Researchers advance toward engineering ‘wildly new genome’

Contact: David Cameron david_cameron@hms.harvard.edu 617-432-0441 Harvard Medical School

In two parallel projects, researchers have created new genomes inside the bacterium E. coli in ways that test the limits of genetic reprogramming and open new possibilities for increasing flexibility, productivity and safety in biotechnology.

In one project, researchers created a novel genome—the first-ever entirely genomically recoded organism—by replacing all 321 instances of a specific “genetic three-letter word,” called a codon, throughout the organism’s entire genome with a word of supposedly identical meaning. The researchers then reintroduced a reprogramed version of the original word (with a new meaning, a new amino acid) into the bacteria, expanding the bacterium’s vocabulary and allowing it to produce proteins that do not normally occur in nature.

In the second project, the researchers removed every occurrence of 13 different codons across 42 separate E. coli genes, using a different organism for each gene, and replaced them with other codons of the same function. When they were done, 24 percent of the DNA across the 42 targeted genes had been changed, yet the proteins the genes produced remained identical to those produced by the original genes.

“The first project is saying that we can take one codon, completely remove it from the genome, then successfully reassign its function,” said Marc Lajoie, a Harvard Medical School graduate student in the lab of George Church.  “For the second project we asked, ‘OK, we’ve changed this one codon, how many others can we change?'”

Of the 13 codons chosen for the project, all could be changed.

“That leaves open the possibility that we could potentially replace any or all of those 13 codons throughout the entire genome,” Lajoie said.

The results of these two projects appear today in Science. The work was led by Church, Robert Winthrop Professor of Genetics at Harvard Medical School and founding core faculty member at the Wyss Institute for Biologically Inspired Engineering. Farren Isaacs, assistant professor of molecular, cellular, and developmental biology at Yale School of Medicine, is co-senior author on the first study.

Toward safer, more productive, more versatile biotech

Recoded genomes can confer protection against viruses—which limit productivity in the biotech industry—and help prevent the spread of potentially dangerous genetically engineered traits to wild organisms.

“In science we talk a lot about the ‘what’ and the ‘how’ of things, but in this case, the ‘why’ is very important,” Church said, explaining how this project is part of an ongoing effort to improve the safety, productivity and flexibility of biotechnology.

“These results might also open a whole new chemical toolbox for biotech production,” said Isaacs. “For example, adding durable polymers to a therapeutic molecule could allow it to function longer in the human bloodstream.”

But to have such an impact, the researchers said, large swaths of the genome need to be changed all at once.

“If we make a few changes that make the microbe a little more resistant to a virus, the virus is going to compensate. It becomes a back and forth battle,” Church said. “But if we take the microbe offline and make a whole bunch of changes, when we bring it back and show it to the virus, the virus is going to say ‘I give up.’ No amount of diversity in any reasonable natural virus population is going to be enough to compensate for this wildly new genome.”

In the first study, with just a single codon removed, the genomically recoded organism showed increased resistance to viral infection. The same potential “wildly new genome” would make it impossible for engineered genes to escape into wild populations, Church said, because they would be incompatible with natural genomes. This could be of considerable benefit with strains engineered for drug or pesticide resistance, for example. What’s more, incorporating rare, non-standard amino acids could ensure strains only survive in a laboratory environment.

Engineering and evolution

Since a single genetic flaw can spell death for an organism, the challenge of managing a series of hundreds of specific changes was daunting, the researchers said. In both projects, the researchers paid particular attention to developing a methodical approach to planning and implementing changes and troubleshooting the results.

“We wanted to develop the ability to efficiently build the desired genome and to very quickly identify any problems—from design flaws or from undesired mutations — and develop workarounds,” Lajoie said.

The team relied on number oftechnologies developed in the Church lab and the Wyss Institute and with partners in academia and industry, including next-generation sequencing tools, DNA synthesis on a chip, and MAGE and CAGE genome editing tools. But one of the most important tools they used was the power of natural selection, the researchers added.

