Developing A More Precise Medicine for Bees.

Members of the Snow lab prepare to install packages of bees at Barnard College.

​I have been fascinated by the cellular and molecular aspects of disease since my first biology class in high school. For most folks with that type of interest the obvious path is to study human disease with the goal of finding new therapies and diagnostic tools. So, I pursued a PhD in biomedical sciences and was trained in uncovering the cellular and molecular mechanisms underlying diseases of the blood and cancer in humans. By the time I was doing my post-doctoral work, I had a growing interest in the food system and the organisms that are part of it.  After taking a beekeeping class in 2009, I became captivated by honey bees with their critical role in pollination in both natural and agricultural ecosystems and decided to apply my biomedical training towards developing approaches to help protect honey bee health. Since that fateful decision, it has been quite a journey with a steep learning curve and lots of ups and downs. ​​The support I have gotten from Project Apis m. (PAm) has been instrumental in helping me to move from a beginner to making potentially important contributions in the field of honey bee health.

My lab focuses on how infection by the fungal pathogen Nosema ceranae contributes to honey bee disease and on developing a better understanding how bees respond to diverse stressors at the cellular level.

Nosema spores viewed under a microscope.

Nosema infection is a ubiquitous and persistent bee health challenge that causes individual mortality and can contribute to colony collapse. We know too little about N, ceranae as a species and about the whole group to which it belongs, the microsporidia. There are no easy and reliable diagnostic methods and very few treatments (with only one registered one). The treatments are expensive, of uncertain value for bee health outcomes, may be hard on bees, and have been intermittently unavailable on the market.

There have been significant efforts by many labs to identify novel treatment strategies for combatting N. ceranae infection. A key goal of this work is to identify therapeutic strategies that reduce infection levels with minimal impact to honey bee host cells. My main strategy takes an approach widely used in the biomedical field to find drugs to treat human disease. Specifically, we have used our cell and molecular understanding of honey bee and Nosema biology to predict processes that when pharmacologically inhibited will affect the infectious agent (N. ceranae) more than the host, thereby reducing or eliminating infection.

We know too little about N, ceranae as a species and about the whole group to which it belongs, the microsporidia. There are no easy and reliable diagnostic methods and very few treatments (with only one registered one).

In our first PAm funded project, we used natural and synthetic versions of a drug that targets aminoacyl-tRNA synthetases, key players in the process of protein synthesis. We predicted that Nosema would be more sensitive to these drugs based on molecular analysis of the process in Nosema cells and honey bee cells. While these drugs did reduce infection levels, we found that the most effective doses were toxic to bees at longer exposure times 1.

As part of this project we characterized the honey bee response to these drugs. We found that bees mounted a stress response to the treatment that likely explained their reduced sensitivity to the drugs when compared to Nosema 2. Importantly, this work helped us to identify and characterize some novel biomarkers of stress in honey bees that can now be used to document and measure sublethal toxicity of various treatments in bees3.

​As with all research endeavors, the best laid predictions often don’t hold up in the complexity of the real world, but the lessons we learned here with support from PAm were invaluable in taking the next steps targeting another cellular entity; the proteasome.

 The proteasome is a complex that helps degrade cellular proteins and comparisons of the Nosema proteasome to that of host cells suggested a simpler structure and possibly reduced function. We tested a number of drugs that target the proteasome and found that most of the compounds did reduce infection levels. Excitingly, we found a number that appeared to eliminate infection completely at doses well below those that reduced bee survival 4.

In our second and third PAm funded projects, we are now carefully evaluating our original lead compound and some derivatives for efficacy while also looking at a number of possible detrimental effects of these compounds on honey bee health. We are using a number of biomarkers to test for sublethal toxicity while also testing immune function and potential impact on the microbiome. The ultimate goal of this work is to obtain the most complete assessment of these drugs and their efficacy and possible negative effects on individual bees in the laboratory setting to inform our plans to move to the next step of rigorous field trials.

Undergraduate researchers in the Snow lab. From left to right: Fatoumata Wague, Meghna, Mallapan, Natalie Lovinger, Eliana Elikan, Parker Parrella

A critical part of my mission at this institution is to promote the participation and success of women in STEM fields. Through their grant support, PAm has helped me support many talented undergraduates.

The support I have received from PAm over the years to study N. ceranae biology has been transformative. The funding provided ($124,000 in three grants over the last 6 years) has helped me to become an expert in the field while developing the theoretical and technical foundation for applying my biomedical training and background to discover new therapies and diagnostic tools. The funds have helped me to build a robust research program, directly supporting work reported several published papers and manuscripts. 

These grants have fostered collaborations with other researchers and helped make our program competitive in obtaining federal grants to study this problem with the ultimate goal of helping beekeepers. My work is performed at Barnard College, a highly competitive college for women associated with Columbias University. A critical part of my mission at this institution is to promote the participation and success of women in STEM fields. Through their grant support, PAm has helped me support many talented undergraduates (who do most of the research in lab). These undergraduate researchers have learned about the theory, practice, and culture of science, been included as coauthors on publications, and the vast majority have continued on in STEM fields after graduation.

I am incredibly grateful for the support I have received from PAm over the years to study Nosema ceranae which has been indispensable my achievements as a researcher and mentor over the last 6 years. Thank you, PAm. 

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By: Dr. Jonathan Snow, Department of Biology, Barnard College 

References:
1. Snow, J.W. (2020). Prolyl-tRNA synthetase inhibition reduces microsporidia infection intensity in honey bees. Ann Abeille 51, 557–569. 10.1007/s13592-020-00742-9.

2. Flores, M.E., McNamara-Bordewick, N.K., Lovinger, N.L., and Snow, J.W. (2021). Halofuginone triggers a transcriptional program centered on ribosome biogenesis and function in honey bees. Insect Biochem Molec, 103667. 10.1016/j.ibmb.2021.103667.

3. Shih, S.R., Bach, D.M., Rondeau, N.C., Sam, J., Lovinger, N.L., Lopatkin, A.J., and Snow, J.W. (2021). Honey bee sHSP are responsive to diverse proteostatic stresses and potentially promising biomarkers of honey bee stress. Scientific Reports 11, 22087. 10.1038/s41598-021-01547-1.
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4. Huntsman, E.M., Cho, R.M., Kogan, H.V., McNamara-Bordewick, N.K., Tomko, R.J., and Snow, J.W. (2021). Proteasome Inhibition Is an Effective Treatment Strategy for Microsporidia Infection in Honey Bees. Biomol 11, 1600. 10.3390/biom11111600.