Face to Face Feature: Dr. Joseph Bondy-Denomy, Ph.D.

UCSF Faculty Fellow
University of California, San Francisco
Department of Microbiology and Immunology

Common Fund Connection: Dr. Bondy-Denomy is an Early Independence awardee.

Briefly tell us your discipline and where you are conducting your research.
I study how bacteria protect themselves from viral attack. The viruses that infect bacteria are called bacteriophages (literally, “bacteria eaters”) and have been studied for more than a century to understand their potential use as a therapeutic and as a model system to understand many fundamental aspects of biology. I study an immune system that bacteria have, called CRISPR-Cas, which they use to block bacteriophage infection. In my lab at UCSF, we study the ways in which bacteriophages combat the CRISPR-Cas system and inactivate its function. We are also interested in the response from the CRISPR-Cas system itself, and the potential alternative functions that it may fulfill for the bacterium.

Can you tell us about your research?
Bacteria are the most widespread and successful organisms on the planet. There are also more bacteria in our bodies than our own cells, and while the famous ones make us sick, most are simply using our bodies as a vessel and some are even good for us. Interestingly, bacteria can get sick too, when infected by very specific viruses that only attack bacteria. I am interested in how bacteria defend themselves attack by these viruses. This question has been around for decades and we continue to discover interesting ways that bacteria defend themselves and these discoveries teach us new things about fundamental aspects of biology. We like to think of bacteria-virus interactions as a battlefield at the molecular level, and we are excited to discover the weapons each side brings to the fight. 

Why did you become an scientist?
As an undergraduate at the University of Waterloo, I fell in love with microbiology in my lectures and more importantly in the lab. Working at Western University and McGill University as a co-op student gave me the opportunity to see what it is like to be a full time lab researcher and I loved it so much, I knew I had found my home. I found a great lab at the University of Toronto for my PhD and haven’t looked back!

Can you share a story about the first time you made a breakthrough in the lab?
Breakthroughs for me are an accumulation of experiments. One can never let themselves get too excited about a single result, because it could disappear so quickly. The desire to repeat the experiment and test assumptions in an orthologous manner is essential. Having said that, over the course of ~1 month, where I thought I had discovered bacteriophage genes that turn off the CRISPR-Cas system in Pseudomonas aeruginosa, was undoubtedly the most exciting time of my career thus far. 

What advice would you give to someone just starting out as a researcher?
Do experiments. Do a lot of experiments. Read papers, talk to smart people, develop your ideas and then test them. Look hard at the data, don’t ignore things that seem to not make sense, and then repeat!

What are you most proud of in your work?
I am most proud that I am contributing to opening up a brand new field of research within the field of CRISPR-Cas and the world of microbiology. Beyond the science itself, I am happy to have generated something that others can now work on to expand our body of knowledge rapidly. 

What scientific fact/finding in science still surprises you even though it is well-known?
The amount of information stored in DNA, such a ‘simple’ array of four bases. What it can code for, how it has a built in mechanism for high-fidelity replication, and how much we still need to learn about what it all means. 

What scientific breakthrough would excite you most?
From the standpoint of the medical community, an effective HIV/malaria/TB vaccine would be the most exciting for me. From the basic science standpoint, the best breakthrough would be one I can not predict. It is something that would make me say “no way…” 

If you could have one day in another profession, what would you want to do?
No question about it, I would be playing baseball for the Toronto Blue Jays. 

In the past 30 years, what discovery do you think has had the greatest impact on biomedical research?
If I can call it a discovery, high throughput sequencing. This has led to so many new discoveries, tools, applications, etc. And now, in the last ten years, I would say that CRISPR technology, coupled with HTS is an added layer on the incredible utility of HTS.

Face to Face Feature: Dr. Deirdre R. Meldrum, Ph.D.

ASU Senior Scientist
Director, Center for Biosignatures Discovery Automation
The Biodesign Institute at Arizona State University
Professor of Electrical Engineering in School of Electrical, Computer, & Energy Engineering
Arizona State University

Common Fund Connection: Dr. Meldrum is a Single Cell Analysis and Library of Integrated Network-Based Cellular Signatures (LINCS) awardee.

