Human chromosomes (grey) capped by telomeres (white). Credit: PD-NASA; PD-USGOV-NASA

A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally thought.

The key to immortalization is an enzyme called telomerase, which keeps chromosomes healthy in cells that divide frequently. The enzyme lengthens the caps, or telomeres, on the ends of chromosomes, which wear off during each cell division.

When the telomeres get too short, the ends stick to one another, wreaking havoc when the cell divides and in most cases killing the cell. The discovery of telomerase and its role in replenishing the caps on the ends of the chromosomes, made by Elizabeth Blackburn and Carol Greider at UC Berkeley and John Szostak at Harvard University in the 1980s, earned them a Nobel Prize in Physiology or Medicine in 2009.

Because telomeres get shorter as cells age, scientists theorized that cancer cells - which never age - become immortalized by turning on production of telomerase in cells that normally don't produce it, allowing these cells to keep their long telomeres indefinitely. An estimated 90 percent of all malignant tumors use telomerase to achieve immortality, and various proposed cancer therapies focus on turning down the production of telomerase in tumors.

The new research, which studied the immortalization process using genome-engineered cells in culture and also tracked skin cells as they progressed from a mole into a malignant melanoma, suggests that telomerase plays a more complex role in cancer.

"Our findings have implications for how to think about the earliest processes that drive cancer and telomerase as a therapeutic target. It also means that the role of telomere biology at a very early step of cancer development is vastly underappreciated," said senior author Dirk Hockemeyer, a UC Berkeley assistant professor of molecular and cell biology. "It is very likely that what we find in melanoma is true for other cancer types as well, which would warrant that people look more carefully at the role of early telomere shortening as a tumor suppressing mechanism for cancer."

The results will be reported online August 17 as a "first release" publication from the journal Science.

From nevus to cancer

Hockemeyer and his UC Berkeley colleagues, in collaboration with dermatopathologistBoris Bastian and his colleagues at UCSF, found that immortalization is a two-step process, driven initially by a mutation that turns telomerase on, but at a very low level. That mutation is in a promoter, a region upstream of the telomerase gene - referred to as TERT - that regulates how much telomerase is produced. Four years ago, researchers reported that some 70 percent of malignant melanomas have this identical mutation in the TERT promoter.

The TERT promoter mutation does not generate enough telomerase to immortalize the pre-cancerous cells, but does delay normal cellular aging, Hockemeyer said, allowing more time for additional changes that turns telomerase up. He suspects that the telomerase levels are sufficient to lengthen the shortest telomeres, but not keep them all long and healthy.

If cells fail to turn up telomerase, they also fail to immortalize, and eventually die from short telomeres because chromosomes stick together and then shatter when the cell divides. Cells with the TERT promoter mutation are more likely to up-regulate telomerase, which allows them to continue to grow despite very short telomeres.

Yet, Hockemeyer says, telomerase levels are marginal, resulting is some unprotected chromosome ends in the surviving mutant cells, which could cause mutations and further fuel tumor formation.

"Before our paper, people could have assumed that the acquisition of just this one mutation in the TERT promoter was sufficient to immortalize a cell; that any time when that happens, the telomere shortening is taken out of the equation," Hockemeyer said. "We are showing that the TERT promoter mutation is not immediately sufficient to stop telomeres from shortening."

It is still unclear, however, what causes the eventual up-regulation of telomerase that immortalizes the cell. Hockemeyer says that it's unlikely to be another mutation, but rather an epigenetic change that affects expression of the telomerase gene, or a change in the expression of a transcription factor or other regulatory proteins that binds to the promoter upstream of the telomerase gene.

"Nevertheless, we have evidence that the second step has to happen, and that the second step is initiated by or is occurring at a time where telomeres are critically short and when telomeres can be dysfunctional and drive genomic instability," he said.

In retrospect, not a surprise

Though most cancers seem to require telomerase to become immortal, only some 10 to 20 percent of cancers are known to have a single-nucleotide change in the promoter upstream of the telomerase gene. However, these include about 70 percent of all melanomas and 50 percent of all liver and bladder cancers.

Hockemeyer said that the evidence supporting the theory that the TERT promoter mutation up-regulated telomerase has always been conflicting: cancer cells tend to have chromosomes with short telomeres, yet have higher levels of telomerase, which should produce longer telomeres.

According to the new theory, the telomeres are short in precancerous cells because telomerase is turned on just enough to maintain but not lengthen the telomeres.

