Therapies

New broad-spectrum antiviral protein can inhibit HIV, other pathogens in some primates

Anonymous — Wed, 18 Jan 2017 22:31:27 +0000

New broad-spectrum antiviral protein can inhibit HIV, other pathogens in some primates Anonymous (not verified) Wed, 01/18/2017 - 15:31

CUBT - CU Boulder Today

�ֲ��ý Boulder researchers have discovered that a protein-coding gene called Schlafen11 (SLFN11) may induce a broad-spectrum cellular response against infection by viruses including HIV-1.

The new research, which was recently published in the journal PLOS Pathogens, found that SLFN11's antiviral potency is highest in non-human primate species such as chimpanzees and orangutans, but less effective in humans and gorillas, indicating that the gene's effects have become highly species-specific over time when it comes to fighting off HIV-1.

"The findings suggest that HIV-1 has been able to take advantage of this relaxed selection in humans," said Alex Stabell, a graduate researcher in CU Boulder's BioFrontiers Institute and lead author of the new research.

The human immune system contains various protein-encoding genes that are able to recognize the foreign signatures of RNA viruses and prevent their replication, providing a genetic line of defense against animal-based (zoonotic) diseases. HIV-1 is one of several zoonotic retroviruses that has been able to subvert these defenses and adapt to human hosts via mechanisms that are still being studied. HIV-1 was passed to humans from primates.

In 2012, researchers demonstrated that the SLFN11 gene is capable of limiting HIV-1 replication early in the virus's lifecycle, but the mere presence of SLFN11 in humans has not, to date, provided an effective bulwark against the disease.

"The immune system contains some of the most rapidly evolving genes in mammalian genomes, and what we are finding is that the immune systems of even very closely-related species, such as humans and chimpanzees, differ in dramatic ways," said Sara Sawyer, an associate professor in the BioFrontiers Institute and senior author of the new study.

To investigate why, the CU Boulder researchers analyzed data from primate genome projects around the country to get a broader picture of the gene's evolutionary history and compare its antiviral effects in other primate species.

"We examined different versions of this gene in other primate species, looking for positive selection over time," said Stabell. "Genes tend to want to be conserved, to stay the same. But a rapidly adapting retrovirus can force their hand."

The analysis found that over millions of years, the antiviral effectiveness of the gene diverged by species to the point where the SLFN11 proteins encoded by chimpanzees, orangutans, gibbons and marmosets now inhibit HIV-1 replication far more effectively than those produced by human, gorillas and bonobos.

The researchers also found that SLFN11 can have antiviral effects beyond just HIV-1. Even when HIV-1 is absent from a host's system, the gene broadly restricts protein production based on non-optimized codons, essentially reprogramming cells to create a general antiviral state.

The findings could provide new avenues of inquiry for future pharmaceutical and gene therapy research centered on HIV-1.

Originally published by CU Boulder Today

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Scientist develops a new way to look at a cellular shapeshifter

Anonymous — Fri, 21 Oct 2016 06:00:00 +0000

Scientist develops a new way to look at a cellular shapeshifter Anonymous (not verified) Fri, 10/21/2016 - 00:00

BioFrontiers

Tubulin, a protein found in your cells, quietly lends itself to many life processes. It sorts itself into long chains, forming tubes that provide scaffolding for living cells. A versatile shapeshifter, tubulin can arrange itself into different structures during different types of cell behavior. Tubulin gained prominence for medical applications when Taxol, a chemical first found in the bark of the Pacific Yew tree, was developed as a treatment for ovarian, breast and lung cancers. Taxol binds to tubulin and makes it hard for the tubes to grow and shrink, preventing cancer cells from proliferating.

“Tubulin is one molecule that does many things in cells,” says Assistant Professor of Physics, Loren Hough, a member of the BioFrontiers Institute. “We're trying to understand how tubulin can play so many different roles."

Hough is focused on the ends of tubulin molecules, called the C-terminal tails. These tails coat the surfaces of the microtubules formed by tubulin. He is studying, in part, how much influence these tails exert on tubulin and its behavior. To answer some of the mysteries of tubulin, Hough developed a method to probe the C-terminal tails of tubulin using nuclear magnetic resonance spectroscopy, or NMR.

