In Their Own Words: Science and Serendipity

A career at Los Alamos has taught bioscientist Babs Marrone the value of team building, taking scientific risks, and going with the flow.

August 25, 2023

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I was twenty years into a successful career in biology when I decided to change direction, for the second time. Having grown up in lush, green New England, my garden in New Mexico could never quite compare, and I had grown acutely aware of the impacts of drought on my environment. I began to think more about the existential threat of climate change. As a human on this planet, I could see the looming crisis for everyone. But as a human scientist on this planet, I wanted to do something to help. Serendipitously, my colleagues at Los Alamos were talking about building a biofuels program, so I embraced the opportunity to jump in.

My work in the biological sciences until that point had spanned neuroscience to DNA sequencing to bioforensics, and my expertise in a technique called flow cytometry had been an essential tool for each of these endeavors. I saw ways flow cytometry would be an asset to developing biofuels, and I was eager to develop the technology to do it. My jump into biofuels was in about 2008, and since that time, we’ve made a lot of progress in the field. But the truth is that the challenge of climate change and transitioning to clean energy will take technologies that have not yet even been invented.

I worked on the Human Genome Project (HGP) when I first came to Los Alamos in the mid-1980s. Thinking about it now, I see a lot of parallels between where we were at the start of the HGP and where we are today, beginning our transition away from fossil fuels. I really feel like we are at a tipping point. In the 1980s, we knew we needed a cultural revolution in biology to embark on sequencing the genome, but we also knew that we did not have the tools and technologies in hand to complete the work. Somehow, with national labs, universities, industry, and the government pulling together, we succeeded—in part by developing novel technologies along the way.

I see us in a similar situation now, with goals to achieve carbon neutrality by 2050 to limit the course of climate change. We have started this process with the science and technologies available today, but we must continue to create new technologies to get us to net zero emissions. We must be receptive to new perspectives and opportunities, and remember that science can be transformed in ways that we have not yet envisioned. Creating a sustainable future where the bioeconomy (making products using biology) will play a central role will be another all-hands-on-deck effort. We can’t take our foot off of the innovation pedal; there is too much at stake.

Should I stay or should I go?

I came to Los Alamos in 1985 to join a burgeoning neuroscience group in the Life Sciences (now Bioscience) Division. I had already begun to establish my research in neuroendocrinology; I was evaluating a class of cells in the female reproductive system and their role in hormone production. I had read about a technology developed at Los Alamos in the 1960s called flow cytometry and I immediately saw how I could apply it to my project. Flow cytometry is a technique that analyzes and sorts single cells, and it would give me a way to quickly characterize the cells I needed to study at different stages of their development.

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Schematic for the first flow cytometer (circa 1965) invented by Los Alamos scientist Mack Fulwyler. Flow cytometers are now used worldwide in research and clinical labs. The device uses vibrations to create droplets from a stream of solution. Cells or particles suspended in the solution then become entrained in droplets, and a charge is applied so that droplets can be sorted according to their volume or size using light scatter or fluorescence. Droplets of interest, now separated from the rest, can be analysed further.

The invention of flow cytometry is one of my favorite innovation stories. In 1965, a Los Alamos scientist named Mack Fulwyler was evaluating blood cells in solution and needed a way to quickly identify and isolate specific types of cells for further study. After reading about the invention of the ink-jet printer, which uses vibration to create a stream of individual tiny ink droplets, he was inspired to create something new. Fulwyler’s prototype flow cytometer suspended blood cells in droplets of solution, making them easier to separate and sort than if they were in a steady stream. It has been more than forty years since I first read about Mack Fulwyler, and I am still amazed by the brilliance and serendipity of this origin story.

