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I'm Andrew Johnson, and this is why I research.
Andrew is a postdoctoral research fellow in the DePaolo lab at the University of Washington. His research focus is primarily on host-microbiota interactions, and their influence on inflammatory and metabolic disease. He completed his PhD at the University of Oxford with Professor Fiona Powrie, studying regulatory T cell and dendritic cell responses to microbiota in the context of inflammatory bowel disease, and postdoctoral study with Dr. Jerrold Olefsky at the University of California San Diego, studying the immune response to dietary change and the inflammatory basis of metabolic disease. In addition to his primary research, Andrew leads projects within the Center for Microbiome Sciences and Therapeutics (CMiST) translating fundamental research on the microbiota into new therapeutic products. He has developed culture-based techniques to rapidly build bacterial strain libraries from clinical samples, to highlight functional and genetic changes that are associated with disease, and established a cost-structure to work with industry and academic partners.
Could you elaborate on the experiences that inspired you to become a scientist or that significantly influenced your goals in research?
As a kid, I was always interested in biology and the natural world. I actually originally wanted to be a marine biologist, but ultimately decided that the chemistry and cellular interactions that underpin ‘life’ were most interesting to me. During my undergraduate degree, I had the opportunity to spend a year doing research at a biotech company called UCB-Celltech in Cambridge, UK. I had a fantastic mentor, who is still a good friend, and a wonderful time exploring an area of T cell biology that was just coming to the fore in terms of clinical relevance; a type of T cell called Th17. I also got to learn about how drug development works and how biological research can actually end up transforming people’s lives.
The microbiome’s role in human physiology and disease has sparked great interest for its therapeutic potential. How did you become interested in the microbiome-gut interactions?
Yes, although I’m usually one to play down the hype, the microbiome has incredible potential for transforming how we approach health. I first began studying how we respond to microbes as part of my doctoral work with Fiona Powrie, who is a fantastic immunologist specializing in Th17 and Treg cells in the intestines. We had just finished characterizing which Treg cell, Dendritic cell and Macrophage populations are present in different regions of the gastrointestinal tract and began to study how they respond to different types of commensal bacteria. As is often the case in science, once you scratch the surface of something you realize how little we really know about it, and that was definitely the case with the microbiome. It still blows my mind how diverse bacteria are, even what we currently define as a single species can in fact be a large collection of different strains that vary both across and within people and can behave very differently when it comes to activating the immune system.
Your research projects have explored how the immune system responds to microbiota. In your opinion, what are some critical obstacles to therapeutic applications?
I think the biggest obstacle we face currently is simply a lack of knowledge both of how gut bacteria function, and the optimal therapeutic strategies that we can use to manipulate them. Human data is almost exclusively based on associations between the relative abundance of microbial species/genes with a disease, and the translatable value of mechanistic studies in the mouse has not yet been proven. Really in order to target bacteria therapeutically I believe we need to know down to the strain level how they act in relation to their human hosts. Only after knowing that can we apply some precision to their targeting. To overcome this obstacle, we really need a re-birth in microbial culture-based techniques and to establish clinically relevant bacterial strain libraries for people to study. I joined the Center of Microbiome Sciences and Therapeutics to work with clinicians and companies to drive that work forward. Once disease-relevant functions have been defined, the next obstacle to overcome is the lack of high throughput assays which we can use to screen for therapeutic agents (e.g. small molecules) that either interfere with or mimic bacterial actions.
Lastly, it is now clear that most of the diseases we would like to target with the microbiome, such as Inflammatory Bowel Disease, are mechanistically very heterogeneous. What triggers disease in one person may well not be the cause in another. We need a way to diagnose people based on the bacterial strain/behavior that we think is actually driving the inflammation in their system so that we can target it accordingly. This personalization of medicine has great therapeutic potential, but raises some challenges for BioPharma. Although successful personalization massively improves the chances of success clinically, it also reduces the potential market size for any drug, making the economics of such development challenging. These obstacles are not trivial, especially given that gut bacteria can be fastidious to grow and manipulate, but nor are they in any way insurmountable.
Some of the more immediate microbiome-targeted applications are likely to be:
Give us your elevator pitch. Why is your research important to the general public?
There are trillions of microbes living inside you all the time, and how they behave has a major impact on your health. Growing these microbes in the laboratory and studying the different ways in which they interact with us will open up new therapeutic ways to treat and prevent disease.
During your postdoctoral-training you have seamlessly transitioned between the academia and biopharma. In your opinion, what are some unique benefits of each environment?
Honestly, I’m just really passionate about developing products and therapies from our work, and I truly believe that will take a collaborative approach between academia and biopharma, so it’s always felt very natural to me to move between academia and industry and also to collaborate extensively across both. Speaking very generally, academia offers the chance to pursue very novel, entrepreneurial research. It’s a very creative environment where a lot of different disciplines come together. Biopharma by comparison is generally a lot more focused towards answering the precise questions you need to bring a product to the clinic, and so you often more rapidly see the value of your work. BioPharma is also a place where good research tends to be valued independent of whether the conclusion is positive or negative to the hypothesis, which is not always the case in academia where grant funding usually depends on obtaining positive data. I would note also that the lines between academia and industry are becoming more blurred as both companies and universities invest in startup efforts that can elaborate some of the entrepreneurial work of academia with a product focus.
What advice would you provide to your peers involved in translational research that would better prepare them for a biotech environment?
I think it’s very important that anyone who wants to work in biotech setting really understands how research becomes a product, and that they are able to talk about their work and design their projects with that in mind. I would really encourage students and postdocs to try and build collaborations and contacts with biopharma companies as often as possible and wherever possible. Even just reaching out for a conversation and the chance to discuss your work will help you understand biotech better and what companies are looking for. Also, if someone is yet to start their PhD I would strongly recommend they take a year or two to work as a research associate at a Biopharma company. I think the experience and contacts you obtain at that stage will really help you in the future.