Hough wanted to measure how tubulin C-terminal tails influence cellular processes, but to do NMR he had to figure out how to get specific atoms into them first, as part of the isotopic labeling process. These atoms are easy to incorporate into bacteria, but tubulin cannot be made in bacteria because bacteria lack the suite of proteins that help tubulin fold into its correct shape. Hough brought in a helper: Tetrahymena thermophila. This small but mighty protozoan is common in freshwater ponds and is used frequently as a model organism in biological research. As it turns out, bacteria are a favorite snack of Tetrahymena, so Hough incorporated the isotopes into the bacteria, which were then devoured by the Tetrahymena. With the isotopes digested by the Tetrahymena, Hough was at last able to see the C-terminal tails in action using NMR, as described in a paper recently published in ACS Chemical Biology.

“There is beautiful physics regarding tubulin in general,” says Hough. “I thought the C-terminal tails might be affecting what we know about tubulin from a biophysical perspective. We think tubulin tails are like a knob the cell uses to control different features, but we don't know how the tails are used for this tuning. It’s exciting to be tackling these questions.”

Hough was awarded a New Investigator Maximizing Investigators’ Research Award (MIRA) from the National Institutes of Health this year to further the research in his lab. This grant, from the National Institute of General Medical Science, is meant to support the work of young faculty. Hough’s $1.8 million MIRA grant will run five years.

“The MIRA is great. It’s going to give our lab the ability to push this project forward, as well as other research on disordered proteins,” says Hough. “We’re looking forward to taking this work on tubulin C-terminal tails even further over the next five years.”

The Hough lab is part of the physics department's Biophysics group. At the �ֲ��ý BioFrontiers Institute, researchers from the life sciences, physical sciences, computer science and engineering are working together to uncover new knowledge at the frontiers of science and partnering with industry to make their discoveries relevant.

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Live Cells reveal cancer process

Anonymous — Thu, 11 Aug 2016 06:00:00 +0000

Live Cells reveal cancer process Anonymous (not verified) Thu, 08/11/2016 - 00:00

BioFrontiers

A deep look inside the live cells reveals a key cancer process

Telomerase, a powerful enzyme found at the ends of chromosomes, can keep humans healthy, or promote cancer growth. Researchers at the �ֲ��ý in Boulder used a process called single-molecule imaging to look into the complicated processes that this enzyme uses to attach itself to the ends of chromosomes. This new understanding could help researchers develop better diagnostics and drugs for treating cancer and other diseases.

The findings, which were recently published in the journal Cell, show that telomerase has a small window of opportunity, lasting only minutes, to connect to the telomeres at the ends of chromosomes. The team was surprised to find that telomerase may probe each telomere thousands of times, rarely forming a stable connection, in order to be successful at connecting to the chromosomes. Researchers believe that inhibiting telomerase from attaching to cancer cells is a target for better treatment of the disease.

Telomeres have been studied since the 1970’s for their role in cancer. They are constructed of repetitive nucleotide sequences that sit at the ends of our chromosomes like the ribbon tails on a bow. This extra material protects the ends of the chromosomes from deteriorating, or fusing, with neighboring chromosome ends. Telomeres are consumed during cell division and, over time, will become shorter and provide less cover for the chromosomes they are protecting. The enzyme, telomerase, replenishes telomeres throughout their lifecycles.

Telomerase is the enzyme that keeps cells young. From stem cells to germ cells, telomerase helps cells continue to live and multiply. Too little telomerase produces diseases of bone marrow, lungs and skin. Too much telomerase results in cells that over proliferate and may become “immortal.” As these immortal cells continue to divide and replenish, they build cancerous tumors. Scientists estimate that telomerase activation is a contributor in up to 90 percent of human cancers.

“This discovery changes the way we look at how telomerase recruitment works in general,” says �ֲ��ý Boulder Distinguished Professor and Nobel laureate Thomas Cech, who is director of CU’s BioFrontiers Institute and the lead author on the study. “It’s exciting to see this in living cells as it happens. Single-molecule imaging freezes the process, allowing us to study it. We are the only ones who have done this type of imaging of telomerase.”

The research team included coauthors, Jens Schmidt (pictured, left), a postdoctoral fellow and staff scientist, Arthur Zaug. They used the CRISPR genome editing and single molecule imaging to track telomerase’s movements in the nuclei of living human cancer cells. CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, uses segments of DNA that contain short copies of base sequences. The team used single-molecule imaging, attaching fluorescent protein tags to human cancer cells so that the enzymatic process was visible under a powerful microscope.

