Earth

What will the SARS-CoV-2 outbreak look like ten years from now as it passes from pandemic to endemic, maintained at a constant baseline level in populations without being fueled by outside infections? Data from four endemic human coronaviruses, which circulate globally and cause only mild symptoms, may hold some answers, say Jennie Lavine and colleagues. Their analysis of the immunological and epidemiological data for these viruses helped them develop a model to predict the trajectory of SARS-CoV-2 as it becomes endemic. Most importantly, the authors say, their model incorporates distinct components of immunological protection--susceptibility to reinfection, weakening of the disease after reinfection, and transmissibility of the virus after reinfection--that each wane differently. Lavine et al. suggest that endemic SARS-CoV-2 may become a disease of early childhood, where the first infection occurs between 3 and 5 years old, and the disease itself would be mild. Older individuals could still become infected, but their childhood infections would provide immune protection against severe disease. How fast this shift comes depends on how fast the virus spreads and what kind of immune response the SARS-CoV-2 vaccines induce. If the vaccines induce short-lived protection against becoming reinfected but reduce the severity of the disease, as is the case with other endemic coronaviruses, SARS-CoV-2 may become endemic more quickly, the model suggests. The authors also note that if primary infections of children are mild when the virus becomes endemic, widespread vaccination may not be necessary. But if primary infections become severe in children, as in the case of more deadly but contained coronaviruses such as MERS, childhood vaccinations should be continued.

A new study conducted at the New England Aquarium finds that as climate change causes the ocean to warm, baby sharks are born smaller, exhausted, undernourished, and into environments that are already difficult for them to survive in.

In a recently published paper in the journal Scientific Reports, lead author Carolyn Wheeler, a Ph.D. candidate at the University of Massachusetts Boston and at the ARC Centre of Excellence for Coral Reef Studies at James Cook University, examined the effects of increased temperatures on the growth, development and physiological performance of epaulette sharks--an egg-laying species found only on the Great Barrier Reef. Wheeler studied the sharks as embryos and hatchlings, under the supervision of Dr. John Mandelman, Vice President and Chief Scientist of the Anderson Cabot Center for Ocean Life at the New England Aquarium.

"We found that the hotter the conditions, the faster everything happened, which could be a problem for the sharks," said Wheeler. "The embryos grew faster and used their yolk sac quicker, which is their only source of food as they develop in the egg case. This led to them hatching earlier than usual." Wheeler said the hatchlings were not only smaller, but they needed to feed almost immediately while lacking significant energy.

"The ocean faces increasing threats from humans, such as the effects of climate change, and it is vital to conduct scientific research to help strengthen the management and protection of those ocean species most negatively impacted and vulnerable," Mandelman said. "In this case, we addressed a pressing threat--ocean warming--and the potential impacts on a species that could serve as a model for other egg laying species among sharks and their relatives."

The Aquarium has a successful breeding program for epaulette sharks, allowing the researchers to use some of the eggs to study climate change impacts on a shark species native to the other side of the world. The research was housed at the Aquarium's Animal Care Center in Quincy, Mass. under the direction of Barbara Bailey, Curator of Husbandry and Sustainability.

"This work included the efforts of staff, volunteers and interns across a number of departments. I was very excited to find a connection between the animals in our exhibits and the opportunity to contribute to an incredibly important scientific study," said Bailey.

Co-author and Associate Professor Jodie Rummer, Wheeler's co-supervisor at James Cook University, says the waters of the Great Barrier Reef will likely experience summer averages nearing or even exceeding 31°C/87.8°F by the end of the century. Sharks do not care for their eggs after they are laid, meaning a shark egg must be able to survive unprotected for up to four months. Rummer cites rising ocean temperatures as a major concern for the future of sharks, particularly those that lay eggs.

"The epaulette shark is known for its resilience to change, even to ocean acidification. So, if this species can't cope with warming waters, then how will other, less tolerant species fare?" Rummer said.

Sharks and the class of animals they belong to, which includes rays and skates, are slow growing. They also do not reproduce often compared to other fishes. The populations of many of these creatures are already threatened across the globe. The study suggests the sharks of the future will be born--or hatch, in this case--not only at a disadvantage but into environments already at the warmest they can tolerate.

Epaulette sharks reared through the New England Aquarium's husbandry and sustainability program can be seen on exhibit in the Shark and Ray Touch Tank at the Aquarium's main building on Boston's Central Wharf. The Aquarium is currently closed to the public as part of the City of Boston's restrictions to slow the spread of COVID-19.

Typically characterized as poisonous, corrosive and smelling of rotten eggs, hydrogen sulfide's reputation may soon get a face-lift thanks to Johns Hopkins Medicine researchers. In experiments in mice, researchers have shown the foul-smelling gas may help protect aging brain cells against Alzheimer's disease. The discovery of the biochemical reactions that make this possible opens doors to the development of new drugs to combat neurodegenerative disease.

The findings from the study are reported in the Jan. 11 issue of the Proceedings of the National Academies of Sciences.

"Our new data firmly link aging, neurodegeneration and cell signaling using hydrogen sulfide and other gaseous molecules within the cell," says Bindu Paul, M.Sc., Ph.D., faculty research instructor in neuroscience in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine and lead corresponding author on the study.

The human body naturally creates small amounts of hydrogen sulfide to help regulate functions throughout the body, from cell metabolism to blood vessel dilation. The rapidly burgeoning field of gasotransmission shows that gases are major cellular messenger molecules, with particular importance in the brain. However, unlike conventional neurotransmitters, gases can't be stored in vesicles. Thus, gases act through very different mechanisms to rapidly facilitate cellular messaging. In the case of hydrogen sulfide, this entails the modification of target proteins by a process called chemical sulfhydration, which modulates their activity, says Solomon Snyder, D.Phil., D.Sc., M.D., professor of neuroscience at the Johns Hopkins University School of Medicine and co-corresponding author on the study.

Studies using a new method have shown that sulfhydration levels in the brain decrease with age, a trend that is amplified in patients with Alzheimer's disease. "Here, using the same method, we now confirm a decrease in sulfhydration in the AD brain," says collaborator Milos Filipovic, Ph.D., principal investigator, Leibniz-Institut für Analytische Wissenschaften - ISAS.

For the current research, the Johns Hopkins Medicine scientists studied mice genetically engineered to mimic human Alzheimer's disease. They injected the mice with a hydrogen sulfide-carrying compound called NaGYY, developed by their collaborators at the University of Exeter in the United Kingdom, which slowly releases the passenger hydrogen sulfide molecules while traveling throughout the body. The researchers then tested the mice for changes in memory and motor function over a 12-week period.

