Lisa Blum is an enterprising young scientist and postdoctoral fellow at Stanford University School of Medicine, working in the lab of Dr. Bill Robinson. Earlier this year she was recognized as a Bay Area Lyme Foundation Emerging Leader and received a $100,000 project grant. Here she talks about her research, life at Stanford, and the impact of the award.  

2014 Blum ELA picture Resized_156

Q: Earlier this year, your project, “Sequencing of Antibody Responses to Borrelia burgdorferi Infection — Generation of Recombinant Antibodies with Diagnostic and Therapeutic Utility” helped earn you recognition as a Bay Area Lyme Emerging Leader.  Tell us about your project and what you hope to accomplish.

Antibodies are proteins produced by the immune system that protect us from infections, but in some cases the antibodies themselves can damage the human body. Our goal is to characterize antibodies produced during different stages of Lyme disease, and to generate monoclonal antibodies that can be used to improve on existing Lyme disease treatments and diagnosis.

Q: What is DNA barcoding? How might a layperson understand what you are doing?

Each of us is capable of making more than 10 million different antibodies at a given time, and this diversity is what gives us the ability to protect ourselves against thousands of different pathogens we could potentially be exposed to (bacteria, viruses, etc.). Each antibody is produced by several genes within a single B-cell, and in order to produce more of an antibody and find out what it binds to, we need to pair those genes together. One of the major challenges in understanding antibody responses is finding out which gene sequences came from the same B-cell. We address this by adding a DNA barcode (a unique synthetic DNA sequence) to the genes from each cell before pooling hundreds or thousands of cells together for next-generation sequencing.

Lisa Blum in Lab_DSC_0252

Q: What are the implications for Lyme patients? Once you are able to sequence and characterize the antibodies, how will that lead to new diagnostics or treatments?

Although the sequences themselves can give us interesting scientific insights into Lyme disease, the most important direct implications for patients will be from the monoclonal antibodies we produce. If our method uncovers antibodies that can bind and neutralize Borrelia, these antibodies could be used therapeutically to replace or assist antibiotic treatment. The same monoclonals would also be useful as improved positive controls in diagnostic assays that measure antibodies in patient serum.

Q: You are looking at three different types of patient samples — early and late untreated Lyme disease as well as post-treatment Lyme disease samples. Explain why?

Patients who don’t get antibiotics until late in the disease (months after the initial infection) can develop antibodies that protect them from being re-infected with the same strain of Borrelia, while those who are treated early in the infection usually don’t. At the same time, there are some patients who develop mild or acute symptoms, while others develop post treatment Lyme disease (PTLD) and become chronically ill. This heterogeneity makes it difficult to understand Lyme disease by looking at only one subset of patients. We want to learn more about the differences between these groups of people by studying the antibodies produced by plasmablasts (a specialized type of B-cell) during each stage of disease.

Q: This technology has been used to characterize rheumatoid arthritis and influenza.  How or in what way has that work informed this project?

During an immune response, B-cells divide to increase in number. As they divide, the antibodies produced by these ‘daughter’ B-cells mutate and become slightly different from each other. We refer to these groups of related antibodies as clonal families. One of the major findings of our Influenza study was that antibodies from clonal families were more likely to bind to Influenza proteins, and they bound 100 times more tightly than ‘singleton’ antibodies (antibodies where we didn’t observe any clonally related sequences). We have used this information to help us decide which antibodies from each Lyme disease patient will be expressed and analyzed at the protein level. We believe that clonal family antibodies are likely to have the same importance in Lyme disease as they do for Influenza.

Q: Why has it been so difficult to develop more accurate diagnostics for Lyme disease? What are the biggest challenges?

Lyme disease diagnosis is difficult because different patients make different antibodies during infection, and a single test may not detect them all. On top of that, people with other infections or illnesses can sometimes make antibodies that behave similarly to those generated by Lyme bacteria, leading to false positives. PCR tests will only come up positive if there are sufficient numbers of Borrelia in the sample while culture tests can take months for a definitive result. In the future, tests to detect anti-Borrelia antibodies may use multiplex platforms to compensate for the heterogeneity of antibody responses between individuals.

Q: Tell us about how winning the Emerging Leader Award has affected your research this past year.

Winning the ELA has brought me a number of chances to talk directly with people whose lives have been affected by Lyme disease. They all want to know how it’s possible that we still don’t have sensitive, accurate testing and more efficient treatments for Lyme disease. Hearing their stories gives me extra motivation to keep pushing forward with this project.

The funding itself has also been hugely enabling. Priorities for federal research funding are based on a variety of factors, including politics, scientific interest, and the prevalence of each disease. Due to the challenges in diagnosing Lyme disease, its prevalence is likely to be underestimated. Funding such as that provided through the ELA enables researchers like me to work on Lyme disease, rather than on infections that are given higher priority in the national research agenda.

Q: Have there been any surprises in the work so far?

So far, we have been getting results in line with what we expected at the start. Science is all about the unknown, so a surprise could still happen at any time!

Q: A successful outcome on this project will lead to what next?

A successful outcome will be to produce and characterize a panel of Borrelia-specific monoclonal antibodies, and the next steps would be studying the protective effects of these antibodies. We ultimately want to test them in vitro and in vivo to see if they can neutralize Borrelia and prevent or cure an infection.

Q: You did your undergraduate work in food science.  How did you come to study immunology and Lyme disease?

When I was an undergraduate in food science, my main interests were food microbiology and food-borne diseases. I worked in a lab studying new methods to prevent E. coli infection, and then a different lab where I worked on a diagnostic test for food-borne parasites. Later it seemed like a natural transition for me to switch from studying the organisms that cause disease to studying the way the human host responds to these infections.

Q: Knowing what you do about Lyme disease, what do you think is most important for the general public to understand about Lyme?

Especially in this part of the country, a lot of people don’t check for ticks after spending time outdoors. I think the most important thing for the general public to be aware of is that they can get Lyme disease from a tick bite in California (and 48 other US states as well as countries around the world!), and tick bites also have the potential to spread other infections. Checking yourself for ticks only takes a minute and should be part of the outdoor routine, just like putting on sunscreen before you leave.

Q: Moving to Stanford from Cornell must have been a big adjustment — what do you enjoy most about the Bay Area?  What do you miss most from New York?

I’m originally from California, but I spent almost 10 years in NY state. It’s great to be back, and I love living in the Bay Area. There are always so many exciting things going on here, and it’s great to be able to bike to work year-round. What I really enjoy most is living closer to my family. I do miss having ‘real’ seasons (e.g., a Fall where the leaves change), but I definitely don’t miss waking up early every morning to scrape the ice and snow off of my car.

Q: What do you know now that you wish someone had told you when you were first starting your research career? How might you advise someone else just getting started?

Research isn’t like a class in school, where you can potentially get 100%, A+. It’s more like baseball, where successfully hitting 3 out of 10 makes someone a world-class player. Even for the most meticulous scientists, not every idea pans out, and sometimes experiments just don’t work and we don’t know why. I’ve noticed that this can be a very difficult transition for some of the students I work with, who are used to getting high scores on everything they do. You have to be able to persevere, without focusing on the things that didn’t work, because just one hit can be incredibly rewarding.

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