“At the end of the day, the goal is to target telomerase as an approach to treat cancer,” say Schmidt. “You can inhibit telomerase across the board, but the challenge is isolating the telomerase in cancer cells from the telomerase participating in the normal processes of healthy cells. This research brings us closer to understanding these processes.”

Tracking malaria's evolution

Anonymous — Mon, 12 Oct 2015 06:00:00 +0000

Tracking malaria's evolution Anonymous (not verified) Mon, 10/12/2015 - 00:00

BioFrontiers

A new paper published Nature Communications, coauthored by a researcher at the �ֲ��ý’s BioFrontiers Institute, looked at the genetic strategy used by the human malaria parasite and how old it is from an evolutionary perspective. BioFrontiers’ Aaron Clauset, an assistant professor of computer science, was part of a team that analyzed genetic data from apes and found that the genetic strategy used by the parasites that cause a malaria infection is the same, whether the disease is in humans or other primates. The team compared the genes of ape malaria parasites with those of human malaria to determine if the two use the same strategies for prolonging the disease.

Malaria is a complex disease process where the parasite invades red blood cells and the disease produces proteins on the cell’s surface. Genes called “var genes” create these proteins, which are recognized by the immune system’s antibodies. These antibodies bind onto the cell surface then kill the cell that contains the parasite. To confuse the host’s immune system, the parasite switches the types of var genes it uses on the surface of the cell so that antibodies can’t bind with the cell surface and kill the host cell and parasite. In addition, the parasite’s var genes, once they are in the cell, mix genetic information in a process called recombination so that antibodies are faced with an almost infinite number of different proteins the prevent the host cell from being killed.

The study, led by Daniel Larremore, an Omidyar Fellow at the Santa Fe Institute and a researcher at the Center for Communicable Disease Dynamics (CCDD) and the Department of Epidemiology at Harvard School of Public Health, used fecal and blood samples from wild chimpanzees and western lowland gorillas, as well as chimpanzees living in a sanctuary to better understand the patterns in the var genes. They looked at similarities between the genes that are implicated with severe malaria in humans and those in other primate malaria parasites. The fecal and blood samples were leftover samples collected for previous genetic studies.

The team analyzed a small region of the gene sequence using network techniques and identified patterns that were consistent across different types of primate malaria parasites. The research team analyzed 369 new sequence fragments from ape parasite species of wild living and sanctuary apes and added 353 previously known sequences. Larremore received his PhD in applied math from CU-Boulder. After receiving his PhD, he had a joint postdoctoral position in Clauset’s lab and Harvard’s CCDD.

“Malaria is an important system to work on,” says Clauset. “It’s both a major public health issue, especially in developing countries and places where climate change is bringing it back, and a fascinating evolutionary system. The malaria parasite has an ever-changing bag of genetic tricks it uses to prolong an infection, and understanding how it does this will help develop better treatments for this disease and help us understand how some other diseases, like HIV, maintain their evolvability over long periods of time. ”

Malaria is difficult to treat in humans because the malaria parasite has an extensive and ever-changing set of tricks to avoid detection by the immune system. Apes, humans, and even birds and reptiles, have their own version of malaria. This study showed that malaria in all primates (including humans) use the same genetic system to evolve new ways to avoid detection by the host's immune system. The wild primate blood samples showed several strains of malaria. Because the disease evolved with primates, their immune systems are equipped to manage it so it causes fewer, less severe symptoms. Humans suffer much more severe symptoms than primates, and even death, from the disease. The researchers believe this is because malaria jumped from primates to humans after the two split from a common ancestor: Human immune systems have had less time to evolve to manage the disease.

“Our results show that human malaria uses the same genetic strategy as ape malaria to prolong an infection. This insight may help us identify components of this immune evasion system that could become targets for a vaccine,” says Clauset. “It may also help us understand other diseases that use similar strategies, like the pneumococcus and HIV.”

The study was supported by grants from the National Institutes of Health and the Wellcome Trust.

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Using evolution to fight disease

Anonymous — Thu, 25 Jun 2015 06:00:00 +0000

Using evolution to fight disease Anonymous (not verified) Thu, 06/25/2015 - 00:00

BioFrontiers

New BioFrontiers lab uses evolution to fight disease

by Paul McDivitt

Photo: Sara Sawyer

Ebola comes from bats, HIV from primates, and new strains of influenza from birds and pigs. With zoonotic diseases – those capable of transmission from animals to humans – grabbing headlines across the globe, understanding how they work has never been more important.

