Tag Archives: medical research

Engineering Mosquitoes to be Flying Vaccinators

Mosquitoes Engineered Into Flying Vaccinators by Emily Singer

Researchers in Japan have transformed mosquitoes into vaccine-carrying syringes by genetically engineering the insects to express the vaccine for leishmaniasis–a parasitic disease transmitted by the sandfly–in their saliva. According to a study in Insect Molecular Biology, mice bitten by these mosquitoes produced antibodies against the parasite. It’s not yet clear whether the immune response was strong enough to protect against infection.

“Following bites, protective immune responses are induced, just like a conventional vaccination but with no pain and no cost,” said lead researcher Shigeto Yoshida, from the Jichi Medical University in JapanYoshida, in a press release from the journal. “What’s more continuous exposure to bites will maintain high levels of protective immunity, through natural boosting, for a life time. So the insect shifts from being a pest to being beneficial.”

Researchers consider the project more of a proof of principle experiment than a viable public health option, at least for now.

Very cool.

Statistical Errors in Medical Studies

I have written about statistics, and various traps people often fall into when examining data before (Statistics Insights for Scientists and Engineers, Data Can’t Lie – But People Can be Fooled, Correlation is Not Causation, Simpson’s Paradox). And also have posted about reasons for systemic reasons for medical studies presenting misleading results (Why Most Published Research Findings Are False, How to Deal with False Research Findings, Medical Study Integrity (or Lack Thereof), Surprising New Diabetes Data). This post collects some discussion on the topic from several blogs and studies.

HIV Vaccines, p values, and Proof by David Rind

if vaccine were no better than placebo we would expect to see a difference as large or larger than the one seen in this trial only 4 in 100 times. This is distinctly different from saying that there is a 96% chance that this result is correct, which is how many people wrongly interpret such a p value.
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So, the modestly positive result found in the trial must be weighed against our prior belief that such a vaccine would fail. Had the vaccine been dramatically protective, giving us much stronger evidence of efficacy, our prior doubts would be more likely to give way in the face of high quality evidence of benefit.
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While the actual analysis the investigators decided to make primary would be completely appropriate had it been specified up front, it now suffers under the concern of showing marginal significance after three bites at the statistical apple; these three bites have to adversely affect our belief in the importance of that p value. And, it’s not so obvious why they would have reported this result rather than excluding those 7 patients from the per protocol analysis and making that the primary analysis; there might have been yet a fourth analysis that could have been reported had it shown that all important p value below 0.05.

How to Avoid Commonly Encountered Limitations of Published Clinical Trials by Sanjay Kaul, MD and and George A. Diamond, MD

Trials often employ composite end points that, although they enable assessment of nonfatal events and improve trial efficiency and statistical precision, entail a number of shortcomings that can potentially undermine the scientific validity of the conclusions drawn from these trials. Finally, clinical trials often employ extensive subgroup analysis. However, lack of attention to proper methods can lead to chance findings that might misinform research and result in suboptimal practice.

Why Most Published Research Findings Are False by John P. A. Ioannidis
Continue reading →

Norway Reduces Infections by Reducing Antibiotic Use

Norway conquers infections by cutting use of antibiotics

Twenty-five years ago, Norwegians were also losing their lives to this bacteria. But Norway’s public health system fought back with an aggressive program that made it the most infection-free country in the world. A key part of that program was cutting back severely on the use of antibiotics.

Now a spate of new studies from around the world prove that Norway’s model can be replicated with extraordinary success, and public health experts are saying these deaths — 19,000 in the U.S. each year alone, more than from AIDS — are unnecessary.

“It’s a very sad situation that in some places so many are dying from this, because we have shown here in Norway that Methicillin-resistant Staphylococcus aureus [MRSA] can be controlled, and with not too much effort,” said Jan Hendrik-Binder, Oslo’s MRSA medical advisor. “But you have to take it seriously, you have to give it attention and you must not give up.”