“When an engineering team designs a new cellphone, it’s a huge investment of time and money. They really want that cell phone to work,” Church said. “With E. coli we can make a few billion prototypes with many different genomes, and let the best strain win. That’s the awesome power of evolution.”

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Funding was from Department of Energy [DE-FG02-02ER63445], NSF [SA5283-11210], NIH [NIDDK-K01DK089006], DARPA [N66001-12-C-4040, N66001-12-C-4020, N66001-12-C-4211], Arnold and Mabel Beckman Foundation, Department of Defense NDSEG Fellowship, NIH-MSTP-TG-T32GM07205, NSF graduate fellowship, NIH Director’s EarlyIndependence Award [Grant 1DP5OD009172-01], U.S. Office of Naval Research [N000141010144], Agilent Technologies, Wyss Institute, and Department of Defense NDSEG Fellowship, and Air Force Contract #FA8721-05-C-0002.

Written by JAKE MILLER

Harvard Medical School has more than 7,500 full-time faculty working in 11 academic departments located at the School’s Boston campus or in one of 47 hospital-based clinical departments at 16 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Cambridge Health Alliance, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital and VA Boston Healthcare System.

The Wyss Institute for Biologically Inspired Engineering at Harvard University uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, andCharité – Universitätsmedizin Berlin, the Institute crosses disciplinary andinstitutional barriers to engage in high-risk research that leads to transformative technological breakthroughs. By emulating Nature’s principles, Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing. These technologies are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and new start-ups. The Wyss Institute recently won the prestigious World TechnologyNetwork award for innovation in biotechnology.

Dzhokhar Tsarnaev’s wounds contradict original police arrest version

Джохар Царнаев Бостон террорист

Photo: EPA

Trauma surgeon Stephen Ray Odom, of Beth Israel Deaconess Medical Center, testified on April 22 that alleged Boston bomber Dzhokhar Tsarnaev suffered from a “high-powered injury” that resulted in wounds to the middle ear, the skull base, his vertebrae and his pharynx.

 A trauma surgeon detailed the suspect’s condition in a hearing the day the Chechen immigrant, who was lying in a Boston hospital bed, was first charged over the bombing attacks that killed three people and wounded about 264.

 Tsarnaev was arrested on 19 April, four days after the bombing attack, at the conclusion of a day-long lockdown of most of the Boston area that began when he and his older brother allegedly killed a police officer at the Massachusetts Institute of Technology, carjacked a man and engaged in a gunbattle in the suburb of Watertown that ended with 26-year-old Tamerlan Tsarnaev dead and Dzhokhar on the run.

 Police found the younger Tsarnaev hiding in a boat in a backyard.

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 Tsarnaev also sustained multiple wounds to his legs and arm but was alert and aware of his surroundings, Odom said.

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 However, the photographs released by Sgt. Sean Murphy, a tactical photographer with the Massachusetts State Police, shows Tsarnaev standing upright holding his hands in the air as an act of submission before being apprehended by police.

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 Based on the released photos, it’s obvious that Tsarnaev had not suffered from a gunshot wound to the face at this point. If he had, he most likely wouldn’t have been mobile, let alone able stand and walk towards police surrendering himself.

 Dr. Odom’s report does not state whether the wounds were self-inflicted, or caused by police during the shootout.

 Initial reports stated that police fired at Tsarnaev using rubber bullets (which is debunked through the audio of the video below), however once photos of the boat riddled with bullet holes emerged, police retracted that story replacing it with allegations that Tsarnaev was armed and firing at police.

 

 These allegations were also later debunked when reports revealed that Tsarnaev was not found with any weapons.

 According to the government’s narrative, Tsarnaev thought he was dying so he searched the boat, was able to find a pen and wrote messages inside the interior of the boat.

 It seems ridiculous to imagine Tsarnaev writing all these messages during his final moments. And of course the public can’t view the messages because the boat was so badly riddled with bullet holes, yet it was reportedly legible enough for police to make it out.

 While inconsistencies continue to plague this case, one thing is certain and that’s that the story is sure to change again, evolving in a manner that compliments the government’s agenda.

