[Source:ScienceDaily] - Researchers from The University of Arizona and Columbia University have discovered that tiny filaments on bacteria can bundle together and pull with forces far stronger than experts had previously thought possible.
The team of researchers, including Magdalene "Maggie" So, a member of the BIO5 Institute and the department of immunobiology in the UA College of Medicine, studied Type IV pili -- or filaments -- on the surface of Neisseria gonorrhoeae, the bacterium that causes the infectious disease gonorrhea. The research results help them understand the role that Type IV pili play in initiating a variety of infectious diseases -- including tuberculosis -- and how retracting pili allow bacteria to crawl and to exchange genes with each other.
When a bundle of Type IV pili retracts, it pulls with a force in the nanoNewton range, which is 10 times the force of a single retracting filament. The study demonstrates the power and cooperative nature of the nanomotors that cause Type IV pili to retract.
"The motor that causes these filaments to pull is one of the strongest nanomotors known in biology," So said.
In previous studies, the same group of investigators measured single filament retraction forces in the 50 to 100 picoNewton range. This force allows the bacterium to move an object 10,000 times its own body weight. Retraction forces from a bundle are roughly 10 times higher, allowing the bacterium to move objects 100,000 times its body weight.
Pilus retraction forces are an important factor in how N. gonorrhoeae starts an infection. So, who has studied these microbes for more than 20 years, says N. gonorrhoeae communicates with a human cell by pulling on it. These pulling forces perturb the normal circuitry of the cell. As a result, the infected cell is fooled into lowering its defenses against the infecting microbe.
So said that the team of investigators came up with a new method to measure the tremendous forces applied by retracting pili. They allow bacteria to sit on a dense brushwork of tiny elastic pillars. The pili attach to these pillars. When pili retract, they bend the pillars. By measuring how the pillars bend, the investigators calculate the retraction forces.
An article about the research, titled "Cooperative Retraction of Bundled Type IV Pili Enables Nanonewton Force Generation," was published in the latest issue of PLoS Biology.
Authors of the PLoS Biology article are Nicolas Biais and Mike Sheetz, Columbia University; Benoit Ladoux, Université Paris 7; So and Dustin Higashi, both from the UA.
Adapted from materials provided by University of Arizona.
Monday, April 21, 2008
Scientists Explore Human Gene Pool With Help From Microsoft Research
[Source: Microsoft Corp.] - Projects show potential of computer science to profoundly impact prediction and treatment of genetic diseases.
Breakthrough research with the ability to predict and prevent adverse drug responses within prescription medicine, and provide greater insight into the cause of neurodegenerative illnesses such as Parkinson's disease and Alzheimer's disease, are just two of six research projects Microsoft Research today announced it will support through its Computational Challenges of Genome Wide Association Studies (GWAS) program.
The supported projects were selected from 40 proposals submitted from 39 academic institutions worldwide. Microsoft Research's goal with funding computational challenges associated with GWAS research is to aid researchers in the correlation of genetic patterns with patients' responses to drugs, diseases, aging or the expression of genetic disorders. The ultimate goal is to enable lifesaving research through the use of technology.
"The Microsoft Research GWAS program provides crucial funding at the interface between information management and quality healthcare," said Michael Kane, an assistant professor of Computer Technology at Purdue University and one of the researchers selected to receive support under the GWAS program. "Patient-specific genotyping to assure prescription drug safety and drug effectiveness is a major step toward the emergence and adoption of personalized medicine, and this support is key to facilitating that vision. Microsoft Corp. has recognized the important role information technology will play in the future of healthcare. Ultimately, this is about technology that helps to save lives."
As part of the program, more than $850,000 was shared among six research institutions.
"When it comes to performing genetic analysis, researchers are often hampered by the data itself, whether it's inconsistencies in format, the inability to visualize it, or sheer volume," said Kristin Tolle, program manager for biomedical computing on the External Research & Programs (ER&P) team at Microsoft Research. "Through this program, Microsoft Research is encouraging the development of computer-science solutions to improve data access, standardization, visualization and tools to help scientists study the human genome. "Of all the research areas Microsoft collaborates with, none may have as much real impact on global economies and the lives of ordinary people as healthcare," Tolle said.
Enabling this research is part of ER&P's broader efforts to move research in new directions across nearly every field of computer science, engineering and general science. Through this and other regional and global programs, Microsoft Research is partnering with researchers and scientists to address some of the toughest, most urgent scientific and societal challenges -- such as those in healthcare -- through enabling technologies that can provide real solutions.
Other examples of Microsoft's support of healthcare-related research include the program Cell Phones as a Platform for Healthcare, which sought novel healthcare solutions that are accessible, affordable and relevant for smart mobile phones; and the Intelligent Systems for Assisted Cognition Awards, which provided funding for technologies to assist people living with disorders such as autism and Alzheimer's disease. In the past six months alone, Microsoft External Research & Programs has awarded more than $2.5 million to academic researchers and scientists in support of healthcare research.
John Pearson is one of the six winners and a description of the project follows:
Translational Genomics Research Institute, John Pearson: "A Universal Data Format for Genotype Microarrays." Combining data generated in genome research is problematic due to the variety of software platforms in use today. Pearson will work to create a universal data format that would accommodate multiple vendor platforms into a single file and software library. The software library would allow for open use by the research community and commercial proprietary use by platform vendors.
Breakthrough research with the ability to predict and prevent adverse drug responses within prescription medicine, and provide greater insight into the cause of neurodegenerative illnesses such as Parkinson's disease and Alzheimer's disease, are just two of six research projects Microsoft Research today announced it will support through its Computational Challenges of Genome Wide Association Studies (GWAS) program.
The supported projects were selected from 40 proposals submitted from 39 academic institutions worldwide. Microsoft Research's goal with funding computational challenges associated with GWAS research is to aid researchers in the correlation of genetic patterns with patients' responses to drugs, diseases, aging or the expression of genetic disorders. The ultimate goal is to enable lifesaving research through the use of technology.