Behavioral tests on the mice showed that hydrogen sulfide improved cognitive and motor function by 50% compared with mice that did not receive the injections of NaGYY. Treated mice were able to better remember the locations of platform exits and appeared more physically active than their untreated counterparts with simulated Alzheimer's disease.

The results showed that the behavioral outcomes of Alzheimer's disease could be reversed by introducing hydrogen sulfide, but the researchers wanted to investigate how the brain chemically reacted to the gaseous molecule.

A series of biochemical experiments revealed a change to a common enzyme called glycogen synthase β (GSK3β). In the presence of healthy levels of hydrogen sulfide, GSK3β typically acts as a signaling molecule, adding chemical markers to other proteins and altering their function. However, the researchers observed that in the absence of hydrogen sulfide, GSK3β is overattracted to another protein in the brain called Tau.

When GSK3β interacts with Tau, Tau changes into a form that tangles and clumps inside nerve cells. As Tau clumps grow, the tangled proteins block communication between nerves, eventually causing them to die. This leads to the deterioration and eventual loss of cognition, memory and motor function that is characteristic of Alzheimer's disease.

"Understanding the cascade of events is important to designing therapies that can block this interaction like hydrogen sulfide is able to do," says Daniel Giovinazzo, M.D./Ph.D. student, the first author of the study.

Until recently, researchers lacked the pharmacological tools to mimic how the body slowly makes tiny quantities of hydrogen sulfide inside cells. "The compound used in this study does just that and shows by correcting brain levels of hydrogen sulfide, we could successfully reverse some aspects of Alzheimer's disease," says collaborator on the study Matt Whiteman, Ph.D., professor of experimental therapeutics at the University of Exeter Medical School.

The Johns Hopkins Medicine team and their international collaborators plan to continue studying how sulfur groups interact with GSK3β and other proteins involved in the pathogenesis of Alzheimer's disease in other cell and organ systems. The team also plans to test novel hydrogen sulfide delivery molecules as part of their ongoing venture.

Climate changes prompt many important questions. Not least how it affects animals and plants: Do they adapts, gradually migrate to different areas or become extinct? And what is the role played by human activities? This applies not least to Greenland and the rest of the Artic, which are expected to see the greatest effects of climate changes.

'We know surprisingly little about marine species and ecosystems in the Arctic, as it is often costly and difficult to do fieldwork and monitor the biodiversity in this area', says Associate Professor of marine mammals and instigator of the study Morten Tange Olsen from the GLOBE Institute at the Faculty of Health and Medical Sciences, University of Copenhagen.

To address these questions, researchers from the University of Copenhagen, Aarhus University and the Greenland Institute of Natural Resources collected water samples in West Greenland with the help of local hunters and fishermen. Their method is simple: Go out to sea in a small boat and collect water in bottles. The content, however, is far more complex. The bottles with seawater contain so-called environmental DNA, which can provide insight into how climate changes and human activities impact the biodiversity. The researchers have chosen to focus on the bowhead whale, which constitutes a key species in the Arctic ecosystem and therefore is a good indicator of changes in water temperatures and sea ice cover.

'The water samples contain enough DNA from bowhead whales to determine their presence, genetic diversity, the composition of the population and patterns of migration. You can actually monitor the marine biodiversity of the Arctic simply by going out in a small boat and collecting water in bottles, which is subsequently analysed in the DNA laboratory. This way, we are able to keep an eye on how humans and climate changes impact the bowhead whale and other marine life in the Arctic', says Morten Tange Olsen.

Footprint in a bottle

Together with local hunters and fishermen in Qeqertarsuaq (Godhavn), the researchers collected more than 100 one-litre water samples from Disko Bay in West Greenland in May 2017 and 2018. In May, the sea ice has just broken up and bowhead whales visit the area to forage. The samples were collected from small boats along transects and specifically in the 'footprint' of bowhead whales - the small ripples on the water surface created when the whales come up to breathe and dive again.

'There is a lot more bowhead whale DNA in such a footprint than in a random water sample collected at the same time in the same area. You can find bowhead whale DNA in a footprint at least 10 minutes after the whale dove', says Natasja Lykke Corfixen, who helped initiate the study as part of her master's thesis at the Faculty of Science at the University of Copenhagen and the Greenland Institute of Natural Resources.

By optimising the DNA methods in the laboratory, the researchers hope to be able to sequence the whale's entire genome based on water samples. 'So far we have managed to sequence mitochondrial genomes from the water samples, and we are currently testing various methods for capturing the whale's entire genome, as well as the genomes of the algae and crustaceans that form part of their food chain', says PhD Student at the GLOBE Institute Dóra Székely.

Health and genetics based on a water sample

The researchers hope that by optimising DNA extraction and sequencing protocols, and learning more about the connection between genes, behaviour and health, they will eventually be able to use the method to monitor the health status of the bowhead whale and many other animals.

'The field of Environmental DNA is seeing rapid development and is increasingly used for biodiversity monitoring in lakes, rivers, wetlands and, to some extent, the sea. We have shown that the method is also useful in the Arctic, and that it can be used to monitor not just the presence of a species, but also its diversity and patterns of movement. By further developing this simple method we are able to significantly increase our knowledge of marine biodiversity, and hopefully the impact of both climate changes and human activities', says Morten Tange Olsen.

GAINESVILLE, Fla. --- Entomologist Akito Kawahara's message is straightforward: We can't live without insects. They're in trouble. And there's something all of us can do to help.

Kawahara's research has primarily focused on answering fundamental questions about moth and butterfly evolution. But he's increasingly haunted by studies that sound the alarm about plummeting insect numbers and diversity.

Kawahara has witnessed the loss himself. As a child, he collected insects with his father every weekend, often traveling to a famous oak outside Tokyo whose dripping sap drew thousands of insects. It was there he first saw the national butterfly of Japan, the great purple emperor, Sasakia charonda. When he returned a few years ago, the oak had been replaced by a housing development. S. charonda numbers are in steep decline nationwide.

While scientists differ on the severity of the problem, many findings point to a general downward trend, with one study estimating 40% of insect species are vulnerable to extinction. In response, Kawahara has turned his attention to boosting people's appreciation for some of the world's most misunderstood animals.