 Voice of Russia, infowars.com, The Guardian

http://voiceofrussia.com/news/2013_08_23/Dzhokhar-Tsarnaev-had-fractured-skull-and-injured-legs-and-arms-before-his-capture-3652/

All Hackable from fetal monitors used in hospitals to pacemakers implanted in people

FDA, facing cybersecurity threats, tightens medical-device standards

 

By  and , Published: June 12 | Updated: Thursday, June 13, 6:01 AM

The Food and Drug Administration is tightening standards for a wide range of medical devices — from fetal monitors used in hospitals to pacemakers implanted in people — because of escalating concerns that the gadgets are vulnerable to cybersecurity breaches that could harm patients.

Increasingly, officials said, computer viruses and other malware are infecting equipment such as hospital computers used to view X-rays and CT scans as well as devices in cardiac catheterization labs.The security breaches cause the equipment to slow down or shut off entirely, complicating patient care. As more devices operate on computer systems that are connected to each other, the hospital network and the Internet, the potential for problems rises dramatically, they said.

“Over the last year, we’ve seen an uptick that has increased our concern,” said William Maisel, deputy director of science and chief scientist at the FDA’s Center for Devices and Radiological Health. “The type and breadth of incidents has increased.” He said officials used to hear about problems only once or twice a year, but “now we’re hearing about them weekly or monthly.”

The FDA, in an effort to reduce the risks, for the first time is directing device manufacturers to explicitly spell out how they will address cybersecurity. On Thursday, the agency issued draft guidelines that, when finalized later this year, will allow the agency to block approval of devices if manufacturers don’t provide adequate plans for protecting the gadgets and updating their security protections over their commercial lifetimes. The FDA is also issuing a safety communication to manufacturers and hospitals.

The Department of Homeland Security, which is working with the FDA to reduce these vulnerabilities, recently received reports from two researchers that found potential weaknesses in 300 medical devices produced by about 50 vendors, an official said. The department also is planning to release an advisory on medical devices Thursday.

Government officials and patient safety advocates say they do not know of any cases in which patients have been directly injured because of a device compromised by a computer virus. And there is no evidence any implantable devices have been corrupted by viruses or other malware. Nor is there evidence that hackers have deliberately targeted a hospital network or medical device for malicious cyberattacks.

Still, experts say, hospitals and device manufacturers need to use multiple defenses to guard against the threats posed by the Internet.

“There’s almost no medical device that doesn’t have a network jack on the back,” said John Halamka, chief information officer at Beth Israel Deaconess Medical Center in Boston. “To fight the evils of the Internet, not only do you have to have a moat, you have to have a drawbridge, burning oil to pour on attackers, and guys with arrows.”

Hospitals use thousands of medical devices, including ventilators that help patients breathe, monitors that measure a patient’s vital signs, and pumps that deliver medicine. Implantable devices include pacemakers, insulin pumps and defibrillators, many of which can be remotely monitored through a wireless network, making them susceptible to hacking.

Officials said security risks go beyond potential attacks from computer viruses, citing the uncontrolled distribution of passwords for software that is only supposed to be accessed by a few people and the failure by manufacturers to provide timely security software updates.

To be sure, modern medical devices have saved countless lives. But too many medical professionals are in a “complacent denial stage” and brush off problems as completely hypothetical, said Kevin Fu, who heads the Archimedes center for medical-device security at the University of Michigan.

In 2010 and 2011, he said, several hospitals were forced to temporarily close their cardiac catheterization labs because critical devices were infected. In at least one case, a patient had to be moved to another hospital for angioplasty, a procedure that widens blocked arteries.

The equipment problem in one facility was caused when someone plugged a USB drive, a portable device that stores data, into a device and infected it. Fu said he did not have information about the other cases and declined to name the hospitals, because of privacy concerns.