"The Microsoft Research GWAS program provides crucial funding at the interface between information management and quality healthcare," said Michael Kane, an assistant professor of Computer Technology at Purdue University and one of the researchers selected to receive support under the GWAS program. "Patient-specific genotyping to assure prescription drug safety and drug effectiveness is a major step toward the emergence and adoption of personalized medicine, and this support is key to facilitating that vision. Microsoft Corp. has recognized the important role information technology will play in the future of healthcare. Ultimately, this is about technology that helps to save lives."
As part of the program, more than $850,000 was shared among six research institutions.
"When it comes to performing genetic analysis, researchers are often hampered by the data itself, whether it's inconsistencies in format, the inability to visualize it, or sheer volume," said Kristin Tolle, program manager for biomedical computing on the External Research & Programs (ER&P) team at Microsoft Research. "Through this program, Microsoft Research is encouraging the development of computer-science solutions to improve data access, standardization, visualization and tools to help scientists study the human genome. "Of all the research areas Microsoft collaborates with, none may have as much real impact on global economies and the lives of ordinary people as healthcare," Tolle said.
Enabling this research is part of ER&P's broader efforts to move research in new directions across nearly every field of computer science, engineering and general science. Through this and other regional and global programs, Microsoft Research is partnering with researchers and scientists to address some of the toughest, most urgent scientific and societal challenges -- such as those in healthcare -- through enabling technologies that can provide real solutions.
Other examples of Microsoft's support of healthcare-related research include the program Cell Phones as a Platform for Healthcare, which sought novel healthcare solutions that are accessible, affordable and relevant for smart mobile phones; and the Intelligent Systems for Assisted Cognition Awards, which provided funding for technologies to assist people living with disorders such as autism and Alzheimer's disease. In the past six months alone, Microsoft External Research & Programs has awarded more than $2.5 million to academic researchers and scientists in support of healthcare research.
John Pearson is one of the six winners and a description of the project follows:
Translational Genomics Research Institute, John Pearson: "A Universal Data Format for Genotype Microarrays." Combining data generated in genome research is problematic due to the variety of software platforms in use today. Pearson will work to create a universal data format that would accommodate multiple vendor platforms into a single file and software library. The software library would allow for open use by the research community and commercial proprietary use by platform vendors.
Thursday, April 17, 2008
No stopping stem cells
[Source: BEN NORRIS, Arizona Daily Sun] - A renowned scholar and advocate for stem cell research took the stage of the High Country Conference Center Saturday to preach the benefits of embryonic stem cell treatment.
Christopher Scott, a Stanford University researcher and author, has spent much of the past decade studying both the scientific and ethical issues surrounding the controversial topic. "This issue becomes so polarizing," Scott said. "It just drives the wedge deeper. The point of this should be to open the door and get everyone's point of view. We need good, pragmatic people."
Scott was the keynote speaker at a conference of honors college students from throughout the western U.S.
Booking the scholar is quite a feat for NAU and the new conference center. Scott's work has been featured on NPR's Science Friday program and has earned him a coveted fellowship at King's College in London.
Scott has given more than 50 talks at colleges and conferences throughout the country, explaining his position and promoting his 2007 book "Stem Cells Now." Controversy surrounds the stem cells scientists wish to use, taken from embryos donated by potential mothers for in vitro fertilization.
Scott said many of these embryos are simply discarded after a few months of going unused because potential parents tend to donate more than is necessary.
"This raises important ethical and political questions," Scott said. "Should we let them go or should we use them for public benefit."
The argument is most heated between two factions: those who believe life begins with the embryo and those who believe the embryo is basically a collection of cells.
"An important topic is whether a 2-day-old embryo is human," Scott said. "Most scholars and ethicists have moved beyond that discussion. It will be very hard to meet in the middle. If you think it is murder, there is no middle ground."
Indeed, Scott admits he has come across some pretty fierce opposition from right-to-life groups, but always tries to keep the conversations civil. He faced no public opposition during his presentation at the conference center Saturday.
ON THE EDGES OF MEDICINE
During his presentation, Scott showed the audience slides of bladders and kidneys reshaped with the help of stem cell technology.
Scott said the first embryonic stem cell clinical trials in the United States are slated to begin in the next three months. Researchers and medical professionals plan to attempt a stem cell transplant to treat spinal injuries.
Scot said researchers are also interested to learn if using stem cells can reverse or slow the progress of macular degeneration, a condition that eventually leads to blindness.
Scientists also believe stem cell research can lead to the regeneration of heart, liver, kidney and muscle cells, to name a few.
"This is now a world phenomenon," Scott said. "The U.S. is one of dozens of countries doing this research."
Although the United States government prohibits federal funding of all but a few stem cell lines, research is not prohibited in all 50 states.
CONFERENCE A PLATFORM FOR STUDENTS, TOO
The weekend-long conference, hosted by NAU and the High Country Conference Center, brought honors students from more than 40 colleges and universities throughout the western United States.
Students had a chance to present their own research during breakout sessions. Topics ranged from discussions in bioscience to history and political issues.
"This is a great experience for the audience and the presenters," said Michael Evertson, a sophomore from Central Arizona College, who gave his presentation on the history of progressive rock music. "I came to enjoy the presentations and make some networking connections."
Kelly Lintecum, also a sophomore at the same college, gave her presentation on avian flu. She hopes to study bioscience at either NAU or ASU, but has not made up her mind just yet.
"I'm here to improve my public speaking skills," Lintecum said. "It's also important to represent my school."
Honor students from NAU also made sure to show up for the event. Zeke Lihosit, a freshman history major volunteered to help with the organization and setup, not to mention testing the waters for a presentation of his own next time the conference rolls around.
"This is my first time at a conference like this," Lihosit said. "It's pretty cool to see all these students present their ideas and research."
