Sensory Illusion Causes Cells to Self-Destruct Might Help Cancer Therapeutics

Cancer Therapeutics

via UCSF

Study Reveals Importance Of Timing For Cellular Signals, Suggests Possible Tactic For Cancer Therapeutics

Magic tricks work because they take advantage of the brain’s sensory assumptions, tricking audiences into seeing phantoms or overlooking sleights of hand. Now a team of UC San Francisco researchers has discovered that even brainless single-celled yeast have sensory biases that can be hacked by a carefully engineered illusion, a finding that could be used to develop new approaches to fighting diseases such as cancer.

“The ability to perceive and respond to the environment is a basic attribute of all living organisms, from the greatest to the smallest,” said Wendell Lim, PhD, the study’s senior author. “And so is the susceptibility to misperception. It doesn’t matter if the illusion is based on molecular sensors within a single cell or neurons in the brain.”

In the new study, published online Nov. 19, 2015 in Science Express, Lim and his team discovered that yeast cells falsely perceive a specifically timed pattern of stress – caused by alternating between low and mildly increased sodium levels – as a massive, continuously increasing ramp of stress. In response, the microbes end up over-responding and killing themselves. The results, Lim says, suggest a whole new way of looking at the perceptual abilities of simple cells and could even be used to develop new approaches to fighting diseases using the power of illusion.

Timing of stress response is yeast cells’ ‘Achilles heel’

“This discovery was a bit of an accident actually,” said Lim, chair of the Department of Cellular and Molecular Pharmacology at UCSF, director of the UCSF Center for Systems and Synthetic Biology, and a Howard Hughes Medical Institute (HHMI) investigator. “We were interested in the general issue of how cells interpret information over time. Frequency is a key aspect of all our communications, whether it’s hearing language or transmitting radio signals, but do cells themselves use this kind of information? It’s something we don’t know much about.”

To explore this question, two postdoctoral fellows in Lim’s lab, Ping Wei, PhD, now at Peking University School of Life Sciences, and Amir Mitchell, PhD, set up a system that allowed them to expose yeast to a mild stressor – a small increase in salt in the yeast’s environment – and to oscillate between the increased salt level and the baseline level at different frequencies.

Normally, sensor molecules in a yeast cell detect changes in salt concentration and instruct the cell to respond by producing a protective chemical. After this transient response, the cell can resume growing happily as if conditions had not changed. The researchers found that the cells were perfectly capable of adapting when they flipped the salt stress on and off every minute or every 32 minutes. But to their surprise, when they tried an eight-minute oscillation of precisely the same salt level the cells quickly stopped growing and began to die off.

“That was just a jaw-dropping moment,” said Mitchell. “These cells should be able to handle this level of osmotic stress, but at one particular frequency they just go haywire. We’d never seen anything like this before.”

Could sensory illusions be used to fight cancer?

Mitchell, who was first author on the new study, went on to inspect the cellular mechanism underlying this unexpected, frequency-dependent toxicity. Using mathematical modeling and experiments in which he tweaked the molecular wiring of the mitogen activated protein kinase (MAPK) pathway that mediates the cells’ salt-sensing system, he revealed a sensory misperception: Because of the way the MAPK pathway is set up, the cells interpret an eight-minute oscillation as an ever-increasing staircase of salt concentration. This leads to excessive activation of the cells’ protective response, and ultimately to their death (see Movie).

Read more: Sensory Illusion Causes Cells to Self-Destruct



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Wisconsin Scientists Grow Functional Vocal Cord Tissue in the Lab

via University of Wisconsin

via University of Wisconsin-Madison

University of Wisconsin scientists have succeeded in growing functional vocal-cord tissue in the laboratory, a major step toward restoring a voice to people who have lost their vocal cords to cancer surgery or other injuries.

Dr. Nathan Welham, a speech-language pathologist, and colleagues from several disciplines, were able to bioengineer vocal-cord tissue able to transmit sound, they reported in a study published today in the journal Science Translational Medicine.

About 20 million Americans suffer from voice impairments, and many have damage to the vocal-cord mucosae, the specialized tissues that vibrate as air moves over them, giving rise to voice.

While injections of collagen and other materials can help some in the short term, Welham says not much can be done for people who have had larger areas of their vocal cords damaged or removed.

Voice is a pretty amazing thing, yet we don’t give it much thought until something goes wrong,” says Welham, an associate professor of surgery in the UW School of Medicine and Public Health. “Our vocal cords are made up of special tissue that has to be flexible enough to vibrate, yet strong enough to bang together hundreds of times per second. It’s an exquisite system and a hard thing to replicate.”

Welham and colleagues began with vocal-cord tissue from a cadaver and four patients who had their larynxes removed but did not have cancer. They isolated, purified and grew the cells from the mucosa, then applied them to a 3-D collagen scaffold, similar to a system used to grow artificial skin in the laboratory.

