Cancer

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 University of Colorado 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 ��񱦵� 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.”

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Bioinformatics answers questions

Anonymous — Fri, 05 Jun 2015 06:00:00 +0000

Bioinformatics answers questions Anonymous (not verified) Fri, 06/05/2015 - 00:00

BioFrontiers

Bioinformatics answers questions of cancer and career path

Phil Richardson, an author on a paper recently published in Nature, developed a love for bioinformatics in BioFrontiers' Robin Dowell's lab. His next move: pursuing a graduate degree in medical genomics.

At some point in school, we were taught that humans are a diploid species, made of cells with two sets of chromosomes – one set contributed by each parent. This idea neatly packaged the way we believed cells carried on with dividing themselves and creating more cells, but it isn’t the only way. Polyploidy occurs when cells have more than two complete sets of chromosomes. Polyploids are common: Plants, some fish and amphibians are polyploid. Aneuploidy is yet another chromosomal mix – one where there is an abnormal number of chromosomes in a cell due to extra or missing chromosomes. While being diploid looks much simpler on paper, recent research points to the chromosomal flexibility of the ancestors of many diploid species, because as it turns out, polyploidy and aneuploidy appear to be pretty helpful in smoothing out the evolutionary ride.

In a recent paper in Nature, BioFrontiers Institute faculty member, Robin Dowell, an assistant professor of Molecular, Cellular and Developmental Biology, describes the influence that polyploidy has on accelerating evolutionary adaptation. By studying Saccharomyces cerevisiae, a helpful species of yeast well-known in winemaking, baking and beer brewing, Dowell was able to show that many individual strains can switch between polyploidy and aneuploidy, and they do so to adapt to evolutionary and environmental changes.

“To me, the interesting thing that came out of this study is that being aneuploid can help polyploids,” says Dowell. “When faced with a lot of evolutionary or environmental pressure, polyploid cells can switch quickly to being aneuploid. It seems like it becomes a short-term solution for these cells.”

Dowell’s lab is, in part, focused on studying how chromosomes influence adaptation and how these adaptations affect cellular processes. These processes are poorly studied because genetic data creates huge datasets and many labs lack the computational tools and abilities to dig through them. Dowell’s lab, in the Jennie Smoly Caruthers biotechnology building, blends a biological wet lab with a computational dry lab resulting in research that has the capability to look deeply at bioinformatics.

Phil Richmond is part of Dowell’s lab and a co-author on the Nature paper. He did much of the groundwork for this research as an undergraduate in the Department of Molecular, Cellular and Developmental Biology at CU-Boulder. His job was to comb through the data of 130 genome-sequenced strains, narrowing the dataset to 78 that were of acceptable quality to study.

“One of my biggest contributions on this project was benchmarking a way to track mutations in the genes,” says Richmond. “Everything was built for humans with a diploid assumption and the current tools couldn’t find mutations in polyploid yeast. This was my first really cool experience in digging into genomics.”

Polyploidy and aneuploidy become interesting study subjects when it comes to cancer. From a cancer standpoint, polyploidy is a mistake in replication of chromosomes, and the odds of a polyploid cell becoming cancerous are increased. Some cancers appear to start when the cell divides and extra chromosomes go into one cell instead of splitting evenly between two. As this happens over and over, a cell can quickly become what scientists call “self-interested” and become a soft tumor.

Genetic sequencing is showing promise as a powerful tool for learning about different types of cancers. Richmond started at CU-Boulder as a pre-medical student and quickly fell in love with biology. Dowell hired him into her lab as a sophomore where he filed papers and washed glassware, but it wasn’t long before Dowell recruited him for a programming project.

“I had never programmed anything,” says Richmond. “But since then, the number of tools available and people that are interested in bioinformatics has grown exponentially, and I’ve been riding that wave ever since. I’m no expert in any of the fields I’ve collaborated in, but my bioinformatics skillset has allowed me to be useful in a lot of different projects. I chose a path that will just keep growing.”

Richmond would love to see cancerous tumors undergo genetic sequencing so that doctors will know what they are treating and how best to treat it. He believes that, although sequencing costs are still relatively high, it might be more cost effective in the long run to sequence a tumor rather than have a patient take the wrong drugs without results.