"Our paper reconciles contradictory information about the cancers that carry these mutations," Hockemeyer said.

The finding also resolves another recent counterintuitive finding: that people with shorter telomeres are more resistant to melanoma. The reason, he said, is that if a TERT promoter mutation arises to push a precancerous lesion - the mole or nevus - toward a melanoma, the chances are greater in someone with short telomeres that the cell will die before it up-regulates telomerase and immortalizes the cells.

The study also involved engineering TERT promoter mutations in cells differentiated from human pluripotent stem cells and following their progression toward cellular immortality. The results were identical to the progression seen in human skin lesions obtained from patients in UCSF's Helen Diller Family Comprehensive Cancer Center and examined in the Clinical Cancer Genomics Laboratory, which Bastian directs.

Explore further: Unraveling the mystery of why cancer cells survive and thrive

More information: K. Chiba el al., "Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism," Science (2017). science.sciencemag.org/lookup/ 1126/science.aao0535

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Two-step process leads to cell immortalization and cancer - Medical Xpress

Research associate Francesca Di Cara (front), associate professor Andrew Simmonds and Richard Rachubinski, professor and chair of the Department of Cell Biology, discovered that peroxisomes are necessary for proper functioning of the innate immune system. Credit: Melissa Fabrizio

A new addition to the fight against bacteria comes in the unlikely form of an organelle that previously had no link to the immune response. University of Alberta researchers have found that peroxisomes are required for cells in the innate immune response to bacteria and fungi.

The discovery was first made in fruit flies. Research Associate Francesca Di Cara, together with Richard Rachubinski, professor and chair of the Department of Cell Biology, and Andrew Simmonds, cell biology associate professor, partnered to create fruit flies that could be used specifically for studying peroxisomal disorders, which are rare genetic diseases affecting humans.

Di Cara found that peroxisomes are necessary for proper functioning of the innate immune system, the body's first line of defense against microorganisms. The innate immune system is an ancient system of immunity that identifies, captures and processes a pathogen, and then presents it to the acquired immune system.

The peroxisomes also communicate to other organs that there is an infection. The team discovered that when the organelle's basic function is altered, this communication is lost and the organism does not fight the bacteria.

"Understanding how the body fights infection has an impact on human health," says Di Cara. "We have to understand who the 'fighters' in the organism are before we can identify what's failing in the battle against bacterial infections."

Peroxisomes are 'chemical factories' that process complex fat molecules into simple forms and modify reactive oxygen molecules, which together act to signal to cells and tissues to respond appropriately to changes in their environment.

Along with their collaborator Nancy Braverman from McGill University, the researchers used a mouse model to confirm that what they observed in the flies also occurred in a mammalian system.

"To find organelles like peroxisomes that had no link whatsoever to fighting bacterial infections was a critical discoveryit will help expand the roles of what this important organelle does in innate immunity against bacterial and fungi, and its involvement in viral signaling and the lethal peroxisome genetic diseases," says Rachubinski. "As the threat of bacterial infections continues to grow, this discovery can help move our understanding of immunity forward."

The work was recently published in Immunity.

Explore further: Drosophila innate immunity: Another piece to the puzzle

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Peroxisomes identified as 'fighters' in the battle against bacterial infections - Medical Xpress

BERKELEY, CA, Aug. 17, 2017 About 500 people gathered this week at the University of California Berkeley to assess the rapid adoption of gene editing techniques that appear to hold immeasurable promise for human, animal and plant health and growth.

The two-day conference, CRISPRcon, is named for new techniques Clustered Regularly Interspaced Short Palindromic Repeats called CRISPR-Cas systems.

Over the years, researchers have found various methods of editing the genes of organisms. They involve amending the DNA within an organisms nucleus, rather than inserting transgenic materials from other organisms into the nucleus. Since 2013, scientists have been pursuing an efficient approach of directly targeting sites in a cells chromosomes. The technique uses the cells own bits of RNA strands to guide its Cas proteins in ways that apply highly specific amendments to the DNA, thus altering the organism itself.

In agriculture, scientists are now increasingly applying genome editing to vanquish diseases and enable great leaps forward: for example, to develop resistance to citrus greening for citrus trees or to bestow immunity to porcine epidemic diarrhea virus (PEDv) for pigs.

