A step toward letting medical devices communicate

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Plug and play: Two pulse oximeters, which measure blood oxygen levels, are linked with hardware that uses data from either device to control an intravenous drug device (not shown).
Credit: CIMIT

 

MIT Technology Review, September 24, 2009, by David Talbot  —  In a key practical step toward the long-sought goal of linking different hospital devices together to better manage patients and their care, a Boston research group has come up with a software platform for sharing information among gadgets ranging from blood-pressure cuffs to heart-lung machines.

“The vision of fully interoperable medical devices has been around for at least a quarter-century, but lack of adequate standards and lack of manufacturers’ desire to foster such integration has left us in a kind of Dark Ages,” says Peter Szolovits, an MIT computer scientist in the Harvard/MIT Division of Health Sciences and Technology, who was not involved with developing the new standards. He adds that they are “a critical component of making health-care information technology smarter, safer, and more efficient.”

When doctors disconnect a heart-lung machine after finishing heart surgery, they need to turn on the ventilator quickly, or the patient will suffer brain damage. Right now, however, there is no way for the heart-lung machine to sense whether the ventilator was switched on correctly and keep running if it wasn’t. Even the most high-technology medical devices used in hospitals don’t “talk” to each other in the way that, say, your PC “talks” to your printer.

The new standards for the Integrated Clinical Environment (ICE)–written by a research group convened by the Center for Integration of Medicine and Innovative Technology (CIMIT), a hospital/academic consortium in Boston–consist of a set of high-level design principles. Among other things, the standard says that an ICE must include a device analogous to a jet airliner’s “black box” that collects data. This black box will initially prove that integrating different systems can be safe enough to win regulatory approval. But in everyday practice, it will also be crucial to troubleshooting and improving interoperability. The standard also says that there must be only one overarching algorithm that interprets data from all connected machines to avoid conflicting instructions or warnings; and that if one piece fails, the failure must not be able to spread to other parts of the system.

“This is about building a comprehensive platform, like the Web, that allows the global community to innovate and build cool things on top of it that improve patient safety,” says Julian Goldman, director of CIMIT’s Medical Device Interoperability Program, who led the group that developed the standards, which will be published this fall by the standards body ASTM International.

“Any technologically sophisticated person would assume that if you are receiving a potent intravenous medication in a hospital, and at the same time your blood pressure is being measured by an automated cuff every 15 minutes, that we have a way to [automatically] stop that medication infusion if it causes your blood pressure starts to fall or rise rapidly,” says Goldman, who is also an anesthesiologist at Massachusetts General Hospital and medical director of Partners HealthCare Biomedical Engineering, “but it’s impossible to do that today.”

This lack of interoperability can lead to serious errors. It also means that clinicians waste time chasing false alarms set off by individual gadgets. For example, today’s telemetry monitors track heart rhythms, while other gadgets monitor heart rate and levels of blood oxygen. Sudden changes in activity and movement can cause sudden heart-rhythm fluctuations, triggering urgent warnings. But such alarms could be eliminated if an integrated system also checked heart rate and oxygen levels; if these were unchanged, no heart-attack warning would be necessary.

David Osborn, manager of international standards at Philips Healthcare, says that while the new standards will help, “the document put together so far is a high-level framework. The devil is in the details, and the details haven’t been written yet.” However, he adds, “harm is occurring to patients more often than we’d like to admit, and this can be a step toward a solution, if we can get beyond the framework.”

Szolovits says that the eventual goal is an integrated clinical environment, in which all devices are interconnected, in plug-and-play fashion, for better management. Currently, devices made by different manufacturers operate on their own, and, in general, they cannot communicate with one another. Several medical associations, including the American Medical Association, have called for interoperability.

“Even at leading modern hospitals, I have seen pulmonary technicians run around the foot of a patient’s bed to transfer ventilator settings from a device on one side of the bed to a computer system on the other,” says Szolovits. “Not only is such a process laughable to watch, but it increases the risk of errors, corrupts data, and possibly even puts patients at risk.”

A new blood test could improve cancer-screening compliance

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Tissue test: Healthy colon tissue (shown top), with surface cells dyed green and internal stromal cells dyed red. In cancerous colon tissue (bottom), the tissue structure is broken down, and surface and internal cells are mixed together. Credit: OncoMethylome Sciences 

MIT Technology Review, September 23, 2009, by Michael Day  —  A blood test designed to enable simple screening for colon cancer has been hailed by experts as a major advance. The test detects cancer due to a chemical change called methylation that occurs disproportionately in two key genes in colorectal tumor cells.

Since more people should be willing to have a simple blood test, the screening method could help identify those patients who need a more invasive, more diagnostically rigorous colonoscopy.