Briefly tell us your discipline and where you are conducting your research: My degrees are in Civil Engineering (B.S.) and Electrical Engineering (M.S., Ph.D.). I perform research that requires the integration of multiple disciplines including biology, genomics, and medicine with engineering, physics, biochemistry, computing, bioinformatics, modeling, control systems, automation, and materials science to address research and development challenges at the boundary between human health and disease, the health of the environment, and the invention of technologies designed to measure the critical parameters that govern the outcomes. I am conducting my research with a highly interdisciplinary team in the Center for Biosignatures Discovery Automation in the Biodesign Institute at Arizona State University.

Can you tell us about your research?
Our first Common Fund project, entitled “In situ single cell laser lysis and downstream qRT-PCR profiling,” is part of the Single Cell Analysis Program with the goal of understanding the link between cellular heterogeneity (cells that are different or diverse), tissue function and emergence of disease.  This investigation is especially important to the understanding of cancer because tumors are highly heterogeneous.  We developed an innovative system called Single-cell QUantitative In-situ RT-PCR (SQUIRT-PCR) that can analyze each individual cell in a tissue while maintaining the 3D spatial information of the cell in the tissue. SQUIRT-PCR uses a microfluidic platform combined with a two-photon laser to serially lyse individual cells at known coordinates within a 3D tissue fragment. The contents of each cell are harvested for downstream analyses such as DNA sequencing, gene expression analysis by qRT-PCR or RNA-seq, or mass spectrometry for proteomics. We have developed the system for broader use in basic research and disease diagnostics in the clinic.  

Our second Common Fund project, entitled “Live-cell microarray for high-throughput observation of metabolic signatures,” is part of the Library of Integrated Network-Based Cellular Systems (LINCS) Program.  LINCS is a multi-dimensional database representing a variety of cells exposed to perturbagens and their respective responses. Computational tools enable researchers to utilize this network of information to understand cell pathways, view normal and disease states, discover biosignatures, and develop new therapeutics. The goal of our LINCS project was to make measurements of the dynamics of O2, pH, glucose, ATP, and potassium at the single-cell level in a high-throughput microarray assay to provide biologists with novel, biologically relevant insights into cell metabolism and the underlying mechanisms. Our system, called the Cellarium, is a new class of microarray technology that allows dynamic, high-throughput metabolic measurements of live single cells. The data produced from the Cellarium is useful for the LINCS database as well as research, discovery of biosignatures for disease diagnostics, and drug screening for therapeutics.

Why did you become an engineer?
I always enjoyed science, math, and architecture while growing up. I think it was the combination of my curiosity for how things work, the satisfaction in figuring out solutions and the beauty of structural design that led me, ultimately, into becoming an engineer and researcher.  I was fortunate to participate in the Women in Engineering Program and Junior Engineering Technical Society while I was a junior in high school.  That was the beginning of an exciting career where I have had the opportunity to design structures for ships and submarines, design transportation systems, train astronauts on the Shuttle Mission Simulator, and perform research in robotics, genome automation, single cell analysis for human health, and Sensorbots for discovery in the oceans. 

What advice would you give to someone just starting out as a researcher?
There are many important things to do as a junior researcher including constantly asking the question “why”, making sure your research results are valid, gaining strong analytical skills, persevering to success, obtaining as much practice as possible presenting your results, working together with researchers from other disciplines, and meeting as many other researchers as possible to learn and share ideas with one another. Keep your eyes open for surprising opportunities that you can seize.

What scientific breakthrough would excite you most?
Cancer is one of the big unsolved mysteries of human disease. It would be a huge breakthrough to truly understand how cancer works and to figure out how to prevent it.  This would significantly benefit and impact human health.

What is a hobby or passion outside of the lab that you enjoy?
I love athletic sports --- running, bicycling, bicycle touring, swimming, rowing, hiking, skiing --- and travelling all over the world. I love my family and spending time with them.

If you could have one day in another profession, what would you want to do?
Explore space as an astronaut.

