To hear Duke University professor Xinnian Dong tell it, plants can shift from peacetime to wartime production too.

Crops and other plants are often under attack from bacteria, viruses, and other pathogens. When a plant senses a microbial invasion, it makes radical changes in the chemical soup of proteins — the workhorse molecules of life — inside its cells.

In recent years, Dong and her team have been piecing together just how they do it. In a new study published in the journal Cell, Dong and first author Jinlong Wang reveal the key components in plant cells that reprogram their protein-making machinery to fight disease.

Each year, around 15% of crop yield is lost to bacterial and fungal diseases, costing the global economy some $220 billion. Plants rely on their immune system to help them fight back, Dong said.

Unlike animals, plants don’t have specialized immune cells that can travel through the bloodstream to the site of infection; every cell in the plant has to be able to stand and fight to defend itself, quickly shifting into battle mode.

When plants come under attack, they shift their priorities from growth to defense, so cells start synthesizing new proteins and suppress production of others. Then “within two to three hours things return to normal,” Dong said.

The tens of thousands of proteins made in cells do many jobs: catalyzing reactions, serving as chemical messengers, recognizing foreign substances, moving materials in and out. To build a specific protein, genetic instructions in the DNA packed inside the cell’s nucleus are transcribed into a messenger molecule called mRNA. This strand of mRNA then heads out into the cytoplasm, where a structure called a ribosome “reads” the message and translates it into a protein.

In a 2017 study, Dong and her team found that when a plant is infected, certain mRNA molecules are translated into proteins faster than others. What these mRNA molecules have in common, the researchers discovered, is a region at the front end of the RNA strand with recurring letters in its genetic code, where the nucleotide bases adenine and guanine repeat themselves over and over again.

In the new study, Dong, Wang and colleagues show how this region works with other structures inside the cell to activate “wartime” protein production.

They showed that when plants detect a pathogen attack, the molecular signposts that signal the usual starting point for ribosomes to land on and read the mRNA are removed, which keeps the cell from making its typical “peacetime” proteins.

Instead, ribosomes bypass the usual starting point for translation, using the region of recurring As and Gs within the RNA molecule for docking and start reading from there instead.

“They basically take a shortcut,” Dong said.

For plants, fighting infection is a balancing act, Dong said. Allocating more resources to defense means less is available for photosynthesis and other activities in the business of life. Producing too many defense proteins can create collateral damage: plants with an over-active immune system suffer stunted growth.

By understanding how plants strike this balance, Dong said, scientists hope to find new ways to engineer disease-resistant crops without compromising yield.

Dong’s team did the bulk of their experiments in a mustard-like plant called Arabidopsis thaliana. But similar mRNA sequences have been found in other organisms, including fruit flies, mice and humans, so they may play a broader role in controlling protein synthesis in plants and animals alike, Dong said.

This work was supported by grants from the National Science Foundation (IOS-645589, IOS-2041378), National Institutes of Health (R35-GM118036-06) and the Howard Hughes Medical Institute.

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Materials provided by Duke University. Original written by Robin A. Smith. Note: Content may be edited for style and length.

“We already know that climate change is increasing the severity and frequency of extreme weather events,” said Kevin Smiley, the study’s lead author and LSU Department of Sociology assistant professor. “But now researchers are able to pinpoint the extent of damage from a specific extreme weather event such as Hurricane Harvey and the resulting floods.”

Fifty percent less residences impacted equates to about 50,000 fewer homes damaged and billions of dollars saved in residential damage.

“This means that we have quantified the contribution of climate change to the suffering of people who live there,” said Michael Wehner, the study’s co-author and senior scientist at Lawrence Berkeley National Laboratory.

The research, a first of its kind investigation into potential disparities between those impacted by the climate change-induced flooding, finds patterns of racial and economic disparities.

“Part of the reason why low-income neighborhoods flooded has to do with the historical development of Houston along its waterways and surrounding petrochemical corridor,” Smiley said. “There’s a clear climate and environmental justice story as to where these neighborhoods are located.”

How do researchers study the impacts of climate change?

Climate change attribution, which ascertains the connection between climate change and extreme weather events, involves running computational models to estimate how much these changes in climate make extreme weather events, like hurricanes, more severe. Scientists can compare these estimates without climate change to what actually happened to see the difference.

“This is the first end-to-end impact attribution study of a specific weather event following on our previous studies showing a significant increase in Harvey’s precipitation and the resulting flooding increase because of climate change,” Wehner said.

Although popular discussion tends to center around climate change forecasts for the future, the study underscores the fact that climate change is impacting life now.

“Climate change is happening right now with real and substantial costs,” Smiley said. “Three to five extra inches of rainfall from climate change can make the difference between your lawn getting soaked and your house getting flooded leaving it uninhabitable.”

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The new blood test measures DNA fragments shed by damaged cells. Researchers found that these fragments, called cell-free DNA, were elevated in the blood of patients with PAH and increase with disease severity. If future studies confirm the findings, this first-of-its-kind blood test for PAH patients could allow doctors to intervene faster to prevent or delay progression of the disease and possibly save lives. Cell-free DNA is a relatively new analytical technique that is growing in its potential medical uses, which include the early detection of heart- and lung-transplant rejection as well as early detection of cancer.