“This study really brought out one big outlying question,” says Richmond. “When a tumor becomes polyploid, is it the result of some random system, or is it providing an advantage to the cell? We’ve shown that yeast—a eukaryote—is able to adapt faster in the polyploid state, so what we learned is helping us to think of the chromosomal copy number profile in cancer as more of an evolutionary advantage rather than the result of a chaotic and unstable system operating in the cell. This may change the way we approach the treatment of this disease in the future.”

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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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New Technology, New Understanding of p53: The Tumor-Suppressor Gene

Anonymous — Wed, 14 May 2014 06:00:00 +0000

New Technology, New Understanding of p53: The Tumor-Suppressor Gene Anonymous (not verified) Wed, 05/14/2014 - 00:00

BioFrontiers Institute

A major collaboration of Colorado institutions uses new technology to show, after more than 30 years and 50,000 papers on the subject, the direct targets of the gene p53, the most potent “tumor suppressor” gene. The finding is a strong step toward affecting the disease trajectories of nearly all cancer types.

The gene p53 is the most commonly inactivated gene in cancers, responsible for recognizing when a cell’s DNA is damaged and marking damaged cells for death. When p53 acts, cells are stopped or killed before they can survive, grow, replicate and cause cancer. As such, all cancers must deal with p53’s anti-tumor effects. Generally, there are two ways that cancer cells do this: by mutating p53 directly or by making a protein called MDM2 that stops p53 from functioning.

The current study, published in the journal eLife, explores cancer cells’ second strategy, namely these cells’ attempts to block p53 function by producing the protein MDM2. Now, significant work shows the promise of MDM2 inhibitors – the reasoning goes that turning off MDM2 should allow p53 to restart its anti-cancer activities.

“MDM2 inhibitors, which are through phase I human trials, effectively activate p53 but manage to kill only about one in twenty tumors. The question is why. What else is happening in these cancer cells that allow them to evade p53?” says Joaquín Espinosa, PhD, investigator at the University of Colorado Cancer Center, associate professor in the Department of Molecular, Cellular and Developmental Biology at ��񱦵�, and the paper’s co-senior author.

The answer is in what are called “downstream” effects of this gene, because p53 doesn’t act against cancer alone. Instead, it is the master switch that sets in motion a cascade of genetic events that lead to the destruction of cancer cells. Until now, it was unclear exactly which other genes were directly activated by p53.

The imperfect knowledge of p53’s effects isn’t for lack of research interest. Thousands of papers explore p53’s targets and many genetic targets are previously known. Most of these studies determine genetic targets by measuring levels of RNA. Here is how it works:

When a gene is activated, it creates a protein. But between the gene and its protein product is the measurable step of RNA – the more gene-specific RNA, the more often a gene’s informational blueprint is carried to the cell’s manufacturing centers, and the more protein is eventually made. This is a major way genes regulate other genes: they affect the levels of gene-specific RNA. Researchers measure RNA to see which genes are being turned up or down by any other gene.

“But the problem is, measuring overall RNA levels is like looking in a huge bucket full of water – you see the water but you don’t really know where it came from. And imagine you are dripping water into this bucket – it takes a long time for those drips to create a measurable change in the overall water level,” Espinosa says. Also, it’s very difficult with traditional methods to tell whether increased RNA is a direct effect of a gene or whether more RNA in the bucket is a product of two- or three-steps removed signaling – p53 may activate another gene, which activates another, and down the line until the far downstream result is increased RNA.

“Instead, to measure the direct genetic targets of p53, we measured not the water in the bucket, but the faucet dripping into it,” Espinosa says.

"Instead, to measure the direct genetic tarts of p53, we measured not the water in the bucket, but the faucet dripping into it," Espinosa says.

The technique is called GRO-Seq, or Global Run-On Sequencing, and it measures new RNA being created, not overall RNA levels.

“Many teams around the world have been getting cancer cells, treating them with MDM2 inhibitors and waiting hours and hours to see what genes turn on and then only imprecisely. GRO-Seq lets us do it in minutes and the discoveries are massive,” Espinosa says.