The U.S. death toll from the condition is around 50,000 a year. The American Cancer Society recommends that men over the age of 50 have about one colonoscopy every 10 years, and that those at a higher risk be screened earlier and more often. Yet until now, only invasive colonoscopies and stool tests have been available and compliance by those deemed in need of screening is disappointingly low, at less than 50 percent. Screening programs have been shown to cut deaths by allowing more victims to receive earlier, curative treatment so a simpler test could save lives by encouraging more people to get screened.

The developers of the new test, OncoMethylome Sciences, based in Liège, Belgium, say their method, which relies on one three-milliliter sample of blood, has the potential to boost compliance rates and conserve precious health service resources.

The test identifies the presence of methylated SYNE1 and FOXE1 genes, which mark out colorectal cancer cells. The researchers compared test results from 686 healthy control patients with 193 patients already diagnosed with the disease. The test was able to detect colorectal cancer in 77 percent of those subjects with the disease, according to data presented at the Congress of the European Cancer Organization in Berlin, Germany, on Monday. It correctly identified healthy, noncancerous patients in 91 percent of cases.

“This test has potential to provide a better balance of performance, cost-effectiveness, and patient compliance than other options currently available for colorectal cancer screening,” says Joost Louwagie, vice president of product development at OncoMethylome.

Louwagie hopes that with further testing and refinements the test will become more sensitive and provide fewer false-positive results. But he says that even a 77 percent sensitivity would be “very useful” if it were applied to the large numbers of people who decide not to have screening using more-intrusive methods. He stresses, however, that colonoscopies remain the gold standard for diagnosing the disease.

Ernst Kuipers, head of the colorectal screening program and a professor of medicine at Erasmus University Medical Center in Rotterdam, praises the results. “This is an excellent new method, technically very well done,” he says. “It represents a major advance on what we have now.”

Kuipers says the 77 percent accuracy in detecting cancer-containing samples is “a good result.” In comparison, the fecal-immunological screening method that he has been researching is around 60 percent accurate. He notes, however, that the specificity of the blood test–its ability to correctly identify healthy patients–will need to improve. “In practice, everyone over 55 would be screened, perhaps every two years,” he says. “That’s millions of people. So, if you had more than 5 percent false-positive rates, the number of follow-up colonoscopies you’d need to do would become too great.”

Kuipers says that the specificity of the test needs to be at least 95 percent for it to be used in colorectal screening and that a large-scale evaluation will be vital.

With this in mind, Louwagie and colleagues are enrolling people in a prospective colorectal screening study at several German colonoscopy centers. “We plan to complete enrollment of 7,000 people by the end of 2009,” he says.

The trials should also shed more light on how effective the test is at detecting the very earliest stages of colorectal cancer. Such a gene test will not be able to spot precancerous polyps. But it could be particularly effective if it can detect stage-one and stage-two colorectal cancers, which are almost always curable with surgery.

A new paper by Kuipers, due to appear in Journal of the National Cancer Institute, will provide new evidence that colorectal screening can ultimately save health services money, he says. But he believes that the most important measure will be a reduction in the number of colon cancer deaths. Kuipers notes that older, repeat-stool type testing, which was considered ineffective and not very sensitive, has been shown to have cut colorectal cancer deaths by 15 percent. He says that a reasonably sensitive and simple test with higher compliance levels could prevent many more colon cancer deaths.

Inactivated vaccine was more efficacious than live-attenuated vaccine in healthy adults 

Two types of seasonal influenza vaccines are currently licensed: an inactivated formulation, injected intramuscularly, and a live-attenuated formulation, administered by intranasal spray. Now, results from a double-blind trial conducted in Michigan during the 2007-2008 influenza season (and supported in part by the inactivated vaccine’s maker) shed light on the comparative efficacy of these preparations in healthy adults. During that season, influenza A (H3N2) viruses predominated, with a slight antigenic drift from the vaccine strain.

A total of 1952 healthy adults aged 18 to 49 were randomly assigned to receive inactivated vaccine or matching intramuscular placebo, or live vaccine or matching nasal-spray placebo, in a 5:1 vaccine:placebo ratio. Throat-swab specimens were collected from individuals who developed influenza symptoms; culture, PCR, or both were used to confirm the diagnosis.

During the study period, 119 participants (6%) had laboratory-confirmed influenza; 91% of these cases involved influenza A. Efficacy was 68% for the inactivated vaccine and 36% for the live-attenuated preparation, compared with placebo. The inactivated vaccine was 50% more efficacious than the live-attenuated one.

Comment: Interestingly, these results in healthy adults are opposite those seen in young children. The authors speculate that the live-attenuated viruses may be unable to infect some adults because of these individuals’ past exposure to similar strains. Of note, efficacy against influenza B could not be assessed because the circulating influenza B viruses were not included in the vaccine.