That’s the mission of a new team of researchers led by Dr. Sara Sawyer at the BioFrontiers Institute. By analyzing the genomes of hosts and viruses alike, Sawyer and her team hope to shed some light on why humans are resistant to most animal viruses, and how animal viruses evolve the ability to overcome these obstacles and infect humans.

“These are exactly the kinds of targets that we’re after – mammalian genes that determine why viruses infect the species that they do and why they don’t infect the species that they don’t,” said Sawyer.

One example of the work that Sawyer’s lab does is a project studying how HIV – the virus that causes AIDS – jumped from primates to humans, and why the virus affects humans differently than some primates.

“Chimpanzees and humans only differ in their genetic code by two percent, yet HIV doesn’t make chimpanzees nearly as sick as it makes humans,” said Sawyer. “So somewhere in that two percent difference in their genetic code may lie the answer to surviving this devastating disease.”

Sawyer’s team, which moved to Colorado from the University of Texas at Austin, works primarily with HIV, dengue (the virus that causes dengue fever) and influenza.

They utilize samples from a variety of primate, rodent, bat and other mammalian species in order to understand the genetic reasons why some species are susceptible and others aren’t. Genetics may provide the answer to how viruses evolve to infect new species. One of the specialties of this lab is bringing wildlife samples into the lab rather than relying on materials from model organisms (the lab recently received part of a wolf heart in the mail).

The lab, which is housed in the Jennie Smoly Caruthers Biotechnology Building on the CU-Boulder east campus, operates at biosafety level two, which required a substantial retrofit before Sawyer’s team could move in. (The lab does not work with live strains of Ebola, which is highly regulated and requires a biosafety level four lab.)

Sawyer is carving out a niche in the field of virology thanks to her background in evolutionary biology. By applying techniques from evolutionary biology Sawyer hopes to better understand interactions between viruses and their hosts, which could lead to novel methods for preventing future outbreaks. For example, by predicting when and where viruses could transfer to humans, we could implement simple public health measures to protect people – an intriguing prospect given the rapid proliferation of deadly viruses such as Ebola.

“There just aren’t a lot of people doing molecular virology who are also interfacing with nature, and bringing animal samples from the wild into the lab. But, if you are trying to understand where humans are running into these viruses in the natural world, model organisms won’t help you with that,” said Sawyer. “Things can be done to protect people from these viruses, we just know so little about what’s dangerous.”

Sawyer utilizes an evolutionary model called the “host-virus arms race” in her work. This model says that viruses experience constant selection to better infect and spread in their hosts. In turn, though, hosts evolve to perfect their immune arsenal against viruses. This tit-for-tat evolution leads to an arms race that is ever escalating, and drives rapid evolution in both the virus and the host genome.

But studying arms races requires lots of genetic sequencing data. “Like every other field, biology is experiencing a revolution where we’re getting instrumentation that can measure things in enormous numbers,” said Sawyer. “Big data has hit biology.”

Sawyer and her team were impressed by Tom Cech’s interdisciplinary vision for BioFrontiers, and think the institute will help their research as well as the career prospects of current and future members of the lab. She has been particularly impressed in the many bioinformatic training opportunities that are offered in the Jennie Smoly Caruthers Biotechnology Building, including the IQ Biology Interdisciplinary Quantitative Biology PhD certificate program.

“Most of the departments hiring new faculty right now are looking for people doing things like next-generation sequencing, systems biology, bioinformatics, and high-throughput biology,” said Sawyer. “The problem is that there aren’t very many trainees out there that meet that job description, yet that’s what many departments are seeking. I am impressed that Dr. Cech is addressing this problem head-on.”

She believes her team will benefit greatly from training opportunities provided by BioFrontiers, as well as collaboration with other BioFrontiers researchers. Dr. Nick Meyerson, a postdoc in Sawyer’s lab overseeing all of the lab’s projects, agrees.

“Being at an institute like this, where it’s so interdisciplinary, I think it will be very easy to develop new angles on projects and interface with professors that have ideas that we wouldn’t be exposed to anywhere else,” he said.