The discoveries also generate an astounding quantity of data. That’s because the technique requires counting tens of thousands of RNA molecules before and after p53 activation.

“What you get is terabytes of data in the form of short RNA sequences,” Espinosa says.

In addition to the Espinosa team made of molecular biologists specializing in p53, the experiment required designing algorithms to sort through the data – it required computational biologists driving a supercomputer. To address this issue, Espinosa partnered with computational biologist Robin Dowell, DSc, at the University of Colorado at Boulder and the BioFrontiers Institute. Together Espinosa and Dowell co-mentored a postdoctoral fellow, Mary Allen, PhD, who was capable of doing both the molecular biological and computational aspects of the work.

“The data collection took a year and the computational analysis took a year and a half. Mary is a very rare type of scientist who could do both the bench work and the computational work,” Dowell says.

Allen explains that, in all, the experiment generated over 4 terabytes of information, requiring sometimes a week or more for the BioFrontiers supercomputing resource to process single queries.

In addition to many known p53 targets, the study described dozens of new genes directly regulated by p53. Further research will explore which of these genes are necessary for p53’s cancer-killing effect, how cancer cells evade these p53-activated genes, and how doctors may be able to affect cancer cells’ ability to stay safe from these genetic attempts at suppression.

In fact, the study already solves a major outstanding question about cancer cells that die or survive when faced with MDM2 inhibiting drugs. Remember: cancer cells that don’t directly mutate p53 manufacture MDM2, which blocks the gene’s function. Drugs inhibit MDM2, but then only 1/20 tumors die while the majority of remaining tumors arrest their growth but aren’t necessarily killed.

“Previously, using traditional technologies, people concluded that death genes activated by p53 simply take longer than arrest genes and so the action of the arrest genes superseded the action of the death genes,” Espinosa says. “But now we see that p53 activates death genes early on in addition to these arrest genes. Cancer cells get mixed messages and choose to arrest rather than die. That's good news: p53 is doing what we want it to do, but cells are protecting themselves from the death genes. So now we need to focus on understanding these protective mechanisms and how to shut them down.”

The technique of GRO-Seq may have additional, far-reaching applications. For example, the Dowell lab plans to find RNAs whose synthesis is changed by a third copy of chromosome 21 in Down Syndrome individuals.

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BioFrontiers researchers uncover new target for cancer research

Anonymous — Wed, 24 Oct 2012 06:00:00 +0000

BioFrontiers researchers uncover new target for cancer research Anonymous (not verified) Wed, 10/24/2012 - 00:00

BioFrontiers

In a new paper released today in Nature, BioFrontiers Institute scientists at the University of Colorado in Boulder, Tom Cech and Leslie Leinwand, detailed a new target for anti-cancer drug development that is sitting at the ends of our DNA. Researchers in the two scientists’ laboratories collaborated to find a patch of amino acids that, if blocked by a drug docked onto the chromosome end at this location, may prevent cancerous cells from reproducing. The amino acids at this site are called the “TEL patch” and once modified, the end of the chromosome is unable to recruit the telomerase enzyme, which is necessary for growth of many cancerous cells.

Coauthors on the study include postdoctoral fellows, Jayakrishnan Nandakumar and Ina Weidenfeld; University of Colorado undergraduate student, Caitlin Bell; and Howard Hughes Medical Institute Senior Scientist, Arthur Zaug.

“This is an exciting scientific discovery that gives us a new way of looking at the problem of cancer. What is amazing is that changing a single amino acid in the TEL patch stops the growth of telomeres. We are a long way from a drug solution for cancer, but this discovery gives us a different, and hopefully more effective, target,” said Cech. He is the Director of the BioFrontiers Institute, a Howard Hughes Medical Investigator and winner of the 1989 Nobel Prize in Chemistry.

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. An enzyme called telomerase replenishes telomeres throughout their lifecycles.