Assistant Professor of Cell and Development Biology
Perelman School of Medicine / University of Pennsylvania

Common Fund Connection: Dr. Bonasio is an NIH Director's New Innovator Awardee.

Background: Dr. Bonasio's laboratory is part of the Epigenetics Program at the University of Pennsylvania. Epigenetics studies the inheritance of biological traits without changes in DNA. For example, epigenetics explains how different cell types in a multicellular organism maintain their distinct identities through time and cell divisions despite the fact that they all have the same genome.

Can you tell us about your research?
Different cells in our body carry out different tasks although they all have the same set of instructions, or genes. Only some subset of genes is active in each cell type and the mechanisms that keep the other genes inactive have important roles in development, cancer, brain function, and, possibly, behavior.  Like cells in our body, ants in a colony are born with all sets of instructions, those to become queen and those to become worker, but at some point in their early life the caste of the individual is locked in place. We are using modern molecular biology and genetics to study how the different behaviors of queens and workers are specified from the same set of genes.

Why did you become a researcher?
I never thought I would do anything else. I was fascinated by how the world works ever since I can remember. Few things give me more satisfaction than solving a riddle and the world is full of them. 

Tells us why you chose Epigenetics as your field, what hooked you?
Two things: sectored yeast colonies and too many sex combs in fruit flies. Both of these phenomena were fundamental in discovering the molecular mechanisms of epigenetic inheritance and seemed almost magic the first time you read about them. 

In yeast, each colony is made of genetically identical cell but once in a while, if a gene is just in the right place, a daughter cell can “switch” and turn red while surrounded by white cells. This red phenotype is inherited and, as the colony grows, gives rise to a red sector, like a red slice in a white pie. All this without any changes to the DNA. It is still fascinating to this day. 

Sex combs are structures that only form on the forelegs of male fruit flies. A mutant with sex combs on the wrong legs was discovered in 1947 and called Polycomb. It turns out that the machinery that maintains cell identity is defective in that mutant and that the other legs “forgot” they are not supposed to be forelegs. Almost 70 years and 5,000 papers later, we still don’t fully understand how Polycomb works. How could you not get hooked by that?

What scientific fact/finding in science still surprises you even though it is well-known?
One of the biggest wonders of biology, for me, is that all organisms are part of the same life stream. You and the fruit fly (assuming you are not a fruit fly) share about two thirds of your genes. In many cases the corresponding gene taken out of the fruit fly and put into a mouse functions in the same exact way. This is why we can study some processes in model organisms and make discoveries that are at the same time relevant for basic biology and human medicine. Also ribosomes are not bad.

What is a hobby or passion outside of the lab that you enjoy?
I used to have computers as my hobby but the sequencing revolution has brought them straight to my daily professional life, so I fell back to family, friends, and my acoustic guitar. I also bake the occasional focaccia.

If you could have one day in another profession, what would you want to do? 
Jet pilot. I gave up on astronaut when I figured out I was colorblind. 

Professor of Immunology and Chair
Cornell University College of Veterinary Medicine

Common Fund Connection: Dr. August is a Strengthening the Biomedical Research Workforce awardee.

Background: I am an Immunologist by training and perform research examining signals that regulate the activation of immune cells in inflammation, particularly lung inflammation.  I have a faculty position at Cornell University.

Can you tell us about your research?
The majority of graduate students and post-doctoral fellows in universities are being trained for careers in academia, however few will actually get positions in academia. We are funded by the Common Fund to develop and determine the best approaches to broadening the exposure of graduate students and postdocs to experiences that better prepare them for the diversity of careers they may have once they complete their training.  This involves developing programming to expose our graduate students and post doctoral fellows to future careers including Science Communication, Science Policy, Business, Entrepreneurship & Management, and Government, Risk & Compliance.

Tell us why you chose your specific field of study, what hooked you?
I fell in love with Immunology after taking a course as an undergraduate student. I was fascinated by the fact that the immune system has the capacity to recognize almost any antigen, and the manner in which the immune system has evolved to recognize pathogens.

