National Security Sciences Building at Los Alamos National Laboratory. Courtesy/LANLLANL News: A multidisciplinary effortLos Alamos National Laboratory, like many of the Department of Energy national laboratories, is drawing on its rich history in the biological sciences to actively engage in the national effort to study, understand, and answer important questions about the COVID-19 outbreak. Areas covered include disease detection and diagnostics, epidemic modeling, disease prediction and forecasting, decision support, data collection and integration, and medical measures.“Over the last several weeks, the Laboratory has taken extraordinary steps to preserve the ability to execute our mission while assisting our surrounding communities, the state, and our nation during this demanding national emergency,” Los Alamos Director Thom Mason said. “Many are looking to the Laboratory for resources including our expertise, technology, and materials to help combat the COVID-19 virus.”Los Alamos is providing decision-support for business and government, Director Mason said.“We are also collaborating with other national laboratories in the Department of Energy complex to develop an alternative COVID-19 testing method and are evaluating the potential of advanced manufacturing, specifically 3-D printing, to produce scarce medical equipment,” Mason said.Los Alamos’ work in detection and diagnostics is being leveraged to optimize assays for detecting COVID-19 and bioinformaticians are looking at its close genetic relatives to analyze the virus’ evolutionary relationships to other viruses that have been studied. Epidemiological modeling centers are focusing on predicting disease spread to support decision making by government and health agencies. The modeling efforts relies on data collection, data integration, and experienced researchers who can answer questions for decision makers. Medical therapeutics efforts are focusing on ways to leverage our expertise in vaccine optimization, small-molecule discovery, and toxicity testing.A rich history in biological sciencesLos Alamos has decades of experience integrating expertise across biology, chemistry, theory, and engineering. This multi-directorate focus of the Laboratory started in 1945 with studies of radiation health effects, expanded to the impact of radiation on DNA, and went on to include the Human Genome Project in Los Alamos. The Laboratory started GenBank, which is now the repository of DNA used in COVID-19 research.Over the years, Los Alamos has also developed deep expertise in bioinformatics—the information science side of biology.DetectionDetection and modeling begin with understanding historical outbreaks. A Los Alamos database catalogues historic information for key outbreaks of nearly 40 different diseases. That information helps responders select the historic similarities to each new situation, even as an outbreak evolves over the first hours and days. “When an outbreak occurs, we can look at these tools and see if it’s matching what we’ve seen historically,” said Kirsten Taylor-McCabe, a biochemist and national security and defense program manager at Los Alamos. “If it’s not matching, it alerts us that something might be different. It also shows us what happened in the past that people used for mitigative actions, such as contact tracing, vaccination and therapeutic campaigns, and social distancing. Did they work well? What lessons learned can we take away from actions taken in past outbreaks?”Los Alamos has a long history in computational design assays, which assess or measure the presence of pathogens. Bacteria and viruses evolve over time and researchers learn more about their genomes on a daily basis. This information is utilized to optimize assays.“They erode over time,” Taylor-McCabe said. “We need to keep pace with that and deliver assays that will be functional for COVID-19 or for future outbreaks. For diagnostics, we’re trying to leverage ways that we understand the host’s innate immune system. How can we triage what’s going on in the field? How can we understand if you have a bacterial or a viral infection? At Los Alamos, these are the techniques we are trying to leverage for this COVID-19 outbreak.”TestingLos Alamos is leading a Department of Energy–wide laboratory working group on COVID-19 testing and participating in assessments of lab capabilities for near- and long-term testing requirements, both for public health and for the Los Alamos enterprise.COVID-19 modeling“Modeling the epidemic sheds light on its growth rate, time of origin, future case counts, and the effectiveness of mitigation strategies,” said Nick Hengartner, leader of the Theoretical Biology and Biophysics group at Los Alamos. “Realistic epidemic models enable decision makers to validate data quality and play what-if scenarios.”Virus spread“For modeling, we’re looking at the spread of disease. We’re looking at it globally, all the way down to the county level,” Kirsten Taylor-McCabe said. “So in New Mexico we’re looking at the county level, we’re looking at how the disease is spreading, what the forecasts are for when we will see a peak in cases, how many people might be hospitalized, how many people may be in the ICU, how many might need ventilators, both from no intervention scenarios all the way through to high intervention scenarios.”