"Insects provide so much to humankind," said Kawahara, associate curator at the Florida Museum of Natural History's McGuire Center for Lepidoptera and Biodiversity. "In the U.S. alone, wild insects contribute an estimated $70 billion to the economy every year through free services such as pollination and waste disposal. That's incredible, and most people have no idea."

Insects sustain flowering plants, the lynchpins of most land-based ecosystems, and provide food sources for birds, bats, freshwater fish and other animals. But they face a barrage of threats, including habitat loss, pesticides, pollution, invasive species and climate change. If human activities are driving the decline, Kawahara reasons, then people can also be a part of the solution.

In an opinion piece published in a special edition of the Proceedings of the National Academies of Sciences, Kawahara and his collaborators outline easy ways everyone can contribute to insect conservation.

Mow less

If you have a lawn, mowing less can give insect populations a boost. Kawahara suggests reserving 10% of a landscape for insects, either actively replacing a monoculture of grass with native plants or simply leaving the space unmown. These miniature nature preserves provide crucial habitat and food reservoirs for insects, he said, particularly if they remain free of chemical pesticides and herbicides. Benefits for lawn-maintainers include less yardwork and lower expenses.

"Even a tiny patch could be hugely important for insects as a place to nest and get resources," Kawahara said. "It's a stepping stone they can use to get from one place to another. If every home, school and local park in the U.S. converted 10% of lawn into natural habitat, this would give insects an extra 4 million acres of habitat."

If you don't have a lawn, you can still help by cultivating native plants in pots in window boxes or on balconies and patios.

Dim the lights

Nighttime light pollution has spiked since the 1990s, doubling in some of the world's most biodiverse places. Artificial lights are powerful attractants to nocturnal insects, which can exhaust themselves to death by circling bulbs or fall prey to predators that spot an easy target.

You can give insects a hand - and reduce your electric bill - by turning off unnecessary lights after dark and using amber or red bulbs, which are less attractive to insects.

Use insect-friendly soaps and sealants

Chemical pollutants in soaps for washing cars and building exteriors and in coal-tar-based driveway sealants can harm a variety of insect life. Kawahara recommends swapping these out for biodegradable soaps and soy-based sealants. In winter, trading rock salt for salt-free formulations is safer for both insects and pets.

Become an insect ambassador

In the U.S., insects have historically been depicted as devourers of crops, disease vectors and hallmarks of poor sanitation, even though the vast majority do not harm humans. Kawahara said rethinking your own stereotypes of insects and gaining a better understanding of their beauty, diversity and roles is a first step in helping others appreciate them, too.

He recalled leading schoolchildren on an insect-collecting trip during which a student found an elephant stag beetle, an enormous insect with massive jaws - "one of the coolest, most amazing bugs," Kawahara said.

The student wanted to step on the beetle, thinking it was a cockroach.

"Other students were grossed out, too," Kawahara said. "When I saw that, I was dumbfounded. If this was Japan, kids would be clamoring to be the first to get it and keep it as a pet. The juxtaposition of those cultural reactions was striking."

He pointed to media characterizations of Asian giant hornets - which he grew up seeing drink sap from the oak tree outside of Tokyo - as "murder hornets" as another example of how framing insects as dangerous or disgusting has the power to evoke strong reactions from the public.

As antidotes to unfounded fears, walk outdoors to look for local insect life or adopt pet insects, a simple, inexpensive way to introduce children to science, Kawahara said. Documenting what you see on platforms such as iNaturalist not only helps you learn more about your finds, but also provides data for scientific research.

These small steps have the power to effect immediate changes for the planet's insects, Kawahara said.

"The best way for change to happen quickly is for everyone to pitch in. As individuals, we can all do these kinds of activities right away."

Scientists have determined the optimal conditions following a stem cell transplant that could control HIV without the need of an everyday pill, according to a study published today in eLife.

Finding the right balance of stem cell dose, cell type and timing of antiretroviral therapy (ART) could potentially lead to a spontaneous cure of HIV.

There are only two cases of HIV cure to date: the Berlin Patient and the London Patient, who both received stem cell transplants with stem cells from donors that lack a molecule called CCR5, which HIV is attracted to.

"The major obstacle to HIV eradication is a latent reservoir of long-lived infected cells, and cure strategies aim to eliminate all infected cells or permanently prevent viral reactivation from latency," explains first author E. Fabian Cardozo-Ojeda, Senior Staff Scientist at the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, US. "We wanted to recreate the cures seen in the Berlin and London patients but with reduced toxicity."

The team investigated the use of autologous stem cell transplants, where bone marrow stem cells are removed from the patient, engineered using gene editing so that they lack CCR5, and then returned to patients. This technique is being tested in an early clinical trial in people with HIV, but the minimum number of CCR5-edited stem cells required for the long-term remission or cure seen in the Berlin and London patients was unknown.

To determine this, the researchers developed a multi-stage mathematical model to study the dynamics of residual and transplanted stem cells, HIV viral load (the amount of virus in the blood) and how these are affected by the timing of ART withdrawal. They based their model on data from 22 monkeys with simian HIV which were treated with a stem cell transplant, with or without CCR5 gene editing. A subset of the animals then had their ART stopped after a year.

The immune cell dynamics and viral load differed between the animals, but a consistent theme was that the viral load after ART withdrawal was higher in transplanted animals than untreated. This suggests that stem cell transplantation might reduce existing immune cell immunity to HIV. The team speculated that this immunity might be recovered if CCR5 is sufficiently disrupted in the transplanted stem cells.

To explore this, they used their model to calculate the conditions required to achieve viral control after ART withdrawal. They found two important conditions: the first was ensuring a dose of at least five times as many transplanted stem cells as there are residual stem cells after the transplant, and the second was allowing the CCR5-edited stem cells to be at least 76-94% of the total transplanted stem cell population.

"Our model predicts that viral control might be possible following autologous, gene-edited stem cell transplants if a sufficient proportion of edited stem cells are allowed to repopulate the blood before ART is stopped," concludes senior author Joshua T. Schiffer, Associate Professor at the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center. "The results illustrate the capabilities of mathematical models in optimising strategies for HIV cure."

The Korea Institute of Science and Technology (KIST) has announced that the research team led by Dr. Kim Kyoung-Whan at the Center for Spintronics has proposed a new principle about spin memory devices, which are next-generation memory devices. This breakthrough presents new applicability that is different from the existing paradigm.

Conventional memory devices are classified into volatile memories, such as RAM, that can read and write data quickly, and non-volatile memories, such as hard-disk, on which data are maintained even when the power is off. In recent years, related academic and industrial fields have been combining their advantages to accelerate the development of next-generation memory that is fast and capable of maintaining data even when the power is off.

