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Blood test may detect early signs of lung-transplant rejection

New blood test measures the DNA fragments of lung transplant donors in the blood of recipients, in hopes of preventing organ rejection and saving lives.

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Image by kalhh

After receiving a lung transplant, patients face the likely chance that their body’s immune system will reject the transplanted organ. Rejection can happen at any time due to a variety of factors such as a lung infection or an injury to the lungs during transplant surgery. The most deadly type of rejection is chronic lung allograft rejection (CLAD), which develops slowly and often silently without obvious symptoms.

Now, researchers have developed a simple blood test that detects tissue graft injury within the first three months after lung transplant surgery. After further validation, this non-invasive test could identify patients with a high risk of CLAD or death due to graft failure, allowing doctors to intervene early and possibly prevent chronic rejection.

“This test solves a long-standing problem in lung transplants: detection of hidden signs of rejection,” said Hannah Valantine, MD, co-leader of the study and a senior investigator at the National Heart, Lung, and Blood Institute, in a recent news release. “We’re very excited about its potential to save lives, especially in the wake of a critical shortage of donor organs.”

Valantine is also a Stanford professor of medicine and Kiran Khush, MD, associate professor of medicine, is a co-senior author.

The new test measures the amount of DNA fragments circulating freely in a patient’s bloodstream. Since the lung donor and recipients have different genomes, the test can identify and quantify the fragments from both people. If there are a lot more donor DNA fragments, this indicates that the organ is injured.

As recently reported in EBioMedicine, the researchers regularly monitored blood samples from 106 lung transplant patients during the first three months after surgery at several institutions, including Stanford. After dividing the patients into three groups based on the level of donor-derived DNA fragments in their blood, the team found that patients with higher levels were six times more likely to subsequently develop transplant organ failure or die than those with lower levels. And many of these high-risk patients didn’t have symptoms.

“We showed for the first time that donor-derived DNA is a predictive marker for chronic lung rejection and death, and could provide critical time-points to intervene, perhaps preventing these outcomes,” Valantine said in the release. “Once rejection is detected early via this test, doctors would then have the option to increase the dosages of anti-rejection drugs, add new agents that reduce tissue inflammation, or take other measures to prevent or slow the progression.”

The researchers expect commercial versions of the blood test to be available for clinical use soon. They are also planning future studies to evaluate the blood test for other solid organ transplants.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Medical professional in the family? That may boost your health

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Photo by Kevin Curtis

Poor people are more likely to have health problems starting at birth and to die younger than rich people. This stark inequality is firmly established, but the underlying causes and their relative contributions are not well understood.

A new Stanford study investigated whether unequal access to informal health expertise contributes to this problem. Specifically, they explored whether having a physician or nurse in your family improves your health.

The multidisciplinary team analyzed public records for Swedish residents, including socioeconomic, health care, educational and birth records. Despite Sweden’s universal health insurance system and generous social safety net, they found that health inequality still emerged early in life and persisted throughout adulthood — at levels comparable with the United States.

“This health inequity appears to be extremely stubborn,” said Petra Persson, PhD, an assistant professor of economics, in a Stanford news article. “We can throw a universal health insurance system at it and yet substantial inequality persists. So, is there anything else that can help us close that health gap between rich and poor?”

Diving deeper, the researchers divided the Swedish individuals into two groups — those with or without medical professionals in their immediate or extended families.

The team discovered that having medical expertise available from a family member led to far-reaching health improvements at all ages. Those individuals lived longer, were significantly healthier, were more likely to engage in preventive health behaviors and were more likely to adhere to medications. For example, the older relatives of medical professionals were 27 percent more likely to adhere to medications to prevent heart attacks and the younger relatives were 20 percent more likely to be vaccinated against human papillomavirus, their paper reported.

These effects occurred across all incomes, but they were even more pronounced for low-income families. This implies, according to the researchers, that the scarcity of access to medical expertise in low-income households could create and sustain inequality in health outcomes.

However, this may point to new ways to tackle the health disparity. The authors concluded in the paper, “Our analysis suggests that access to expertise improves health not through preferential treatment, but rather through intra-family transmission of ‘low-tech’ (and hence, cheap) determinants of health, likely ranging from the sharing of nuanced knowledge about healthy behaviors, to reminders about adherence to chronic medication, to frequent and trustful communication about existing health.”

Persson added in the piece, “If the government and health care system, including public and private insurers, could mimic what goes on inside families, then we could reduce health inequity by as much as 18 percent.”

