In the dominoes that make up human cells, researchers at the University of Michigan Comprehensive Cancer Center have traced another step of the process that stops cells from becoming cancerous. It starts with the enzyme telomerase, which affects the caps, or telomeres, at the end of a chromosome. Telomeres shorten over time. But telomerase prevents this from happening, making the cell immortal. If cancer is triggered in the cell, the presence of telomerase leads to the growth of the cancer.
Telomerase is kept in control by the protein TRF1, which keeps the telomeres operating correctly. But another protein, Fbx4, can bind to TRF1 and degrade it, causing the telomeres to lengthen.
Now, researchers have discovered, a third protein, TIN2, can step in and override Fbx4 by binding to TRF1 first and preventing Fbx4 from attaching to it.
This finding paves the way for developing a drug that acts like TIN2, keeping everything in check and stopping the first domino from falling.
Results of the study appear in the Feb. 16 issue of Developmental Cell.
"In 90 percent of cancers, no matter what caused the cancer to form, it needs telomerase activity to maintain the cell. Without telomerase, the cell will die. Our work is key to understanding a detailed mechanism for how these molecules interact and how to design a drug to block Fbx4," says senior author Ming Lei, Ph.D., assistant professor of biological chemistry at the University of Michigan Medical School.
The researchers found that the location in the molecule where Fbx4 binds to TRF1 overlaps with where TIN2 binds to TRF1. Where both Fbx4 and TIN2 are present, the TIN2 wins out and binds to the TRF1 first. This blocks Fbx4 from binding to the TRF1, thereby stabilizing TRF1 and keeping the telomere length in control.
The researchers are now looking at peptides that mimic TIN2's binding to TRF1, in order to block Fbx4. The work is still in preliminary stages and no new therapies are being tested in patients.
If a drug is discovered, it could impact all cancer types. Currently, molecularly targeted therapies address a pathway or gene that's involved in only specific types of cancer. But telomerase is involved in all types of cancer.
"If we find a drug that can inhibit telomerase activity in any fashion, that could be a universal cancer drug," says Lei, a Howard Hughes Medical Institute Early Career Scientist.
From the Wire: Nanoparticles are part of a new family of materials being created in the laboratory of SUNY Distinguished Professor and Greatbatch Professor of Advanced Power Sources Esther Takeuchi, PhD, who developed the lithium/silver vanadium oxide battery. The battery was a major factor in bringing implantable cardiac defibrillators (ICDs) into production in the late 1980s. Twenty years later, with more than 300,000 of these units being implanted every year, the majority of them are powered by the battery system developed and improved by Takeuchi and her team.
ICD batteries, in general, now last five to seven years. But she and her husband and co-investigator, SUNY Distinguished Teaching Professor of Chemistry Kenneth Takeuchi, PhD, and Amy Marschilok, PhD, UB research assistant professor of chemistry, are exploring even-better battery systems, by fine-tuning bimetallic materials at the atomic level.
So far, their results show that they can make their materials 15,000 times more conductive upon initial battery use owing to in situ generation of metallic silver nanoparticles. Their new approach to material design will allow development of higher-power, longer-life batteries than was previously possible.
These and other improvements are boosting interest in battery materials and the revolutionary devices that they may make possible.
“We may be heading toward a time when we can make batteries so tiny that they — and the devices they power — can simply be injected into the body,” Takeuchi says.
Right now, her team is exploring how to boost the stability of the new materials they are designing for ICDs. The materials will be tested over weeks and months in laboratory ovens that mimic body temperature of 37 degrees Celsius.
“What’s really exciting about this concept is that we are tuning the material at the atomic level,” says Takeuchi. “So the change in its conductivity and performance is inherent to the material. We didn’t add supplements to achieve that, we did it by changing the active material directly.”
She explains that new and improved batteries for biomedical applications could, in a practical way, revolutionise treatments for some of the most persistent diseases by making feasible devices that would be implanted in the brain to treat stroke and mental illness, in the spine to treat chronic pain or in the vagal nerve system to treat migraines, Alzheimer’s disease, anxiety, even obesity.
And even though batteries are an historic technology, they are far from mature, Takeuchi notes. “I’ve never seen interest in batteries as high as it is now,” she says.
Arizona State University scientists have come up with a new twist in their efforts to develop a faster and cheaper way to read the DNA genetic code. They have developed the first, versatile DNA reader that can discriminate between DNA's four core chemical components?the key to unlocking the vital code behind human heredity and health.
Led by ASU Regents' Professor Stuart Lindsay, director of the Biodesign Institute's Center for Single Molecule Biophysics, the ASU team is one of a handful that has received stimulus funds for a National Human Genome Research Initiative, part of the National Institutes of Health, to make DNA genome sequencing as widespread as a routine medical checkup.
The broad goal of this "$1000 genome" initiative is to develop a next-generation DNA sequencing technology to usher in the age of personalized medicine, where knowledge of an individual's complete, 3 billion-long code of DNA information, or genome, will allow for a more tailored approach to disease diagnosis and treatment. With current technologies taking almost a year to complete at a cost of several hundreds of thousands of dollars, less than 20 individuals on the planet have had their whole genomes sequenced to date.