This is the first major conference at the center to host guests from all over the western United States.
Stem Cell Research Quick Hits
- Stem cell research is a misdemeanor crime in the state of South Dakota
- Researchers are ready to treat spinal injuries and blindness in the first phases of stem cell treatment.
- Stanford researchers used embryonic stem cells to create a mouse whose brain was 1 percent human.
- Despite legislation prohibiting federal funding, Californians approved a bill in 2007 granting the use of state funds to finance research.
- Scientists used stem cell research and tissue regeneration to create a replica kidney roughly the size of a 50-cent piece.
- Adult stem cells can be found in the stomach, blood, skin and in sperm
Source: Christopher Scott, Stanford University researcher
Christopher Scott, a Stanford University researcher and author, has spent much of the past decade studying both the scientific and ethical issues surrounding the controversial topic. "This issue becomes so polarizing," Scott said. "It just drives the wedge deeper. The point of this should be to open the door and get everyone's point of view. We need good, pragmatic people."
Scott was the keynote speaker at a conference of honors college students from throughout the western U.S.
Booking the scholar is quite a feat for NAU and the new conference center. Scott's work has been featured on NPR's Science Friday program and has earned him a coveted fellowship at King's College in London.
Scott has given more than 50 talks at colleges and conferences throughout the country, explaining his position and promoting his 2007 book "Stem Cells Now." Controversy surrounds the stem cells scientists wish to use, taken from embryos donated by potential mothers for in vitro fertilization.
Scott said many of these embryos are simply discarded after a few months of going unused because potential parents tend to donate more than is necessary.
"This raises important ethical and political questions," Scott said. "Should we let them go or should we use them for public benefit."
The argument is most heated between two factions: those who believe life begins with the embryo and those who believe the embryo is basically a collection of cells.
"An important topic is whether a 2-day-old embryo is human," Scott said. "Most scholars and ethicists have moved beyond that discussion. It will be very hard to meet in the middle. If you think it is murder, there is no middle ground."
Indeed, Scott admits he has come across some pretty fierce opposition from right-to-life groups, but always tries to keep the conversations civil. He faced no public opposition during his presentation at the conference center Saturday.
ON THE EDGES OF MEDICINE
During his presentation, Scott showed the audience slides of bladders and kidneys reshaped with the help of stem cell technology.
Scott said the first embryonic stem cell clinical trials in the United States are slated to begin in the next three months. Researchers and medical professionals plan to attempt a stem cell transplant to treat spinal injuries.
Scot said researchers are also interested to learn if using stem cells can reverse or slow the progress of macular degeneration, a condition that eventually leads to blindness.
Scientists also believe stem cell research can lead to the regeneration of heart, liver, kidney and muscle cells, to name a few.
"This is now a world phenomenon," Scott said. "The U.S. is one of dozens of countries doing this research."
Although the United States government prohibits federal funding of all but a few stem cell lines, research is not prohibited in all 50 states.
CONFERENCE A PLATFORM FOR STUDENTS, TOO
The weekend-long conference, hosted by NAU and the High Country Conference Center, brought honors students from more than 40 colleges and universities throughout the western United States.
Students had a chance to present their own research during breakout sessions. Topics ranged from discussions in bioscience to history and political issues.
"This is a great experience for the audience and the presenters," said Michael Evertson, a sophomore from Central Arizona College, who gave his presentation on the history of progressive rock music. "I came to enjoy the presentations and make some networking connections."
Kelly Lintecum, also a sophomore at the same college, gave her presentation on avian flu. She hopes to study bioscience at either NAU or ASU, but has not made up her mind just yet.
"I'm here to improve my public speaking skills," Lintecum said. "It's also important to represent my school."
Honor students from NAU also made sure to show up for the event. Zeke Lihosit, a freshman history major volunteered to help with the organization and setup, not to mention testing the waters for a presentation of his own next time the conference rolls around.
"This is my first time at a conference like this," Lihosit said. "It's pretty cool to see all these students present their ideas and research."
This is the first major conference at the center to host guests from all over the western United States.
Stem Cell Research Quick Hits
- Stem cell research is a misdemeanor crime in the state of South Dakota
- Researchers are ready to treat spinal injuries and blindness in the first phases of stem cell treatment.
- Stanford researchers used embryonic stem cells to create a mouse whose brain was 1 percent human.
- Despite legislation prohibiting federal funding, Californians approved a bill in 2007 granting the use of state funds to finance research.
- Scientists used stem cell research and tissue regeneration to create a replica kidney roughly the size of a 50-cent piece.
- Adult stem cells can be found in the stomach, blood, skin and in sperm
Source: Christopher Scott, Stanford University researcher
UA 'home run' is hit vs. cancer of colon
[Source: Carla McClain, Arizona Daily Star] - Striking a major blow against a top killer — colon cancer — a new drug therapy cuts the threat of this disease by as much as 90 percent in high-risk patients, University of Arizona scientists announced Monday.
The new therapy — combining the drug DFMO and an anti-inflammatory known as sulindac — was tested in patients who had developed precancerous colon polyps, putting them at high risk for full-fledged colon cancer.
Overall, their likelihood of developing more dangerous polyps was cut by 70 percent after three years on the combination therapy.
But in the most threatened patients — those who had large or multiple polyps — the risk of recurrence was slashed by a stunning 95 percent. That is more than double the preventive effect of other known therapies against colon cancer, including aspirin.
"This has really hit a home run," said Dr. David S. Alberts, director of the Arizona Cancer Center, where about 50 of the 300 patients in the study were tested and where much of the basic research and patient analysis was conducted.
"It is by a long shot the most effective therapy we have found to prevent this cancer, with very little toxicity," Alberts said.
In a cautionary note, researchers warned that the DFMO-sulindac therapy faces at least two more years of clinical trials before it will be "ready for prime-time" use in the United States.