A spin memory device is a device that stores data of 0 and 1 in the N pole and S pole directions, respectively, of a very small nanomagnet. It is widely applied in hard disks because the directions of the N pole and S pole are maintained even when the power is off. Thus, the successful commercialization of next-generation spin memory depends on how quickly and easily it can be controlled in the N pole and S pole directions of a nanomagnet.

Until now, spin was injected from the outside to control the N pole and S pole directions of a nanomagnet. Here, spin is a basic unit of magnetism that cannot be divided further, and numerous spins with the same directions as the N pole and S pole are gathered to form a single magnet. Therefore, if many spins are injected into a nanomagnet from the outside, the N pole and S pole directions of the nanomagnet can be controlled. However, its commercialization is arduous because generating and injecting external spins is not energy-efficient.

Recently, it has been reported that spins are formed inside a nanomagnet if electric current is applied to the nanomagnet. However, because no theory on how to analyze the behavior of such spins has been established yet, there has been no studies on the physical results of these spins.

Dr. Kim Kyoung-Whan at the KIST has established a theoretical system by developing a spin diffusion equation that describes the spin conductance in magnetic materials. It was discovered that when the spins formed by electric current is emitted to the outside, only the sign is opposite to that of the spins injected from the outside, and the effects are the same. Therefore, the directions of the N pole and S pole can be controlled by the nanomagnet itself without external spin injection, and the power consumption can be reduced by up to ~60% compared to that of conventional spin devices. Furthermore, memories can be developed in simple structures because they do not need the conventional structure for injecting external spins.

Dr. Kim Kyoung-Whan said, "This study provided an academic basis for spin conductance in magnetic materials. Furthermore, through the new paradigm, it is expected to contribute significantly to solving the optimization problems of power consumption, production yield, etc., which have been the biggest obstacles to the implementation of next-generation spin devices."

Mothers with multiple children report more fragmented sleep than mothers of a single child, but the number of children in a family doesn't seem to affect the quality of sleep for fathers, according to a study from McGill University.

A total of 111 parents (54 couples and 3 mothers of single-parent families) participated in the study published in the Journal of Sleep Research led by McGill doctoral student Samantha Kenny under the supervision of Marie-Hélène Pennestri, Assistant Professor in the Department of Educational and Counselling Psychology.

Participants' sleep patterns were studied for two weeks. Mothers with one baby reported having less interrupted and better-quality sleep than mothers with more than one child, although the total amount of sleep did not differ depending on the number of children. No difference was noted in fathers.

"Experienced mothers perceived their sleep to be more fragmented than that of first-time mothers. Tension in the marital relationship may transpire if childcare is one-sided and not discussed collaboratively," says Pennestri, who is also a researcher at the Hôpital en santé mentale Rivière-des-Prairies (CIUSSS-NIM).

According to the researchers, interventions developed by healthcare providers targeting an equal distribution of daytime and nighttime childcare tasks could be helpful. These interventions should be tailored to each family member, depending on their situation.

As next steps, the researchers aim to explain the differences between mothers and fathers, and determine why mothers with more than one child report worse sleep.

WINSTON-SALEM, N.C. - Jan. 11, 2021 - Most doctors would agree that advanced care planning (ACP) for patients, especially older adults, is important in providing the best and most appropriate health care over the course of a patient's life.

Unfortunately, the subject seldom comes up during regular clinic visits.

In a study conducted by doctors at Wake Forest Baptist Health, only 3.7% of primary care physicians had this conversation with their patients as part of their normal care. Yet in the same study, the researchers found that a new approach involving specially trained nurses substantially increased the frequency of doctors initiating ACP discussions with their patients.

The study is published in the Jan. 11 edition of JAMA Internal Medicine.

"As a primary care doctor I know how important it is to talk to patients about what quality of life means to them - playing with grandkids, cooking, going for a walk - and work to align their health care with those goals," said the study's principal investigator, Jennifer Gabbard, M.D., assistant professor of gerontology and geriatric medicine at Wake Forest School of Medicine, part of Wake Forest Baptist Health.

"We hoped to make it easier for doctors to have this conversation and give their patients a voice, so that if they got sicker, their doctors, caregivers and family would know their wishes and have it documented so it was easily accessible."

The year-long, randomized effectiveness trial enrolled 759 patients from eight primary care practices in North Carolina. The participants, age 65 or older, had multiple chronic conditions and either cognitive or physical impairments or frailty. The volunteers were randomized to either a nurse navigator-led group or a normal care group.

In the nurse-led group, a trained nurse navigator called the study participants before their annual wellness visit to explain advance care planning and to suggest topics to discuss with their doctor during the clinic visit, Gabbard said. That information then was recorded in the doctor's notes to provide a starting point for the conversation. Both patients and providers reported that this priming often made the visits go much more smoothly, Gabbard said.

To make it easier for healthcare providers to initiate a discussion of ACP, Gabbard's team developed an electronic health record documentation tool that provided a communication guide on how to ask questions and what the most common responses were to help guide the conversation. The information gleaned during the wellness visit was then documented in the patient's electronic health record by using the same tool.

"We wanted to create a way to easily document the patient's goals and values and store that information in a central location so regardless of the care setting any provider could find current information regarding the patient's priorities," Gabbard said.

The study showed that in the nurse group ACP was documented in 42% of the visits as compared to only 3.7% in the normal care group.

Findings from this trial suggest a promising new approach to ACP in the out-patient primary care setting and a potentially scalable approach to ACP for vulnerable older adults, Gabbard said.

Diets rich in certain plant-based foods are linked with the presence of gut microbes that are associated with a lower risk of developing conditions such as obesity, type 2 diabetes and cardiovascular disease, according to recent results from a large-scale international study that included researchers from King's College London, the Harvard T.H. Chan School of Public Health, Massachusetts General Hospital (MGH), the University of Trento, Italy, and health science start-up company ZOE.

Key Takeaways

The largest and most detailed study of its kind uncovered strong links between a person's diet, the microbes in their gut (microbiome) and their health.

International study uses metagenomics and blood chemical profiling to uncover a panel of 15 gut microbes associated with lower risks (and 15 with higher risks) for common illnesses such as diabetes and heart disease.

Some of the identified microbes are so novel that they have not yet been named.

These findings could be used to provide personalized dietary advice for better health, based on gut microbiome testing.

