, and could lead to novel diagnostics and therapeutics.     
  
 
  
     
  
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      Our findings demonstrate bacteria can be engineered into living diagnostics capable of non-destructively probing the mammalian gut, which may be vital as we learn more about how the gut microbiota has a profound impact on human health.     For a copy of the paper please follow the link attached to the image, and then click  here .

Gut microbes interact closely with the mammalian host, impacting disease and metabolism. Changes in the microbiota can lead to Crohn’s disease, inflammatory bowel disease (IBD), colorectal cancer and pathogenic infections such as Clostridium difficile. Current techniques for studying microbe/host interactions are limited to evaluating population-level changes through sequencing, but cannot sense localized or low-level chronic inflammation or the early-stages of a pathogenic infection. We have genetically engineered E. coli to monitor, sense, and report on the gastrointestinal (GI) environment. These engineered bacteria are ideal for sensing changes to the gut environment, and could lead to novel diagnostics and therapeutics. 

Our findings demonstrate bacteria can be engineered into living diagnostics capable of non-destructively probing the mammalian gut, which may be vital as we learn more about how the gut microbiota has a profound impact on human health. 

For a copy of the paper please follow the link attached to the image, and then click here.


   
  
 
  
    
  
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        It has been especially challenging to develop therapeutics that impact intracellular, non-enzymatic targets such as transcription factors or the scaffold proteins that maintain signaling cascades. Here we prove that with aptamer-aptamer chimeras, where one aptamer acts as a delivery agent, and the other as a direct protein antagonist, we can disrupt the signaling cascade required for the survival of leukemia cells.     The data presented here show that aptamers can affect previously "undruggable" targets through inhibition of protein-protein interactions. More generally, this strategy may work for other targets that are common to multiple tumorigenic pathways in diseased cells. Furthermore, this may allow for the down-regulation of these pathways with a single therapeutic agent rather than a panel of agents targeting individual signaling cascades.    For a copy of the paper please follow the link attached to the image, then click  here .

 

It has been especially challenging to develop therapeutics that impact intracellular, non-enzymatic targets such as transcription factors or the scaffold proteins that maintain signaling cascades. Here we prove that with aptamer-aptamer chimeras, where one aptamer acts as a delivery agent, and the other as a direct protein antagonist, we can disrupt the signaling cascade required for the survival of leukemia cells. 

The data presented here show that aptamers can affect previously "undruggable" targets through inhibition of protein-protein interactions. More generally, this strategy may work for other targets that are common to multiple tumorigenic pathways in diseased cells. Furthermore, this may allow for the down-regulation of these pathways with a single therapeutic agent rather than a panel of agents targeting individual signaling cascades.

For a copy of the paper please follow the link attached to the image, then click here.


  Many potential therapeutics could be developed into promising treatments if they could be specifically delivered to their targets.   In fact, we could reduce the adverse effects of cancer therapies and increase their efficacy with new delivery agents that specifically target cancer cells. Here we showed that an aptamer could selectively bind cancer cells through a biomarker called nucleolin. This aptamer was also internalized into the nucleus via a novel internalization mechanism, and delivered oligonucleotide drugs directly to cancer cells in vitro.    These results indicate that aptamers can be used as delivery agents to target oligonucleotide drugs such as RNAi, splice-switching oligos (SSO), or therapeutic aptamers directly and specifically to a wide-array of cancer cells.    For a copy of the paper please follow the link attached to the image, then click  here . 

Many potential therapeutics could be developed into promising treatments if they could be specifically delivered to their targets. In fact, we could reduce the adverse effects of cancer therapies and increase their efficacy with new delivery agents that specifically target cancer cells. Here we showed that an aptamer could selectively bind cancer cells through a biomarker called nucleolin. This aptamer was also internalized into the nucleus via a novel internalization mechanism, and delivered oligonucleotide drugs directly to cancer cells in vitro.

These results indicate that aptamers can be used as delivery agents to target oligonucleotide drugs such as RNAi, splice-switching oligos (SSO), or therapeutic aptamers directly and specifically to a wide-array of cancer cells.

For a copy of the paper please follow the link attached to the image, then click here