Lynn L. Estes, PharmD

Published in Journal Watch Infectious Diseases September 23, 2009

Citation(s):

Monto AS et al. Comparative efficacy of inactivated and live attenuated influenza vaccines. N Engl J Med 2009 Sep 24; 361:1260.

Research News from the Howard Hughes Medical Institute

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Howard Hughes Medical Institute, September 24, 2009, by Joseph W. Thornton PhD  —  New research demonstrates that in evolution, proteins can’t go home again –

at least not by their original route. Scientists have long debated whether

natural selection could loop back on itself, allowing an organism to revert to

its ancestral form. Now, by analyzing the molecular evolution of a hormone

receptor found in virtually all vertebrates – the glucocorticoid receptor (GR)

– Howard Hughes Medical Institute researchers have concluded that protein

evolution is irreversible.

 

Joseph W. Thornton, a Howard Hughes Medical Institute (HHMI) early

career scientist at the University of Oregon who led the study, says the results

suggest that evolution acts as an “epistatic ratchet” – meaning the molecular

tinkering that leads to new features in an organism turns, like all ratchets, in

only one direction.  “Our work. . . implies that the biology we have today is just one

of many possible rolls of the evolutionary dice.”

 

– Joseph W. Thornton

Thornton and his colleagues, Jamie Bridgham of the University of Oregon

and Eric Ortlund of Emory University, published their study in the September

24, 2009, issue of the journal Nature.

 

The human GR makes us exquisitely sensitive to the steroid hormone

cortisol, which regulates our response to long-term stress, including changes

in metabolism, immune defenses, and even aspects of memory formation in

the brain.

 

GR is the sister gene of a very similar hormone receptor, the

mineralocorticoid receptor (MR), which responds to different hormones to

regulate salt levels in the body, controlling blood pressure and cardiovascular

health. GR and MR genes are duplicates of a single ancestral gene that last

existed more than 450 million years ago in an ancient vertebrate. The ancient

protein encoded by that gene (AncCR, for ancestral corticoid receptor) was a

less discriminating molecule than the modern GR, says Thornton, and could

be activated by both cortisol and mineralocorticoids.

 

Thornton can speak so authoritatively about this ancient protein because he

has it in his lab’s freezer. His research group “resurrected” the AncCR by

combining computational analysis of gene sequences with biochemical

methods for synthesizing DNA and expressing proteins. First, Thornton

determined the sequence of the ancestral gene by analyzing the receptor

sequences of hundreds of modern vertebrates using a bioinformatics method

called maximum likelihood phylogenetic analysis. Working his way back

down the gene’s family tree, he identified the signature genetic changes

where intermediary forms of the receptor branched off and followed the most

likely conserved genetic sequence all the way back to the earliest common

ancestor.

 

With the probable AncCR sequence in hand, Thornton’s research group

synthesized the gene from scratch and expressed the ancient protein in cells

grown in the laboratory. They then used cutting-edge techniques to

characterize the structure and function of the receptor — tearing it apart and

rearranging it to see how it folds into a functional protein and what hormones

regulate its activity.

 

Once he knew that the GR’s ancestor responded to a wide range of hormones,

Thornton wanted to determine precisely how and when the modern protein’s

unique sensitivity to cortisol evolved. Moving up the phylogenic tree from

the duplication that produced the GR lineage, his group resurrected additional

ancestral receptors. They identified the very last one that functioned like

AncCR and the first one to work like a modern GR. Thornton calls those

ancient receptors AncGR1 and AncGR2. AncGR1 existed about 450 million

years ago in the ancestor of all jawed vertebrates. “That’s the last common

ancestor of you and a shark,” Thornton says. AncGR2 represents the GR

about 40 million years later in the ancestor of all vertebrates with bones —

“the last common ancestor of you and a salmon,” he says.

 

Thornton found his “epistatic ratchet’ in that 40-million-year gap. His first

step was to identify the mutations that caused AncGR2 to evolve its new

function during that interval. He found that seven historical amino acid

changes, when introduced into AncGR1 by DNA engineering, were sufficient

to recapitulate the evolution of cortisol specificity. His group also determined

the order in which the seven mutations had to have occurred to make the

receptor more sensitive to cortisol, while preserving the function of

intermediate forms of the receptor.

 

But when the team’s experiments began to go backward in evolutionary time,

they hit an unexpected evolutionary brick wall. When Bridgham, a research

scientist in Thornton’s laboratory, manipulated AncGR2 to reverse the seven

key mutations, she could not recreate a receptor with the more general

function of AncGR1. Surprisingly, the ancestral states at these mutation sites

had become lethal, yielding a non-functional protein that would not respond

to any hormones. Changing the order of reversed mutations led nowhere,

which led Thornton to the concept of the epistatic ratchet. “During evolution,

the conditions that facilitated the evolution of past states are destroyed as new

states are realized,” he explained.

