TSRI researchers reveal how viruses incapacitate bacterial defense system

March 28, 2017 at 10:11 PM

Picture bacteria and viruses locked in an arms race.

For many bacteria, one line of defense against viral infection is a sophisticated RNA-guided “immune system” called CRISPR-Cas. At the center of this system is a surveillance complex that recognizes viral DNA and triggers its destruction. However, viruses can strike back and disable this surveillance complex using “anti-CRISPR” proteins, though no one has figured out exactly how these anti-CRISPRs work–until now.

For the first time, researchers have solved the structure of viral anti-CRISPR proteins attached to a bacterial CRISPR surveillance complex, revealing precisely how viruses incapacitate the bacterial defense system. The research team, co-led by biologist Gabriel C. Lander of The Scripps Research Institute (TSRI), discovered that anti-CRISPR proteins work by locking down CRISPR’s ability to identify and attack the viral genome. One anti-CRISPR protein even “mimics” DNA to throw the CRISPR-guided detection machine off its trail.

“It’s amazing what these systems do to one-up each other,” said Lander. “It all comes back to this evolutionary arms race.”

The new research, co-led by Blake Wiedenheft of Montana State University, was published recently in the journal Cell. If CRISPR complexes sound familiar, that’s because they are at the forefront in a new wave of genome-editing technologies. CRISPR (pronounced “crisper”) stands for “clustered regularly interspaced short palindromic repeats.” Scientists have discovered that they can take advantage of CRISPR’s natural ability to degrade sections of viral RNA and use CRISPR systems to remove unwanted genes from nearly any organism.

“Although CRISPR-Cas9 is the ‘celebrity’ CRISPR system, there are 19 different types of CRISPR systems, each of which may have unique advantages for genetic engineering. They are a massive, untapped resource,” said Lander. “The more we learn about the structures of these systems, the more we can take advantage of them as genome-editing tools.”

Using a high-resolution imaging technique called cryo-electron microscopy, the researchers discovered three important aspects of CRISPR and anti-CRISPR systems.

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First, the researchers saw exactly how the CRISPR surveillance complex analyzes a virus’s genetic material to see where it should attack. Proteins within the complex wrap around the CRISPR RNA like a grasping hand, exposing specific sections of bacterial RNA. These sections of RNA scan viral DNA, looking for genetic sequences they recognize.

“This system can quickly read through massive lengths of DNA and accurately hit its target,” said Lander. If the CRISPR complex identifies a viral DNA target, the surveillance machine recruits other molecules to destroy the virus’s genome.

Next, the researchers analyzed how viral anti-CRISPR proteins paralyze the surveillance complex. They found that one type of anti-CRISPR protein covers up the exposed section of CRISPR RNA, thereby preventing the CRISPR system from scanning the viral DNA.

“These anti-CRISPR proteins keep the bacteria from recognizing the viral DNA,” Lander explained. He called these anti-CRISPR proteins “exceptionally clever” because they appear to have evolved to target a crucial piece of the CRISPR machinery. If bacteria were to mutate this machinery to avoid viral attacks, the CRISPR system would cease to function. “CRISPR systems cannot escape from these anti-CRISPR proteins without completely changing the mechanism they use to recognize DNA,” he said.

Another anti-CRISPR protein uses a different trick. Based on its location and negative charge, the researchers believe this anti-CRISPR protein acts as a DNA mimic, fooling CRISPR into binding this immobilizing protein, rather than an invading viral DNA.

“These findings are important because we knew that anti-CRISPR proteins were blocking bacterial defenses, but we had no idea how,” said Lander.

The researchers believe this new understanding of anti-CRISPR proteins may eventually lead to more sophisticated and efficient tools for gene editing. Perhaps anti-CRISPR proteins can be used in CRISPR systems to swoop in to block gene editing — or researchers could degrade anti-CRISPR proteins to trigger gene editing. “That might work as an on-off switch for CRISPR,” Lander said.

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http://www.scripps.edu/news/press/2017/20170328lander.html

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Justice Department Joins Lawsuit Alleging Massive Medicare Fraud By UnitedHealth

The Justice Department has joined a California whistleblower’s lawsuit that accuses insurance giant UnitedHealth Group of fraud in its popular Medicare Advantage health plans.

Justice officials filed legal papers to intervene in the suit, first brought by whistleblower James Swoben in 2009, on Friday in federal court in Los Angeles. On Monday, they sought a court order to combine Swoben’s case with that of another whistleblower.

Swoben has accused the insurer of “gaming” the Medicare Advantage payment system by “making patients look sicker than they are,” said his attorney, William K. Hanagami. Hanagami said the combined cases could prove to be among the “larger frauds” ever against Medicare, with damages that he speculates could top $1 billion.