Jennifer Doudna, a UC Berkeley professor of chemistry and cell biology who spoke at the conference, described the cells nucleus as its instruction manual. She lauded researchers for learning to cut and paste bits of text guiding its life functions. The wondrous feature of the new techniques, she said, is that they can be readily used in every aspect of biology; every type of organism.

I have never seen science move at the pace as it is now in the arena of genetics advancements, Doudna said, in part because CRISPR is such a democratizing tool, available and inexpensive for scientists worldwide to employ.

Participants included a range of genome editing proponents hungry to develop its benefits. Thomas Titus, an Illinois pig farmer, said he thinks first about the potential of CRISPR techniques in eliminating, or improving resistance to, swine diseases. He notes that gene editing for resistance to PEDv has already been accomplished by researchers at Kansas State University, and if we would eradicate diseases like that, it would be just astronomical.

Gene editing will have great impact on the future of farming, and especially on livestock production, Titus said. What it comes down to is how we can utilize this technology for the greater good.

Not all at the conference were ready to rush into CRISPR, though. An instant online survey of the auditorium full of attendees, for example, found 46 percent viewing CRISPR systems as a tremendous tool for the benefit of all mankind, while the rest took a more suspicious or nuanced view.

Many commented on the typically long lag between discovery of biological innovations and their acceptance by society. Doudna noted the torturous history of so-called golden rice, which is loaded with Vitamin A but hasnt earned regulatory approval because the trait is transgenic. The costs of implementing some promising genome editing discoveries may slow them, she said.

Dana Perls, a food technology campaigner for Friends of the Earth, said that she sees agricultural industry giants investing in gene editing and promoting its benefits, and she thinks that calls for caution.

The potential benefits is what we hear about, Perls said. However, it is equally important, if not more important, to look at the potential risks.

Potential effects on climate change, human health and food safety, she said, must be examined before genome editing advances are accepted.

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A drug-like molecule developed by Duke Health researchers appears to intercede in an inflammatory response that is at the center of a variety of diseases. Credit: Duke Health

A drug-like molecule developed by Duke Health researchers appears to intercede in an inflammatory response that is at the center of a variety of diseases, including some cancers, rheumatoid arthritis and Crohn's disease.

The molecule, called Takinib, works on a cell-signaling protein called tumor necrosis factor alpha, or TNF-alpha, which is a major contributor to tissue inflammation. In recent years, several biological drugs have been developed to interfere with TNF-alpha and treat both auto-immune disorders and some cancers, but patients often develop resistance or side effects.

The Duke team, lead by Timothy Haystead, Ph.D., a professor in the Department of Pharmacology and Cancer Biology, and Emily Derbyshire, Ph.D., assistant professor in the Department of Chemistry, conducted cell-based experiments to learn how the Takinib molecule influences a series of events to suppress cell death. Their work appears in the Aug. 17 issue of the journal Cell Chemical Biology.

The researchers found that Takinib inhibits an enzyme called TAK-1, which serves as a switch controlling cell survival in the TNF-alpha signaling process.

"The delicate balance between survival and death is often disrupted in disease, and this molecule is able to target the process," Haystead said. "This compound could potentially enhance the positive parts of TNF-alpha by only targeting tumor cells or inflammatory cells."

The compound also appears to be effective in small amounts, potentially reducing the toxicity that has been shown in biological compounds targeting the same inflammatory pathway.

Derbyshire said additional studies are underway to test Takinib in animals, focusing first on the molecule's effects in rheumatoid arthritis to determine whether it could have therapeutic benefit and then expanding to other diseases, including malaria.

"Takinib is unique for its ability to selectively target a pathway, since many inhibitors shut everything down," Derbyshire said. "It appears to have a more surgical ability to inhibit this pathway."

Explore further: Stem cells edited to fight arthritis: Goal is vaccine that targets inflammation in joints

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Lab tests show molecule appears to spur cell death in tumors, inflammation - Phys.Org

A cure for balding could be on the horizon after scientists have found a new way to make hair grow.

Increasing lactate production genetically accelerates the stem cells in dormant hair follicles to get them growing again, a study on mice showed.

Researchers believe the discovery may lead to new drugs to help people who suffer from alopecia, the medical term for hair loss.

Receding hairlines and thinning crowns can becaused by aging, genetics, hormone imbalance, stress, illness and medications. It may be temporary or permanent.