 

To determine why evolution had become irreversible, Thornton looked to the

other mutations that had occurred between AncGR1 and AncGR2. Ortlund,

his collaborator, determined the atomic structures of the resurrected proteins

using X-ray crystallography. By comparing the two structures, Thornton’s

group identified five additional mutations in AncGR2 which would cause

clashes between atoms, destabilizing the protein and making it unable to

function properly, if the rest of the structure were returned to its ancestral

state. And indeed, once these five mutations were set back to their ancestral

states, the protein could then tolerate reversal of the seven key mutations,

yielding a protein with the ancestor’s broad sensitivity. When introduced into

AncGR1 in the forward direction, however, the five “restrictive” mutations

had virtually no impact on the protein’s function.

 

Based on these experiments, protein evolution seems irreversible, says

Thornton. Although the five restrictive mutations must be reversed before the

seven key mutations, reversing those five alone either destroys the receptor’s

function or has no effect, depending on the order in which they are

introduced. Backward evolution would therefore require at least five initial

steps that natural selection would be powerless to drive. Instead, Thornton

says, selection would have to drive the protein to some adaptive state

different from its past.

 

As an organism moves forward in evolutionary time and adapts to new

opportunities or threats, a host of random genetic mutations cause subtle

changes to the structures of its proteins. Some of these rearrangements, like

those Thornton studied, are “restrictive” in blocking the path back to older

states, while others are “permissive,” opening up paths to new functions that

were previously inaccessible. The process is incremental, mutation after

mutation, but cumulative in that once a new organism “works,” the restrictive

mutations can’t be undone without crashing the chain. The evolutionary

bridge back to earlier states gets burned.

 

Thornton points out that his epistatic ratchet touches on the hotly debated

question of whether evolution is driven by contingency or by determination.

That is the granddaddy of all evolutionary arguments–was the evolution of

Homo sapiens an inevitable outcome or a happy accident?

 

Thornton believes that the epistatic ratchet concept he observed in

glucocorticoid receptor evolution supports the argument for contingency.

“Our work suggests that the outcomes of evolution depend crucially on

low-probability chance eventson where an evolutionary trajectory starts and

where it happens to wander along the way,” Thornton says. “It implies that

the biology we have today is just one of many possible rolls of the

evolutionary dice.”

 

Joseph W. Thornton, Ph.D, HHMI Early Career Scientist

 University of Oregon

by Mehmet Oz, MD and Michael Roizen, MD |

You can add color to your next dinner party by inviting the eccentric with the orange hair who lives two doors down. Or you can do it in a far quieter and healthier way: By bringing winter squash to the table. This golden-orange vegetable helps you live longer and better (even if it won’t offer to do the dishes). Here’s just part of its healthy resume:

It reduces the rate at which your arteries age. Varieties such as acorn and butternut are high in potassium, which is part of what makes your nerves and muscles contract when you want them to. It also helps regulate blood pressure, allowing your heart and kidneys to function properly. One cup of cubed squash contains almost 900 milligrams of this mineral, which gets you a long, tasty way toward the 3,000 milligrams a day we recommend.

It keeps your knees (and hips) moving. Winter squash is high in beta cryptoxanthin (you don’t have to spell it; just eat it) and vitamin C, two nutrients credited with helping save joints.

It helps control your appetite. Squash is low in calories (if you don’t douse it in butter and brown sugar, which you don’t need for great taste) and high in fiber, so you eat fewer calories and feel full longer.

Our favorite ways to get it on your plate:

  • Serve it as a side dish. Puree butternut squash with a bit of olive oil, lime juice, and nutmeg.
  • Add cubed or mashed squash to stews, casseroles, and stir-frys.
  • Cut it into the shape of french fries. Mix with a lot of garlic and a little olive oil and then roast in the oven.

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Michael F. Roizen, MD

Michael F. Roizen, MD, is cofounder of RealAge, chief wellness officer at the Cleveland Clinic, and chairman of the RealAge Scientific Advisory Board. Dr. Roizen’s first consumer book, RealAge: Are You as Young as You Can Be?, was a New York Times #1 best-seller and has been translated into more than 20 languages. He has also edited multiple medical journals and coauthored many other books. Most recently, he and Mehmet C. Oz, MD, teamed up to produce their best-selling YOU books, which include YOU: The Owner’s Manual, YOU: On a Diet, YOU: Staying Young, and YOU: Being Beautiful. In addition, Dr. Roizen hosts his own radio show and makes frequent TV appearances on everything from Good Morning America to PBS.