To make their research dream a reality, Lindsay's team has envisioned building a tiny, nanoscale DNA reader that could work like a supermarket checkout scanner, distinguishing between the four chemical letters of the DNA genetic code, abbreviated by A, G, C, and T, as they rapidly pass by the reader. To do so, they needed to develop the nanotechnology equivalent of threading the eye of a needle. In this case, the DNA would be the thread that could be recognized as it moved past the reader 'eye.' During the past few years, Lindsay's team has made steady progress, and first demonstrated the ability to read individual DNA sequences in 2008 -- but this approach was limited because they had to use four separate readers to recognize each of the DNA bases. More recently, they demonstrated the ability to thread DNA sequences through the narrow hole of a fundamental building block of nanotechnology, the carbon nanotube.
Lindsay's team relies on the eyes of nanotechnology, scanning tunneling- (STM) and atomic force- (ATM) microscopes, to make their measurements. The microscopes have a delicate electrode tip that is held very close to the DNA sample. In their latest innovation, Lindsay's team made two electrodes, one on the end of microscope probe, and another on the surface, that had their tiny ends chemically modified to attract and catch the DNA between a gap like a pair of chemical tweezers. The gap between these functionalized electrodes had to be adjusted to find the chemical bonding sweet spot, so that when a single chemical base of DNA passed through a tiny, 2.5 nanometer gap between two gold electrodes, it momentarily sticks to the electrodes and a small increase in the current is detected. Any smaller, and the molecules would be able to bind in many configurations, confusing the readout, any bigger and smaller bases would not be detected.
"What we did was to narrow the number of types of bound configurations to just one per DNA base," said Lindsay. "The beauty of the approach is that all the four bases just fit the 2.5 nanometer gap, so it is one size fits all, but only just so!"
At this scale, which is just a few atomic diameters wide, quantum phenomena are at play where the electrons can actually leak from one electrode to the other, tunneling through the DNA bases in the process. Each of the chemical bases of the DNA genetic code, abbreviated A, C, T or G, gives a unique electrical signature as they pass between the gap in the electrodes. By trial and error, and a bit of serendipity, they discovered that just a single chemical modification to both electrodes could distinguish between all 4 DNA bases.
"We've now made a generic DNA sequence reader and are the first group to report the detection of all 4 DNA bases in one tunnel gap," said Lindsay. "Also, the control experiments show that there is a certain (poor) level of discrimination with even bare electrodes (the control experiments) and this is in itself, a first too."
"We were quite surprised about binding to bare electrodes because, like many physicists, we had always assumed that the bases would just tumble through. But actually, any surface chemist will tell you that the bases have weak chemical interactions with metal surfaces."
Next, Lindsay's group is hard at work trying to adapt the reader to work in water-based solutions, a critically practical step for DNA sequencing applications. Also, the team would like to combine the reader capabilities with the carbon nanotube technology to work on reading short stretches of DNA.
If the process can be perfected, DNA sequencing could be performed much faster than current technology, and at a fraction of the cost. Only then will the promise of personalized medicine reach a mass audience.
The authors on the Nano Letters paper are: Shuai Chang, Shuo Huang, Jin He, Feng Liang, Peiming Zhang, Shengqing Li, Xiang Chen, Otto Sankey and Stuart Lindsay
By STEPHANIE NANO, Associated Press Writer Stephanie Nano, Associated Press Writer – 11 mins ago
NEW YORK – Why people stutter has long been a medical mystery, with the condition blamed over the years on emotional problems, overbearing parents and browbeating teachers. Now, for the first time, scientists have found genes that could explain some cases of stuttering.
"In terms of mythbusters, this is really an important step forward," said Jane Fraser, president of the Stuttering Foundation.
Researchers taking part in a government-funded study discovered mutations in three genes that appear to cause the speech problem in some people. Stuttering tends to run in families, and previous research suggested a genetic connection. But until now, researchers had not been able to pinpoint any culprit genes.
Dennis Drayna, a geneticist and senior author of the study, said he hopes the results help convince doubters that stuttering "is almost certainly a biological problem."
The research — released Wednesday by the New England Journal of Medicine — also points to a possible enzyme treatment for stuttering someday.
Without a known cause, stuttering has been attributed to such things as nervousness, lack of intelligence, stress or bad parenting. Stutterers were told it was all in their heads. Fraser said parents contact her group worried they have done something to cause their children's stuttering. Were they too strict? Too attentive? Didn't pay enough attention?
The gene discovery should lift that guilt, she said.
Drayna and other experts said that while stress and anxiety can make stuttering worse, they do not cause it. "It really is not an emotional disorder. It doesn't come from your interactions with other people," he said.
Stuttering usually starts in children as they are learning to talk. Most youngsters lose their stutter as their brain develops. For some, the stuttering persists. An estimated 3 million Americans stutter. Treatments include speech therapy and electronic devices.