The study was funded by the National Heart, Lung, and Blood Institute (NHLBI) and the NIH Clinical Center, both part of NIH. The findings will appear online in the journal Circulation, a publication of the American Heart Association.

PAH is a rare form of pulmonary hypertension that can cause difficulty breathing, chest pain, and fatigue. The disease, whose exact cause is unknown, is estimated to affect less than 50,000 people in the United States, according to the NIH’s Genetic and Rare Diseases Information Center. It is characterized by progressive narrowing and blockage of the small pulmonary arteries of the lungs, strain on the right side of the heart, and eventual death from heart failure. The damage to the lung in severe cases can require lung transplantation. Patients with PAH have a high death rate, and the condition mostly affects women. Despite treatment advances, it currently has no cure.

Current tests used to monitor PAH severity rely on established risk prediction scores based on clinical symptoms and on the use of an invasive catheter to measure pressure in the lungs. Doctors sometimes use echocardiography, or heart imaging, to measure pressures in the heart as an indirect measurement of lung pressure, but these tests tend to lack reliability and sensitivity.

“Researchers have been actively searching for novel, less-invasive approaches to evaluate PAH severity, disease progression, and response to therapy for more than a decade. These cell-free DNA analyses represent progress toward that goal,” said study co-author Michael A. Solomon, M.D., M.B.A., who is part of the NHLBI Cardiovascular Branch and co-director of the NIH Clinical Center Pulmonary Arterial Hypertension Section.

Sean Agbor-Enoh, M.D., Ph.D., study co-author and chief of the NHLBI’s Laboratory of Applied Precision Omics, agreed. “Here we’re proposing a one-time test where you collect a vial of blood from a patient and use that to predict survival. We’re very encouraged by the early results.”

In the current study, the research team analyzed cell-free DNA from blood samples taken from 209 adult patients, predominately women, diagnosed with PAH at two large U.S. medical centers. The researchers compared the results to cell-free DNA measured from a control group of 48 healthy volunteers without PAH at the NIH Clinical Center.

They found that cell-free DNA was elevated in patients with PAH, and also found that cell-free DNA concentrations increased in proportion to the severity of the disease. Patients with the highest level of cell-free DNA had a 3.8 times greater risk of either death or a need for lung transplantation compared to those with the lowest level of cell-free DNA, the researchers said.

Further analyses of cell-free DNA samples revealed that multiple tissue types — including the heart, blood vessels, fat tissue, and inflammatory cells circulating in the blood — were affected by PAH. The new blood test will allow researchers to better pinpoint the specific tissues involved in the PAH disease process. This knowledge may lead to new drug interventions for PAH, whose current treatment options may slow but not halt or reverse disease progression.

In addition to funding from the Intramural Research Program of the NHLBI, this research is supported by the NIH Clinical Center Research Award for Staff Clinicians Program, the NIH Distinguished Scholar Award, the Lasker Clinical Research Scholars Program, and the Intramural Research Programs of the NIH Clinical Center.

“Much of what we understand about the known two per cent of the genome that codes for proteins comes from looking for long strands of protein-coding nucleotide sequences, or long open reading frames,” explained computational biologist Dr Sonia Chothani, a research fellow with Duke-NUS’ Cardiovascular and Metabolic Disorders (CVMD) Programme and first author of the study. “Recently, however, scientists have discovered small open reading frames (smORFs) that can also be translated from RNA into small peptides, which have roles in DNA repair, muscle formation and genetic regulation.”

Scientists have been trying to identify smORFs and the small peptides they code for, since disruption in these smORFs can cause disease. However, currently available approaches are very limited.

“Much of the current datasets do not provide information that is detailed enough to identify smORFs in RNA,” added Dr Chothani. “The majority also comes from analyses of immortalised human cells that are propagated — sometimes for decades — to study cell physiology, function and disease. However, these cell lines aren’t always accurate representations of human physiology.”

Publishing in Molecular Cell, Chothani and her colleagues in Singapore, Germany, the UK and Australia describe a methodology they developed to address these issues. They screened currently available ribosome profiling datasets for short strands of RNA with periodic three-base sections, covering more than 60 per cent of the RNA’s length. They then conducted their own RNA sequencing and Ribosome profiling to generate a combined data resource of six types of cells and five types of tissue, such as from the heart and the brain, derived from hundreds of patients.

Analyses of these data identified nearly 8,000 smORFs. Interestingly, they were highly specific to the tissues that they were found in, meaning that these smORFs may perform a function specific to their environment. The team also identified 603 microproteins coded by some of these smORFs.

“The genome is littered with smORFs,” said Assistant Professor Owen Rackham, senior author of the study from the CVMD Programme. “Our comprehensive and spatially resolved map of human smORFs highlights overlooked functional components of the genome, pinpoints new players in health and disease and provides a resource for the scientific community as a platform to accelerate discoveries.”

Professor Patrick Casey, Senior Vice-Dean of Research at Duke-NUS, said, “With the healthcare system evolving to not only treat diseases but also prevent them, identifying potential new targets for disease research and drug development could open avenues to new solutions. This research by Dr Chothani and her team, published as a resource for the scientific community, brings important insights to the field.”

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