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Mehmet C. Oz, MD

Mehmet C. Oz, MD, is a member of the RealAge Scientific Advisory Board and vice chairman of cardiovascular services, Department of Surgery, Columbia University Medical Center. For several years, he has also been the health expert for The Oprah Winfrey Show. Beginning in the fall of 2009, he will host his own daily TV hour, The Dr. Oz Show. He has written more than 350 original publications, book chapters, abstracts, and books and has received several patents. In addition, he and Dr. Roizen have coauthored several New York Times #1 best-sellers, including YOU: The Owner’s Manual; YOU: On a Diet; YOU: Staying Young; and YOU: The Smart Patient, which he wrote on his own. Dr. Oz is the founder and chairman of HealthCorps, which is fighting to stem the crisis of child obesity.

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Lifting Fog
By Vicki France
09/23/09
Mt. Horeb, Wisconsin

A company is preparing human trials of a DNA-based, universal influenza vaccine

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MIT Technology Review, September 23, 2009, by Lauren Gravitz  —  The first doses of H1N1 flu (swine flu) vaccine are due to be shipped to hospitals around the country in the next few weeks–seven months after the virus strain was first identified. These vaccine doses will use either inactivated or weakened live viruses to prompt immunity–an approach that can fail if any of the live viruses is strong enough to replicate, or if the inactivated viruses have been killed beyond all immune recognition.

One biomed company is working to completely revolutionize how vaccines are produced and applied. As Inovio CEO Joseph Kim will describe at the EmTech@MIT 2009 conference on Wednesday, the group is developing a vaccination that could someday protect against all flu strains simultaneously– including avian and swine flu–in one shot. The first human trials are set to begin next year.

The flu virus manages to temporarily evade our immune systems year after year because it mutates so quickly. To fight off the most virulent strains as they emerge, researchers have to change the vaccine every year. Today, most influenza vaccines are grown in chicken eggs, a process that takes six months or more, and they only protect against a few strains of flu–whichever ones experts believe will be circulating during the next flu season.

Inovio hopes to swap this arduous process for one that involves a DNA-based vaccine. With this approach, small bits of DNA that are found in every human flu virus are engineered to be taken up by cells, thereby prompting the cells to produce antibodies against different strains of viral invaders in order to marshal the appropriate immune response.

“We felt it was time for a change. Having to guess at which strains to protect society against for the coming fall is a very antiquated system, with very small room for error,” says Kim, who is also a 2002 TR35 Young Innovator. “We don’t accept that for any other vaccine protocol. You don’t change the measles-mumps-rubella vaccine every year.”

DNA vaccines can be quickly modified, are cheap to produce, and have a much longer shelf life than traditional vaccines. But they suffer from one large drawback: typical injections result in very little DNA being taken up by cells. Inovio is working on that problem by combining vaccines with a technique called electroporation, which delivers a tiny electric shock right after injection. The shock momentarily disrupts cell membranes and enhances DNA uptake.

To create the DNA vaccines, Inovio uses a platform it calls SynCon–short for “synthetic construct.” Using genetic data and complex algorithms, the company has developed a process for designing consensus genes–synthetic ones that look similar enough to components from a variety of viruses, eliciting an immune response broad enough to fight off different strains of the same disease. Inovio’s system identifies the amino acids that are most often present in each position of a few of the virus’s most important genes, then strings these together to create an antigen that induces immunity to a virus with any of these genes.

“To me, it’s a wonderful advance,” says Tom Edgington, an immunologist and professor emeritus at Scripps Research Institute in San Diego. “With DNA vaccines, there is no issue about having a live particle in there anywhere. You can make very large amounts of DNA and keep it for years, and you don’t have to infect a half-million eggs every year.”

The H in H1N1 stands for hemagglutinin, the virus’s outer protein and one that human immune systems respond to. There are 15 known versions of the protein, only five of which are specific to human disease. So by targeting these hemagglutinin proteins, Inovio’s system should, at least in theory, be effective not just for seasonal flu, but for avian (H5N1) and swine (H1N1) flu as well. “There’s nothing magical about swine H1N1 versus seasonal flu,” Kim says. “It’s just a divergence from what your body has been exposed to, and looks different enough to the immune system to evade it.”

In animal tests, this certainly seems to be the case. The company has tested the H1 component of the vaccine in mice infected with the virulent, epidemic-causing 1918 version of the H1N1 virus. The vaccine prevented any visible symptoms in inoculated mice, while every single one of the nonvaccinated mice died.

Of course, putting something as novel as an electroporation vaccine into widespread use could prove difficult especially because it requires its own technology, which is currently expensive. “If you have to do electroporation, that could potentially be a difficult thing to implement, certainly more difficult than spraying something up someone’s nose,” says Greg Poland, director of the Mayo Clinic’s Vaccine Research Group, in Rochester, MN. (This is how live, weakened-virus flu vaccines are currently administered; inactivated-virus vaccines are given with the classic needle and syringe.)

As far as the vaccine itself goes, most of the experts are in agreement. “The idea is a very good one, the need is a great one, and any company that would make a dent into this would certainly be a winner,” says virologist Peter Palese, head of the microbiology department at Mount Sinai School of Medicine, in New York City. But, although the company’s animal studies are an improvement over earlier DNA vaccination results, he notes that “the proof of the pudding will lie in human trials.”