"Although the five clinical trials we have completed show this therapy to be no more toxic than plain aspirin, we are always concerned about that issue and want further testing before this goes to the general population," said Eugene Gerner, director of the UA Cancer Center's gastrointestinal cancer program.
Gerner is the study's co-investigator, teaming with Dr. Frank Meyskens, director of the Chao Family Cancer Center at the University of California at Irvine and a former University of Arizona cancer researcher.
Their results won high praise when presented Monday at the annual meeting of the American Association for Cancer Research in San Diego.
Calling the findings "spectacular," Michael Sporn, pharmacology and toxicology professor at Dartmouth Medical School, said they "represent a landmark advance in efforts to stop the current worldwide epidemic of cancer deaths."
Colon cancer — the second-worst cancer killer in the United States — strikes nearly 150,000 Americans every year and kills about 60,000. Only lung cancer kills more.
In recent years, scientists have hurled a myriad of agents — drugs, vitamins and minerals — at high-risk patients, trying to stop colon polyps from recurring after being surgically removed.
But the results have been mixed and often conflicting. Among the most promising therapies, aspirin appears to cut polyp regrowth by slightly less than 30 percent. Celecoxib (brand name Celebrex) — an NSAID, or non-steroidal anti-inflammatory drug, similar to sulindac — has shown a 40 percent risk reduction, but it carries cardiovascular risks. The mineral calcium has at best reduced regrowth by about 20 percent.
The DFMO-sulindac combination more than doubled those rates in some cases and was especially powerful in preventing advanced polyps most likely to lead to cancer.
"That's the real breakthrough," Gerner said. "We have shown for the first time that a combination strategy can dramatically reduce this threat for the patients at highest risk.
"Further testing will tell us if this therapy might be useful for others at risk — those who have a family history of colon cancer, but have not yet developed polyps," Gerner added.
One of the key drugs in the new therapy — DFMO, or difluoromethylornithine — is a synthetic amino acid known to interfere with the carcinogenic process. But used alone, it proved toxic at doses needed for treating advanced cancer. By combining it with the NSAID sulindac, the research team was able to cut the DFMO to one-fiftieth of that dose, all but eliminating toxic effects.
"There is a great hope that we will be able to prevent colon cancer effectively using this method," Meyskens said. "We had not been able to do this before due to the high toxicity of available therapies."
The study involved about 300 patients who had at least one colon polyp within the previous five years. They were given either the daily combination DFMO (500 milligrams) and sulindac (150 mg), or a placebo.
After three years, the risk of a recurrent polyp dropped from 41.1 percent in the placebo group to 12.3 percent with treatment — a 70 percent reduction.
Even more striking, the risk in patients with advanced polyps dropped from 8.5 percent in the placebo group to 0.7 percent in the treatment group — a 92 percent reduction.
And for those in the most danger — patients with multiple previous polyps — the rate of re-growth plunged from 13.2 percent in the placebo group to 0.7 percent in the treatment group — a 95 percent reduction.
The results were so dramatic that the trial was stopped early and the results released.
Finally, an analysis of side effects and toxicity found no significant difference between the treatment and placebo groups.
The study was funded in part by the National Cancer Institute's Specialized Program of Research Excellence in GI Cancers.
The Arizona Cancer Center is one of only five institutions nationwide to receive a GI SPORE grant. Originally funded in 2002, it is the largest new grant awarded to the University of Arizona College of Medicine in the past 10 years. It was renewed in 2007 for another five years and funded at $12 million.
On StarNet: Find more cancer resources, including information on screening and prevention, at go.azstarnet.com/cancer.
The new therapy — combining the drug DFMO and an anti-inflammatory known as sulindac — was tested in patients who had developed precancerous colon polyps, putting them at high risk for full-fledged colon cancer.
Overall, their likelihood of developing more dangerous polyps was cut by 70 percent after three years on the combination therapy.
But in the most threatened patients — those who had large or multiple polyps — the risk of recurrence was slashed by a stunning 95 percent. That is more than double the preventive effect of other known therapies against colon cancer, including aspirin.
"This has really hit a home run," said Dr. David S. Alberts, director of the Arizona Cancer Center, where about 50 of the 300 patients in the study were tested and where much of the basic research and patient analysis was conducted.
"It is by a long shot the most effective therapy we have found to prevent this cancer, with very little toxicity," Alberts said.
In a cautionary note, researchers warned that the DFMO-sulindac therapy faces at least two more years of clinical trials before it will be "ready for prime-time" use in the United States.
"Although the five clinical trials we have completed show this therapy to be no more toxic than plain aspirin, we are always concerned about that issue and want further testing before this goes to the general population," said Eugene Gerner, director of the UA Cancer Center's gastrointestinal cancer program.
Gerner is the study's co-investigator, teaming with Dr. Frank Meyskens, director of the Chao Family Cancer Center at the University of California at Irvine and a former University of Arizona cancer researcher.
Their results won high praise when presented Monday at the annual meeting of the American Association for Cancer Research in San Diego.
Calling the findings "spectacular," Michael Sporn, pharmacology and toxicology professor at Dartmouth Medical School, said they "represent a landmark advance in efforts to stop the current worldwide epidemic of cancer deaths."
Colon cancer — the second-worst cancer killer in the United States — strikes nearly 150,000 Americans every year and kills about 60,000. Only lung cancer kills more.
In recent years, scientists have hurled a myriad of agents — drugs, vitamins and minerals — at high-risk patients, trying to stop colon polyps from recurring after being surgically removed.
But the results have been mixed and often conflicting. Among the most promising therapies, aspirin appears to cut polyp regrowth by slightly less than 30 percent. Celecoxib (brand name Celebrex) — an NSAID, or non-steroidal anti-inflammatory drug, similar to sulindac — has shown a 40 percent risk reduction, but it carries cardiovascular risks. The mineral calcium has at best reduced regrowth by about 20 percent.
The DFMO-sulindac combination more than doubled those rates in some cases and was especially powerful in preventing advanced polyps most likely to lead to cancer.