“Because we have those physical models that are reasonably realistic and we can model them at low levels of geographic aggregation, it allows us to actually validate the data,” said Nick Hengartner. “One of the things that comes out is that we believe that we don’t see everyone who is sick at this time. That is something that our model is able to tell us. It’s also able to tell us if the mitigation strategies that we are implementing are working because we can compare what the models predict with the actual data that we are collecting.”Genetic research“Part of the modeling also uses the basic law of biology—evolution,” Hengartner said. “Things evolve, and by looking at how viruses evolve and putting them in context of related organisms, which is what a phylogenetic tree shows, we can make several conclusions. For example, we know now that COVID-19 is related to but not the same as the SARS virus. We can also see that COVID-19 evolves relatively slowly, which is good news.”The phylogenetic tree also shows close genetic neighbors or related viruses that have been found in bats and pangolins.“When we look at genetic-sequence similarity and we compare it to others, we see that this particular virus not only made use of point mutation, or very small genetic mutations, but it also rearranges its genome a little bit,” Hengartner said. “And looking at the patterns and how it has been rearranged and point mutations, we are very confident to say that this follows what we would expect from a naturally emerging and evolving organism.”Medical measures“One of the interesting proteins of the coronavirus is the crown—it’s those spikes,” Hengartner said, referring to the spiky protuberances that can be seen in microscopic images of the virus. “Those spikes matter because they attach themselves to the surface of a cell and then somehow inject the virus’s RNA into the cell and that’s how the infection happens. For that to happen, this attaching to the cell membrane, there are two receptors. It turns out that having two ways for the virus attach to itself to the membrane is actually not common, and one of these receptors is in the upper lung and the other one is in the lower lung,” Hengartner said.This may give a hint about how COVID-19 progresses as a respiratory disease.“Now that we know that it binds with those receptors, this provides us with an opportunity to say ‘well, are there any therapeutics that could mitigate or disrupt this kind of behavior?’” Hengartner said. “Just looking at the structure of the molecule gives us an idea about what kind of molecules or drugs we should be looking for.”Developing artificial human organs for drug testing“When we have these drug candidates, it would be fantastic to be able to test them rapidly in a human-based system, something that’s clinically relevant to the human,” Taylor-McCabe said. “Right now, drugs go through animal testing. At Los Alamos, we’re trying to bridge that gap with a human organoid platform that would better mimic what would happen within the human host. Our project includes an artificial human heart, lung, and liver. These are systems that would be able to screen some of the drug candidates that are out there.”Supporting vaccine development“People are feverishly trying to develop a vaccine and have already designed vaccines that are in testing phase, but at Los Alamos, we also want to look into the future,” Hengartner said. “One of the risks that we’ve recognized with this coronavirus is that there is an immense pool of other coronaviruses hiding in bats and pangolins and snakes and what not. We would like to come up with a strategy to protect us, not just against this particular strain, but maybe next year’s jump, too.”Los Alamos’ research in this area draws on its experience designing an HIV vaccine, which recently underwent human trials. HIV mutates extremely quickly, giving it a broad diversity that is difficult to address with a single vaccine. Los Alamos addressed that problem by creating a “mosaic” vaccine that is a patchwork of HIV genomes.With COVID-19, Hengartner said, “it doesn’t mutate that fast but we have a broad diversity, so if we can use similar mosaic strategies, we can start thinking about designing a vaccine that will protect us from future infections and outbreaks—and nip this one in the bud at the get-go.”Manufacturing“On the manufacturing side of the house, Los Alamos has been working in a DOE-wide working group, participating in assessments of how the labs can support the need for ventilators, masks, face-shields, and consumable parts for lab testing,” Kirsten Taylor-McCabe said. “We’re in the deep dive phase, trying to figure out how we can help and what is the best way that we can work with the commercial sector.”Research Collaborations with Los AlamosThe Biosurveillance Gateway is a Los Alamos website housing data about the pandemic and giving outside researchers an entry point for accessing Laboratory expertise in COVID-19 modeling, diagnosis, and decision support.“You can also look at who to contact for some of these efforts and submit questions, which we will triage and try to link you up to the scientists that are working in this area,” Taylor-McCabe said.Kirsten Taylor-McCabe is a biochemist and national security and defense program manager, and Nicolas Hengartner is leader of the Theoretical Biology and Biophysics group at Los Alamos National Laboratory.