Today, flow cytometers are ubiquitous in research and clinical labs worldwide, but in the 1980s, flow cytometers were Lab-built, one-of-a-kind, and large—the instrumentation and data acquisition system filled an entire room. I relied on flow cytometry to analyze different cell types from chicken ovarian follicles and I spent my first years in the Life Sciences Division creating a model system to study hormone production. But flow cytometry wasn’t the only thing that attracted me to Los Alamos; I was also drawn to the interdisciplinary research environment. Other members of our neuroscience team were developing superconducting quantum-interference devices to measure magnetic fields and their associated activity in specific brain areas. I found it exciting to work with electrical engineers, physicists, and brain physiologists.

It was disappointing then—but perhaps fortuitous—that less than two years after my arrival, the Laboratory was reorganized and the division leader who had recruited our neuroscience team moved on to another position. Twenty of us neuro-team members were given a choice: find a different project or leave the Lab. I had been fascinated by the brain and behavior since my first days of college, but there I was, faced with the prospect of completely changing my scientific focus. Through my connection with flow cytometry I was able to join a new group that was forming—it was led by a physical chemist named Dick Keller and he needed biologists. With that, I decided to change direction; I joined the Keller team and began a new adventure at the intersection of flow cytometry and DNA.

Genomic revolution

Genetic sequencing—determining the order of molecules that make up DNA—was relatively new and Los Alamos had launched a publicly shared database, called GenBank, to collate all the sequences being generated. The first DNA molecules to be sequenced were single genes for specific studies. The technology existed to sequence more DNA but it was slow—and to sequence an organism’s entire genome would be complicated.

Los Alamos also established a National Flow Cytometry and Sorting Resource (NFCR), funded by the National Institutes of Health (NIH), to create and use novel, purpose-built flow cytometers, including one that would analyze and sort chromosomes, which are highly organized bundles of DNA. This capability was developed in parallel to the Department of Energy (DOE)–funded National Laboratory Gene Library Project (with Lawrence Livermore National Laboratory) to make cloned and ordered “libraries” of DNA fragments, representing each of the 24 human chromosomes, for distribution worldwide to other scientists.

The ability to isolate these libraries laid the foundation for sequencing a highly complex organism, such as a human, because the libraries could facilitate distributing the work: different labs could tackle different chromosomes. Leaders at Los Alamos and elsewhere began to discuss the possibility of sequencing the entire human genome and the DOE and NIH officially teamed up beginning in 1988 to embark on the HGP in collaboration with 20 international partner institutions and thousands of scientists.

Science can be transformed in ways that we have not yet envisioned. 

Being a part of the HGP was truly exciting, and with the Keller team I helped invent a new approach to speed up the sequencing process. We developed a way to use flow cytometry to sequence a single strand of DNA. This approach was in contrast to typical sequencing at the time, which relied on many thousands of copies of DNA fragments to create a detectable signal using a technique called gel electrophoresis. Our single-molecule project was probably two decades ahead of its time and I would not have had an opportunity like that anywhere other than at Los Alamos.

In hindsight, most people see the HGP as the foundational milestone that it was, but at the beginning I remember many in the scientific community were skeptical. One of the concerns was the scientific leap of faith: sequencing technology in 1987 was slow and tedious and the HGP would require monumental advances in sequencing that had not yet been envisioned. But they happened. By investing money—about three billion dollars—and trust in scientific collaboration, the innovations happened. The sequencing technologies that were developed during the HGP were only the beginning and ultimately spurred a genetic revolution that completely changed the future of biological research. Today, sequencing is fast, inexpensive, and an essential component of most research projects.

Bacterial whodunnit

During and after the HGP, my colleagues and I were inspired to use our flow cytometry method of sequencing DNA to benefit other areas of biology. At the time, it was becoming more widespread to identify individual people using a technique called DNA fingerprinting. For instance, a paternity test would compare a parent’s DNA with that from a child, or a criminal investigation would compare a crime scene sample with DNA from a suspect. The standard approach used DNA sequence–specific enzymes to break the DNA into fragments, and then put them into a gel electrophoresis device to view their relative sizes. If the two samples showed fragments of the same size, then the DNA “fingerprints” were considered a match.