"That's the real breakthrough," Gerner said. "We have shown for the first time that a combination strategy can dramatically reduce this threat for the patients at highest risk.
"Further testing will tell us if this therapy might be useful for others at risk — those who have a family history of colon cancer, but have not yet developed polyps," Gerner added.
One of the key drugs in the new therapy — DFMO, or difluoromethylornithine — is a synthetic amino acid known to interfere with the carcinogenic process. But used alone, it proved toxic at doses needed for treating advanced cancer. By combining it with the NSAID sulindac, the research team was able to cut the DFMO to one-fiftieth of that dose, all but eliminating toxic effects.
"There is a great hope that we will be able to prevent colon cancer effectively using this method," Meyskens said. "We had not been able to do this before due to the high toxicity of available therapies."
The study involved about 300 patients who had at least one colon polyp within the previous five years. They were given either the daily combination DFMO (500 milligrams) and sulindac (150 mg), or a placebo.
After three years, the risk of a recurrent polyp dropped from 41.1 percent in the placebo group to 12.3 percent with treatment — a 70 percent reduction.
Even more striking, the risk in patients with advanced polyps dropped from 8.5 percent in the placebo group to 0.7 percent in the treatment group — a 92 percent reduction.
And for those in the most danger — patients with multiple previous polyps — the rate of re-growth plunged from 13.2 percent in the placebo group to 0.7 percent in the treatment group — a 95 percent reduction.
The results were so dramatic that the trial was stopped early and the results released.
Finally, an analysis of side effects and toxicity found no significant difference between the treatment and placebo groups.
The study was funded in part by the National Cancer Institute's Specialized Program of Research Excellence in GI Cancers.
The Arizona Cancer Center is one of only five institutions nationwide to receive a GI SPORE grant. Originally funded in 2002, it is the largest new grant awarded to the University of Arizona College of Medicine in the past 10 years. It was renewed in 2007 for another five years and funded at $12 million.
On StarNet: Find more cancer resources, including information on screening and prevention, at go.azstarnet.com/cancer.
FDA soon may support biomarker tests
[Source: Ann Fernholm, Chronicle Staff Writer] - The Food and Drug Administration is poised to throw its support behind a powerful new method of predicting the safety of experimental drugs, a step that could help pharmaceutical companies bring treatments to market more quickly - and reduce patients' risk.
The process being considered uses seven indicators - known as biomarkers - that signal kidney injury when found in the urine of test subjects.
"Today, the FDA gives approval for a new drug or device, but there has previously been no way to obtain approval for a new and better way to test a drug for its safety," said Raymond Woosley, president and CEO of the nonprofit Critical Path Institute, which is working with the FDA to safely speed drug development.
Currently, experimental drugs are tested in animals before being taken to human clinical trails. But animals' reactions aren't always the best predictor of whether substances will be safe for humans. Drugs harmless to animals can hurt humans, and vice versa. If a drug toxic to the kidneys passes animal tests today, the damage might not show up until it is too late.
"Using current tests, you have lost about 70 percent of the kidney function before you pick it up," says William Mattes, director of toxicology at the Critical Path Institute in Tucson.
The new biomarker process has the potential to save a patient's kidneys.
The ultimate goal of the pharmaceutical industry is to have a range of such marker tests that would signal dangerous side effects like heart failure, liver damage or cancer. Samples of blood, urine or saliva, for example, would be taken from participants in a clinical trial. If certain biomarkers indicated the patient was at risk, the trial could be stopped before any major damage occurs.
Seventeen companies have joined the research into biomarkers at the Critical Path Institute. These include giants like Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck and Co. and Pfizer. The companies contribute their expertise but, according to Woosley, the institute does not accept commercial funding.
Initially, the seven biomarker testing processes will be qualified by the FDA for use in preclinical animal studies, and only as a complement to current tests.
"This qualification process allows the industry to have an accurate view of the application of these biomarkers in drug development. They are not replacing anything that is done today. But the goal, as we gather more and more information, is to eventually be able to include them in clinical trials," said Federico Goodsaid, senior staff scientist at the genomics group at the FDA Office of Clinical Pharmacology.
Goodsaid is responsible for the development of the FDA's biomarker qualification pilot process, which began about a year ago when 23 potential biomarkers for kidney damage were submitted to the federal agency. The evaluation process at the Critical Path Institute has since selected the seven most efficient ones.
Named for the risky period when a drug is taken from the preclinical stage into clinical trials, the Critical Path Institute was founded two years ago by the FDA in collaboration with University of Arizona and Menlo Park's SRI International to break a worrying trend within the pharmaceutical industry: In the past decade the number of innovative therapies submitted for FDA approval dropped by 50 percent, but the cost of drug development increased dramatically.
Meanwhile, scares like the one associated with the painkiller Vioxx, which turned out to cause heart attacks and strokes, have further fueled this trend.
Unique for the Critical Path Institute is that FDA is a cofounder. Today, the European Medicines Agency - an agency similar to the FDA - also participates as an adviser. The agency is expected to qualify the seven biomarker testing method simultaneously with FDA.
"This is the first time they have coordinated their decisions," Mattes said.
Sidney Wolfe, director of the health research group at Public Citizen, a nonprofit public interest organization, supports the use of biomarkers as long as they are properly validated. But he is critical of the FDA's attitude toward present drug safety tests.
"Findings of toxicity in the currently required animal tests are not taken seriously enough by companies or by the FDA," Wolfe said.
He cites two recent examples of drugs in trouble, both of which showed toxicity in laboratory animals: the diabetes drug Avandia from GlaxoSmithKline and Vytorin from Schering-Plough and Merck, a cholesterol-lowering medication.
"Avandia showed evidence of heart damage in animal studies and, for Vytorin, tests showed serious toxicity in laboratory animals, regardless of how low a dose of this combination drug was used," says Wolfe.