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Finding a new strategy for Parkinson's

Anonymous — Tue, 12 May 2015 06:00:00 +0000

Finding a new strategy for Parkinson's Anonymous (not verified) Tue, 05/12/2015 - 00:00

BioFrontiers

If you believe the common adage that you are only using ten percent of your brain, while the other ninety percent remains untapped potential, you are about to be surprised. It’s true that about ten percent of your nervous system is made up of hard-working neurons, diligently delivering messages back and forth between your senses and your brain. Much of the rest of your nervous system is made up of neuroglia (derived from the Greek word “glue”), a mixture of various cell types that spend much of their time supporting neurons so they can continue to support you.

For example, microglia, a type of specialized immune cells, were originally thought to just connect neurons and hold them together. These cells are found all over the brain and spinal cord, responding to damage in the brain and nervous system. While neurons are constantly taking in information about your environment, microglia are hard at work sampling their own environment, patrolling for anything that looks out of place.

BioFrontiers Institute faculty member, Hang Hubert Yin, an Associate Professor of Chemistry and Biochemistry, is eager to tap into that other 90 percent of our nervous system that we’ve been wondering about. In addition to helping protect our brains and nervous system, microglia play an important role in the inflammation that accompanies any damage to your brain. In some cases, though, microglia overreact to perceived damage to the brain and nervous system, introducing inflammation where it should be controlled. Many diseases are associated with these misguided microglia, including Parkinson’s disease, Alzheimer’s disease and Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease.

Yin’s focus is on toll-like receptors (TLR), specifically TLR1 and TLR 2 that sit on the surface of each microglia and form a macromolecular complex called a heterodimer. These are pattern recognition receptors designed to identify danger signals and activate an immune response. Humans have ten known toll-like receptors in their cells. In some cases, toll-like receptors can be activated to provide a powerful immune response to a disease, harnessing the body’s own ability to fight off illness. In other cases, the immune response from these receptors needs to be managed, like in the case of many autoimmune diseases, which turn the body’s immunity on itself. Yin is seeking ways to control the inflammatory response of microglia through these toll-like receptors.

Yin is looking at the role of toll like receptors in microglia so that he can find a potential cure for these neurodegenerative diseases. Finding a drug that can stop inflammation in the nervous system is no small feat. The blood-brain barrier is highly effective in keeping out anything foreign, including drugs that might be helpful. There are a few TLR1/2 inhibitors in development as drug candidates including RNAs, polypeptides and antibodies. However, none of these biologic drugs can cross the blood-brain barrier to work in the central nervous system due to their large sizes. Yin’s team found a small molecule drug that can penetrate that barrier.

“We used the High-throughput Screening facility at the BioFrontiers Institute to screen 15,000 different compounds to identify a novel chemical entity,” says Yin. “Biological drugs for toll-like receptors exist, but can’t get past the blood-brain barrier, limiting their applications. Ours is the first small molecule that can be used as a specific inhibitor for TLR1/2 in the nervous system.”

In a new paper, published in Science Signaling, part of AAAS Science Journals, Yin and his collaborator, Kathy Maguire-Zeiss of Georgetown University Medical Center, describe a new TLR1/2 inhibitor that was used to better understand the cellular processes of Parkinson’s disease. The inhibitor, called CU-CPT22, is a potent, “drug-like” small molecule suppressant of the TLR1/2-mediated proinflammation signaling. Developed at CU-Boulder by the Yin team, CU-CPT22 binds with toll-like receptors 1 and 2, preventing them from overreacting and causing protein misfolding in the nervous system. The small molecule blocks the receptors and fine-tunes the system, balancing out the overprotective microglia and keeping inflammation at bay. Preventing this inflammation may be the key to controlling neurological diseases like Parkinson’s. CU-CPT22 was recently licensed to Brickell Biotech and commercialized by EMD Millipore, Sigma-Aldrich and Tocris for drug development and research purposes.

“This is exciting for us,” says Yin. “We are suggesting an entirely new strategy for treating Parkinson’s disease – one that we think will be more effective, and one with a potential therapeutic that patients may access in the future.”

Learn more about this research on the Science Signaling Podcast.