Before this, no one knew that increasing or decreasing the lactate would have an effect on hair follicle stem cells, said William Lowry, a professor of molecular, cell and developmental biology at the University of California, Los Angeles (UCLA).

Once we saw how altering lactate production in the mice influenced hair growth, it led us to look for potential drugs that could be applied to the skin and have the same effect.

In the study, the researchers found that the metabolic process that takes place in hair follicle stem cells is different from that which takes place in other skin cells.

They discovered that these cells convert glucose into a molecule called pyruvate but this metabolite can take one of two paths.

In can be sent to the powerhouse of a cell (the mitochondria) and used as energy, or the cells can convert it to a different metabolite called lactate the same substance produced during really intense exercise that causes a burning sensation in muscles.

The researchers suspected altering the chemical course of the glucose metabolites could change the behavior of inactive follicles.

Our observations prompted us to examine whether genetically diminishing the entry of pyruvate into the mitochondria would force hair follicle stem cells to make more lactate, and if that would activate the cells and grow hair more quickly, said Dr Heather Christofk, UCLA associate professor of biological chemistry and molecular and medical pharmacology.

To test their theory, the team examined mice that had been genetically engineered to not produce lactate along with those that had been altered to increase lactate production.

They found that blocking lactate prevented hair follicle stem cells from being activated while increasing lactate upped the production of hair.

The team identified two experimental drugs that, when applied to the skin of mice, accelerate hair growth in this way.

These are called RCGD423 and UK5099 and, while they work in different ways, both increased lactate production.

The researchers whose work was published in the journal Nature Cell Biology stress that these medications were used in preclinical tests only.

They have not been tested on humans or approved by the Food and Drug Administration as safe and effective.

Through this study, we gained a lot of interesting insight into new ways to activate stem cells, said Aimee Flores, a predoctoral trainee in Professor Lowrys lab and first author of the study.

The idea of using drugs to stimulate hair growth through hair follicle stem cells is very promising given how many millions of people, both men and women, deal with hair loss.

I think weve only just begun to understand the critical role metabolism plays in hair growth and stem cells in general; Im looking forward to the potential application of these new findings for hair loss and beyond.

Alopecia is the general medical term for hair loss. There are many types of hair loss with different symptoms and causes. Some of the more common types include:

Male-pattern baldness is most common type of hair loss, affecting around half of all men by 50 years of age. It usually starts around the late 20s or early 30s.

It generally follows a pattern of a receding hairline, followed by thinning of the hair on the crown and temples.

It is hereditary and thought to be caused by oversensitive hair follicles, linked to having too much of a certain male hormone.

As well as affecting men, it can sometimes affect women (female-pattern baldness) when hair usually only thins on top of the head.

The causes in women are less well understood, but tends to affect them post menopause.

Alopecia areata causes patches of baldness about the size of a large coin. It can occur at any age, but mostly affects teenagers and young adults. It is caused by a problem with the immune system and has a genetic element.

In most cases, hair will grow back in a few months. But some people go on to develop a more severe form of hair loss, such as:

This is usually caused by complications of another condition, such asdiscoid lupus or scleroderma.

In this type, the hair follicle is completely destroyed and the hair wont grow back.

It occurs in both males and females and mainly adults. It accounts for about 7% of hair loss cases.

This is widespread hair loss that can affect your scalp, face and body.

One of the most common causes of this type of hair loss is chemotherapy. In some cases, other cancer treatments including immunotherapy and radiotherapy may also cause hair loss.

In most cases, hair loss in anagen effluvium is temporary.

This is a common type of alopecia where there is widespread thinning of the hair, rather than specific bald patches. Your hair may feel thinner, but youre unlikely to lose it all and your other body hair isnt usually affected.

It can be caused by your body reacting to hormonal changes, (such as pregnancy), intense emotional stress, intense physical stress, such as childbirth, illness,changes in your diet or some medications.

In most cases, your hair will start to grow back within six months.

Source: NHS Choices

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Drug could cure balding by activating follicle cells - Gears Of Biz

A cluster of spring-loaded daggers inside a bacterium. Green shows them in their 'loaded' form, red after the dagger has been launched. Credit: Leo Popovich

Bacteria have to watch out for amoeba. Hungry amoebae hunt them: they catch them with their pseudopodia and then absorb and digest them.

However, some bacteria know how to defend themselves. One of these is Amoebophilus, which was discovered by researchers at the University of Vienna a few years ago. This bacterium cannot only survive inside amoebae, but also thrive: the amoeba has become its favourite habitat.