Inovio has tested its H1 and H5 components in animals, and the group hopes to start human trials of the H5 component in early 2010. H1 tests, they believe, are just a short distance behind. “We think it would likely take two shots, a month apart, and then a booster every five years,” Kim says.

Inovio isn’t limiting itself to influenza, either. It has an HIV vaccine in development and is also working to create vaccines for diseases that are of greater concern in developing countries: malaria and dengue are at the top of the list. In contrast to the $20 billion flu-vaccine market, though, “such vaccines hold promise but will never even start to pay for themselves,” says Scripps’s Tom Edgington. “It’s a long path to something that helps the public and changes the world.”

NexBio(R) Presents DAS181 (Fludase(R)*) Potently Inhibits Novel Swine-Origin A(H1N1) and NAI-Resistant Influenza Viruses, at ICAAC 2009

SAN DIEGO, Sept. 15 /PRNewswire/ — NexBio, Inc. announced today the
presentation of two studies of DAS181 activity against H1N1 influenza and
NAI-resistant influenza at the 2009 Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC) meeting on Sunday, September 13, 2009, in San
Francisco, CA.  The work was performed in collaboration with researchers at
the Centers for Disease Control and Prevention (CDC), University of Hong Kong,
and Saint Louis University.

DAS181 (Fludase(R)) is an investigational broad spectrum drug candidate being
evaluated in human clinical development for treatment and prevention of
Influenza-Like Illness caused by all strains of influenza and parainfluenza.
Unlike neuraminidase inhibitors (NAI), e.g. Tamiflu(R), which directly target
the influenza virus (“pathogen target”), DAS181 works by inactivating the
human receptor (“host target”) for these viruses; thus, it may be less likely
to encounter acquired resistance compared with currently-available antiviral
drugs. Extensive, prolonged nonclinical influenza studies have not shown the
development of any meaningful resistance. This approach may have advantages
over mono-therapy or combination therapy which directly target the pathogen.
Previously announced preclinical studies conducted in collaboration with the
CDC and others have shown DAS181 to have significant therapeutic and
prophylactic activity in in vivo animal models and in human ex vivo lung
tissue for a highly virulent H5N1 (A/VN/1203/04) strain of influenza.

A “Late Breaker” presentation, entitled “Novel Swine-Origin A (H1N1) Influenza
Viruses are Potently Inhibited by DAS181, a Sialidase Fusion Protein” examined
in vitro, ex vivo, and in vivo models to evaluate the activity of DAS181
against multiple human novel 2009 influenza A/H1N1 viruses (Novel H1N1 or
“Swine Flu”).  The data presented at the meeting suggested that DAS181
exhibited potent inhibitory activity against these Novel H1N1 viruses in these
different models. 

The related presentation, entitled “In Vivo and In Vitro Activity of DAS181
Against NAI-Resistant Influenza Virus” examined the in vivo and in vitro
activity of DAS181 against patient isolates of community-acquired seasonal
influenza from the 2008-2009 influenza season.  All isolates had the H274Y
mutation associated with resistance to Tamiflu.  DAS181 in vitro was an
effective inhibitor of Tamiflu-resistant influenza virus.  In addition, in
vivo mouse challenge studies with another NAI-resistant strain demonstrated
strong sensitivity to DAS181 treatment.

Both studies are presented by Ronald Moss M.D., Executive Vice President,
Clinical Development and Medical Affairs.  “Based on these encouraging data we
are moving forward with our ongoing clinical development of DAS181, and we
will continue to work closely with FDA, CDC, and NIH on this clinical program
during the current pandemic,” stated Dr. Moss. “Because of viral evolution,
alternatives to current treatment strategies are needed to deal with potential
drug resistance. DAS181 may play an important role for public health
preparedness during influenza pandemics.”

ABOUT NEXBIO

NexBio, Inc. is a privately held clinical-stage biopharmaceutical company
located in San Diego. NexBio’s mission is to save lives and to improve the
quality of life by creating and commercializing novel, broad-spectrum
biopharmaceuticals to prevent and treat current and emerging life-threatening
diseases. DAS181 (Fludase(R)), a recombinant fusion protein, inactivates viral
receptors on the cells of the human respiratory tract, thereby preventing and
treating infection by influenza, including potential pandemic strains, and by
parainfluenza viruses (which may cause serious respiratory illness similar to
influenza and for which there is no approved vaccine or therapeutic).  The
DAS181 development program is funded by the National Institute of Allergy and
Infectious Diseases (NIAID), part of the National Institutes of Health, under
BAA Contract HHSN266200600015C and grant U01-AI070281. ViradinTM, invented and
developed by NexBio, is a parenteral protein under development, currently at
lead optimization stage, directed to the treatment of viral hemorrhagic fevers
and bacterial biothreat sepsis.  TOSAPTM is a technology invented and
developed by NexBio and is used to formulate DAS181 for inhalation, as well as
to make nano/microparticles from virtually any type of molecule.  TOSAPTM is
offered for the formulation of compounds of partners, under license.