In about two weeks, the cells grew together to form a tissue with a pliable but strong connective tissue beneath, and layered epithelial cells on top. Proteomic analysis showed the cells produced many of the same proteins as normal vocal cord cells. Physical testing showed that the epithelial cells had also begun to form an immature basement membrane which helps create a barrier against pathogens and irritants in the airway.

Welham says the lab-grown tissue “felt like vocal-cord tissue,” and materials testing showed that it had qualities of viscosity and elasticity similar to normal tissue.

Read more: Wisconsin Scientists Grow Functional Vocal Cord Tissue in the Lab



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Scripps Florida Scientists Reveal Potential Treatment for Life-Threatening Viral Infections



The Findings Point to New Therapies for Dengue, West Nile and Ebola

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown for the first time how a previously unknown process works to promote infection in a number of dangerous viruses, including dengue, West Nile and Ebola.

The new study also points to a potential treatment, an experimental antibiotic that appears to inhibit infection by these deadly viruses, all of which lack vaccines and treatments.

The study, which was published recently by the journal Proceedings of the National Academy of Sciences (PNAS), was led by TSRI Associate Professor Hyeryun Choe.

“Most of these viruses use a specific molecule to enter cells,” Choe said. “In the new study, we were able to show how a second molecule plays a major and previously unknown role in that process. We also show an antibiotic called duramycin inhibits the actions of this molecule. This looks to be a promising broad-spectrum antiviral strategy and deepens our understanding of the entire infection process.”

Emerging Health Concern

The viruses in question belong to several families, including the flavivirus and filovirus families. Flaviviruses like dengue and West Nile viruses cause tens of thousands of deaths each year. Filoviruses like Ebola have emerged as major health concerns, particularly in tropical and subtropical areas such as the recent highly publicized Ebola outbreak in West Africa. Perhaps the greatest concern is dengue virus. More than one third of the world’s population is estimated to be at risk for dengue and more than 100 million people are estimated to be infected annually, according to recent studies.

The viruses take advantage of the process that normally occurs during programmed cell death or apoptosis. During this process, a lipid usually found on the inner side of the cell membranes, specifically phosphatidylserine (PS), shifts to the surface. Apoptosing cells are then recognized by PS receptors on phagocytes—cells that devour invading pathogens and dying cells—and engulfed by them.

When cells are dying from a virus infection, their freshly exposed PS is grabbed by the exiting virus and phagocytes engulf the virus. Once engulfed, the virus quickly turns the cell’s own biology on its head, forcing it to produce copies of the virus.

New Insights

In the new study, Choe and her colleagues showed how another lipid known as phosphatidylethanolamine (PE), which is present on the viral surface, also contributes to the viral entry process.

“Despite the name, we found that PS receptors also detect PE, and viruses are able to take advantage of the abundance of PE on their surface,” said Audrey Stéphanie Richard, the first author of the study and a research associate in the Choe lab. “Through their PE, they latch onto the PS receptors on the host cell, taking control of the process and insuring entry and replication.”

Duramycin blocks viral entry into the cells by binding to the virus’s PE, preventing the virus from using it to latch onto the PS receptors on the cell. Duramycin, which is currently used as an imaging agent, binds specifically to PE.

Disrupting the relationship between these two molecules could open the door to new and novel antiviral strategies, potentially including duramycin and similar PE-inhibitors.

“This new study goes a long way in helping us understand how so-called PS receptors contribute to flavivirus and filovirus infections and how we can block them through the PE-binding compounds,” Choe said.

Read more: Scripps Florida Scientists Reveal Potential Treatment for Life-Threatening Viral Infections



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High yield crops a step closer



Crops with improved yields could more easily become a reality, thanks to a development by scientists.

Researchers studying a biological process that enables tiny green algae to grow efficiently have taken the first steps to recreating the mechanism in a more complex plant.

Their findings could lead to the breeding of high yield varieties of common crops such as wheat, rice and barley.

Concentrating carbon

Algae cells are known to have a specialised mechanism that boosts their internal concentration of carbon dioxide during photosynthesis.

This process supports other mechanisms that convert this store of carbon into the sugars the cells need to grow.

Many staple crops, and nearly all vegetables, have a less efficient method of photosynthesis. They cannot actively raise their internal concentrations of CO2 in the same way as algae.

If crops could be developed using the concentrating mechanism found in algae, they could have a much higher yield than existing varieties.

Component transplant

Plant experts at the University of Edinburgh studied components in algae that play a role in photosynthesis and found that they could function normally in other types of cells.

They then transferred the components to tobacco and cress plants, and found that the parts were able to locate at the correct places in the new cells.

Scientists were able to pinpoint the most critical components involved in efficient plant growth, and to gauge what further research might be needed for improved crops.

Read more: High yield crops a step closer



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Mapping the Genes that Increase Lifespan

Budding Yeast via Buck Institute

Budding Yeast via Buck Institute

Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health.

The research was published online on October 8th  in the journal Cell Metabolism.

“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”

The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.

“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.

“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”

A number of the age-extending genes the team identified are also found inC. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.

The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.

“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”

Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.

“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”

Read more: Mapping the Genes that Increase Lifespan



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