To date, development of cancer therapies has focused on limiting the enzymatic action of telomerase to slow the growth of cancerous cells. With their latest discovery, Cech and Leinwand envision a cancer drug that would lock into the TEL patch at chromosome ends to keep telomerase from binding there. This approach of inhibiting the docking of telomerase may be the elegant solution to the complex problem of cancerous cells. Cech, a biochemist, and Leinwand, a biologist, joined forces to work on their latest solution.

“This work was really made possible by the fact that our labs are so close. My lab was able to provide the cell biology and understanding of genetics, and Tom’s lab allowed us to explore the biochemistry. We have a unique situation at BioFrontiers where labs and people comingle to make discoveries just like this,” said Leinwand. She is the Chief Scientific Officer of the BioFrontiers Institute and a professor of molecular, cellular and developmental biology.

Researchers at the University of Colorado have a significant history in developing marketable biotechnologies. Cech founded Ribozyme Pharmaceuticals, Inc. Leinwand co-founded Myogen with CU professor Michael Bristow, Hiberna and recently launched MyoKardia.

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Biofrontiers researcher rethinks morphine's effects

Anonymous — Mon, 07 May 2012 06:00:00 +0000

Biofrontiers researcher rethinks morphine's effects Anonymous (not verified) Mon, 05/07/2012 - 00:00

BioFrontiers

A ��񱦵�-led research team has discovered that two protein receptors in the central nervous system team up to respond to morphine and cause unwanted neuroinflammation, a finding with implications for improving the efficacy of the widely used painkiller while decreasing its abuse potential.

Scientists have known that a particular protein receptor known as toll-like receptor 4, or TLR4, helps to activate inflammation-signaling pathways to attack foreign substances like bacteria and viruses, said Biofrontiers Institute faculty member and CU-Boulder Assistant Professor Hang “Hubert” Yin of the chemistry and biochemistry department. The new study showed opiod analgesics like morphine also trigger such neuroinflammation by first binding to an accessory protein receptor known as a myeloid differentiation protein receptor 2, or MD-2, which then works in concert with TLR4 to respond to morphine in the central nervous system, said Yin, who led the study.

The new findings should help researchers develop new drugs not only to increase the effectiveness of medical opiates like morphine by preventing neuroinflammation that enhances pain by increasing the excitability of neurons in the pain pathway, but also to influence the TLR4/MD-2 protein complex in a way that may help prevent drug abuse. Such pharmaceuticals could be designed to decrease side effects like tolerance, dependence and addiction not only in opiates, but in methamphetamines, cocaine and even alcohol.

“While inflammation is part of the body’s natural defense system to protect it after injury or infection, too much inflammation is unhealthy,” said Yin. “We hope our new findings on how this particular protein complex works can help us to understand morphine-induced inflammation and eventually lead to therapeutics to make morphine work more efficiently with fewer side effects.”

A paper on the subject is being published this week in the Proceedings of the National Academy of Sciences. Co-authors include CU-Boulder researchers Xiaohui Wang, Lisa Loram, Khara Ramos, Armando de Jesus, Kui Cheng and Annireddy Reddy and Linda Watkins, as well as Jacob Thomas, Andrew Somogyi and Mark Hutchison of Australia’s University of Adelaide. The National Institutes of Health funded the study.

MD-2 is a receptor found on human immune cells in the central nervous system known as glial cells and appears to be left over from millions of years of evolution, said Watkins, a distinguished professor in CU-Boulder’s psychology department. When MD-2 bound to morphine in the study, the glial cells -- which normally act as “housekeeper cells” to clean up debris and support proper neuron function -- excited the neurons that transmit pain signals and hindered the ability of morphine to suppress pain.

The heightened excitement of glia cells by opiates and other drugs appears to amplify the rewarding qualities of several commonly abused drugs, according to the research team. Glial cells, which originally were thought by scientists to hold neurons in the brain together somewhat like glue, outnumber neurons by up to 50 to one.

The team members used a multidisciplinary approach that included biochemistry, biophysics and cellular biology to investigate the TLR4/MD-2 protein complex and to pinpoint the relationship between MD-2 and morphine. As part of the study the team used laboratory “knock-out mice” -- genetically engineered mice in which existing genes or proteins are inactivated -- to infer the function of TLR4 and its relationship with morphine-induced analgesia.