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Unlocking toll-like receptors

Anonymous — Fri, 10 Apr 2015 06:00:00 +0000

Unlocking toll-like receptors Anonymous (not verified) Fri, 04/10/2015 - 00:00

BioFrontiers

BioFrontiers’ Hubert Yin is unlocking the power of toll-like receptors

Hubert Yin has been thinking about one type of cell receptor since he joined the BioFrontiers Institute, and it is a receptor worthy of that kind of time. Yin, an Associate Professor of Chemistry and Biochemistry, is focusing much of his research on toll-like receptors. These are pattern recognition receptors designed to identify pathogen signals and activate an immune response within the cell. Humans have ten known toll-like receptors. In some cases, the immune response from these receptors needs to be managed, like in the case of many autoimmune diseases, which turn the body’s immunity on itself. In other cases, toll-like receptors can be activated to provide a powerful immune response to a disease, harnessing the body’s own ability to fight off illness.

Toll-like receptors are becoming popular research subjects in many labs around the world because they are the body’s first-responders to many of the viruses, bacteria and fungi that are trying to find a home in our cells. In 1989, scientists first proposed the idea that cells are using pattern recognition to weed out pathogens and keep them out of healthy cells. Toll-like receptors that used this pattern recognition were identified nearly a decade later. Scientists also discovered toll-like receptors in plants and smaller organisms, pointing to their role in evolution protecting the host organism from disease.

“These toll-like receptors have been a central interest of my group since 2007,” says Yin. “These receptors are leading us to new ideas for the treatment of different diseases.”

Because these toll-like receptors are so important to fighting off disease, Yin is interested in modulating them in order to fight a wide variety of illnesses, from HIV to various cancers. Last year, he received a patent for an inhibitor for toll-like receptor 4 that could effectively help patients with scleroderma, an autoimmune disease affecting connective tissues. The inhibitor is expected to help patients prevent muscle necrosis and the thickening of skin and connective tissues that are hallmarks of the disease.

Toll like receptors 1 and 2 (TLR1/2), the focus of much of Yin’s attention lately, sit on the surface of the cells, like sentries, in order to respond quickly to attacks. In an article in Science Advances, the newest open-access journal from the AAAS Science Journals (Cheng et al. Science Advances 2015, DOI: 10.1126/sciadv.1400139). Yin’s research team details their work on these receptors. The paper introduces a new group of small molecule agents developed by Yin’s team that can harness the immune response to disease provided by TLR1/2, making it more potent and specific.

“Novel compounds like these could potentially lead to a new generation of cancer therapies,” says Yin. “TLR therapies are very exciting right now and pharmaceutical companies are now starting to introduce innovative programs to develop TLR7 regulators. CU-Boulder has already filed a patent for our work on TLR1/2, and the intellectual property for this technology has been licensed for commercialization to both EMD Millipore and Tocris Bioscience by CU’s Office of Technology Transfer. We’re excited to see what comes out of this work.”

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Research on small cellular changes may lead to big cancer solutions

Anonymous — Tue, 10 Mar 2015 06:00:00 +0000

Research on small cellular changes may lead to big cancer solutions Anonymous (not verified) Tue, 03/10/2015 - 00:00

BioFrontiers

Among cancers, scientists have spent their entire research careers looking for cellular similarities that may lead to a single cure for many cancers –– the rare chance to have a single answer to a multifaceted problem. In 1997, scientists discovered a gene that they believed was the key to cellular immortality. Telomerase Reverse Transcriptase, or TERT, is a catalytic piece of telomerase, and while cellular immortality sounds like a good idea, it is actually how cancerous tumors grow and proliferate in cancer patients.

In the late nineties, the unanswered question was whether or not TERT was a cancer-causing gene. Scientists spent the next decade hunting for the mutations that activate it but no one was able to find mutations in TERT. Two years ago, two groups of researchers discovered that TERT didn’t have any mutations at all. Instead, the mutations were occurring in the regulatory region that controls the expression of the gene. These mutations showed up in melanoma, and in many cancers found in the brain, liver and bladder.

“It was at that point that I realized we had all the tools and expertise in our lab to understand the mechanisms of these mutations. What my lab did with our collaborators at CU’s Anschutz Medical Campus was to trace the effect of the mutation from the DNA to the increased RNA levels, to the increased protein levels, to the increased telomerase levels,” says BioFrontiers Director Tom Cech, who recently published his team’s findings in the journal, Science. “We were able to show this effect in 23 bladder cancer cell lines by comparing those with mutations to those without mutations.”