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Babs Marrone (front row, 4th from the left) and fellow team members pose for a photo to celebrate the Los Alamos National Laboratory Distinguished Performance Award for The National Flow Cytometry Resource in 1993.

My team and I developed a novel technique to do the same type of analysis using flow cytometry instead of a gel to determine the sizes of the DNA fragments. Our patented DNA fragment sizing flow cytometry instrumentation was highly sensitive and sped up the analysis process significantly. It also enabled a broader range of fragment lengths to be simultaneously evaluated. The NFCR supported our work for several years, and we developed various approaches to identify bacteria in food and medical or environmental samples. We also participated in programs for the DOE and the Federal Bureau of Investigation (FBI) to develop our fingerprinting approach as a way to rapidly identify pathogens.

In 2003, when the Department of Homeland Security was created, Los Alamos became a partner in the National Bioforensics Analysis Center, and our pathogen detection method was transitioned to these organizations. We used our fragment-sizing technology to identify variations in the genomes of potential threat organisms. For instance, the bacterium that causes anthrax, Bacillus anthracis, can easily be confused with its non-lethal cousin, Bacillus thuringiensis, if a scientist is just looking at the bacterium under a microscope. But our highly specific, sequence-based detector could accurately distinguish between the two Bacillus species. I worked closely with the FBI for several years as part of their Scientific Working Group on Microbial Forensics, during which time we produced guidelines and several journal articles about sampling and handling microbial evidence.

We can’t take our foot off of the innovation pedal; there is too much at stake.

Flow cytometers were tools we used for these projects, but our success hinged on the fact that scientific tools are not static. We redesigned and adapted the concept of flow cytometry to meet the needs of each scientific challenge. This is what we have to do to meet our challenges with climate change. We must look at our current tools not as final solutions in their own right but as jumping-off points to get us to the next level of innovation.

When machines meet microbes

It was after this extensive work in bioforensics that I changed course in 2008 to tackle bioenergy and the threat of climate change. As the HGP was finishing in the mid-2000s, the DOE formed the Joint Genome Institute and our scientists began to focus on sequencing the genomes of microorganisms deemed valuable for various purposes, especially bioenergy. For instance, photosynthetic microbes such as microalgae and cyanobacteria could be used to produce biodiesel. By sequencing these photosynthetic microbes’ genomes, we could learn which species are best suited for biofuel production on a large scale, and we could look for other species that shared the same characteristics. I immediately saw how flow cytometry and cell sorting could facilitate this screening process. I felt passionate about reducing our dependence on nonrenewable resources in the future, and I was ready for a change. Our first major DOE program, the National Alliance for Advanced Biofuels and Bioproducts (NAABB), was a Los Alamos–led consortium of 39 institutions that focused on developing algae-based fuels and products. Although the NAABB ended in 2013, it ignited my passion for biofuels and bioproducts and helped us establish the bioenergy capability in the Bioscience Division that continues today.

It is clear to me that bio-based innovation is critical to meet the challenges of climate change. For instance, although biofuels have been tricky to implement on a large scale, they are now being blended with conventional fuels for use in current combustion engines to reduce emissions. Biofuels are also considered transition fuels for hard-to-electrify transportation sectors such as aviation. Bioproducts that are better for the environment, like biodegradable plastics, are being developed to replace conventional ones, reducing both plastic pollution and petroleum consumption. Finally, advances in biomanufacturing, such as making chemicals or materials from plants and other organic material, or using microbes as machinery for mass production, will accelerate our ability to achieve national carbon neutrality goals by 2050.

Among my many bioenergy projects, one close to my heart began in 2018 when my colleagues and I decided to tackle the problem of plastic pollution with a large, multidisciplinary project called BioManIAC (BioManufacturing with Intelligent Adaptive Control). This project included experts in biology, chemistry, and machine learning, and our goal was to create a unique process for designing novel bioplastics. We identified biopolymers, the building blocks of bioplastics, that microbes could produce or degrade and compared them to traditional plastics. We studied the relationship between the chemical structures of biopolymers and their physical properties, like melting temperature and elasticity. Machine learning helped us bypass much trial-and-error research as we looked for the optimal biopolymers to make new kinds of bioplastics that would do the job of conventional plastics, but also more easily biodegrade when they are no longer of use.

