Author Archives: Kevin Jiang

Bioengineered kidney makes urine after transplantation

Posted on by
Reply

Here’s research that could take the piss out of disease—and it’s no joke. For the first time, scientists reporting in Nature Medicine have created lab-grown kidneys in rats that produce urine after transplantation.

If the work can be replicated in humans, patients suffering from end-stage kidney disease could one day have “an organ that’s grown on demand—a tailored organ that can be transplanted and replaces the failing organ,” says study author Harald Ott, a bioengineer at the Massachusetts General Hospital in Boston.

Stem cell tracking system promises more targeted regenerative therapies

Posted on by
Reply

Ultrasound MachineStem cells hold enormous potential for repairing or regenerating damaged tissue. But delivery of these cells to their target location remains a major obstacle. Now, researchers at the Stanford University School of Medicine in California have developed a novel nanoparticle-based system that allows stem cells to be tracked in real time in a living mouse for up to a year after injection. This work, if replicated in humans, could finally allow scientists to verify if these cells are going where they’re intended.

“Delivering stem cells to specific tissues is a very big challenge, since basically all investigators have to shoot blindly,” says Sanjiv Gambhir, director of Stanford’s molecular imaging program who led the work published online today in Science Translational Medicine. “For these cell therapies to succeed, you need imaging systems.”

Gambhir and his team started with a type of nanoparticle already used in clinical trials to guide cancer drug delivery. They then attached two imaging agents to the nanoparticle: gadolinium, a contrast agent picked up by magnetic resonance imaging (MRI), and a fluorescent compound called fluorescein. Although the resulting composite nanoparticle was less than a micron in diameter, it aggregated once absorbed by a cell, making it large enough be imaged by ultrasound and MRI.

After injecting bone marrow stem cells labeled with these particles into the hearts of healthy mice, the researchers found that they could track the cells using a standard ultrasound device. The MRI contrasting agent allowed the team to monitor long term survival or deposition patterns of labeled stem cells without harming the animals. And when necessary, the fluorescent tag allowed for accurate post-mortem examinations as well. Nanoparticle imaging also demonstrated remarkable sensitivity, as the researchers were able to visualize as few as 75,000 stem cells with ultrasound, and a few hundred thousand with MRI.

Although the materials utilized in the study have already been used in clinical trials, Gambhir acknowledges that this new composite nanoparticle requires strenuous safety testing before it could be ready for human use. Still, he was encouraged by the finding that the nanoparticles did not affect stem cell differentiation or division.

The researchers first plan to test the system in larger animal studies with other populations of stem cells. Ghambir believes it could be ready for human testing within the next five years. “This enables cell therapy to understand why it’s failing. This allows you to connect the dots,” he says.

Check out the video of labeled stem cells being injected into a mouse heart below (stem cells circled in red):

Red blood cell production relies on white blood cell help

Posted on by
Reply


Red and white blood cellsRed blood cell production in the bone marrow is a precarious process. Too few RBCs and you can become anemic; too many and you could be suffering from polycythemia vera, a rare, so-called ‘myeloproliferative’ genetic disorder marked by an abnormally high RBC count. Now, researchers have identified a surprising player in the regulation of RBC production under these disease conditions. Reporting online today in Nature Medicine, two independent teams describe the pivotal role of macrophages—amoeba-like white blood cells responsible for digesting harmful foreign microbes and removing old or dying cells—for generating RBCs in both anemic and over-proliferative conditions.

In one study, geneticist Stefano Rivella and his colleagues at the Weill Cornell Medical College in New York administered a drug that selectively kills macrophages in a mouse model of polycythemia vera. In these mice, RBCs are generated at almost twice the normal amount, leading to viscous blood, enlarged organs and increased risk for strokes and heart disease. The drug, called clodronate, appeared to cure these symptoms, however, drastically lowering macrophage population and bringing RBC counts back to normal levels compared with a control group of animals treated with saline.

These findings were independently confirmed by Paul Frenette, a stem cell biologist at the Albert Einstein College of Medicine, also in New York. His team used a genetically modified mouse in which macrophages expressed a gene that made them vulnerable to a toxin and arrived at similar conclusions. “When we depleted macrophages in this disease, we actually corrected the disease,” Frenette says. “Maybe this could be a new therapy for this type of disease, which is unexpected.”

Continue reading →

Potential treatment for severe influenza found in Omega-3 fatty acids

Posted on by
Reply

shutterstock_129688976Omega-3 fatty acids, which have an important role in promoting healthy growth and development, have made headlines in recent years for, among other things, their possible cardiovascular benefits. Found in high levels in fish oil, these fatty acids are the most consumed non-vitamin or non-mineral supplement in the US. Now, researchers have discovered another potential use for these fat building blocks: using them as a treatment for flu.