Another problem occurred some years ago at Beth Israel. Fetal monitors for women with high-risk pregnancies were infected by malware that slowed the devices’ response time. No patients were harmed and the problem was eventually fixed, Halamka said. Beth Israel now is one of the most aggressive hospitals in the country in countering cybersecurity risks.

It is nearly impossible to quantify how often cybersecurity incidents involving medical devices occur, because no one really keeps track, officials and experts say. The FDA has a database that allows people to report adverse events. But when medical devices fail, causing problems for patients, the people reporting the problems are usually not trained to identify malware as a cause.

Device manufacturers can solve the problems most easily but have the least incentive, because doing so is expensive, experts said. Hospitals, which buy the devices, want improved security but lack the resources or technical expertise to make the software fixes to the equipment. Experts say manufacturers typically refuse to apply software patches, claiming the FDA does not allow updates to regulated devices, but FDA officials say that is not the case.

“Medical device manufacturers have some of the smartest engineers on the planet,” Fu said. “But cybersecurity is uncharted territory for this industry.”

The federal government’s push for more hospitals and other providers to adopt electronic health records is also likely to increase connectivity — and risk, according to Jim Keller, vice president of health technology evaluation and safety at ECRI Institute, a patient safety organization that works with hospitals to improve medical-device and other technology safety.

“It’s an area that is not being addressed in a significant way by hospitals,” Keller said.

Average consumers expect that “when they go to a health-care institution or provider’s office, that there are laws and rules that the hospital has to comply with to keep the equipment safe from being tampered with and that people are complying,” said Deven McGraw, a health privacy expert at the Center for Democracy & Technology, an advocacy group.

“The reality,” she said, “is a little more complicated.”

At Beth Israel, there are about 15,000 devices on the hospital’s network on a typical day. About 500 of them are running on older operating systems that are most susceptible to malware infection, most often medical devices that are outside the direct control of the hospital, Halamka said.

The hospital uses firewalls to isolate these devices from the Internet. In some cases, smaller manufacturers have agreed to provide software fixes.

The hospital runs scans on the entire network every month to identify new risks and is doubling its information technology budget next year to address cybersecurity risks, Halamka said. But the ultimate answer, he said, is for manufacturers to build their systems in a way that supports the use of anti-virus software and permits fixes.

The Veterans Health Administration has also been among the most aggressive in working to eliminate cybersecurity vulnerabilities. Several years ago, it created a protection program aimed at quickly identifying and eliminating malware and viruses that arise in its tens of thousands of medical devices. It also scans flash drives and other portable media for viruses and limits the number of devices connected to the Internet.

“It’s served us well,” said Lynette Sherrill, deputy director of the Department of Veteran Affairs’ health information security division. “We’re trying to stay ahead of the curve.”

At a VA sleep lab in the Northeast several years ago, all of the computer systems became infected with Conficker malware. The sleep lab had to shut down temporarily and scrambled to move appointments until the problem was fixed.

Industry experts said they will work closely with FDA to address concerns.

Mark Leahey, president of the Medical Device Manufacturers Association, noted that there has been no reports of patients being hurt by security failures but added that the industry want to collaborate with “all the stakeholders” to fix any vulnerabilities.

Bernie Liebler, director of technology and regulatory affairs for the Advanced Medical Technology Association, another trade group, said viruses that infect networks are only one type of vulnerability. Human carelessness, such as leaving a password taped to a computer, is another.

“Ever since I’ve been in this industry, patient safety has been our biggest priority, and I don’t see that changing,” Liebler said. “You can’t get into the business of manufacturing medical devices and not want to make them safe.” He added: “I think FDA is really just trying to get a step ahead. . . . I expect this is going to be a joint effort of a lot of people with the same goal in mind.”

Academic researchers, government officials and industry experts have been ratcheting up their warnings in recent years about the potential vulnerabilities of medical devices.

In March 2012, a public-private federal advisory committee raised concerns about the security of medical devices, particularly those with wireless capabilities, according to its chairman, Daniel Chenok. He wrote to numerous government officials warning that a “lack of cybersecurity preparedness for millions of software-controlled medical devices puts patients at significant risk of harm.” He also noted that no agency had primary responsibility for ensuring the security of medical devices.