Together with the Viennese discoverers of the bacterium, scientists from ETH Zurich have now found a mechanism that they assume is crucial for the survival of Amoebophilus inside the amoeba. The bacterium has devices to shoot micro-daggers. It can use the daggers to pierce the amoeba from inside and thus escape digestion.

Escape from the amoeba's gut

The shooting mechanism consists of a sheath attached to the bacterium's inner membrane by a baseplate and an anchoring platform. Joo Medeiros, a doctoral student in Professor Martin Pilhofer's group at ETH, explains the mechanism: "The sheath is spring-loaded and the micro-dagger lies inside it. When the sheath contracts, the dagger is shot outwards extremely quickly through the bacterial membrane."

Bacteria absorbed by the amoeba end up in a special digestive compartment surrounded by a membrane. "Our results suggest that the bacteria are able to shoot the dagger into the membrane of the amoeba's digestive compartment," says Dsire Bck, also a doctoral student in Pilhofer's group and lead author of the study published in the journal Science. This results in disintegration of the compartment, which is an inhospitable environment for the bacteria, and release of the bacteria. Once outside the digestive compartment but still inside the amoeba, the bacteria can survive and even multiply.

The process by which the digestive compartment is destroyed is not yet known. "It may be that rupture of the membrane is due solely to mechanical reasons," says Pilhofer. However, it is conceivable that the daggers of the Amoebophilus bacteria are impregnated with a kind of arrow poison - with membrane-degrading enzymes. The blueprints for such enzymes are contained in the bacteria's genome, as Matthias Horn, professor at the University of Vienna, and his colleagues were able to show.

Precise milling

The scientists applied a completely new method, used only by a handful of research laboratories worldwide - including that of Pilhofer - to determine the three-dimensional structure of the daggers and their shooting mechanisms at high resolution. Bck froze amoebae after they had absorbed bacteria at minus 180C.

Much like a palaeontologist using a hammer and chisel to free fossils from stone, Medeiros then used a focused ion beam as a "nano-chisel" to work on the frozen specimens. With impressive precision, he was able to mill away the amoeba and the bulk of the bacterium, excavating the molecular daggers and their shooting devices in order to finally produce a three-dimensional electron tomogram.

First image of the overall structure

Systems related to the micro-daggers are also found elsewhere in biology: viruses that specialise in the infection of bacteria (bacteriophages) use such systems to inject their genome into microorganisms. Some bacteria can even release similar micro-devices into their surroundings to fight off competing microorganisms.

The scientists present for the first time the complete spatial structure of a shooting mechanism inside a cell in its natural context. They also show for the first time details of the baseplate and membrane anchor. "In the past, cell biologists investigated the function of such systems and structural biologists elucidated the structure of individual components," says Pilhofer. "With the cryo-focused ion beam milling and electron cryo-tomography technologies that we have established at ETH Zurich, we can now close the gap between cell biology and structural biology."

Multi-barrel guns

Micro-daggers had previously been found only as individual devices. In Amoebophilus, however, the scientists from Zurich and Vienna have now found apparatuses that occur in clusters of up to 30. "You could call them multi-barrel guns," says Pilhofer.

The researchers also used genomic comparisons to investigate how Amoebophilus evolved its daggers. "The relevant genes are very similar to those of the bacteriophage injection systems," says Pilhofer. "We assume that the genes from ancestors of today's bacteriophages established themselves in the bacteria's genome a long time ago."

Also present in other bacteria

Genomic comparisons suggest that the micro-daggers occur not only in Amoebophilus, but also in numerous other bacterial species from at least nine of the most important bacterial groups. The researchers have yet to investigate whether these bacteria also use their daggers in order to avoid digestion by amoebae, or whether the daggers serve quite different purposes. They have their work cut out for a long time to come.

Finally, the scientists would like to use the new method of cryo-focused ion beam milling to elucidate the structure of other complex molecular systems. "The technique could help to address many other questions in cell, infection and structural biology. We are already working with other research groups and offering them our expertise," says Medeiros.

Explore further: Plague bacteria take refuge in amoebae

More information: "In situ architecture, function, and evolution of a contractile injection system" Science (2017). science.sciencemag.org/lookup/ 1126/science.aan7904

Journal reference: Science

Provided by: ETH Zurich

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Bacteria stab amoebae with micro-daggers - Phys.Org