Recently, you contributed an editorial piece on the association between the neonatal microbiota and atopy. Could you elaborate on the correlation between the microbiome’s composition in neonates and their risk of developing asthma?
This was a really interesting paper by Fujimura et al, (Nat. Med. 2016). They found that certain microbial compositions in the stool of children aged one month were associated with increased risk of developing atopy, a hyperallergic reaction, later in life. It is interesting because it supports the “window-of-opportunity” hypothesis in microbiome research. This hypothesis basically argues that what happens very early on in life, when you are first colonized with microbes, can have a major impact on diseases that manifest much later on. It’s an idea supported by other associations, such as with early life antibiotic treatment, and by mouse models, but is very hard to prove in the human without very extensive, longitudinal studies. It’s worth noting too (and we mention this in our comment) that microbial compositions at the genus or species level that have so far been associated with disease are rarely either necessary or sufficient for a given phenotype, so there must be other factors at play here as well, such as strain level variation, diet and human genetics.
As part of the DePaolo’s lab your recent published work demonstrates a key role for microbiota surveillance by TLR1 receptors in protection from colonic inflammation. What are the implications of these findings for the treatment of inflammatory bowel diseases (IBD)?
Toll-like receptors (TLRs) are a family of receptors that sense different microbial products. TLR1 for example senses microbial lipoprotein. TLRs have mostly been studied in the context of infections, where they play a role in initiating immune defense. However, the role of TLRs in the day-to-day control of our resident microbiota is not clear. Our recent work, which was pioneered by a previous postdoc, Karishma Kamdar, showed that TLR1-deficient mice fail to control their microbiota, meaning that we can find bacteria adherent to the intestine wall, and penetrating to the liver, the blood and the spleen. This is important because similar increases in mucosa-adherent bacteria have been found in IBD patients where they are thought to chronically stimulate the immune system causing the unresolved inflammation and tissue damage that is characteristic of this disease.
In our paper we described how the bacteria that penetrate in TLR1-deficient mice cause increased IL-1ß secretion, expansion of innate lymphoid cell numbers, and epithelial derangements including increased cell proliferation and a reduced mucus layer. When we exposed these mice to dextran sodium sulfate, a commonly employed intestinal injury technique that models some features of IBD, we found TLR1-deficient mice had a dramatically worse course of disease. This is one example of an emerging theme in IBD research, that immune-deficiencies can actually cause increased inflammation by allowing bacteria to evade our normal defensive barriers and penetrate into the gut wall. Although it’s obviously a big step from a mouse model to human disease, we are excited to better understand the impact of TLR1-deficiency on our ability to contain bacteria, not least because different forms of the TLR1 gene are present in humans, including variants that alter the ability of TLR1 to sense bacteria.
Finally, what are some of your life’s passions outside of the laboratory?
I’m a keen runner (especially trail running) and cyclist. During my postdoctoral work in San Diego I took up triathlons and that’s continued ever since. I like traveling and experiencing different cultures. I also enjoy the Seattle Arts scene, especially theatre and poetry.
Select Publications by Dr. Andrew Johnson:
Kamdar, K., Johnson, A. M. F., Chac, D., Myers, K., Kulur, V., Truevillian, K., & DePaolo, R. W. (2018). Innate Recognition of the Microbiota by TLR1 Promotes Epithelial Homeostasis and Prevents Chronic Inflammation. The Journal of Immunology, 201(1), 230–242. https://doi.org/10.4049/jimmunol.1701216
Johnson, A. M. F., & DePaolo, R. W. (2018). Infectious Scarring: Setting the Trigger for Intestinal Inflammation. Cell Host and Microbe. https://doi.org/10.1016/j.chom.2018.01.017
Johnson, A. M. F., Hou, S., & Li, P. (2017). Inflammation and insulin resistance: New targets encourage new thinking: Galectin-3 and LTB4are pro-inflammatory molecules that can be targeted to restore insulin sensitivity. BioEssays. https://doi.org/10.1002/bies.201700036
Johnson, A. M. F., & DePaolo, R. W. (2017). Window-of-opportunity: neonatal gut microbiota and atopy. Hepatobiliary Surgery and Nutrition, 6(3), 190–192. http://doi.org/10.21037/hbsn.2017.03.05
Li, P., Liu, S., Lu, M., Bandyopadhyay, G., Oh, D., Imamura, T., Johnson, A.M.F, … Olefsky, J. M. (2016). Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance. Cell, 167(4), 973–984.e12. https://doi.org/10.1016/j.cell.2016.10.025
Monibas, R. M., Johnson, A. M. F., Osborn, O., Traves, P. G., & Mahata, S. K. (2016). Distinct hepatic macrophage populations in lean and obese mice. Frontiers in Endocrinology. https://doi.org/10.3389/fendo.2016.00152
Lackey, D. E., Lazaro, R. G., Li, P., Johnson, A., Hernandez-Carretero, A., Weber, N., … Osborn, O. (2016). The role of dietary fat in obesity-induced insulin resistance. American Journal of Physiology - Endocrinology And Metabolism, 311(6), E989–E997. https://doi.org/10.1152/ajpendo.00323.2016
Johnson, A. M. F., Costanzo, A., Gareau, M. G., Armando, A. M., Quehenberger, O., Jameson, J. M., & Olefsky, J. M. (2015). High fat diet causes depletion of intestinal eosinophils associated with intestinal permeability. PLoS ONE, 10(4). https://doi.org/10.1371/journal.pone.0122195