“Given the complexity of the technical issues involved, the board finds that diffusion of responsibility when it comes to the cybersecurity of medical devices raises a growing concern,” he wrote.

In May 2012, the Department of Homeland Security issued a bulletin focusing on potential security risks involving medical devices. It noted that the proliferation of wireless technology in the medical world “opens up both new opportunities and new vulnerabilities” and said that protecting “against theft of medical information and malicious intrusion is now becoming a major concern.”

A report issued by the Government Accountability Office this past summer contained similar findings. The agency suggested that the FDA expand and intensify its focus on information security risks.

Several years ago, Fu and other researchers demonstrated how a combination heart defibrillator and pacemaker was vulnerable to computer hacking in a lab. The researchers gained wireless access to the device and reprogrammed it to deliver jolts of electricity that would have potentially been fatal if the device had been in a person.

Fu said he believes the manufacturer fixed the problem, but not before a producer for the television series “Homeland” used it in the plot line for an episode in which the vice president dies after a terrorist hacks into his pacemaker and sends lethal jolts of electricity.

 

http://www.washingtonpost.com/national/health-science/facing-cybersecurity-threats-fda-tightens-medical-device-standards/2013/06/12/b79cc0fe-d370-11e2-b05f-3ea3f0e7bb5a_print.html

Caught just in time: ‘Bombers were about to plant MORE devices but plot was spoiled by release of CCTV photos’

EEV: There is no doubt extreme and conflicting reports on the Boston event. We expect it should be very easy to track where all these alleged weapons came from. In addition, police footage from the car camera’s should be able to easily validate the story.

  • The Boston  bombers were reportedly planning more attacks across the city
  • However, the  released of the photographs of the suspects ‘forced them out of their  hideout’
  • Footage released  on Saturday shows Dzhokhar Tsranaev  laying flat under a tarp in a boat. Police used a robot  to pull the tarp off the boat
  • Police  tracked him with thermal imaging cameras and engaged him in a furious exchange  of gun-fire that began shortly after 7pm
  • Stand-off  continued until 8:45pm when Tsarnaev surrendered
  • Dzhokhar has been  hospitalized at the Beth  Israel Deaconess Medical Center. He is ‘intubated and sedated’ and cannot yet  speak
  • Tamerlan Tsarnaev  had injuries from head to toe and all limbs intact when he arrived at the  hospital. He died early on Friday

By  Snejana Farberov, Daily Mail Reporter and James Nye

PUBLISHED: 22:16 EST, 20  April 2013 |  UPDATED: 13:12 EST, 21 April 2013

The Boston bombers were planning more attacks  across the city and were already building the bombs to do this says the city’s  police commissioner Ed Davis.

Davis says it’s his belief that 19-year-old  Dzhokhar Tsarnaev and his 26-year-old brother Tamerlan ‘were going to attack  other individuals’ — and Davis says that’s based on the evidence at the scene  and the cache of weapons the brothers had at their disposal.

However, Davis claims releasing photos of the  two Boston Marathon bombing suspects ‘forced them out of their hideout’ and  spurred them into Thursday and Friday’s deadly night time car chaos and gun  battle with law enforcement.

‘It forced them out of their hideout and they  decided to commit further violent acts. But it’s my belief that they were  already manufacturing explosive devices. Further violent acts were inevitable,’  Davis told The Boston  Globe.

The suspects ‘were not making those  explosives for nothing,’ Davis told The Globe. ‘There was a plan there, and I  believe that tragically Sean Collier lost his life, but he was truly protecting  the citizens of the city’

Handguns, a rifle and at least six bombs,  three of which detonated were found at the scene on Friday after officers had  their first showdown with the Boston bombing brothers in Watertown,  Massachusetts.

And it is believed that federal prosecutors  are putting the final touches together on charges against Dzhokhar Tsarnaev,  despite his throat wound leaving him unable to speak.