UnitedHealth spokesman Matt Burns denied any wrongdoing by the company. “We are honored to serve millions of seniors through Medicare Advantage, proud of the access to quality health care we provided, and confident we complied with program rules,” he wrote in an email.

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Burns also said that “litigating against Medicare Advantage plans to create new rules through the courts will not fix widely acknowledged government policy shortcomings or help Medicare Advantage members and is wrong.”

Medicare Advantage is a popular alternative to traditional Medicare. The privately run health plans have enrolled more than 18 million elderly and people with disabilities — about a third of those eligible for Medicare — at a cost to taxpayers of more than $150 billion a year.

Although the plans generally enjoy strong support in Congress, they have been the target of at least a half-dozen whistleblower lawsuits alleging patterns of overbilling and fraud. In most of the prior cases, Justice Department officials have decided not to intervene, which often limits the financial recovery by the government and also by whistleblowers, who can be awarded a portion of recovered funds. A decision to intervene means that the Justice Department is taking over investigating the case, greatly raising the stakes.

“This is a very big development and sends a strong signal that the Trump administration is very serious when it comes to fighting fraud in the health care arena,” said Patrick Burns, associate director of Taxpayers Against Fraud in Washington, a nonprofit supported by whistleblowers and their lawyers. Burns said the “winners here are going to be American taxpayers.”

Burns also contends that the cases against UnitedHealth could potentially exceed $1 billion in damages, which would place them among the top two or three whistleblower-prompted cases on record.

“This is not one company engaged in episodic bad behavior, but a lucrative business plan that appears to be national in scope,” Burns said.

On Monday, the government said it wants to consolidate the Swoben case with another whistleblower action filed in 2011 by former UnitedHealth executive Benjamin Poehling and unsealed in March by a federal judge. Poehling also has alleged that the insurer generated hundreds of millions of dollars or more in overpayments.

When Congress created the current Medicare Advantage program in 2003, it expected to pay higher rates for sicker patients than for people in good health using a formula called a risk score.

But overspending tied to inflated risk scores has repeatedly been cited by government auditors, including the Government Accountability Office. A series of articles published in 2014 by the Center for Public Integrity found that these improper payments have cost taxpayers tens of billions of dollars.

“If the goal of fraud is to artificially increase risk scores and you do that wholesale, that results in some rather significant dollars,” Hanagami said.

David Lipschutz, senior policy attorney for the Center for Medicare Advocacy, a nonprofit offering legal assistance and other resources for those eligible for Medicare, said his group is “deeply concerned by ongoing improper payments” to Medicare Advantage health plans.

These overpayments “undermine the finances of the overall Medicare program,” he said in an emailed statement. He said his group supports “more rigorous oversight” of payments made to the health plans.

The two whistleblower complaints allege that UnitedHealth has had a practice of asking the government to reimburse it for underpayments, but did not report claims for which it had received too much money, despite knowing some these claims had inflated risk scores.

The federal Centers for Medicare & Medicaid Services said in draft regulations issued in January 2014 that it would begin requiring that Medicare Advantage plans report any improper payment — either too much or too little.

These reviews “cannot be designed only to identify diagnoses that would trigger additional payments,” the proposal stated.

But CMS backed off the regulation’s reporting requirements in the face of opposition from the insurance industry. The agency didn’t say why it did so.

The Justice Department said in an April 2016 amicus brief in the Swoben case that the CMS decision not to move ahead with the reporting regulation “does not relieve defendants of the broad obligation to exercise due diligence in ensuring the accuracy” of claims submitted for payment.

The Justice Department concluded in the brief that the insurers “chose not to connect the dots,” even though they knew of both overpayments and underpayments. Instead, the insurers “acted in a deliberately ignorant or reckless manner in falsely certifying the accuracy, completeness and truthfulness of submitted data,” the 2016 brief states.

The Justice Department has said it also is investigating risk-score payments to other Medicare Advantage insurers, but has not said whether it plans to take action against any of them.

Categories: Cost and Quality, Courts, Health Industry, Medicare

Tags: CMS, Medicare Advantage

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Lead Poisoning’s Lifelong Toll Includes Lowering Social Mobility, Researchers Find

Cynthia Brownfield was lucky. When her daughter, then 2 years old, tested for high levels of lead in her blood, she could do something.

Brownfield, a pediatrician in St. Joseph, Miss., got her home inspected and found lead in the windows. She got them replaced and had her pipes fixed, too. Her daughter, now 12, was probably affected, says Brownfield. But quick action minimized the exposure. Her daughter is now a healthy, fully-functioning preteen.