In a study published today in Cell, a modified omega-3 fatty acid known as protectin D1 was found to markedly increase the chances of survival in mice with infected with various strains of influenza, including the H1N1 strain behind the 2009 ‘swine flu’ epidemic.

“The authors show for the first time that [protectin D1] actually disrupts replication of influenza,” says Charles Serhan, an anesthesiologist at Brigham and Women’s Hospital in Boston. “It provides a natural template for new therapeutic development.”

When given microgram doses of protectin D1 intravenously 12 hours before and immediately after infection with a strain of influenza A, three out of eight treated animals survived past a two-week end point; by comparison, all seven control counterparts died within eight days. Mice infected with the 2009 strain of H1N1 swine flu fared even better when treated in this manner—all six survived, compared with only two out of six in the group that received only a saline solution.

Protectin D1 given two days post-infection appeared nearly as effective in preventing death in mice as Peramivir, an intravenous anti-viral drug marketed by BioCryst Pharmaceuticals of Durham, North Carolina. Approved in Japan and Korea for treating severe flu, Peramivir did not move past phase III clinical trials in the US for efficacy, but was subject to an emergency FDA authorization in 2009 as a treatment for H1N1 swine flu.

Remarkably, while less than half of treated animals survived past two weeks on either therapeutic alone after infection with influenza A, none died after receiving protectin D1 and Peramivir in conjunction.

In a petri dish model using human lung cells, protectin D1 appeared to reduce the virulence of influenza by blocking the export of viral mRNA from a cell’s nucleus, according to the new study. This is reflected in a massive decrease in the infection rate of cells.

Derived from omega-3 fatty acids, protectin D1 is one of a family of similar fat molecules with apparent antiinflammatory and antibiotic properties. Naturally produced, these compounds are thought to play a protective effect in the lung, brain and other organs. This study is the first to demonstrate anti-viral qualities for these molecules, with protectin D1 showing the greatest efficacy.

“I see this as opening a whole new avenue of research,” says Serhan, who was the first to characterize protectin D1 in 2007. He notes that this could represent a new class of antivirals that work by both reducing excessive inflammation and by disarming replication of the virus. The risk for side effects could be low as well since “it’s a natural mechanism,” says Serhan.

Many questions remain as to protecin D1’s therapeutic potential in humans, as well as if these omega-3 fatty acid-derived molecules could treat other types of viral infections. Future clinical trials and research are needed to prove efficacy and safety, says Serhan. For now, he recommends not over-doing it with fish oil supplements, until scientists know more about the underlying mechanisms. “You don’t want to be deficient in [omega-3], but I wouldn’t go the other direction. There could be unwanted side effects.”

Image: Shutterstock

Competition intensifies over market for DNA-based prenatal tests

Posted on by
Reply

Prenatal DNA testing has been a fiercely contested market of late. Yet another competitor entered the fray last week when Natera, a startup based in San Carlos, California, announced the 1 March launch date of a commercial test that can detect chromosomal abnormalities in the developing fetus from just a drop of an expectant mother’s blood—and with a sensitivity on par of that of more invasive techniques such as amniocentesis and chorionic villus sampling, both of which carry an elevated risk of miscarriage.

Natera now joins three other California-based firms—Sequenom, Verinata Health (a division of sequencing giant Illumina) and Ariosa Diagnostics—in offering such products for women at high risk of having babies with Down’s syndrome or other chromosomal miscounts known as aneuploidies. With US health insurers, including Aetna and Wellpoint, saying they plan to cover the new tests, the market for DNA-based prenatal screening now provides “a billion dollar opportunity,” according to David Ferreiro, an analyst at Oppenheimer & Co. in Boston.

Between the four new tests, Verinata’s and Sequenom’s currently offer the widest range of screening options, with the ability to identify disorders associated with an extra X or Y sex chromosome, such as Klinefelter’s (XXY) and triple X syndrome. This flexibility is reflected in the cost: Sequenom’s MaterniT21 PLUS carries a list price of $2,762, almost twice as much as Natera’s Panorama, which can detect a missing X chromosome but not other kinds of sex chromosome irregularities.

The tests’ sensitivities vary depending on the chromosome, but all companies claim to be able to identify a fetus with Down’s syndrome, caused by three copies of chromosome 21, more than 99 times out of 100. Detecting extra copies of chromosome 13—a condition known as Patau’s syndrome—is more difficult, and Ariosa’s Harmony test does poorest here, with only 80% sensitivity. But it’s also the cheapest, with a sticker price of just $795 (see chart for the full comparison).