A key solution may be in creating a closer, longer-term relationship between patients and their doctors, the authors said. But they also warned that the U.S. appears to be moving away from this “old-fashioned” primary care model when their results suggest that we want to do the reverse.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

“The brain is just so amazing:” New Instagram video series explains neuroscience

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Photo by Photo by Norbert von der Groeben

Many people make New Year’s resolutions to exercise more or eat healthier. Not Stanford neurobiology professor Andrew Huberman, PhD. This year he set out to educate the public about exciting discoveries in neuroscience using Instagram.

Huberman’s sights are high: he pledged to post on Instagram one-minute educational videos about neuroscience an average of five times per week for an entire year. I recently spoke with him to see how he’s doing on his resolution.

Why did you start the Instagram video series?

“Although I’m running a lab where we’re focused on making discoveries, I’ve also been communicating science to the general public for a while. I’ve found that there’s just immense interest in the brain — about diseases, what’s going on in neuroscience now, and how these discoveries might impact the audience. The brain is just so amazing, so the interest makes sense to me.

I don’t spend much time on social media, but Instagram seemed like an interesting venue for science communication because it’s mostly visual. My lab already had an Instagram account that we successfully used to recruit human subjects for our studies. So at the end of last year, I was talking with a friend about public service. I told him I was thinking about creating short, daily educational videos about neuroscience — a free, open resource that anyone can view and learn from. He and some other friends said they’d totally watch that. So I committed to it in a video post to 5000 people, and then there was no backing down.”

What topics do you cover?

“I cover a lot of topics. But I feel there are two neuroscience topics that will potentially impact the general public in many positive ways if they can understand the underlying biology: neuroplasticity — the brain’s ability to change— and stress regulation. My primary interest is in vision science, so I like to highlight how the visual system interacts with other systems.

I discuss the literature, dispel myths, touch on some of the interesting mysteries and describe some of the emerging tools and technologies. I talk a bit about my work but mostly about work from other labs. And I’m always careful not to promote any specific tools or practices.”

How popular are your videos?

 “We have grown to about 8,000 followers in the last six weeks and it’s getting more viewers worldwide. According to the stats from Instagram, about a third of my regular listeners are in Spanish-speaking countries. Some of these Spanish-speaking followers started requesting that I make the videos in Spanish so they could share them. Last week I started posting the videos in both English and Spanish and there’s been a great response. My Spanish is weak but it’s getting better, so I’m also out to prove neural plasticity is possible in adulthood. By the end of the year I plan to be fluent in Spanish.

I’ve also had requests to do it in French, German, Chinese and Dutch but I’m not planning to expand to additional languages yet. I think my pronunciation of those languages would be so bad that it would be painful for everybody.

Currently, my most popular video series is about the effects of light on wakefulness and sleep — such as how exposure to blue light from looking at your phone in the middle of the night might trigger a depression-like circuit. But my most popular videos include Julian, a high school kid that I mentor. People have started commenting #teamjulianscience, which is pretty amusing.”

What have you learned?

“It’s turned out to be a lot harder to explain things in 60 seconds than I initially thought. I have to really distill down ideas to their core elements. Many professors are notorious for going on and on about what they do, saying it in language that nobody can understand. My goal is to not be THAT professor.

I’ve also learned that I don’t blink. Sixty seconds goes by fast so I just dive in and rattle it off. After a couple of weeks, people started posting “you never blink!” — so now I insert blinks to get them to stop saying that.

I’ve also found the viewer comments and questions to be really interesting. They cue to me what the general public is confused about. But I’ve also found that many people have a really nuanced and deep curiosity about brain science. It’s been a real pleasure to see that.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Seeing the Web of Microbes

New Web-based Tool Hosted at NERSC Helps Visualize Exometabolomic Data

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WoM The Web: Microcoleus vaginatus and six heterotrophic biocrust isolates in M. vaginatus extract. The metabolite composition of the control medium is represented by the solid tan circles. Hollow circles are metabolites that were only identified after microbial transformation (indicating production/release by at least one of the organisms and not initially present in the control medium). Connecting lines indicate an increase (red) or decrease (blue) in the metabolite level in the spent medium compared to the control.

Understanding nutrient flows within microbial communities is important to a wide range of fields, including medicine, bioremediation, carbon sequestration, and sustainable biofuel development. Now, researchers from Lawrence Berkeley National Laboratory (Berkeley Lab) have built an interactive, web-based data visualization tool to observe how organisms transform their environments through the increase and decrease of metabolites — enabling scientists to quickly see patterns in microbial food webs.