The PREDICT 1 study analyzed detailed data on the composition of participants' gut microbiomes, their dietary habits, and cardiometabolic blood biomarkers. The researchers found evidence that the microbiome is linked with specific foods and diets, and that, in turn, certain microbes in the gut are linked to biomarkers of metabolic disease. Surprisingly, the microbiome has a greater association to these markers than other factors, such as genetics. Their report, authored by Dr. Francesco Asnicar (University of Trento) and Dr. Sarah Berry (King's College London) and coordinated by Tim Spector (King's College London) and Nicola Segata (University of Trento), appears in Nature Medicine.

Dr. Sarah Berry, Reader in Nutrition Sciences at King's College London said, "As a nutritional scientist, finding novel microbes that are linked to specific foods, as well as metabolic health, is exciting. Given the highly personalised composition of each individuals' microbiome, our research suggests that we may be able to modify our gut microbiome to optimize our health by choosing the best foods for our unique biology."

For example, the findings reveal that having a microbiome rich in Prevotella copri and Blastocystis species was associated with maintaining a favorable blood sugar level after a meal. Other species were linked to lower post-meal levels of blood fats and markers of inflammation.

Professor Tim Spector, Epidemiologist from King's College London, who started the PREDICT study program and is scientific founder of ZOE explains, "When you eat, you're not just nourishing your body, you're feeding the trillions of microbes that live inside your gut."

Researchers also discovered that the makeup of subjects' gut microbiome was strongly associated with specific nutrients, foods, food groups and overall diet composition. The researchers found robust microbiome-based biomarkers of obesity, as well as markers for cardiovascular disease and impaired glucose tolerance, which are key risk factors for COVID. These findings can be used to help create personalized eating plans designed specifically to improve one's health.

"I am very excited that we have been able to translate this cutting edge science into an at-home test in the time it has taken for the research to be peer reviewed and published," says Spector. "Through ZOE, we can now offer the public an opportunity to discover which of these microbes they have living in their gut. After taking ZOE's at-home test, participants will receive personalized recommendations for what to eat, based on comparing their results with the thousands of participants in the PREDICT studies. By using machine learning, we can then share with you our calculations of how your body will respond to any food, in real-time through an app."

The researchers found in subjects who ate a diet rich in healthy, plant-based foods were more likely to have high levels of 'good' gut microbes. Conversely, diets containing more highly processed plant-based foods were more likely to be associated with the 'bad' gut microbes.

"We were surprised to see such large, clear groups of what we informally call 'good' and 'bad' microbes emerging from our analysis," affirmed Nicola Segata, PhD, professor and principal investigator of the Computational Metagenomics Lab at the University of Trento, Italy and leader of the microbiome analysis in the study. "It is also exciting to see that microbiologists know so little about many of these microbes that they are not even named yet. This is now a big area of focus for us, as we believe they may open new insights in the future into how we could use the gut microbiome as a modifiable target to improve human metabolism and health."

PREDICT 1 was an international collaboration to study links between diet, the microbiome, and biomarkers of cardiometabolic health. The researchers gathered microbiome sequence data, detailed long-term dietary information, and results of hundreds of cardiometabolic blood markers from just over 1,100 participants in the U.K. and the U.S. PREDICT 2 completed its primary investigations in 2020 with a further 1,000 U.S participants, and PREDICT 3 launched a few months ago.

DALLAS - Jan. 11, 2021 - A set of biomarkers not traditionally associated with cell fate can accurately predict how genetically identical cells behave differently under stress, according to a UT Southwestern study. The findings, published by Cell Reports as a Dec. 1 cover story, could eventually lead to more predictable responses to pharmaceutical treatments.

Groups of the same types of cells exposed to the same stimuli often display different responses. Some of these responses have been linked to slight differences in genetics between individual cells. However, even genetically identical cells can diverge in behavior.

One example can be found in budding yeast, or yeast that are actively dividing. When these microorganisms are deprived of glucose - the sugar molecules they use for energy - all cells stop dividing. However, when this nutrient becomes available again, some cells start dividing once more while others no longer divide but remain alive, even in batches of yeast that are genetic clones. What drives the differences in behavior between these re-dividing "quiescent" cells and never-dividing "senescent" cells has been a mystery, say study leaders N. Ezgi Wood, Ph.D., a postdoctoral fellow at UTSW, and Mike Henne, Ph.D., assistant professor of cell biology and biophysics at UTSW.

Previous studies of behavioral differences in genetically identical cells have focused on genes that decide cell fate. However, Wood, Henne, and their colleagues took a different tact: They looked at the behavior of other biomarkers associated with basic cell maintenance, such as cell cycling, stress response, intracellular communication, and nutrient signaling.

The researchers note that the role each of these factors plays in deciding cell fate is not yet clear. Learning more about the factors that prompt cells to act differently could eventually steer researchers in new directions. For example, the knowledge could be useful in helping cells uniformly respond to cancer chemotherapies or antibiotics, areas in which cells often take divergent paths.

"How two identical cells side by side take different paths is a very basic biological question - we see it from bacteria to mammalian cells," Wood says. "Our results show that factors not traditionally associated with cell fate can, in fact, play an important role in this process, and gets us closer to answering the question of why this phenomenon takes place and how we might control it."

To explore these questions, researchers genetically modified yeast cells so that five different protein markers associated with these maintenance tasks glowed with different colors inside the cell when they were present. They then set up an experiment in which these cells lived in a microfluidics chamber that was continuously flushed with liquid media. For two hours, this media was rich with the nutrients that these cells needed to survive and multiply, including glucose. Then, for the next 10 hours, the researchers cut off the glucose supply, starving the cells. At the end of this period, they reintroduced glucose, allowing the cells to recover. During this 16-hour cycle, a camera continuously monitored individual cells, looking for differences between those that became quiescent or senescent when glucose was available again.

When they reviewed the camera footage, researchers quickly saw that despite the cells growing in an asynchronized fashion, or at different points in their cell cycles, starvation stopped the cell cycle. A closer look showed that a protein inhibitor of the cell cycle known as Whi5 tended to collect in the nuclei of quiescent cells during starvation, while Whi5 in senescent cells disappeared altogether.

Similarly, the two populations exhibited differences in the proteins Msn2 and Rtg1 that are associated with stress response. Although these proteins collected in the nuclei of all the cells when they were starved, they had a sustained presence in the nuclei of senescent cells even after glucose returned, yet largely exited the nuclei of quiescent cells when starvation ended.