"This is a very difficult disorder to study," said Drayna, who is with the National Institute on Deafness and Other Communication Disorders. "You can't study it in cells in a dish. You can't study it in a test tube. You can only study it in awake humans."
To find the genes, Drayna and others first looked at a large, inbred Pakistani family with many members who stuttered, and discovered a mutation on chromosome 12. Then they found the same mutation and two other mutated genes in a group of nearly 400 other people from Pakistan, the U.S. and England who stutter.
They didn't find the mutations in a similar group of people who don't stutter, except in one Pakistani volunteer.
The researchers estimate that the three gene variants account for 9 percent of all stuttering cases. But they are looking for other stuttering genes. In fact, between 50 percent and 70 percent of stuttering cases are thought to have a genetic component, Drayna said.
"The task of connecting the dots between genes and stuttering is just beginning," Simon E. Fisher of England's Oxford University wrote in an accompanying editorial.
The three implicated genes normally help run the "recycling bin" where cells of the body send their garbage. The mutations apparently interfere with that, affecting brain cells that control speech.
"People had suggested all sorts of causes for stuttering over the years. An inherited disorder of cell metabolism was never on anyone's list," Drayna said.
Two of the stuttering genes have previously been tied to rare diseases that can occur when the cell's recycling bin malfunctions.
Other related disorders are now being treated by replacing a missing enzyme, and that could eventually be a treatment method for some kinds of stuttering, the researchers said.
Kristin Chmela, a speech therapist from suburban Chicago who specializes in treating stuttering, said she was teased and bullied for her own stuttering while growing up, and "there were lots of days where I was afraid to go to school."
She said she is looking forward to sharing the gene discovery with those she treats: "It's going to be very interesting to see the reaction on some of their faces."
Stuttering may have genetic underpinnings, according to a new study. For the first time, scientists have identified specific genetic alterations that they believe play a key role in giving rise to the speech disorder.
These alterations, or mutations, are located on three particular genes, and are thought to cause a glitch in the way cells dispose of cellular "garbage."
"For hundreds of years, the cause of stuttering has remained a mystery for researchers and health care professionals alike, not to mention people who stutter and their families," said Dr. James F. Battey, Jr., director of the National Institute on Deafness and Other Communication Disorders (NIDCD), the organization that led the study. "This is the first study to pinpoint specific gene mutations as the potential cause of stuttering," and might lead to an expansion in treatment options, he said.
The results were published online Feb. 10 in the New England Journal of Medicine.
Stuttering is a speech disorder in which a person repeats or prolongs sounds, syllables, or words, disrupting the normal flow of speech. The result can severely hinder communication. Most children who stutter outgrow it, although many do not; roughly 1 percent of adults stutter worldwide. Current therapies for adults who stutter have focused on such strategies as reducing anxiety, regulating breathing and rate of speech, and using electronic devices to help improve fluency.
Stuttering tends to run in families, and researchers have long suspected a genetic component. Previous studies of a group of families from Pakistan pointed to chromosome 12 as a site that may be involved in the disorder. (A chromosome is a long sequence of DNA that contains many genes.)
In the current study, researchers took a closer look at this chromosome. They identified mutations in a gene known as GNPTAB in the affected family members. The GNPTAB gene is carried by all higher animals, and gives cells instructions for making an enzyme that assists in breaking down and recycling cellular components.
They then analyzed the genes of 123 Pakistani individuals who stutter — 46 from the original families and 77 who are unrelated — as well as 96 unrelated Pakistanis who don't stutter, and who served as controls. Individuals from the United States and England also took part in the study, 270 who stutter and 276 who don't. The researchers found some individuals who stutter possessed the same mutation as that found in the large Pakistani family.
The scientists then looked at two other genes which are closely tied to the role of GNPTAB. They found individuals who stuttered showed mutations in these genes while control groups did not.
Several of the newly identified "stuttering genes" are thought to contribute to certain metabolic disorders. People with these disorders cannot properly break down cell waste, causing deposits to build up in their cells. These deposits can ultimately cause health problems in the body's joints, skeletal system, heart and liver, as well as developmental problems in the brain. They are also known to cause problems with speech.
So why don't people who stutter also have these metabolic disorders? For many of these metabolic diseases, a person needs to have two defective copies of a gene, said study author Dennis Drayna, a geneticist with the NIDCD. But in the current study, nearly all of the unrelated individuals who stuttered had only one copy of the mutated gene, he said.
The findings open new research avenues into possible treatments for stuttering. For example, current treatment methods for some metabolic disorders involve injecting a manufactured enzyme into a person's bloodstream to replace the missing enzyme. The researchers wonder if enzyme replacement therapy might be a possible method for treating some types of stuttering in the future.
Right now, about 9 percent of people who stutter are known to possess mutations in one of the three genes, the researchers say. Next, they plan to conduct a worldwide study to better determine the number of people who carry these mutations. A long-term goal is to better understand how metabolic defects may affect structures within the brain that are essential for fluent speech.