The most serious charge available to federal  prosecutors would be the use of a weapon of mass destruction to kill people,  which carries a possible death sentence. Massachusetts does not have the death  penalty.

CBS  News‘ John Miller has claimed  investigators believe the wound to the back of his neck is evidence that  Dzhokhar attempted to end his own life at the culmination of Friday’s dramatic  standoff.

‘They say it appears from the wound that he  might have stuck a gun in his mouth, and fired and actually just went out the  back of his neck without killing him.’

Scroll down  for video.

This photo released by the FBI early Friday April 19, 2013, shows what the FBI is calling suspect number 2 behind
This photo released by the FBI early Friday April 19, 2013, shows what the FBI is calling the suspects together, walking through the crowd in Boston on Monday

Dzhokhar Tsarnaev and his  26-year-old  brother Tamerlan ‘were going to attack other individuals’ —says  Boston police commissioner Davis and  says that opinion is based on the evidence  at the scene and the cache of weapons  the brothers had at their  disposal.

Planning further atrocities?: Dzhokhar Tsarnaev and his 26-year-old brother Tamerlan were believed to be about to unleash further terror attacks on Boston according to the city's police commissioner Planning further atrocities?: Dzhokhar Tsarnaev and his  26-year-old brother Tamerlan were believed to be about to unleash further terror  attacks on Boston according to the city’s police commissioner

Dzhokhar Tsarnaev, is seen in this undated still image taken from surveillance video on Friday
Dzhokhar Tsarnaev, is seen in this undated still image taken from surveillance video on Friday (left) as he is seen climbing into that same day morning after a police gun battle. He was later found in the boat and captured

Dzhokhar Tsarnaev, is seen in this undated still image  taken from surveillance video on Friday (left) as he is seen  climbing into that  same day morning after a police gun battle. He was  later found in the boat and  captured

Handguns, a rifle and at least six bombs,  three of which detonated were discovered at the scene on early friday after  officers first came face-to-face with the Tsarnaev brothers on a residential  street in Watertown, Massachusetts.

Police chief Edward Deveau revealed that a  lone officer was the first to encounter Tamerlan and Dzhokar Tsarnaev and that  before he could call for back-up, the two brothers exited the Honda and BMW’s  they were driving and began firing.

‘They jump out of the car and unload on our  police officer,’ said Deveau.

‘They both came out shooting — shooting  guns, handguns. He’s under direct fire, very close by. He has to jam it in  reverse and try to get himself a little distance.’

Eventually, five other officers, including  two off-duty cops arrived and there began a close quartered gun-fight in a ‘very  tight area’ in the middle of suburban Watertown.

‘We estimate there was over 200 shots fired  in a five- to 10-minute period,’ said Deveau.

He also revealed that the two brothers  detonated a pressure cooker bomb – lending credence to the theory that the  brothers were planning further terrorist strikes across the city.

‘We find the pressure cooker embedded in the  car down the street, so there’s a major explosion during this gunfight (with) my  officers — six of my officers that I’m extremely proud of,’ Deveau  said.

The pair also threw two other ‘rough’ and  crude explosives at the officers, by lighting them.

And then at the culmination of the gun fight,  Tamerlan Tsarnaev begins to advance on the pinned down officers.

Concealed: The suspect appears to be laying flat in the boat in the final moments before his captureStill: The suspect appears to be laying flat in the boat  in the final moments before his capture

He all of a sudden comes out from under cover  and just starts walking down the street, shooting at our police officers, trying  to get closer,” Deveau said. “Now, my closest officer is five to 10 feet away,  and they’re exchanging gunfire between them. And he runs out of ammunition —  the bad guy — and so one of my police officers comes off the side and tackles  him in the street.

‘We’re trying to get him handcuffed. There’s  two or three police officers handcuffing him in the street — the older brother.  At the same time, at the last minute — they obviously have tunnel vision, it’s  a very, very stressful situation — one of them yells out, ‘Look out!’ and here  comes the black SUV, the carjacked car, directly at them,’ said  Deveau.