The researchers found another useful marker for separating these two populations in the nucleus-vacuole junction (NVJ), an interface that connects the nucleus to the vacuole, the small digestive organelle that cells use to sequester waste products. While quiescent cells tended to enlarge their NVJs during starvation, senescent cells did not.

Although each of these findings gave clues to which path cells would take after starvation started, none showed any predictive powers before starvation took place. But when the researchers examined Rim15, a protein that plays a key role in nutrient signaling, they found that cells with elevated Rim15 before starvation tended to become quiescent while those with lower concentrations of this protein were more likely to become senescent.

On their own, none of these factors served as an accurate predictor of cell fate. But when Wood, Henne, and their colleagues performed a statistical analysis incorporating all of them, they were able to accurately predict which cells became quiescent and which became senescent with an accuracy of nearly 90 percent before they reintroduced glucose. In fact, they say, cells seem to reach a "decision point" where it's unlikely that they'll change their direction about four hours into starvation.

As the planet continues to warm, the twin challenges of diminishing water supply and growing energy demand are intensifying. But because water and energy are inextricably linked, as we try to adapt to one challenge - say, by getting more water via desalination or water recycling - we may be worsening the other challenge by choosing energy-intensive processes.

So, in adapting to the consequences of climate change, how can we be sure that we aren't making problems worse?

Now, researchers at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab), UC Berkeley, and UC Santa Barbara have developed a science-based analytic framework to evaluate such complex connections between water and energy, and options for adaptations in response to an evolving climate. Their study, "Evaluating cross-sectoral impacts of climate change and adaptations on the energy-water nexus: A framework and California case study," was published recently in the open-access journal Environmental Research Letters.

"There have been many analyses on how climate change could affect the water and energy sectors separately, but those studies were not typically looking at interactions and feedbacks between the two," said lead author Julia Szinai of Berkeley Lab's Climate and Ecosystem Sciences Division. "Our paper develops a generalized framework that identifies how climate change affects these coupled water and electricity systems, and potential adaptations to future gaps in supply and demand. By doing so, we illustrate often-overlooked tradeoffs and synergies in adapting to climate change."

"In developing this project, Julia led a remarkable effort to integrate the climate impacts and feedbacks between the energy and water sectors," said co-author Daniel Kammen, a professor of energy and resources at UC Berkeley. "What is critical to planning our future under climate change is to capture - in both simplified and full dynamical models ¬- how interdependent are our infrastructure choices."

In applying the framework they developed to California, which relies on the snowpack for a good deal of its water and expends significant amounts of energy to transport water from the northern to the southern part of the state, they found that there are two possible adaptation pathways: one that is energy intensive and one that can actually save both water and energy.

"One of the most important points of the paper is that adapting our water system to climate change can either significantly exacerbate electricity grid stress, or on the flip side, it could help to alleviate it," said co-author and Berkeley Lab climate scientist Andrew Jones. "If we focus on adapting the water system by using big transfers of water across basins, or by using energy-intensive desalination, that's just going to make the electricity problem much more difficult. If, on the other hand, we adapt the water system by conserving water, it's actually a win-win situation because you're also reducing the energy required for water."

Currently, a staggering 19% of California's electricity consumption goes toward water-related applications, such as treating it, transporting it, pumping it, and heating it. Additionally, about 15% of in-state electricity generation comes from hydropower. Such interdependencies are referred to as the water-energy nexus. The state has already seen some impacts that climate change could have on these highly interdependent water-energy systems; for example, extended droughts and reduced snowpack have resulted in spikes in electricity consumption from groundwater pumping and hydropower deficits, which were made up by generating electricity using dirtier fossil fuels.

Looking ahead, the researchers integrated data across a number of fragmented studies to estimate the overall range of possible water and energy futures under various climate scenarios for the state at the end of the century. Their analysis found that the greatest direct climate change impact on the electricity sector in California will likely come from two factors: higher air conditioning loads and decreased hydropower availability. In the water sector, the greatest and most uncertain impact of climate change is on future water supplies. In the worst case, available water supplies could decrease 25%, and in the best case could increase 46%.

Applying their framework to California's water-energy future, they found that, if the state were to adapt to the worst-case water scenario by choosing the most energy-intensive technologies, it could result in an energy imbalance as large as that caused by climate change itself (increased air conditioning use and decreased hydropower availability being the climate change factors having the greatest direct energy imbalance impact).

"I think this is the first study to show that water sector adaptation can have as large of an impact on the electricity sector as the direct effect of climate change itself," said Jones. "So, if we pursued the energy-intensive path to water sector adaptation then it is as large as the direct effect of climate change, in the worst case."

Co-author Ranjit Deshmukh, a professor of environmental studies at UC Santa Barbara and faculty scientist at Berkeley Lab, noted, "Going forward, the electricity sector could leverage its close coupling with the water sector to enable balancing of increasing wind and solar generation in California as the state strives to meet its low-carbon-emission goals. For example, energy-intensive equipment such as water pumps or desalination plants, with adequate water storage, could be operated during times of plentiful solar and wind energy, and turned off at other times."

Next, Szinai, a UC Berkeley graduate student, said she plans to develop detailed models of both water and electricity systems so researchers can run simulations under various climate change and climate change adaptation scenarios, ultimately aiding planners in building out both the electrical grid and water resources.

"This study has highlighted the benefit of coordinated adaptation planning between the two sectors, so we're now linking a more detailed water resources management model and an electricity planning model that can demonstrate resilient pathways for building out electricity infrastructure in the Western U.S. when climate change impacts are included from the water sector," she said.

The genetic material of plants, animals and humans is well protected in the nucleus of each cell and stores all the information that forms an organism. For example, information about the size or color of flowers, hair or fur is predefined here. In addition, cells contain small organelles that contain their own genetic material. These include chloroplasts in plants, which play a key role in photosynthesis, and mitochondria, which are found in all living organisms and represent the power plants of every cell. But is the genetic material actually permanently stored within one cell? No! As so far known, the genetic material can migrate from cell to cell and thus even be exchanged between different organisms. Researchers at the Max Planck Institute of Molecular Plant Physiology (MPI-MP) in Potsdam have now been able to use new experimental approaches to show for the first time how the genetic material travels. They published their results in the journal Science Advances.

After a short time, the two partners grow together at the graft junction, resulting in a physiological connection between the two plants. "We were able to observe that genome transfer from cell to cell occurs in both directions with high frequency at this site", explains Dr. Alexander Hertle, first author of the study.