The World Health Organization says antibiotic resistance is one of the leading public health threats on the planet. A six-month investigation by The Associated Press found overuse and misuse of medicines has led to mutations in once curable diseases like tuberculosis and malaria, making them harder and in some cases impossible to treat.

Now, in Norway’s simple solution, there’s a glimmer of hope.

Antibiotics Breed Superbugs Faster Than Expected

We continue to endanger ourselves by using antibiotics inappropriately. This is one of many things that happen when the public at large is ignorant about science and ignores scientific evidence. I don’t believe people want to put other people’s lives in danger. But our behavior in the face of the evidence has us doing just that. I believe because we don’t value science rather than because we don’t care about putting others (and ourselves) in danger. Antibiotics Breed Superbugs Faster Than Expected

Bacteria don’t just develop resistance to one drug at a time, but to many — and at accelerated rates. That’s because antibiotics boost bacterial production of free-radical oxygen molecules that damage bacterial DNA. Repairs to the DNA cause widespread mutations, giving bacteria more chances to randomly acquire drug-resistant traits.
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Drug resistance is a serious public health concern. According to the federal Centers for Disease Control and Prevention, 70 percent of 1.7 million infections acquired in hospitals every year are resistant to at least one drug. Those infections annually kill 99,000 Americans — more than double the number that die in car crashes.

Drugs that once destroyed almost any bacteria now kill only a few, or don’t work at all. In the case of some drugs, like Cipro, the decline is dramatic: Where in 1999 it worked against 95 percent of E. coli, it treated only 60 percent by 2006. Against lung infection-causing Acinobacter, its effectiveness fell by 70 percent in just four years.

Though drug resistance is ultimately inevitable, conventional wisdom holds that antibiotics consumed at suboptimum doses hasten the process. Bugs that would have succumbed to a larger dose live to multiply, pushing the strain as a whole closer to resistance. That happens when a prescription goes unfinished, or when antibiotics used on farms enter food and water at low levels.
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Of the 35 million pounds of antibiotics consumed annually in the United States, 80 percent goes to farm animals. Much of it is used to treat diseases spread by industrial husbandry practices, or simply to accelerate growth. As a result, farms have become giant petri dishes for superbugs, especially multidrug-resistant Staphylococcus aureus, or MRSA, which kills 20,000 Americans every year – more than AIDS.

Alarming cases of farm-based MRSA and other diseases led to a proposed Congressional law restricting the use of agricultural antibiotics. That bill, supported by the American Medical Association and American Public Health Association, is opposed by farm lobbyists and remains stuck in committee.

Researchers Find Switch That Allows Cancer Cells to Spread

Researchers discovered of a specific protein called disabled-2 (Dab2) that switches on the process that releases cancer cells from the original tumor and allows the cells to spread and develop into new tumors in other parts of the body.

The process called epithelial-mesenchymal transdifferientiation (EMT) has been known to play a role in releasing cells (epithelial cells) on the surface of the solid tumor and transforming them into transient mesenchymal cell: cells with the ability to start to grow a new tumor.

This is often the fatal process in breast, ovarian, pancreatic and colon-rectal cancers.

Searching to understand how the EMT process begins, Ge Jin, who has joint appointments at the Case Western Reserve University School of Dental Medicine and the Lerner Research Institute at the Cleveland Clinic, began by working backwards from EMT to find its trigger. The researchers found that a compound called transforming growth factor-ÃŸ (TGF-ÃŸ) triggers the formation of the Dab2 protein. It was this protein, Dab2, that activated the EMT process.

He discovered that when the researchers knocked out Dab2, EMT was not triggered. “This is the major piece in cancer research that has been missing,” Jin said. Most tumors are epithelial in origin and have epithelial markers on their surface. The EMT process takes place when some of those cells dislodge from the surface and undergo a transformation into a fibrous mesenchymal cell maker with the ability to migrate.

“EMT is the most important step in this process,” said Jin. He was part of a six-member research team, led by Philip Howe from the Department of Cancer Biology at the Lerner Research Institute in a National Institute of Cancer-funded study. The research group studied the biological processes that initiated the cancer spread by using cancer cells in animal models.