“The exciting thing about this research is that we have discovered that there is not just one receptor that detects morphine, there is a second one that nobody knew about before, namely MD-2/TLR4,” said Watkins. “We have shown this protein complex essentially cuts morphine off at the knees, preventing it from doing its job in controlling pain.”

As part of the study, several “small molecule inhibitors” developed and tested by the research team to target and deactivate TLR4/MD-2 demonstrated that the morphine-induced inflammation is exclusively tied to the protein complex.

Millions of Americans suffer from chronic, debilitating pain that makes it extremely painful to perform even the simplest activities like showering and dressing, and which differs from pain associated with injuries, which generally heal. Chronic pain sufferers include victims of cancer and AIDS who have nerve damage.

It is estimated that four out of every 10 people in the United States are likely to be in chronic pain, costing the nation as much as $635 billion annually in lost productivity and health care expenses. The United States is one of the world’s highest users of morphine, which has been around since the 1850s and which ironically was first marketed as a cure for opium and alcohol addiction.

Yin said the CU-Boulder researchers have been working with the University of Colorado Technology Transfer Office, or TTO, and have filed a group of related patents on potential therapeutics for optimizing current pain management therapies. Several of the small molecule inhibitors used in the study to target and inactivate the TLR4/MD-2 protein complex have been exclusively optioned to BioLineRX, a publicly traded drug development company in Israel, through CU’s TTO.

“Using interdisciplinary approaches to look for unconventional drug targets is a central theme in my work,” said Yin. “Even in graduate school, I was attracted to the idea of ‘rational design’ -- using computer simulation and synthetic chemistry to design something useful like cancer drugs. Working across disciplines is where the future of science lies.”

See more on Hubert Yin's research at:

Futurity.org
Nature

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Undergrad selected for cancer award

Anonymous — Thu, 08 Mar 2012 07:00:00 +0000

Undergrad selected for cancer award Anonymous (not verified) Thu, 03/08/2012 - 00:00

BioFrontiers

Yin Lab Student Selected for Cancer Award

Sara Coulup, a junior undergraduate majoring in biochemistry, has been selected by the American Association of Cancer Research (AACR) for a 2012-2013 Thomas J. Bardos Science Education Award for Undergraduate Students.

This two-year award is intended to inspire young science students to enter the field of cancer research and provide a unique educational opportunity for these students in the development of their careers in science.

Coulup, a student in Biofrontiers faculty member, Hubert Yin's lab, will present her research at the AACR Annual Meeting in Chicago this month. Sara has also been a Norlin Scholar and a recipient of BURST/HHMI undergraduate research grants at CU.

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Stopping cancer's knock on the door

Anonymous — Tue, 06 Dec 2011 07:00:00 +0000

Stopping cancer's knock on the door Anonymous (not verified) Tue, 12/06/2011 - 00:00

BioFrontiers

Stopping cancer's knock on the door

As a self-proclaimed “science nerd” in a Beijing high school, Hubert Yin considered biochemistry to be the ultimate in cool. It was the only science, he felt, that was capable of explaining what he thought was the most complex, most beautiful thing on earth– life at the molecular level.

This sense of awe led him to graduate at the top of his class at Peking University in applied chemistry, and then propelled him to the other side of the globe for a doctorate in organic and bioorganic chemistry from Yale, and post-doctoral work at the University of Pennsylvania School of Medicine. Now he is an assistant professor of chemistry and biochemistry, a University of Colorado Cancer Center Investigator, and a Biofrontiers Institute faculty member at the ��񱦵�.

“I was totally amazed by this ‘in depth’ understanding of how life works,” says Yin. “I was attracted to the idea of rational design where we use all of these fun toys, like computer simulation and protein engineering, to design something novel and useful, like cancer drugs.”

Yin is searching for unconventional drug targets: the ones that have been overlooked by drug companies. His focus is on cell membrane proteins, which act as windows and doors to the inner workings of all cells. Some viruses knock on the doors of the cell, hijacking normal cell functions, allowing them to gain entry through the cell membrane and take over the cell. Scientists have yet to discover just how that “knock on the door” occurs.