Using a new experimental setup, the researchers were able to observe structural changes in the cell walls in the wound tissue of the graft site. "The cell walls formed protrusions, creating junctions between the two partners. The size of those created pores allows the migration of an entire plastid. Therefore, the genome does not migrate freely, but encapsulated from cell to cell," Hertle continues. However, to actually make this possible, the plastids have to shrink and become mobile. These rod-shaped plastids are equal to an amoeba and grow back to normal size after transfer into the target tissue.

The researchers have thus uncovered a new pathway for intercellular exchange of very large cell structures, which may also be used by parasitic plants, such as mistletoe, to carry out gene exchange with their host. In addition, it now needs to be clarified whether mitochondria and the nuclear genome also use similar transfer mechanisms.

The transfer of genetic material occurs quite frequently in plants. This can either result in a new combination of the genetic material, or alternatively the recipient cell can establish both genetic variants in parallel. This union of two different genomes, called allopolyploidization, is very interesting in evolutionary terms, as it leads to the formation of new plant species and is widespread in many plant groups. Many important crops, such as bread and durum wheat, oats, cotton, canola, coffee, and tobacco have such combined genomes from at least two crossed species.

In order to understand the mechanisms of genome transfer from cell to cell, the researchers led by Ralph Bock at MPI-MP conducted experiments with tobacco plants using grafting, which is commonly used in agriculture. Here, two different tobacco plants were grafted onto each other and the cells of the junction were observed microscopically in real time. To differentiate between the genome of nucleus and plastids, fluorescent reporter proteins were integrated and expressed from both genomes and the researchers used a trick using a specialization of the chloroplasts. In the plastids, a gene is integrated by transformation that encodes a chloroplast-specific fluorescence protein, which is produced exclusively in plastids and cannot leave them. This creates an absolutely specific and stable label for the plastids.

Metabolites are organic molecules that take part in or are created during the biochemical reactions constantly taking place in an organism. For the human body, more than 110,000 metabolites have been identified. Metabolites play a role in metabolic syndrome, which is the situation in which several medical conditions occur simultaneously; the conditions include obesity, high blood pressure and high blood sugar. Metabolic syndrome is associated with a higher risk of developing cardiovascular disease, type-2 diabetes and different kinds of cancer. The presence of certain metabolites can be an indicator for particular pathological conditions related to metabolic syndrome. Efficiently measuring and monitoring the presence is therefore important for early diagnosis. Now, Tomoki Ogoshi*, Atsushi Hirao*, and Masaya Ueno (*correspondence authors) from Kanazawa University and colleagues have developed a biosensor for a low-molecular-weight metabolite known as 1-MNA. The sensor relies on the physicochemical properties of pillar[6]arene, a channel-like molecule.

The researchers investigated the metabolite 1-MNA (1-methylnicotinamide), recently discovered to be present in higher levels in aggressive cancer cell lines. These cancers have increased NNMT (nicotinamide N-methyltransferase) activity in which 1-MNA is a byproduct. Detecting 1-MNA could be therefore crucial for the timely diagnosis and treatment of such cancers.

Ogoshi and colleagues hypothesized that pillar[n]arenes could be used as biosensors for metabolites like 1-MNA. Pillar[n]arenes are pillar-shaped macrocyclic compounds with a polygonal cross-section (pentagonal and hexagonal for n = 5 and 6, respectively). The researchers found that pillar[6]arene (P6A) forms host-guest a complex with 1-MNA; the metabolite can bind to it because the hexagonal cavity inside P6A offers just the right environment for doing so. They also found that when 1-MNA is bound to P6A, the fluorescent response of the latter significantly decreases -- an effect that can be exploited as an indicator for the presence or absence of 1-MNA (strong or weak fluorescent response, respectively).

Importantly, the scientists could show that the P6A fluorescence detection mechanism works for biological samples. Specifically, they were able to detect 1-MNA in urine, albeit with a low sensitivity. Ogoshi and colleagues conclude that additional experiments "will help to improve the sensitivity and specificity of the biosensors", and that their work "should contribute to the development of low-cost, easy, and rapid methods for the detection of human metabolites for diagnosis".

[Background]

Metabolic syndrome

Metabolic syndrome refers to the combination of diabetes, high blood pressure (hypertension) and obesity. Patients with metabolic syndrome are at a greater risk for developing certain cardiovascular diseases as well as different types of cancer. Metabolic syndrome is often associated with being overweight and a lack of physical activity, and is also linked to insulin resistance (a key feature of type-2 diabetes).

Now, Tomoki Ogoshi from Kanazawa University and colleagues have developed a biosensor for a metabolite known as 1-MNA. Being able to efficiently detect metabolites associated with certain pathologies is an important step forward towards the development of treatments for pathologies associated with metabolic syndrome.

Pillar[n]arenes

Pillar[n]arenes, collectively named pillararenes (and sometimes pillarenes), are cyclic organic molecules consisting of n so-called hydroquinone units, which can be substituted. Hydroquinone, also known as quinol, has the chemical formula C6H4(OH)2. It consists of a benzene ring with two hydroxyl (OH) groups bound to it at opposite sides of the benzene hexagon.

The first pillararene was synthesized in 2008 by Tomoki Ogoshi and colleagues from Kanazawa University. The name pillararene was chosen since the molecules are cylindrical (pillar-like) in shape and composed of aromatic moieties (arenes).

Now, Ogoshi, Hirao and colleagues have shown that pillar[6]arene (n = 6) can be used as biosensors for the metabolite 1-MNA -- an important result given that detecting low-molecular-weight metabolites is challenging.

NEW YORK, NY (Jan. 11, 2021)--Thousands of different genetic mutations have been implicated in cancer, but a new analysis of almost 10,000 patients found that regardless of the cancer's origin, tumors could be stratified in only 112 subtypes and that, within each subtype, the Master Regulator proteins that control the cancer's transcriptional state were virtually identical, independent of the specific genetic mutations of each patient.

The study, published Jan. 11 in Cell, confirms that Master Regulators provide the molecular logic that integrates the effect of many different and patient-specific mutations to implement the transcriptional state of a specific tumor subtype, thus greatly expanding the fraction of patients who may respond to the same treatment.

More specifically, rather than looking for drugs targeting mutated genes associated with increasingly smaller patient subsets, the new study suggests that a much larger fraction of patients may respond to novel drug classes designed to target Master Regulator proteins.

The new analysis of thousands of tumors from all types of cancers also found that the key genetic programs necessary for the survival of cancer cells are mechanistically controlled by only 24 Master Regulator modules--dubbed MR-Blocks--each one comprising just a handful of such proteins working in concert.