This visualization tool — the first of its kind — is a key part of a new data repository, the Web of Microbes (WoM) that contains liquid chromatography mass spectrometry datasets from the Northen Metabolomics Lab located at the U.S. Department of Energy’s Joint Genome Institute (JGI). The Web of Microbes project is an interdisciplinary collaboration between biologists and computational researchers at Berkeley Lab and the National Energy Research Scientific Computing Center (NERSC). JGI and NERSC are both DOE Office of Science user facilities.

“While most existing databases focus on metabolic pathways or identifications, the Web of Microbes is unique in displaying information on which metabolites are consumed or released by an organism to an environment such as soil,” said Suzanne Kosina, a senior research associate in Berkeley Lab’s Environmental Genomics & Systems Biology (EGSB) Division, a member of the DOE ENIGMA Scientific Focus Area, and lead author on a paper describing WoM published in BMC Microbiology. “We call them exometabolites since they are outside of the cell. Knowing which exometabolites a microbe ‘eats’ and produces can help us determine which microbes might benefit from growing together or which might compete with each other for nutrients.”

Four Different Viewpoints

WoM is a python application built on the Django web development framework. It is served from a self-contained python environment on the NERSC global filesystem by an Apache web server. Visualizations are created with JavaScript, cascading style sheets, and the D3 JavaScript visualization library.

Four different viewing methods are available by selecting the tabs labeled “The Web”, “One Environment”, “One Organism”, and “One Metabolite.” “The Web” view graphically displays data constrained by the selection of an environment, while the other three tabs display tabular data from three constrainable dimensions: environment, organism, and metabolite.

“You can think of the 3D datasets as a data cube,” said NERSC engineer Annette Greiner, second author on the BMC Microbiology paper. “The visualization tool allows you to slice the data cube in any direction. And each of these slices gives one of the 2D views: One Environment, One Organism, or One Metabolite.”

The most intuitive way to view the data is via The Web, which displays an overview of connections between organisms and the nutrients they act on within a selected environment. After choosing the environment from a pull-down menu, The Web provides a network diagram in which each organism is represented as a little box, each metabolite as a circle, and their interactions as connecting lines. The size of the circle scales with the number of organisms that interact with that metabolite, whereas the color and shade of the connecting line indicate the amount of increase (red) or decrease (blue) in the metabolite level due to the microbial activation.

“Having a lot more connecting lines indicates there’s more going on in terms of metabolism with those compounds in the environment. You can clearly see differences in behavior between the organisms,” Greiner said. “For instance, an organism with a dense number of red lines indicates that it produces many metabolites.”

Although The Web view gives users a useful qualitative assessment of metabolite interaction patterns, the other three tabular views provide more detailed information.

The One Environment view addresses to what extent the organisms in a single environment compete or coexist with each other. The heatmap table shows which metabolites (shown in rows) are removed or added to the environment by each of the organisms (shown in columns), where the color of each table cell indicates the amount of metabolic increase or decrease. And icons identify whether pairs of organisms compete (X) or are compatible (interlocking rings) for a given metabolite.

“For example, if you’re trying to design a bioreactor and you want to know which organisms would probably work well together in the same environment, then you can look for things with interlocking rings and try to avoid the Xs,” said Greiner.

Similarly, the One Organism heatmap table allows users to compare the actions of a single microbe on many metabolites across multiple environments. And users can use the One Metabolite table to compare the actions of multiple organisms on a selected metabolite in multiple environments.

“Ultimately, WoM provides a means for improving our understanding of microbial communities,” said Trent Northen, a scientist at JGI and in Berkeley Lab’s EGSB Division. “The data and visualization tools help us predict and test microbial interactions with each other and their environment.”

Participatory Design

The WoM tools were developed iteratively using a participatory design process, where research scientists from Northen’s lab worked directly with Greiner to identify needs and quickly try out solutions. This differed from the more traditional approach in which Greiner completes a coherent design for the user interface before showing it to the scientists.

Both Greiner and Kosina agreed that collaborating together was fun and productive. “Instead of going off to a corner alone trying to come up with something, it’s useful to have a user sitting on my shoulder giving me feedback in real time,” said Greiner. “Scientists often have a strong idea about what they need to see, so it pays to have frequent interactions and to work side by side.”

In addition to contributing Greiner’s expertise in data visualization and web application development, NERSC hosts WoM and stores the data. NERSC’s computing resources and well-established science gateway infrastructure should enable WoM to grow both in volume and features in a stable and reliable environment, the development team noted in the BMC Microbiology paper.