Can you share a story about the first time you made a breakthrough in the lab?
I was exploring the signaling pathway induced by the T cell co-stimulatory receptor CD28. After many tries trying to determine the pathway players, I ran an SDS-PAGE gel of proteins from T cells, and developed a western blot, probing with anti-phosphotyrosine antibodies to recognize proteins that were tyrosine phosphorylated. I noticed that there was a protein around 70 kDa that was heavily tyrosine phosphorylated, and had seen in the literature that a novel kinase had just been discovered which had the same size. I speculated that this was the kinase and once I was able to get antibodies against this kinase, I found that this kinase was the Tec kinase Itk.  I have been working on this kinase off and off for my whole career.

What advice would you give to someone just starting out as a researcher? 
I would suggest that someone just starting out get as much quantitative training as they can, to practice patience, and to read broadly. 

What scientific fact/finding in science still surprises you even though it is well-known?
The fact that there is a whole regulatory system that relies on small RNA specific still boggles my mind.  This system is layered onto the well established protein regulatory systems, and suggest that biological pathways are always more complex than we initially imagine.

What is a hobby or passion outside of the lab that you enjoy?
I enjoy listening to and mixing electronic music.

Assistant Professor
Ecology & Evolution
University of Chicago

Common Fund Connection: Dr. Cobey is a New Innovator Awardee.

Background: I’m in the Ecology & Evolution Department at the University of Chicago. It’s a great home for me because ecology and evolution force a “big picture” perspective on problems. My colleagues and I study the dynamics, such as competition and mutation, that structure populations of genes and species over different scales. 

Can you tell us about your research?
My group investigates the co-evolution of hosts and pathogens. We know in a general sense that many pathogens, such as influenza and HIV, evolve to escape host immunity, but we don’t understand the details. It turns out that when we’re exposed to a pathogen, parts of our immune system start mutating and evolving rapidly—over days to weeks—to recognize the pathogen. We’re trying to understand how immune populations evolve (they’re known as B cells, and they produce antibodies) so we can better shape them through vaccination. We also want to understand the specific selective pressures different B cell populations impose on pathogens so we can better anticipate pathogen evolution.

Tell us why you chose your specific field of study, what hooked you?
I’m excited by the idea that many patterns in nature can be explained by relatively simple processes, like evolution, simple models of growth and competition, and some degree of chance. The power of simple explanations presents the tantalizing idea that we might eventually know enough to predict what’s going to happen. If we could predict how pathogens evolve, or whether a vaccine will induce the right response in a person, it would be a beautiful demonstration of theory. The opportunity to indirectly reduce illness and suffering is also very important to me.

What advice would you give to someone just starting out as a researcher?
Progress in many areas is limited by analysis and insight, not data. This makes it all the more important to study math and statistics to help guide your thinking and identify patterns. But I think a basic curiosity about the way nature works is as important as technical ability. Simple questions about how and why things happen as they do can feel a little embarrassing when you first dive into the literature, but you should hang on to them and use them as a scaffold for new knowledge as you read and conduct research. And finally, if you don’t know something, don’t be scared: practice teaching yourself. 

What scientific fact/finding in science still surprises you even though it is well-known?
I can’t think of a more fundamental finding in my discipline, but I’m still surprised by the speed and apparent open-endedness of evolution. The emergence of pandemic strains of influenza and antibiotic resistance in bacteria is a constant reminder that new strategies are always around the corner. And yet they also reveal a vast space of things that we haven’t seen, or which appeared but failed to take off.

What scientific breakthrough would excite you most?
Building on the last question, I would like to understand the impacts of random chance, competition, and evolutionary constraints on the diversity of life. Could there ever be an airborne equivalent of HIV? Or unicorns? Have we not seen them (or more precisely, their intermediate ancestors) because they violate some basic physical requirements, were outcompeted, or never appeared in the first place due to chance? I’m not sure a single breakthrough could address this question, but progress would be exciting.

If you could have one day in another profession, what would you want to do? 
I would probably want to follow around an economist. It’s easy to draw parallels between ecological communities and economies, and I’d enjoy seeing how economists describe the distributions of firms, their dynamics, and economic stability. (In the interest of full disclose, if I were to answer this question in January, I’d be happy with just about any job somewhere warm and sunny.)