“We were in the financial position where we could hire a plumber and change the windows,” she said. But others — even her own patients — may not be so fortunate. This reality may have implications even more far-reaching than generally accepted.

Findings published Tuesday in JAMA break new ground by suggesting the effects of childhood lead exposure continue to play out until adulthood, not only harming an individual’s lifelong cognitive development, but also potentially limiting socioeconomic advancement. Specifically, Duke University researchers tracked a generation of kids based on data collected through a nearly 30-year, New Zealand-based investigation known as the Dunedin Multidisciplinary Health and Development Study.

They studied the development of more than 1,000 New Zealanders born between April 1972 and March 1973. Because at that time gasoline still contained lead, exposure was common, creating a sizeable sample that included people across class and gender. More than half in that data set had been tested for lead-exposure at age 11, and the study tracked brain development and socio-economic status over the years — making for “a natural time” to use them to study lead’s health effects, said Aaron Reuben, a PhD candidate in neuropsychology at Duke University, and the study’s first author.

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By the time study participants reached age 38, a pattern emerged: Children who were exposed to lead early in life had worse cognitive abilities, based on how their exposure level. The difference was statistically significant. They were also more likely to be worse off, socioeconomically, than those who had not been exposed to lead. The study found that no matter what the child’s IQ, the mother’s IQ, or the family’s social status, lead poisoning resulted in downward social mobility. That was largely thanks to cognitive decline, according to the research.

“Regardless of where you start out in life, exposure to lead in childhood exerts a downward pull to your trajectory,” Reuben said.

Though this research was set in New Zealand, it offers insight into a problem experts said is fairly ubiquitous in the United States and across the globe. The CDC estimates that as many as half a million children between ages 1 and 5 had blood lead levels high enough to cause concern: 5 micrograms per deciliter and up. At least 4 million households across the country have children experiencing significant lead exposure.

Last year’s water crisis in Flint, Mich., brought lead exposure front and center as a public health concern. Meanwhile, a Reuters investigation published this winter found elevated lead levels in almost 3,000 communities around the country. The Centers of Disease Control and Prevention recently changed its guidelines to suggest that any childhood exposure to the chemical is harmful, and is pushing to get rid of lead poisoning in kids by 2020.

In the U.S., children at risk are typically poorer and racial minorities — in part because they more often live in older houses with lead paint. This is a stark difference from the research population, which tended to be white. However, because the study spanned a period of time in which lead was still used in gasoline, the lead exposure measured in the study spanned a wider class spectrum.

That adds greater consequence to these findings, many said.

“Kids who are poor, or who have some of these other social determinants of health that are negative — they end up with a double whammy. Whatever health consequences they have from being poor, those are added to the additional consequences of being exposed to lead,” said Jerome Paulson, an emeritus professor and pediatrician at George Washington University. Paulson has researched lead’s effects on children, although he wasn’t involved with this study.

“If you want to talk about ‘breaking out of poverty,’ kids who have lead exposure are probably going to have more difficulties,” he added.

That said, these conclusions aren’t perfect. For instance, the research doesn’t account any variation in how the children who were tested may have been previously exposed to lead, or how their continued lead exposure through adulthood may have differed. Those who worked in jobs like construction, for instance, may have had greater lead exposure than those in white-collar jobs, Paulson noted. But on the whole, he said, it makes a strong case for the long-term impact of childhood lead exposure.

Pennsylvania, Maryland and Massachusetts, which all have cities with concentrated areas of older housing, have identified lead poisoning as a major child health hazard. The CDC has also embraced “primary prevention” — testing homes for lead and removing it before people move in and risk exposure. But securing resources for lead testing, screening and abatement poses its own set of challenges.

The JAMA study illustrates, in part, one such difficulty. Lead poisoning happens over years, not overnight. So illustrating the impact, even if it’s ultimately significant, is hard to do.

“Prevention doesn’t have a lot of pizzazz. If you prevent something from happening, it’s a wonderful thing, but it’s hard to measure and take credit for,” said David Bellinger, a neurology professor at Harvard Medical School and a professor in the environmental health department of the university’s public health school, who wrote a commentary that ran alongside the JAMA paper.

And funding for such programs is often unreliable, said Donna Cooper, the executive director of Public Citizens for Children and Youth, a Pennsylvania-based nonprofit that advocates on behalf of young people. For instance, the White House’s initial budget plans would boost some lead abatement funds but slash other grants used for similar purposes. And for many states, she said, even what’s long been available isn’t enough to meet the scope of the concern.

“We have very clear CDC guidance on what should be done, and no money to back it up,” Cooper said. “It ebbs and flows with the headlines.”

Categories: Public Health

Tags: Children’s Health, Disparities, Study

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