Bladder cancer cell lines were available at Anschutz and Cech’s research team worked with colleagues there, including Dan Theodorescu, Director of the CU Cancer Center, to use those lines because their cellular workings could be applied to a variety of different cancers. Bladder cancer itself is no small threat. The National Institutes of Health report that this cancer caused more than 15,000 deaths in 2014 alone, and nearly 75,000 new cases were diagnosed in the same year. Treatment for this type of cancer is not easy either, involving some combination of chemotherapy, biological therapy with bacteria or completely removing the bladder.

One of the most valuable parts of the study was the team of collaborators doing the research including: Staff Scientist, Art Zaug; Postdoctoral Researcher, Sumit Borah; Graduate Student Linghe Xi, and an undergraduate with a triple major in biology, biochemistry and neuroscience, Natasha Powell. This team worked across the two CU campuses to gain access to unique bladder cancer cell lines available at the Anschutz Medical Campus. The team in the Cech lab also had a process for measuring the number of TERT protein molecules and the very small changes in enzyme activity within cells.

Using these tools the research team pushed beyond the current limitations of technology in measuring molecular changes within cells. Computer analysis of the data further confirmed that a finding of high telomerase levels could predict whether a patient’s bladder cancer was fatal or survivable. At some point in the future, doctors may be able to measure telomerase activity in cancer patients and prescribe a treatment schedule according to the severity of the cancer. Using this technique, telomerase could be a biomarker for certain cancers and Cech hopes his research will give medical diagnostic companies the knowledge they need to develop a test that could be used easily in a doctor’s office.

“We hope that this research will stimulate drug companies to find telomerase inhibitors to slow and change cancer to a more treatable version. We’re also interested in seeing if this research applies to other types of cancers, which would create an opportunity where a single drug could impact many different kinds of cancers,” says Cech.

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Amy Palmer wins NIH Pioneer Award

Anonymous — Thu, 09 Oct 2014 06:00:00 +0000

Amy Palmer wins NIH Pioneer Award Anonymous (not verified) Thu, 10/09/2014 - 00:00

BioFrontiers

Few people think of metals as being vital to our health. Although most people are aware of iron, zinc is just as important, and is involved in a much wider array of biological functions. Ten percent of the proteins used to build our cells, tissues and genes are predicted to bind with zinc. As humans grew in evolutionary complexity, we adopted zinc as a main ingredient to power the creation of our genome. This metal is involved in the susceptibility to illnesses and infections. A lack of it can cause life-threatening diarrhea, a decrease in the ability to heal wounds and delayed growth and maturation in children.

“As a graduate student, I studied copper, which is also an essential metal that plays important roles in biology,” says Associate Professor of Chemistry and Biochemistry and BioFrontiers faculty member, Amy Palmer. “After working with copper, I started reading about zinc in the brain. As far back as the 1950s, doctors studied zinc-rich areas of the brain, and nobody was sure what it was doing there. Metal ions, like zinc, play such an important role in biology. They are essential…we can’t live without them, but the misbalance of metals is central in many diseases.”

Palmer was recently awarded a Pioneer Award from the National Institutes of Health (NIH), which are given to scientists proposing highly innovative approaches to major contemporary challenges in biomedical research. The Pioneer Award, now in its eleventh year, challenges investigators at all career levels to develop groundbreaking approaches that could have an efficacious impact on a broad area of biomedical or behavioral science. The award will span five years and provide a total of $3.7 million dollars in research funding for Palmer’s work.

“It’s a really enabling award,” says Palmer. “It is intentionally designed to allow you to take your research program in a new and different direction. It lets you do pioneering work that is unlikely to be funded by other research grants. It’s for high-risk, high-reward science, and it will allow us to start an entirely new program.”

Zinc availability is highly dynamic and Palmer is hoping to find out how it functions at a basic level – in the cell. She is investigating the prospect that zinc may be a global regulator of protein function, which may help to explain why zinc is involved in so many cellular processes. To accomplish this she’ll develop new technology to map the zinc proteome and define how changes in zinc affect gene expression and cellular metabolism. She hopes to gain an understanding of how zinc changes as certain diseases progress, which may result in biomarkers that could identify illnesses early on in their development. Learning how zinc interacts in the cell may change how we think about cellular regulation and how nutrition affects cells.