“If we can understand the signaling pathway for modulating EMT, then we can design drugs to delay or halt EMT cells and control tumor progression,” Jin said. Beyond cancer, Jin said. “The process we discovered may lead to understanding how other diseases progress.”

Microbes Flourish In Healthy People

Bugs Inside: What Happens When the Microbes That Keep Us Healthy Disappear? by Katherine Harmon

The human body has some 10 trillion human cells—but 10 times that number of microbial cells. So what happens when such an important part of our bodies goes missing?
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“Someone who didn’t have their microbes, they’d be naked,” says Martin Blaser, a professor of microbiology and chair of the Department of Medicine at New York University Langone Medical Center in New York City.
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Even though it is such an apparently integral and ancient aspect of human health, scientists are still grasping for better ways to study human microbiota—before it changes beyond historical recognition. Borrowing models from outside of medicine has helped many in the field gain a better understanding of this living world within us. “The important concept is about extinctions,” Blaser says. “It’s ecology.”
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The first step in understanding these systems is simply taking stock of what archaea, bacteria, fungi, protozoa and viruses are present in healthy individuals. This massive micro undertaking has been ongoing since 2007 through the National Institutes of Health’s (NIH) Human Microbiome Project. So far it has turned up some surprisingly rich data, including genetic sequencing for some 205 of the different genera that live on healthy human skin.

Despite the flood of new data, Foxman laughs when asked if there is any hope for a final report from the Human Microbiome Project any time soon. “This is the very, very beginning,” she says, comparing this project with the NIH’s Human Genome Project, which jump-started a barrage of new genetic research. “There are basic, basic questions that we don’t know the answers to,” she says, such as how different microbiota are between random individuals or family members; how much microbiota change over time; or how related the microbiota are to each other on or inside a person’s body.

Printing Bone, Muscle and More

A Pittsburgh-based research team has created and used an innovative ink-jet system to print “bio-ink” patterns that direct muscle-derived stem cells from adult mice to differentiate into both muscle cells and bone cells.

The custom-built ink-jet printer, developed at Carnegie Mellon’s Robotics Institute, can deposit and immobilize growth factors in virtually any design, pattern or concentration, laying down patterns on native extracellular matrix-coated slides (such as fibrin). These slides are then placed in culture dishes and topped with muscle-derived stem cells (MDSCs). Based on pattern, dose or factor printed by the ink-jet, the MDSCs can be directed to differentiate down various cell-fate differentiation pathways (e.g. bone- or muscle-like).

“This system provides an unprecedented means to engineer replacement tissues derived from muscle stem cells,” said Johnny Huard, professor of orthopedic surgery at the University of Pittsburgh School of Medicine and director of the Stem Cell Research Center at Children’s Hospital of UPMC. Huard has long-standing research findings that show how muscle-derived stem cells (MDSCs) from mice can repair muscle in a model for Duchenne Muscular Dystrophy, improve cardiac function following heart failure, and heal large bone and articular cartilage defects.

Weiss and Campbell, along with graduate student Eric Miller, previously demonstrated the use of ink-jet printing to pattern growth factor “bio-inks” to control cell fates. For their current research, they teamed with Phillippi, Huard and biologists of the Stem Cell Research Center at Children’s Hospital to gain experience in using growth factors to control differentiation in populations of MDSCs from mice.

The team envisions the ink-jet technology as potentially useful for engineering stem cell-based therapies for repairing defects where multiple tissues are involved, such as joints where bone, tendon, cartilage and muscle interface. Patients afflicted with conditions like osteoarthritis might benefit from these therapies, which incorporate the needs of multiple tissues and may improve post-treatment clinical outcomes.

The long-term promise of this new technology could be the tailoring of tissue-engineered regenerative therapies. In preparation for preclinical studies, the Pittsburgh researchers are combining the versatile ink-jet system with advanced real-time live cell image analysis developed at the Robotics Institute and Molecular Biosensor and Imaging Center to further understand how stem cells differentiate into bone, muscle and other cell types.