Noninvasive Prenatal Genetic Tests Compared{credit}Nature Medicine{/credit}

For now, the DNA-based tests are only thought to provide a screening tool for select populations, and are not considered definitively diagnostic by clinician groups such as the National Society of Genetic Counselors, who worry about the possibility of erroneous results, the lack of data in low-risk populations and the limited number of aneuploidies tested. Thus, most experts—and many of the companies themselves—still recommend that women whose DNA-based tests come back positive follow up with conventional tests such as amniocentesis. Although the additional testing will still mean invasive procedures for some pregnant women, and their attendant complications, “you are limiting those invasive tests to only the high risk groups,” says Joan Scott, a genetic counselor and executive director of the National Coalition for Health Professional Education in Genetics in Lutherville, Maryland.

Ultimately, “women and their providers [need to be] well informed about the benefits and limitations that are inherent in all these tests,” says Scott. “It’s not a cut and dried decision.”

A version of this story appears in the April 2013 issue of Nature Medicine.

US budget cuts imperil domestic and global biomedical research

Posted on by
Reply

{credit}Shutterstock{/credit}

In the medical world, the term ‘sequestration’ is usually preceded by the word ‘pulmonary’ or ‘splenic’ and is used to describe rare diseases that are the focus of research grants funded by the US National Institutes of Health (NIH). But sequestration has now taken on a new meaning.

On Friday (1 March), a series of sweeping federal budget cuts totaling more than a trillion dollars over the next ten years are scheduled to automatically go into effect unless a legislative bargain is reached—and their impact on biomedical research could be dire, with consequences felt both in the US and abroad.

“We are going to maim our innovation capabilities if you do these abrupt deep cuts at NIH,” former agency director Elias Zerhouni, now head of global R&D at the French drug company Sanofi, told the Washington Post. “It will impact science for generations to come.”

The NIH, already suffering through half-a-decade of stagnant funding, will receive a 5.1% cut across the board—a reduction of $1.5 billion from a total budget of $31 billion. Should this happen, the agency’s operation plan is straightforward: fewer projects will get new funding and existing ones will be supported at lower levels. “Cuts will result in slower progress against our most common diseases, such as Alzheimer’s, cancer, AIDS, diabetes and heart disease,” Francis Collins, the NIH’s current director, said at a press conference addressing sequestration last week.

United for Medical Research, a coalition of universities, biotech companies and research associations, estimates that cuts to the NIH budget could lead to 20,000 fewer jobs and a $3 billion economic impact this fiscal year. Potentially more troubling is the effect of sequestration on new researchers. Lower success rates for NIH grants, which have steadily declined since their peak in the early 2000’s, could stall the careers of young investigators. Even training grants, which fund graduate students at universities, are at risk of being cut, said Collins. “This is not a spigot you turn off and turn back on later. If we lose the talents of this up and coming generation, they’re not coming back,” he said.

Although the NIH is the single largest funding source for biomedical research, other agencies—including the Food and Drug Administration, the Agency for Healthcare Research and Quality, the Department of Defense, the Centers for Disease Control and Prevention, the National Science Foundation, and the Agency for International Development—would all receive sequestration cuts.

Combined, the US agencies are the largest funder of research in the world. Their significant contributions to global health and the potential harm sequestration could cause are highlighted in a report released today by the Global Health Technologies Coalition, a group of nonprofit organizations.

With the development of potential HIV preventatives, improved malaria drugs and other global health products, US government research funding has already saved millions of lives and provided economic benefits around the world. If the research pipeline were to be interrupted now, scientific regression, increased long-term costs and needless deaths would result, the report argues. “There is much to lose by pulling back now,” the authors write.

Injectable gel repairs damage after heart attack in pigs

Posted on by
Reply

Processed hydrogel floats in a beaker{credit}UC San Diego Jacobs School of Engineering{/credit}

As you read this sentence, on average at least one person in the US will have started to clutch her chest. The blood flow to her heart will become blocked and cardiac muscle cells will start to die off and get replaced with scar tissue. This person has just suffered a heart attack and most likely will go on to develop heart failure, a weakening of the heart’s ability to pump blood and oxygen. In five years time, there’s a 50/50 chance she’ll be dead.

There are currently no treatments that can repair the damage associated with this so-called ‘myocardial infarction’ (MI), but a potential solution is now showing promise in a large-animal model. Reporting today in Science Translational Medicine, a team of bioengineers at the University of California–San Diego (UCSD) has developed a protein-rich gel that appears to help repair cardiac muscle in a pig model of MI.