According to Greiner, the data itself doesn’t take up much storage space but that may change. Currently, only Northen’s group can upload data but the team hopes to support multiple user groups in the future. For now, the Berkeley Lab researchers are excited to share their data on the Web of Microbes where it can be used by scientists all over the world. And they plan to add more data to the repository as they perform new experiments.

Kosina said it also made sense to work with NERSC on the Web of Microbes project because the Northen metabolomics lab relies on many other tools and resources at NERSC. “We already store all of our mass spectrometry data at NERCS and run our analysis software on their computing systems,” Kosina said.

Eventually, the team plans to link the Web of Microbes exometabolomics data to mass spectrometry and genomics databases such as JGI’s Genome Portal. They are also working with the DOE Systems Biology Knowledgebase (KBase) to allow users to take advantage of KBase’s predictive modeling capabilities, Northen added, which will enable researchers to determine the functions of unknown genes and predict microbial interactions.

This is a reposting of my news feature originally published by Berkeley Lab’s Computing Sciences.

Blocking Zika: New antiviral may treat and prevent infection, a Stanford study suggests

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Image of the surface of the Zika virus by Purdue University/courtesy of Kuhn and Rossmann research groups

The Zika virus, which made headlines in 2016 following an outbreak in South America, is transmitted by mosquitos and can cause serious birth defects and neurological problems. Researchers are searching for antiviral treatments or effective vaccines to address this global health threat, but there are currently no approved treatments.

Now, Stanford researchers are taking a different approach — investigating cellular factors of humans that are essential for Zika to propagate. One of those factors is a type of protein called Hsp70, which helps proteins fold correctly and performs a wide range of housekeeping and quality-control functions in cells.

Based on a series of experiments in mosquito and human cells, the Stanford study found that certain Hsp70 proteins are required in multiple steps of the Zika virus’ lifecycle. By blocking Hsp70 with an Hsp70 inhibitor drug, the researchers were able to prevent virus replication, as recently reported in Cell Reports.

One advantage of targeting the human host protein to thwart Zika is that it is less likely to promote drug resistance, Judith Frydman, PhD, senior author of the paper and a professor of genetics and of biology at Stanford, told me.

“The emergence of drug-resistant variants is a major obstacle for the development of antiviral therapies,” she continued. “We hypothesize that because Hsp70 is required for several different steps in the Zika virus cycle, it would be difficult for Zika to acquire enough mutations to develop resistance to the Hsp70 inhibitors. This opens the way to both therapeutic and prophylactic use of these drugs for short courses of treatment without losing effectiveness due to resistance.”

In addition, the team found that the Hsp70 inhibitors showed negligible toxicity to the host cells at the concentrations needed to fully block virus production. They demonstrated this lack of toxicity in both human cells and mice.

“The virus has a much higher demand for Hsp70 than the host cellular processes,” Frydman said. “We can exploit the viral ‘addiction’ to Hsp70 for treatment to prevent the virus from producing the proteins it needs to replicate and infect cells. But most importantly, we show Hsp70 inhibitors can be administered to animals at therapeutically effective doses. To my knowledge, this is the first drug that actually works for Zika-infected animals, protecting them from lethal infection and disease symptoms.”

The researchers believe their new approach could serve to create broad-spectrum antivirals that work against other existing and emerging viruses. In fact, this class of drugs could also treat other insect-borne viruses including Dengue virus and Yellow Fever, Frydman said.

“Our findings provide new strategies to develop a novel class of antivirals that will not be rendered ineffective by the emergence of drug resistance,” Frydman said. “This unique property of targeting host factors used for viral protein folding therapeutically may close a fundamental gap in antiviral drug development.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

A look back at the military’s influence on American nutrition

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Image of early 1940s poster by Office for Emergency Management, Office of War Information, Domestic Operations Branch, Bureau of Special Services

If you think of our military’s influence on food, you may picture MREs — meals, ready-to-eat — which are the main operational food rations for the U.S. Armed Forces. You may even have some MREs in your earthquake supply bin.

But according to Hannah LeBlanc, a history of science doctoral candidate at Stanford, the U.S. military has had a more fundamental and far-reaching impact on American nutrition than MREs. In fact, she argues, American nutrition was profoundly altered during the mid-1900s when the U.S. government poured funding into nutrition research. The legacies from this research include the food pyramid, recommended dietary allowances and much more.

LeBlanc’s dissertation reveals that the government hired nutritionists and issued propaganda films about nutrition because they needed healthy soldiers to fight in World War II at a time when many men were physically weakened from malnutrition during the Great Depression. And the government studied physiology in hopes of improving their soldiers’ physical endurance and food processing to preserve food longer.