Despite the widespread affects of zinc deficiency among humans, it is currently difficult and expensive to test for it in the doctor’s office. The World Health Organization estimates that 30 percent of humans are currently zinc deficient, and as many as 800,000 children die every year because of zinc deficiencies. In fact, zinc supplementation is considered to be as important as providing clean water for the prevention of human death in developing countries. Palmer’s research into this important metal may bring greater understanding as to how it is used by our bodies, and what it can tell us about our health.

"Supporting innovative investigators with the potential to transform scientific fields is a critical element of our mission,”’ said NIH Director Francis S. Collins, M.D., Ph.D. "This program allows researchers to propose highly creative research projects across a broad range of biomedical and behavioral research areas that involve inherent risk but have the potential to lead to dramatic breakthroughs."

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Sie Fellows focused on quality of life in Down syndrome

Anonymous — Thu, 10 Jul 2014 06:00:00 +0000

Sie Fellows focused on quality of life in Down syndrome Anonymous (not verified) Thu, 07/10/2014 - 00:00

BioFrontiers

Mary Allen holds up a valentine sent to her from a childhood friend. It sits in her cubicle where she is hard at work tearing apart genomic data looking for patterns. This friend, who has Down syndrome, is part of the reason that Allen, a postdoctoral researcher in Robin Dowell’s lab at the BioFrontiers Institute, became interested in studying aneuploidy. Aneuploidy means that cells have too many, or too few, of one or more chromosomes. In the case of Down syndrome, there is an extra copy of chromosome 21. Allen is exploring what makes people with this extra chromosome survivors.

“Down syndrome is actually not all that survivable,” says Allen. “Only 25 percent of embryos with three copies of chromosome 21 survive to live birth. These people who are surviving and living long lives have something in their DNA—from their genetic background—that is helping them.”

Down syndrome is the most commonly occurring chromosomal condition and more than 400,000 people in the United States are currently living with it. Allen is right about them being survivors. According to the Global Down Syndrome Foundation, life expectancy for people with the syndrome has increased dramatically from 25 years in 1983 to 60 years now, due in part to better educational programs, health care and support from families and communities.

Allen is taking genetic sequencing data from people with Down syndrome and their parents to understand how that extra copy of chromosome 21 puts this population at higher risk for health issues such as heart defects, thyroid conditions, leukemia, Alzheimer’s disease, and respiratory and hearing problems. She is also trying to understand why they are at lower risk for heart attack, stroke, and solid tumor cancers. Allen isn’t out to find a cure for Down syndrome. Her goal is to find what in their DNA is helping these survivors, and how can we design targeted molecular therapy to help them have better lives.

“Once you have had a friend with Down syndrome, stopping the occurrence of the syndrome isn’t on the table,” says Allen. “They are just such great people.”

Allen recently was awarded a Sie Foundation Postdoctoral Fellowship to continue her Down syndrome research for the next two years. This fellowship was created under the Anna and John J. Sie Endowment Fund for the BioFrontiers Institute, which is targeted specifically at funding research to prevent the cognitive and medical ill effects associated with the extra chromosome 21. The fellowship is offered as a collaboration between BioFrontiers and the Linda Crnic Institute for Down Syndrome at the �ֲ��ý, Anschutz Medical Campus.

The BioFrontiers Institute also awarded Sie Fellowships to Geertruida Josien Levenga of CU-Boulder’s Institute of Behavioral Genetics and to Alfonso Garrido-Lecca of CU-Boulder’s Department of Molecular, Cellular and Developmental Biology. Dr. Levenga is a neuroscientist whose research holds promise for ameliorating the seizures that afflict so many individuals with Down syndrome. Dr. Garrido-Lecca will test the hypothesis that alteration of microRNA levels in individuals with Down syndrome contributes to some of their health challenges.

Dr. Allen sees the new fellowship as welcome news for her work. Research funding for Down syndrome has always been extremely low. The National Institutes of Health in 2012 allocated only $50 in research funding per person living with the condition, versus $270 for Fragile X research, $329 for multiple sclerosis research and $2,867 for cystic fibrosis research. Individuals with Down syndrome have special health needs, like heart conditions and decreased immunity, which can be helped by further research. In addition, since Alzheimer’s disease, leukemia, low muscle tone and weight gain are seen at a high incidence in people with Down syndrome, researching the syndrome may lead to treatments for these associated disorders in the broader population.

“Research on the smaller ear canals of people with Down syndrome is now helping people who suffer from deafness and other auditory disorders,” says Allen. “Unlocking the cellular processes behind one disorder can help us with so many others.”

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