The researchers delivered the hydrogel via a catheter directly into the damaged regions of the porcine heart, and showed that the product promoted cellular regeneration and improved cardiac function after a heart attack. Compared to placebo-treated animals, the pigs that received a hydrogel injection displayed a 30% increase in heart volume, a 20% improvement in heart wall movement and a 10% reduction in the amount of scar tissue scar three months out from their heart attacks. “We hope this will be a game-changing technology that can actually prevent heart failure after heart attack,” says UCSD’s Karen Christman, who led the study.

Christman and her team developed their hydrogel by stripping muscle cells from pig hearts, leaving behind a network of proteins that naturally self-assembles into a porous and fibrous scaffold upon injection into heart tissue. They previously tested its safety and efficacy in rats, where they found increased cardiac function and no toxicity or cross-species reactivity.

Similar strategies using naturally-derived scaffolding, such as small intestinal submucosa from pigs in wound patching, are well established. The UCSD study now shows the clinical potential of this approach for cardiac regeneration after a heart attack in a large animal that more approximates humans. Christman has already formed a company based on the technology, called Ventrix, and she hopes to move the product into human safety trials within the year.

Jeffrey Karp, a bioengineer at the Brigham and Women’s Hospital in Boston who is working on a glue that can bind cardiac tissue in live rat and pig hearts (as reported in a news feature this month in Nature Medicine), believes this is promising technology. “Promoting regeneration following myocardial infarction is one of the holy grails in medicine,” he says.

But, Karp warns, “it will be important to validate these results in additional pre-clinical studies, and compare efficacy with other approaches prior to marching onward to the clinic.”

Check out the video for the production process of the hydrogel:

Biotech comes to its ‘antisenses’ after hard-won drug approval

Posted on by
Reply

“With any brand new technology, you never know when the world will be ready for it.” So said Paul Boni, an analyst at Punk, Ziegel & Knoll, in 1998 (as quoted by the New York Times), after the US Food and Drug Administration (FDA) approved its first gene-silencing ‘antisense therapy’, a drug known as Vitravene (fomivirsen), for the treatment of cytomegalovirus infections in individuals with weakened immune systems.

The arrival of Vitravene, a short strand of 21 DNA molecular units that blocks viral replication, was hailed as a major milestone for the biotech industry and was widely anticipated to usher in a new era of antisense products. But no more came. And by the middle of the last decade, Isis Pharmaceuticals, the Carlsbad, California–based company behind Vitravene, ended up pulling the therapy from the market because improvements in other antiretrovirals had effectively eliminated the drug’s target market. Boni’s cautionary words proved all too prescient.

Making antisense of the drug pipeline: Antisense therapies in mid- to late-stage clinical development.

Fifteen years after that first approval, however, antisense technology finally seems ready to make an impact. Late last month, Isis won approval for another antisense drug—Kynamro (mipomirsen), for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder in which the body lack the ability to remove ‘bad’ cholesterol from the bloodstream. The drug is now being marketed by the French giant Sanofi, and several other antisense products are currently in late-stage clinical development.

“This is the end of the beginning for antisense,” says Isis’s chief executive Stanley Crooke. “We feel this is a critical step in the final validation of the technology.”

First developed 35 years ago, the strategy of silencing genes by introducing short antisense stretches of DNA or other nucleic acids that are complementary to an mRNA target has proven useful in laboratory experiments, but translating the technology into the clinic has presented a challenge. For Kynamro, the key was a chemical alteration at both ends of the DNA strand. With this change, the product has an enhanced half-life, stronger affinity for its target RNA and a reduced proinflammatory side effect—all improvements in areas that have previously sunk antisense candidates in clinical testing.

This modification, Crooke says, “is the critical step that we took about 12 years ago, the product of thousands of tiny incremental steps.” Isis currently has 26 candidate antisense drugs in its preclinical and clinical pipeline for treating a range of cardiovascular, metabolic and other types of disorders—the vast majority of which incorporate this chemistry, including an antisense drug that rescued hearing in a mouse model of human deafness, as reported earlier this month in Nature Medicine.

Continue reading →

US report calls for international action in the fight against counterfeit drugs

Posted on by
Reply

Seized counterfeit Viagra {credit}Wikimedia Commons{/credit}

The distribution of counterfeit drugs represents a significant and ever increasing public health concern. Estimated to generate $70 billion in annual sales worldwide, fake or ineffective medications can harm or kill patients, increase legitimate medicine costs, fund criminal activity and even fuel drug-resistance in diseases such as tuberculosis and malaria.