Prion Proteins, Without Genes, Can Evolve

‘Lifeless’ prion proteins are ‘capable of evolution’

scientists transferred prion populations from brain cells to other cells in culture and observed the prions that adapted to the new cellular environment out-competed their brain-adapted counterparts. When returned to the brain cells, the brain-adapted prions again took over the population.

Charles Weissmann, head of Scripps Florida’s department of infectology who led the study, said: “On the face of it, you have exactly the same process of mutation and adaptive change in prions as you see in viruses.

“This means that this pattern of Darwinian evolution appears to be universally active. “In viruses, mutation is linked to changes in nucleic acid sequence that leads to resistance.

“Now, this adaptability has moved one level down- to prions and protein folding – and it’s clear that you do not need nucleic acid (DNA or RNA) for the process of evolution.”
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He said: “The prion protein is not a clone, it is a quasi-species that can create different protein strains even in the same animal. “The abnormal prion proteins multiply by converting normal prion proteins.

“The implication of Charles Weissmann’s work is that it would be better to cut off that supply of normal prion proteins rather than risk the abnormal prion adapting to a drug and evolving into a new more virulent form.

Bionic Vision

Micro Machines and Opto-Electronics on a Contact Lense

Fiction now meets reality with prototype contact lenses developed by Babak Parviz at the University of Washington, in Seattle. Dr. Parviz’s prototype lenses can be used as biosensors to display body chemistry or as a heads up display (HUD). Powered by radio waves and 330 microwatts of power from a loop antenna that picks up power beamed from nearby radio sources, future versions will also be able to harvest power from a cell phone.

In his early 2008 lab tests, rabbits safely wore contact lenses with metal connectors for electronic circuits. The prototype lenses contained an electric circuit as well as red light-emitting diodes for a display. The lenses were tested on rabbits for up to 20 minutes and the animals showed no adverse effects.
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Contact lenses as replacements for smart phone displays — even to monitor blood glucose levels — might best be done while not operating heavy equipment. “The true promise of this research is not just the actual system we end up making, whether it’s a display, a biosensor, or both,” comments Dr. Parviz. “We already see a future in which the humble contact lens becomes a real platform, like the iPhone is today, with lots of developers contributing their ideas and inventions. As far as we’re concerned, the possibilities extend as far as the eye can see, and beyond.”

The Only Known Cancerless Animal

Unlike any other mammal, naked mole rate communities consist of queens and workers more reminiscent of bees than rodents. Naked mole rats can live up to 30 years, which is exceptionally long for a small rodent. Despite large numbers of naked mole-rats under observation, there has never been a single recorded case of a mole rat contracting cancer, says Gorbunova. Adding to their mystery is the fact that mole rats appear to age very little until the very end of their lives.

The mole rat’s cells express p16, a gene that makes the cells “claustrophobic,” stopping the cells’ proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells’ growth barely changed, whereas regular mouse cells became fully cancerous.

“It’s very early to speculate about the implications, but if the effect of p16 can be simulated in humans we might have a way to halt cancer before it starts.” says Vera Gorbunova, associate professor of biology at the University of Rochester and lead investigator on the discovery.

In 2006, Gorbunova discovered that telomerase—an enzyme that can lengthen the lives of cells, but can also increase the rate of cancer—is highly active in small rodents, but not in large ones.

Until Gorbunova and Seluanov’s research, the prevailing wisdom had assumed that an animal that lived as long as we humans do needed to suppress telomerase activity to guard against cancer. Telomerase helps cells reproduce, and cancer is essentially runaway cellular reproduction, so an animal living for 70 years has a lot of chances for its cells to mutate into cancer, says Gorbunova. A mouse’s life expectancy is shortened by other factors in nature, such as predation, so it was thought the mouse could afford the slim cancer risk to benefit from telomerase’s ability to speed healing.

While the findings were a surprise, they revealed another question: What about small animals like the common grey squirrel that live for 24 years or more? With telomerase fully active over such a long period, why isn’t cancer rampant in these creatures?