The official announcement of the qualification of the seven biomarkers for kidney injury is expected from the FDA any day.
"It is in a very advanced stage of that process," Goodsaid said. "We should have some news soon."
What are biomarkers?
A biomarker is an indicator that can be used to test a biological function. Some biomarkers turn up when organs are injured and cells within the damaged tissue release substances into the blood, urine or saliva. These substances can then be used to detect dangerous side effects.
E-mail Ann Fernholm at afernholm@sfchronicle.com.
The process being considered uses seven indicators - known as biomarkers - that signal kidney injury when found in the urine of test subjects.
"Today, the FDA gives approval for a new drug or device, but there has previously been no way to obtain approval for a new and better way to test a drug for its safety," said Raymond Woosley, president and CEO of the nonprofit Critical Path Institute, which is working with the FDA to safely speed drug development.
Currently, experimental drugs are tested in animals before being taken to human clinical trails. But animals' reactions aren't always the best predictor of whether substances will be safe for humans. Drugs harmless to animals can hurt humans, and vice versa. If a drug toxic to the kidneys passes animal tests today, the damage might not show up until it is too late.
"Using current tests, you have lost about 70 percent of the kidney function before you pick it up," says William Mattes, director of toxicology at the Critical Path Institute in Tucson.
The new biomarker process has the potential to save a patient's kidneys.
The ultimate goal of the pharmaceutical industry is to have a range of such marker tests that would signal dangerous side effects like heart failure, liver damage or cancer. Samples of blood, urine or saliva, for example, would be taken from participants in a clinical trial. If certain biomarkers indicated the patient was at risk, the trial could be stopped before any major damage occurs.
Seventeen companies have joined the research into biomarkers at the Critical Path Institute. These include giants like Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck and Co. and Pfizer. The companies contribute their expertise but, according to Woosley, the institute does not accept commercial funding.
Initially, the seven biomarker testing processes will be qualified by the FDA for use in preclinical animal studies, and only as a complement to current tests.
"This qualification process allows the industry to have an accurate view of the application of these biomarkers in drug development. They are not replacing anything that is done today. But the goal, as we gather more and more information, is to eventually be able to include them in clinical trials," said Federico Goodsaid, senior staff scientist at the genomics group at the FDA Office of Clinical Pharmacology.
Goodsaid is responsible for the development of the FDA's biomarker qualification pilot process, which began about a year ago when 23 potential biomarkers for kidney damage were submitted to the federal agency. The evaluation process at the Critical Path Institute has since selected the seven most efficient ones.
Named for the risky period when a drug is taken from the preclinical stage into clinical trials, the Critical Path Institute was founded two years ago by the FDA in collaboration with University of Arizona and Menlo Park's SRI International to break a worrying trend within the pharmaceutical industry: In the past decade the number of innovative therapies submitted for FDA approval dropped by 50 percent, but the cost of drug development increased dramatically.
Meanwhile, scares like the one associated with the painkiller Vioxx, which turned out to cause heart attacks and strokes, have further fueled this trend.
Unique for the Critical Path Institute is that FDA is a cofounder. Today, the European Medicines Agency - an agency similar to the FDA - also participates as an adviser. The agency is expected to qualify the seven biomarker testing method simultaneously with FDA.
"This is the first time they have coordinated their decisions," Mattes said.
Sidney Wolfe, director of the health research group at Public Citizen, a nonprofit public interest organization, supports the use of biomarkers as long as they are properly validated. But he is critical of the FDA's attitude toward present drug safety tests.
"Findings of toxicity in the currently required animal tests are not taken seriously enough by companies or by the FDA," Wolfe said.
He cites two recent examples of drugs in trouble, both of which showed toxicity in laboratory animals: the diabetes drug Avandia from GlaxoSmithKline and Vytorin from Schering-Plough and Merck, a cholesterol-lowering medication.
"Avandia showed evidence of heart damage in animal studies and, for Vytorin, tests showed serious toxicity in laboratory animals, regardless of how low a dose of this combination drug was used," says Wolfe.
The official announcement of the qualification of the seven biomarkers for kidney injury is expected from the FDA any day.
"It is in a very advanced stage of that process," Goodsaid said. "We should have some news soon."
What are biomarkers?
A biomarker is an indicator that can be used to test a biological function. Some biomarkers turn up when organs are injured and cells within the damaged tissue release substances into the blood, urine or saliva. These substances can then be used to detect dangerous side effects.
E-mail Ann Fernholm at afernholm@sfchronicle.com.
Wednesday, April 16, 2008
New Method Can Rapidly ID Optimal Drug Cocktails
[Source: ScienceDaily] — UCLA researchers have developed a feedback control scheme that can search for the most effective drug combinations to treat a variety of conditions, including cancers and infections. The discovery could play a significant role in facilitating new clinical drug-cocktail trials.
The best known use of drug cocktails has been in the fight against HIV, the virus that causes AIDS. Drug cocktails also have been used to combat several types of cancer. Often, drugs that might not be effective in combating diseases individually do much better in combination.
With the use of the new closed-loop feedback control scheme, an approach guided by a stochastic search algorithm, researchers at the UCLA Henry Samueli School of Engineering and Applied Science and UCLA's Jonsson Comprehensive Cancer Center have devised an invaluable means of identifying potent drug combinations fast and efficiently. Their findings appear in the March 17 online version of the journal Proceedings of the National Academy of Sciences.
It has long been a difficult challenge for clinical researchers to determine the optimal dose of individual drugs used in combination. For example, a researcher testing 10 different concentrations of six drugs in every possible arrangement would be faced with 1 million potential combinations.
"With the development of this optimization method, we've overcome a major roadblock," said study author Chih-Ming Ho, UCLA's Ben Rich-Lockheed Martin Professor and a member of the National Academy of Engineering. "There have always been too many choices and too many combinations to sort through. It was like finding a needle in a haystack."