For more information about NexBio, Inc., please visit http://www.nexbio.com

* FDA has yet to approve the name Fludase.

DISCLOSURE NOTICE:
This release contains forward-looking information about the research and
development program of NexBio and the potential efficacy of product candidates
that might result from programs that involve substantial risks and
uncertainties. Such risks and uncertainties include, among other things, the
uncertainties inherent in research and development activities; decisions by
regulatory authorities regarding whether and when to permit the clinical
investigation of or approve any drug applications that may result from the
programs as well as their decisions regarding labeling and other matters that
could affect the commercial potential of product candidates that may result
from the program; and competitive developments

20090924-1

Many bacteria produce various D-amino acids (the mirror images of the more common L-amino acids) to govern the chemistry of their cell walls. The illustration shows the mirror image forms of L- and D-methionine with Vibrio cholerae, the cause of cholera. 

Howard Hughes Medical Institute, September 22, 2009, by Matthew K. Waldor MD, PhD  —   The insides of cells are swimming with amino acids, essential chemical building blocks of life. But flip one of these molecules around, so that it is a mirror image of its former self, and the cell will take notice. New research from Howard Hughes Medical Institute (HHMI) scientists indicates that in the overwhelmingly “left-handed” world of amino acids, the “right-handed” versions of a few of these molecules act as signals that can spur bacteria to adapt to changing environmental conditions.

Amino acids are best known as the building blocks of proteins, which themselves form the biological machinery of all cells. The 20 amino acids that make up proteins each consist of four clusters of atoms branching out from a central carbon atom, like fingers around a palm. These chemical side chains can be arranged clockwise or counterclockwise-orientations chemists call “D” and “L.” Just like left and right hands, a D-amino acid has precisely the same “fingers” as its L counterpart, but is a mirror image.

This difference is biologically crucial, since amino acids interact with molecules that are very sensitive and can recognize only one of the two orientations. In the biological world, this is almost always the L form. No one knows for sure why D-amino acids are scarce, but one possibility is that a chance occurrence established this orientation bias billions of years ago, in the common ancestor of modern life.

HHMI investigator Matthew Waldor and his colleagues found that certain bacteria convert specific amino acids to their D forms when it is time to slow growth. When these D-amino acids are released into the environment, they change the way nearby bacteria construct their cell walls. Waldor and his colleagues published their findings in the September 18, 2009, issue of the journal Science.

Waldor’s lab at Brigham and Women’s Hospital studies microorganisms that cause disease in the human gastrointestinal tract. Nearly all such bacteria, including those that cause cholera, Vibrio cholerae, are shaped like bent rods. Curious whether this common shape has anything to do with the microbes’ virulence, Waldor’s team had been looking for gene mutations that would cause these bacteria to assume a different shape. Eventually, they succeeded when they found that bacteria carrying a mutation in a gene called mrcA had both rod-shaped and spherical forms.

Vibrio cholerae begins life with a period of exponential growth, then stops growing and becomes stationary before dividing again. The mutant cholera strain the group had stumbled upon looked like normal, bent-rod cholera during its exponential growth phase, but became spherical in the stationary phase. Waldor and his colleagues were surprised to discover that the bacteria appeared to be releasing some substance into their own environment that triggered this shape change.

Bacteria are protected by a cell wall made of a strong, elastic polymer called peptidoglycan which determines a bacterium’s shape. Inserting additional polymer elements allows a cell to expand, and conversely, when a cell stops growing, it can slow peptidoglycan synthesis to conserve resources. According to Waldor, researchers had long been puzzled as to how peptidoglycan production and assembly were regulated, because these processes take place in a space external to the inner membranes, away from the main compartment of the cell – the cytoplasm – where nearly all regulatory factors reside.

When the team realized their morphing cholera mutant might hold clues to how peptidoglycan synthesis is regulated, they refocused their research and set out to identify the factor triggering the shape change. They began by taking a closer look at the type of molecules floating in the cells’ culture medium, and discovered the presence of some unusual amino acids: the D forms of the amino acids methionine and leucine.

They found that cholera bacteria use an enzyme called a racemase to create large quantities of D-methionine and D-leucine from their L counterparts. The racemase inhabits the cell’s periplasmic space between the inner and outer membranes, and begins synthesizing D-amino acids when the cell stops growing, the team found. The D-amino acids then alert the cell’s wall-building proteins to slow their production of peptidoglycan, as demand has waned.