A seat at the table

As I look to the future and the promising initiatives that stand to make clean energy a reality, I know this is an opportunity not only for scientific innovation but also for diversity and inclusivity. If we make it a priority at the outset and plan to include women and local communities in the new energy economy, then we can set the example. Women are historically underrepresented in many areas of energy science like physics and engineering, as well as in the fossil-fuel industry itself. If we can make space for women in the new clean-energy economy, everyone will benefit. Job creation and support services for women will ultimately create strong, vibrant communities.

It is important to get this right. I have seen firsthand how well-intentioned rules to prevent discrimination can backfire, or how diversity measures can come across as token gestures. For example, when I came to the Lab in 1985, all technical women in the Life Sciences Division were assigned to the division office instead of the individual technical groups. Although this was probably an effort to protect us from discrimination, in reality it marginalized us.

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Graduate student Marcos Hernandez demonstrates the elasticity of a new blend of polymers to determine its feasibility as a building block for new bioplastics. Understanding how the elasticity of a polymer is related to its chemical structure is a key aspect of the BioManIAC project's goal of designing novel bioplastics.

Fortunately, the situation for women scientists at the Lab has improved significantly during my tenure. We have more seats on committees, we have more leadership roles, and we have more flexibility to help balance work and life. The number of times I’m the only woman in the room or the only woman on the team has decreased. We’re almost there, but it has taken a long time and there is more to do. Access to childcare remains a challenge. When I was pregnant with my daughter in 1993, there were only four daycare slots available in town for infants, and she got the last one. I guess that is another serendipitous turn of events because I do not know where my career would be if we had not lucked out with that daycare spot. Sometimes it can be the most basic things that make or break a career.

My accomplishments are inextricably tied to the many colleagues I have had the honor to work with: peers, postdocs, and students as well as supportive management. At Los Alamos, I have had the opportunity to serve as a team leader, a group leader (three times), and a program manager. Through the breadth of these experiences, I have seen that a supportive community is key to all successes—scientific, institutional, or personal.

Bio @ LANL

Throughout my career at the Lab, I have often been asked, “Why is there a bioscience group at Los Alamos? Isn’t it a national security lab?” The answer is in the question. Bioscience research at Los Alamos began in 1947 to study the effect of ionizing radiation on the human body. This initial quest led to decades of innovation, and branched into bioscience achievements that support national security in multiple ways. Some were directly related to Laboratory nuclear programs, such as developing flow cytometry–based diagnostic tests to determine a nuclear worker’s sensitivity to beryllium (a precursor to chronic beryllium disease). Other programs address national security more broadly, such as work by Lab bioscientists during the COVID-19 pandemic to model disease spread, identify how the virus is evolving, and develop new approaches for detection.

One of the reasons bioscience has an important place at Los Alamos is the same reason I was attracted to the Lab at the beginning of my career: modern biology is very interdisciplinary. Solving big problems in climate change, energy, health, and the environment requires that biologists work with physicists, chemists, mathematicians, and engineers. I truly believe that innovation occurs at the intersection of disciplines, and future advances in bio-inspired technologies will take a concerted effort from all of us. In fact, flow cytometry itself is a perfect example of how unrelated endeavors can converge to create something novel. Serendipity may happen, but fostering an environment where scientists from different backgrounds and specialties can work together is key to facilitating new solutions to problems.

The parallels between the past and present are very clear to me. In looking to achieve carbon neutrality, we do not yet have all the tools. This is today’s “big science” challenge. If we work together, calling on the international community and combining our expertise, we will create the innovations that are needed. And thirty years from now, those new tools will be ubiquitous.