Yin is studying this process with the Epstein-Barr virus (shown, left), also known as Human Herpesvirus-4 (HHV-4), which was identified in 1964 as a cancer-causing virus. It is one of the most common viruses in humans, affecting approximately 95 percent of the U.S. population by adulthood. It is also infamously known as the virus that causes mononucleosis.

HHV-4 is one of at least six viruses that are known to cause cancer, and it is associated with some of the rare cancers: Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma and other central nervous system lymphomas. Because it is so common and is associated with so many cancers, HHV-4 is an attractive target for the development of cancer vaccines and treatment.

Computer simulations have allowed Yin to study the process viruses use to knock on the doors of cells. He has rebuilt the Latent Membrane Protein, or LMP-1, down to the last atom using computer simulations in a membrane environment. LMP-1, when activated, induces an inflammatory response to HHV-4, which allows cancers to grow within the cell. Using these computer simulations, he hopes to predict how and why cells open their doors to these dangerous invaders.

“Our strength is bridging ‘in silico’ computer simulations with wet-lab experimental approaches,” says Yin who collaborated with fellow CU-Boulder biochemist and Biofrontiers Institute faculty member, Natalie Ahn, as well as CU-Boulder biologist, Jennifer Martin. Ahn provided her expertise in mass spectroscopy to understand the structure of the LMP-1 molecule. Martin is an expert on the Epstein-Barr virus and contributed her knowledge on the nature of the virus and how it causes cancer.

Yin’s next step is to take the data provided by the computer simulations of the membrane protein and use it to predict how it will react to potential drugs. It is even more difficult than it sounds. These proteins have defied exploration by many scientists before Yin. But these drugs may provide a process for treating HHV-4, and stopping deadly lymphomas in their tracks.

“Trying to achieve something that took nature millions of years to develop is an outstanding intellectual challenge,” says Yin. “And multidisciplinary approaches are the means we must take to approach this problem.”

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Biomarkers light the way to cancer diagnosis

Anonymous — Tue, 13 Sep 2011 06:00:00 +0000

Biomarkers light the way to cancer diagnosis Anonymous (not verified) Tue, 09/13/2011 - 00:00

BioFrontiers

Biomarkers light the way to cancer diagnosis

In an 18-year study released this summer by the National Cancer Institute, widespread screening for ovarian cancer was found to be ineffective in catching the disease. In fact, the screening often did more harm than good, leading women to unnecessary surgery and the complications that often come with it.

Similar issues have been raised about annual mammography screenings increasing breast cancer risk in women with a predisposition to the disease. The low-dose radiation used in the screening ratcheted up the susceptibility to cancer for women who were already at a higher risk—the women who need the screenings the most. Biofrontiers scientist, Hubert Yin, is on the hunt for a better way to find cancer early, without harming patients in the process.

Hubert, an assistant professor in chemistry and biochemistry, is studying biomarkers, which are traceable substances that allow scientists to track a process within the body. Using a biomarker is like tying a balloon to a friend moving through a crowd. Because you can see the balloon above the crowd, you are easily able to locate your friend. In Hubert’s experiments, the balloons are fluorescent molecules called a fluorophores, which chemically attach themselves to cells that indicate cancer is present, glowing so they can be seen and tracked.

Microvesicles are the objects of the fluorophores’ chemical spotlight. They are shed from the surface of cells and can actually help the spread and release of metastatic cancer cells. The presence of microvesicles is a key indicator that cancer is at work, and fortunately, they are easy to find in a simple blood or urine sample. Once Hubert chemically attaches fluorophores to these microvesicles, screening someone for cancer becomes as easy as looking for the glow. A lack of microvesicles means there is nothing for the fluorophores to attach to, which means they don’t glow. And no glow means no cancer.

“This is a great diagnostic concept,” he says. “Biomarkers like fluorophores give us efficient, non-invasive ways to detect cancer before it is diagnosed and after it is treated. Being a smaller, research focused organization gives us an advantage over big pharmaceutical companies when it comes to designing biomedical solutions. It is easier for us to collaborate across labs, and to innovative methods that lead us in the direction of new ways of treating cancer.”

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