The team constructed a mutant that does not produce the racemase, and therefore could not manufacture the D-amino acids. So when they stopped growing, their walls continued to expand. They contained more — but weaker — peptidoglycan chains that left the cells 20 times more likely to rupture than normal rod-shaped cells. Waldor says this indicates that D-amino acids serve as a check on peptidoglycan production. “Our work suggests this is a new fundamental [regulatory] mechanism,” he says.

The importance of D-amino acids doesn’t end there, adds Hubert Lam, a co-author and postdoctoral researcher in Waldor’s lab. After examining the cholera bacteria, the team looked for the actions of D-amino acids in other species. They turned to Bacillus subtilis, a commonly studied bacteria that is far from V. cholerae on the evolutionary tree. They found evidence that the presence of D-amino acids reduced peptidoglycan production in B. subtilis, as well. They speculate that D-amino acids may act as a signaling molecule between individual B. subtilis cells in a population.

“D-amino acids appear to be produced when bacteria are with other bacteria,” says Lam. Adding the D-amino acids to cultures of growing B. subtilis appeared to stop growth of their cell walls, suggesting that the molecules may serve as a sort of brake for population growth. As a population expands, bacteria may release D-amino acids essentially to let one another know they are there, and the population as a whole should slow growth to avoid consuming limited resources too quickly.

The team says there is still much to be learned. While it’s clear that D-amino acids affect the structure of the cell wall, the molecular mechanisms involved have yet to be worked out. In addition, there is a lot to be learned about amino acids’ potential role in signaling between individuals – or even between different species. According to Lam, “the sheer amount of D-amino acids being produced is very unexpected.” Producing so much of anything takes a lot of energy, and so evolutionarily, it must be important, he says. 

About Matthew K. Waldor, M.D., Ph.D, HHMI Investigator

 Brigham and Women’s Hospital

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Dr. Waldor is also Professor of Medicine and Microbiology at Harvard Medical School and an attending physician in infectious diseases at Brigham and Women’s Hospital, Boston. As an undergraduate at Yale University, he studied philosophy and biology. He carried out his doctoral work with Larry Steinman and received his M.D. and Ph.D. degrees from Stanford University. After an internal medicine residency at Brigham and Women’s Hospital and an infectious disease fellowship at Massachusetts General Hospital, he did postdoctoral research with John Mekalanos at Harvard University.

Matthew Waldor studies the evolution, cell biology, and pathogenicity of enteric bacteria that cause human disease.

For the full story, go to:  http://www.hhmi.org/news/waldor20090918.html

By Darrell G. Kirch and Edward D. Miller

WashingtonPost.com, September 22, 2009  —  Whatever version of health-care reform emerges, the legislation needs to address two problems with the health-care system: uncoordinated care among physicians, hospitals, and other providers; and a payment system that encourages often unnecessary care. Those of us on health-care’s front lines think that these problems can be addressed effectively in “Health-care Innovation Zones” (HIZ’s), proposed by Rep. Allyson Schwartz (D-Penn.) in a new bill.

In a Health-care Innovation Zone, a regional alliance consisting of an academic medical center, local hospitals, physicians and other health-care organizations coordinates and delivers the full spectrum of care in ways that reward quality. These Innovation Zones could also test new, more patient-centered models of care, such as the medical home and “accountable care organizations,” as well as new payment models that have the potential to vastly improve care and reduce costs.

At Johns Hopkins Medicine, one of the nation’s leading academic medical centers, the much-talked about theory of such new care and payment models is already being tested. The JHM alliance serves a large group of over 135,000 economically, medically and socially challenged Medicaid patients as well as close to 30,000 military beneficiaries and their families. Through a network of owned and contracted providers located across Maryland, and using tools such as predictive modeling, JHM has reduced expenditures for patients with highly complex medical needs and a history of substance abuse; reduced the total costs of caring for our patients with end-stage renal disease by 47 percent; exceeded national benchmarks on all measures of clinical quality for our dialysis population; reduced the odds of hospital admissions for patients at the end of life; and earned high patient satisfaction ratings across the state. Indeed, our member satisfaction for our military health plan is in the 98th percentile.

We believe that other academic medical centers, using all the tools that could be applied within a Health-care Innovation Zone, could achieve the same outcomes. Many academic medical centers already have aligned networks of faculty physicians and teaching hospitals. They already provide the full range of health services, from preventive care to the most complex. They already have cutting-edge technology and strong investments in health information technology. They already provide a disproportionate share of vital urban health services and nearly half of the nation’s hospital-based charity care. And because they work in partnership with one another, they can share what works — and what doesn’t work. In short, academic medical centers should serve as the anchors of Health-care Innovation Zones and contributors to the rational redesign of our health care system.

Darrell G. Kirch is president and CEO of the Association of American Medical Colleges. Edward D. Miller is dean of the medical faculty and CEO of Johns Hopkins Medicine.

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