In one test case, the research team examined how to best prevent a viral infection of host cells. Using the closed-loop optimization scheme, they were able to identify, out of 100,000 possible combinations, the drug cocktails that completely inhibited viral infection after only about a dozen trials. In addition, they found that total inhibition of the virus occurred at much lower drug doses than would be necessary if the drugs were used alone; in fact, the concentrations of the drugs were only about 10 percent of that required when used individually.
"Viruses grow very rapidly and change rapidly as well. Because of that, a virus can become resistant to a particular drug," said Genhong Cheng, a member of the research team at the UCLA Center for Cell Control and UCLA's Jonsson Comprehensive Cancer Center. "This is why it's so important to be able to use a combination of more than one drug. If the virus mutates to become resistant to one drug, it is still sensitive to the other drugs."
Drug combinations can also be used effectively to inhibit infectious diseases because resistance to a single drug is very common, according to Ren Sun, UCLA professor of molecular and medical pharmacology and a member of the research team.
"If we can apply multiple drugs against one infectious agent, it probably will prevent the occurrence of drug resistance," said Sun, who is also a researcher at the Jonsson Cancer Center. "But, of course, when you use multiple drugs, side effects will be strong. With this model, there is a way to optimize the combination to reduce the side effects while maintaining efficacy that will be very beneficial."
"What the search scheme does is it tries to detect trends for optimal output," said Pak Wong, a former UCLA graduate student who participated in the study and is now an assistant professor of mechanical engineering at the University of Arizona. "Basically, the algorithm sees a trend and a direction and drives the trend in that direction. It's like mountain climbing and finding a way to get to the peak. So you keep going, and soon you rapidly find the peak while being guided by a smart search scheme."
In an example used to illustrate the prevention of viral infection of host cells, researchers started with arbitrarily chosen dosages of the drugs. The percentage of non-infected cells under this initial drug-cocktail treatment was fed into the stochastic search algorithm, which essentially helps guide a random search process. The algorithm then suggested the next drug concentrations for producing a higher percentage of non-infected cells. This closed-loop feedback control scheme is carried out continuously until the best combination is found. Randomness is built into the search decision, preventing the trap at local optimum levels and allowing the search process to continue until the optimal drug cocktail is identified.
The model also provides an alternative approach to studying cellular functions. Molecular biologists can identify all the players of a particular regulatory pathway in order to decipher how to block or augment that pathway. Cells are complex systems with many redundant functions, and it is difficult to predict how a cell will respond to multiple stimulations at one time. The model overlooks these details and lets the system determine what works best for itself. If researchers are more interested in how the cellular network functions, this approach can provide an initial bird's-eye view, but it also allows them to home in on the important molecular activities controlled by the best drug combinations.
This search scheme is an extremely effective and versatile tool that can be applied to combat numerous diseases, including cancer, the researchers say, and its multidimensional properties will likely make it useful in a wide variety of additional situations.
The next steps are animal and clinical testing.
The study was funded and supported by the Center for Cell Control, a nanomedicine development center funded by the National Institutes of Health through the Roadmap for Medical Research, and by the Institute for Cell Mimetic Space Exploration, a NASA-sponsored institute.
Adapted from materials provided by University of California - Los Angeles, via EurekAlert!, a service of AAAS.
The best known use of drug cocktails has been in the fight against HIV, the virus that causes AIDS. Drug cocktails also have been used to combat several types of cancer. Often, drugs that might not be effective in combating diseases individually do much better in combination.
With the use of the new closed-loop feedback control scheme, an approach guided by a stochastic search algorithm, researchers at the UCLA Henry Samueli School of Engineering and Applied Science and UCLA's Jonsson Comprehensive Cancer Center have devised an invaluable means of identifying potent drug combinations fast and efficiently. Their findings appear in the March 17 online version of the journal Proceedings of the National Academy of Sciences.
It has long been a difficult challenge for clinical researchers to determine the optimal dose of individual drugs used in combination. For example, a researcher testing 10 different concentrations of six drugs in every possible arrangement would be faced with 1 million potential combinations.
"With the development of this optimization method, we've overcome a major roadblock," said study author Chih-Ming Ho, UCLA's Ben Rich-Lockheed Martin Professor and a member of the National Academy of Engineering. "There have always been too many choices and too many combinations to sort through. It was like finding a needle in a haystack."
In one test case, the research team examined how to best prevent a viral infection of host cells. Using the closed-loop optimization scheme, they were able to identify, out of 100,000 possible combinations, the drug cocktails that completely inhibited viral infection after only about a dozen trials. In addition, they found that total inhibition of the virus occurred at much lower drug doses than would be necessary if the drugs were used alone; in fact, the concentrations of the drugs were only about 10 percent of that required when used individually.
"Viruses grow very rapidly and change rapidly as well. Because of that, a virus can become resistant to a particular drug," said Genhong Cheng, a member of the research team at the UCLA Center for Cell Control and UCLA's Jonsson Comprehensive Cancer Center. "This is why it's so important to be able to use a combination of more than one drug. If the virus mutates to become resistant to one drug, it is still sensitive to the other drugs."
Drug combinations can also be used effectively to inhibit infectious diseases because resistance to a single drug is very common, according to Ren Sun, UCLA professor of molecular and medical pharmacology and a member of the research team.
"If we can apply multiple drugs against one infectious agent, it probably will prevent the occurrence of drug resistance," said Sun, who is also a researcher at the Jonsson Cancer Center. "But, of course, when you use multiple drugs, side effects will be strong. With this model, there is a way to optimize the combination to reduce the side effects while maintaining efficacy that will be very beneficial."
"What the search scheme does is it tries to detect trends for optimal output," said Pak Wong, a former UCLA graduate student who participated in the study and is now an assistant professor of mechanical engineering at the University of Arizona. "Basically, the algorithm sees a trend and a direction and drives the trend in that direction. It's like mountain climbing and finding a way to get to the peak. So you keep going, and soon you rapidly find the peak while being guided by a smart search scheme."