Nutrition was also viewed as a national security issue during the Cold War — combating hunger as a means to protect our democracy. LeBlanc explained in a recent Stanford news release, “If you’re hungry, communism’s promises of food and well-being are going to be appealing.”

LeBlanc came to these conclusions by delving into a dozen archives throughout the U.S. for primary sources, such as military memos, government budgets and propagandistic nutrition films.

LeBlanc’s advisor, Londa Schiebinger, PhD, argues in the news release that this work can act as a reminder to pay attention to who is funding and directing our research: “Since the 1950s, there’s been this idea that science is merely objective. And, yes, we discover truth in science, but research priorities are very much determined by society.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

How yellow fever shaped 19th-century New Orleans: A Q&A

Stanford historian explains how frequent yellow fever epidemics in nineteenth-century Louisiana generated cultural and social norms in its fatal wake.

Development of Yellow Fever_crop.png

I was intrigued when I came across the Stanford profile of Kathryn Olivarius, PhD, a historian of 19th-century America. Her research primarily explores how epidemic yellow fever disrupted society in the antebellum South, generating cultural and social norms in its fatal wake. To learn more, I spoke with her recently.

As a historian, what got you interested in fellow fever?

“When I embarked on my PhD, I wanted to write about how slavery changed in Louisiana after 1803 with the Louisiana Purchase, as the region shifted from Spanish and French to American rule. But while sitting in Tulane’s archives and perusing letters, diaries, plantation ledgers and ship manifests, what impressed me the most was how much people spoke about disease. And the disease they feared the most was undoubtedly yellow fever  — a disease that struck antebellum New Orleans at epidemic levels nearly every third summer.

Yellow fever victims experienced a sudden onset of headache, back pains, jaundice, nausea and chills. Within days, they oozed blood through their external orifices, writhed in pain and vomited up partly coagulated blood. About half of all people who contracted yellow fever in the 19th century died, while the survivors gained lifetime immunity.

In my view, yellow fever played a critical role in Louisiana’s asymmetrical social organization, on the schedule and character of the cotton market, on capitalism itself and on the entire system and ideology of racial slavery. So I decided to focus on the disease for my PhD and my forthcoming book.”

How did the disease impact the social structure of 19th-century Louisiana?

“Antebellum New Orleans sat at the heart of America’s slave and cotton kingdoms. But it was also the nation’s necropolis, the city of the dead, with yellow fever routinely killing about 8 percent of its population between July and October. In some neighborhoods — particularly those with high densities of immunologically-naive recent immigrants from Germany, Ireland and the American North — yellow fever deaths could reach 20 or even 30 percent.

These repeated epidemics generated a hierarchy of ‘acclimated’ survivors who leveraged their immunity for social, economic and political power and ‘unacclimated’ recent immigrants who languished in social and professional purgatory. Until whites could prove they were acclimated, they struggled to find steady, well-paid employment, housing, spouses and a political voice. From the employer’s perspective, it wasted time and money to train someone for a detail-oriented job only to watch him sicken and die by the autumn.”

How did this affect slavery?

“Because of the disease, the commercial-civic elite of New Orleans argued that they required large-scale black slavery — publicly proclaiming that black people were naturally immune to the disease based on spurious and racially-specific visions of medicine and biology. It became a powerful proslavery argument with many whites claiming that black slavery was natural, even humanitarian, as it distanced white people from labor, spaces and activities that would kill them. Some even argued black immunity signaled divine sanction for widespread slavery, with God creating black slaves specifically to labor in the cane and sugar fields of the Mississippi Valley.

But in private, most slavers would not buy an unacclimated slave. The slave market essentially shut down in August, September and October in order to protect the health of potential buyers and their valuable slave property. This inconsistency suggests that the widespread belief in black immunity was less a reflection of biological reality but instead a social tool, a means to epidemiologically-justify racial slavery.”

Do you believe anything similar is happening today?

“Yellow fever still kills thousands of people each year. It’s endemic in 47 countries, mostly in Africa and Central and South America. The Intergovernmental Panel on Climate Change’s report released last year also suggests that Americans may become more familiar with this disease again as ecologies change and mosquito populations migrate. Zika, spread by the same mosquito as yellow fever, has been an increasing problem in recent years.

In terms of the social impact of disease, there are certainly modern analogues of societies in the midst of terrifying epidemics rationalizing mass death or singling out certain marginalized groups as the cause. The most obvious comparison in the U.S. is probably HIV/AIDS in the 1980s with gay people, intravenous drug users and Haitians who were blamed for the disease’s spread and who faced severe discrimination on the basis of their alleged-vulnerability.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.