The analysis, which has the potential to streamline and improve cancer treatment in the future, was led by Andrea Califano, Dr., Cory Abate-Shen, PhD, and Mariano Alverez, PhD, at Columbia University's Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center.

"In today's personalized medicine, we try to identify which one out of thousands of possible genetic mutations or, even worse, mutational patterns may have triggered an individual's disease, and then we hope we have drugs that can target the activity of the related proteins," says Califano, the Clyde and Helen Wu Professor of Chemical and Systems Biology and chair of systems biology at Columbia University Vagelos College of Physicians and Surgeons. "But instead of requiring drugs targeting each different mutation, our study suggests that we may just need a few dozen different drugs that can target MR-Blocks," he adds.

"Identifying the handful of MR-Blocks that are active in each individual's cancer will guide us in selecting the most appropriate drug or drug combination to treat them," Califano says. This hypothesis is already being tested in a number of clinical trials, including in breast cancer, pancreatic cancer, and neuroendocrine tumors, as well as in the Columbia Precision Oncology Initiative, a large-scale program aiming to assess the value of genomic, immunotherapeutic, and Master Regulator-based treatments in 3,000 patients across eight aggressive tumor types.

Personalized Therapy Benefits Only a Few Cancer Patients

Most cancer patients receive the same treatment, which has been tested on thousands and thousands of patients. When those options fail, however, patients may opt for a personalized approach, which involves identifying the genetic mutations in the patient's tumor to guide the selection of drugs that target those mutations.

But few patients actually draw benefit from this approach, Califano says, because most tumors lack druggable mutations and the few that have them often fail to respond or relapse rapidly following an initial response. "Relying solely on the identification of genetic mutations to guide personalized treatment has not turned out to be the slam-dunk that we were all hoping for. Large-scale studies have shown that only to 5% to 10% of patients benefit and most of them eventually progress to a drug-resistant form of the tumor. Additional approaches are thus sorely needed," he explains. "For instance, targeting the oncogene BRAF with inhibitors such as vemurafinib provides extraordinary short-term response in melanoma patients with mutations in this gene. Yet relapse occurs within a few months, such that little if any overall survival benefit is observed."

Califano and his colleagues have focused on a different approach to personalized therapy. Using advanced mathematics and physics-based methodologies to model complicated biological systems, such as the molecular interactions that implement the biological logic of the cell, Califano and his team crunch data from thousands of cancer samples to understand how genetic mutations influence the activity of all of the proteins in a malignant cell. Indeed, genes are important only because they represent the blueprint to make proteins, while the latter are the molecules that preside over specific functions in the cell, including turning a normal cell into a tumor.

"If you model the cell like a complex electronic circuit, it becomes easy to identify the specific components where the aberrant signals arising from mutated genes eventually converge," he says. "Rather than the individual mutations, these components represent the most universal vulnerabilities of the cancer cell."

Many of these points of convergence are proteins that ultimately determine the cell's fate, even though they are rarely affected by mutations.

Califano calls these proteins, which are both necessary and sufficient for cancer cell maintenance across virtually all cancers, "Master Regulators." "You can think of Master Regulators as the narrow opening at the bottom of a funnel," he says. "The top of the funnel collects the effects of all relevant genetic mutations in the cell and 'canalizes' them into that narrow opening.

"We think it will be more effective and efficient to simply plug the end of the funnel, by targeting one or more Master Regulators, than to target all the mutated proteins feeding into it."

Master Regulator Blocks

Though master regulators have been identified in several specific cancers, the new study looked for Master Regulators across 20 different cancer types, as well as for any overlap they may have across multiple cancers.

To accomplish this goal, Califano's team developed a computational tool called Multi-Omics Master-Regulator Analysis (MOMA) to analyze gene expression and gene alterations in tumors. They used MOMA to analyze 9,738 tissue samples from the Cancer Genome Atlas repository of the National Cancer Institute.

The analysis identified 407 Master Regulators across the various cancers and found that these are organized into only 24 unique and highly interconnected modules, or Master Regulator Blocks (MR-Blocks). Each MR-Block contains only a handful of Master Regulators working in concert to control particular hallmarks of cancer cell behavior. For example, MR-Block:2, the most frequently activated block in the most aggressive cancers, comprises 14 regulators of cell growth, DNA repair, cell division, and cell proliferation. Activation of this block was found to be predictive of poor outcomes in many different types of cancer. In contrast, MR-Block:24 was found to be associated with inflammatory programs and immune response and was thus a predictor of good outcome in melanoma.

On average, between two and six MR-Blocks were activated in each individual tumor.

Targeting MR-Blocks as Therapy

Califano's team also demonstrated that the activity of MR-Blocks in cell lines could be modulated with drugs, favorably affecting cell behavior in several types of cancer.

Targeting MR-blocks, rather than individual mutated proteins, promises to potentially prevent cancer cells from developing resistance, since individual MR-Blocks capture the effect of an extremely large number of potential mutations in their upstream pathways, which would otherwise inevitably lead to drug resistance.

"We've shown that if you target MR-Blocks, it's very hard for the cell to go around the blockade," Califano says. "The cell would have to reprogram itself, and that's something that a cell doesn't like to do and most often, albeit with some exceptions, of course, leads to cell death."

Califano envisions that in the future, each patient's cancer may be decomposed into its specific MR-Blocks and be treated with drugs designed to target them, either individually or in combination. The good news is that a tumor needs to aberrantly activate and inactivate many genetic programs to survive. Thus, even targeting just one of several MR-Blocks is likely to induce cancer cell demise, Califano says.

Unfortunately, even though the technology to readily identify which MR-Blocks are active in a patient's cancer already exists, few if any drugs have been developed specifically to target them. As a result, Califano's lab developed algorithms to assess the ability of existing drugs to inhibit or activate individual MR-blocks. For instance, the study shows that four FDA-approved and experimental drugs already exist that are capable of activating MR-Block:14 in prostate cancer, thus dramatically reducing the cell's ability to migrate and metastasize. Drugs designed specifically to target Master Regulators should outperform existing drugs, Califano says. As a result, a number of collaborations are under way to start developing this new class of inhibitors despite the fact that, until very recently, Master Regulators were considered to be largely "undruggable" proteins.

"This is a new concept, so there's been little development of such drugs," Califano says. "But we're already testing drug candidates, and initial validation in both pre-clinical and clinical studies has very much exceeded our expectations"