In an example used to illustrate the prevention of viral infection of host cells, researchers started with arbitrarily chosen dosages of the drugs. The percentage of non-infected cells under this initial drug-cocktail treatment was fed into the stochastic search algorithm, which essentially helps guide a random search process. The algorithm then suggested the next drug concentrations for producing a higher percentage of non-infected cells. This closed-loop feedback control scheme is carried out continuously until the best combination is found. Randomness is built into the search decision, preventing the trap at local optimum levels and allowing the search process to continue until the optimal drug cocktail is identified.
The model also provides an alternative approach to studying cellular functions. Molecular biologists can identify all the players of a particular regulatory pathway in order to decipher how to block or augment that pathway. Cells are complex systems with many redundant functions, and it is difficult to predict how a cell will respond to multiple stimulations at one time. The model overlooks these details and lets the system determine what works best for itself. If researchers are more interested in how the cellular network functions, this approach can provide an initial bird's-eye view, but it also allows them to home in on the important molecular activities controlled by the best drug combinations.
This search scheme is an extremely effective and versatile tool that can be applied to combat numerous diseases, including cancer, the researchers say, and its multidimensional properties will likely make it useful in a wide variety of additional situations.
The next steps are animal and clinical testing.
The study was funded and supported by the Center for Cell Control, a nanomedicine development center funded by the National Institutes of Health through the Roadmap for Medical Research, and by the Institute for Cell Mimetic Space Exploration, a NASA-sponsored institute.
Adapted from materials provided by University of California - Los Angeles, via EurekAlert!, a service of AAAS.
Multiple Myeloma Research Consortium and Sunesis Pharmaceuticals Present Data On SNS-032 At American Association of Cancer Research Annual Meeting
[Source Genetic Engineering News] - The Multiple Myeloma Research Consortium (MMRC) in collaboration with Sunesis Pharmaceuticals presented preclinical data on the activity of Sunesis' cell cycle inhibitor, SNS-032, in multiple myeloma cell assays and animal models. The data was presented orally at the 2008 Annual Meeting of the American Association of Cancer Research.
Suzanne Trudel, MD, Assistant Professor, University Health Network (UHN) in Toronto, Canada, and Project Leader for the MMRC Validation Team, which performed the studies, presented data showing that SNS-032 demonstrated growth inhibitory effects in different multiple myeloma cell lines as well as myeloma cells prepared from patient samples. In addition, SNS-032 demonstrated activity in a transgenic animal model with multiple myeloma characteristics similar to those observed in humans. These studies, resulting from extensive collaborative efforts between the MMRC, Emory University's Winship Cancer Institute and Sunesis demonstrated preclinical, single-agent activity of SNS-032 in multiple myeloma and support its further investigation as a potential therapeutic candidate. SNS-032, a potent and selective inhibitor of cyclin-dependent kinases (CDKs) 2, 7 and 9, is currently in a Phase 1 clinical trial in patients with chronic lymphocytic leukemia (CLL) or multiple myeloma.
"Sunesis is proud to collaborate with the MMRC and the Validation Team to advance this important clinical program in the quest for a cure for multiple myeloma. It highlights the importance of collaborations between industry and oncology field experts in order to more rapidly and appropriately evaluate new treatments for cancer therapy," said Rachael Hawtin, PhD, Associate Director, Biology, Sunesis.
The MMRC Validation Team, composed of leading myeloma scientists from the Dana-Farber Cancer Institute, Mayo Clinic-Scottsdale, H. Lee Moffitt Cancer Center and UHN, tests compounds in a variety of multiple myeloma cell-based systems and animal models. The team represents a unique research and development model, typically not included in foundation activities, with the major goal of prioritizing compounds to enter myeloma clinical trials by testing their preclinical activity in myeloma specific systems.
"The team is very encouraged by the success of the first project to enter the MMRC validation model and the selection of this research as an oral presentation at the AACR. The results demonstrate modest single agent activity in mice," says Dr. Trudel
Suzanne Trudel, MD, Assistant Professor, University Health Network (UHN) in Toronto, Canada, and Project Leader for the MMRC Validation Team, which performed the studies, presented data showing that SNS-032 demonstrated growth inhibitory effects in different multiple myeloma cell lines as well as myeloma cells prepared from patient samples. In addition, SNS-032 demonstrated activity in a transgenic animal model with multiple myeloma characteristics similar to those observed in humans. These studies, resulting from extensive collaborative efforts between the MMRC, Emory University's Winship Cancer Institute and Sunesis demonstrated preclinical, single-agent activity of SNS-032 in multiple myeloma and support its further investigation as a potential therapeutic candidate. SNS-032, a potent and selective inhibitor of cyclin-dependent kinases (CDKs) 2, 7 and 9, is currently in a Phase 1 clinical trial in patients with chronic lymphocytic leukemia (CLL) or multiple myeloma.
"Sunesis is proud to collaborate with the MMRC and the Validation Team to advance this important clinical program in the quest for a cure for multiple myeloma. It highlights the importance of collaborations between industry and oncology field experts in order to more rapidly and appropriately evaluate new treatments for cancer therapy," said Rachael Hawtin, PhD, Associate Director, Biology, Sunesis.
The MMRC Validation Team, composed of leading myeloma scientists from the Dana-Farber Cancer Institute, Mayo Clinic-Scottsdale, H. Lee Moffitt Cancer Center and UHN, tests compounds in a variety of multiple myeloma cell-based systems and animal models. The team represents a unique research and development model, typically not included in foundation activities, with the major goal of prioritizing compounds to enter myeloma clinical trials by testing their preclinical activity in myeloma specific systems.
"The team is very encouraged by the success of the first project to enter the MMRC validation model and the selection of this research as an oral presentation at the AACR. The results demonstrate modest single agent activity in mice," says Dr. Trudel
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