Developing countries are disproportionately affected—researchers reported in The Lancet that more than a third of antimalarial drugs are falsified in sub-Saharan Africa, for example—but no country is immune. As recently as last Tuesday, the US Food and Drug Administration (FDA) issued yet another warning to healthcare providers in the country over batches of counterfeit Avastin (bevacizumab), the blockbuster cancer medication marketed by South San Francisco’s Genentech. This was the third such alert for Avastin in a year.

Although internationally acknowledged as a major public health problem, the fight against counterfeiting has been marred by issues of inconsistent regulatory responses, unclear solutions and even the ambiguity over definition of the term ‘counterfeit’. In response, the US Institute of Medicine, with funding from the FDA, released a report today detailing the scope of the problem and offering recommendations for solutions.

The committee emphasized the need for cooperation between international governments, big pharma companies and civil society groups, such as academia, non-governmental organizations and non-profits—all of which have had contentious relationships of late when it comes to combating counterfeits. (See our April 2010 ‘focus on counterfeit drugs’ for more.)

For example, some member states of the World Health Organization (WHO), including India and Brazil, have accused Western governments of being influenced by major pharmaceutical companies and attempting to use anti-counterfeit measures to stifle unpatented, unregistered or generic drug competition. Versions of these drugs with legitimate formulations represent the only affordable sources of medication in many low-income communities, and some are labeled as counterfeit even if they are neither fake nor ineffective.

“I was shocked in talking with all the stakeholders how deep the suspicion was, and how it caused really a harmful dynamic and lack of cooperation,” committee chair Lawrence Gostin, a global health legal scholar at the Georgetown University Law Center in Washington, DC, told Nature Medicine.

Continue reading →

Proposal to overhaul disease’s name could boost awareness and funding

Posted on by
Reply

{credit}Shutterstock{/credit}

There’s an idea in linguistics known as the Whorfian hypothesis. It proposes that language is inexorably linked with how we perceive and think about the world. The classic argument is this: an Inuit person, possessing different names for snow, has the ability to think about, and even see, subtle differences in snow that speakers of some other languages do not.

Could the same apply to biomedicine?

Last week, a panel convened by the US National Institutes of Health (NIH) released a series of recommendations about how best to study and diagnose a common hormonal disorder in women known as polycystic ovary syndrome (PCOS). At the top of their list: a call for a name change.

It might seem counterintuitive that a name could be critical to scientific investigation. After all, a disease such as PCOS, which affects one in ten women of reproductive age and is a major cause of infertility, is still just that—no more or less common, no more or less severe, regardless of the name. Still, the semantics of a particular moniker can have potential repercussions, from levels of research funding to how patients find the right doctor.

PCOS affects an estimated five million women in the US and encompasses a range of symptoms, including high levels of the male hormone androgen, insulin-resistance, an increased risk of type 2 diabetes, abnormal hair growth and growths on the ovaries. However, little is known about the underlying causal mechanisms of the disease. As a result, there are currently no cures, only treatments for symptoms. Combined with the fact that many women express only some of these symptoms, the diagnostic criteria for PCOS are still under debate.

A distraction and an impediment

Late last year, the NIH called for an independent panel—four experts not involved in PCOS research—to assess this issue. Over the course of the December 2012 workshop, the panelists soon came to a realization: “We believe the name ‘PCOS’ is a distraction and an impediment to progress.  It causes confusion and is a barrier to effective education of clinicians and communication with the public and research funders,” panel member Robert Rizza, executive dean for research at the Mayo Clinic in Rochester, Minnesota, said in a teleconference last week unveiling the committee’s findings.

After reviewing the current state of research and different diagnosing standards, Rizza and his colleagues concluded that the presence of “polycystic ovary”—which is actually a misnomer, as the numerous ‘cysts’ on the ovary are really immature eggs known as follicles—is not sufficient to diagnose PCOS. Some women with excess follicular growth show no signs of having the disease; others show some combination of symptoms but have no ovarian abnormalities.

In their report, the panelists agreed with the relatively-contentious ‘Rotterdam criteria‘, which require patients to have two out of three major symptoms—increased androgen levels, irregular periods, and “polycystic ovary”—for a diagnosis. Therefore, they wrote, “It is time to expeditiously assign a name that reflects the complex metabolic, hypothalamic, pituitary, ovarian and adrenal interactions that characterize the syndrome,” and not just focus on one particular symptom. But being outsiders to PCOS research, they declined to propose a new name.

“Our feeling was that this was the right time to rebrand,” panelist Timothy Johnson, chair of the department of obstetrics and gynecology at the University of Michigan Medical School in Ann Arbor, told Nature Medicine. “The new name would really make people think about the disease in a broader way, do research in a broader way and get a broader range of funding.”

Continue reading →