‘They dive out of the way, and he (the  younger brother) drives over his brother and drags him a short distance down the  street.’

Tamerlan was pronounced dead later on at  hospital and Dzhokar drove off in the Mercedes SUV about two blocks and then  exited the car and ran off into Watertown.

This comes as previously unseen video of the  dramatic capture of the Boston bomber shows a police robot  ripping apart the  tarp concealing the suspect and numerous flash bang  grenades being thrown into  the boat where he lay.

In the final moments before his capture on  Friday night, Dzhokhar Tsranaev appeared to lay still inside a boat in a  backyard in Watertown, Mass. on Friday before he was taken into custody.

Doctors also revealed grizzly details on how  his brother, Tamerlan, had wounds from head to toe, ‘every region of his body had injuries [though] his legs and arms were  intact,’ they  said about his condition when he was hospitalized on  Friday morning shortly  before he died.

Watertown police chief Edward Deveau  has  also given the most detailed yet account of events on Friday. Boston had been on  edge after two  bombs ripped through the crowd near the finish line of the  Boston  Marathon on Monday. The city was  gripped with fear as the suspects were being hunted down, after the FBI  released photos of the men behind the attacks on Thursday night.

Violence broke out in the early morning hours  Friday when police received reports  of a robbery of a convenience store in  Kendall Square near MIT and a Sean Collier, an MIT police officer, was shot multiple  times.

In hiding: The dramatic footage released by police shows where the teenager lay hiding in a boat in the quiet suburban neighbourhood of Watertown In hiding: The dramatic footage released by police shows  where the teenager lay hiding in a boat in the quiet suburban neighbourhood of  Watertown
BlastBlast: Video appears to show a flash grenade being  thrown into the boat where the suspect hid
Show of forceShow of force: The Massachusetts State Police has  released this video showing an explosion resulting from a grenade thrown into  the boat where the suspect lay

 VIDEO  RAW: Thermal imaging camera shows Dzhokhar Tsranaev’s  final moments before arrest

CaughtCaught: Dzhokhar Tsarnaev lies on the ground of the  property of 67 Franklin Street in Watertown after authorities apprehended him.  He had to have medical assistance to breathe

Speaking to CNN following Dzhokhar’s  capture, Deveau said that a single officer was the first to encounter  the two  cars that Tamerlan and Dzhokhar Tsarnaev were driving, just  before 1am Friday.

One of the vehicles was a Mercedes SUV the  brothers had carjacked earlier that night.

Before the officer could call for backup, the  two cars came to a stop and the brothers got out.

‘They jump out of the car and unload on our  police officer,’ Deveau said.

‘They both came out shooting — shooting  guns, handguns. He’s under  direct fire, very close by. He has to jam it in  reverse and try to get  himself a little distance.’

Five others officers arrived on the scene in  the middle of an intense  shootout during which Deveau says over 200 rounds were  fired in 5-10  minutes.

The chief  said that one of the suspected  bombers lobbed an explosive at the  officers, which later turned out to be a  pressure cooker bomb like the  ones used in the marathon attack Monday.

The brothers also allegedly threw  other  explosives at police, which Deveau described as ‘very rough  devices.’

Two of the bombs detonated and two did not.

The pressure-cooker bomb exploded, and the  lid was found embedded in a nearby car, Deveau said.

At one point, the older brother came directly  toward police, firing a gun  at officers as he inched closer toward him, but  Tamerlan Tsarnaev’s luck ran out along with his ammunition, allowing one of the  officers to  tackle him.

The older of the two Chechen brothers  suspected of bombing the Boston Marathon was wounded but alive following a  police gun battle when his younger brother ran him over with a car,  possibly  causing his death.

In hiding: Dzhokhar was discovered by Massachusetts resident David Henneberry hiding in his boat. Police used thermal imaging to monitor his movementsIn hiding: Dzhokhar was discovered by Massachusetts  resident David Henneberry hiding in his boat. Police used thermal imaging to  monitor his movements
Revealed: How heat sensors found the Boston terror suspect - the cameras showed how the man moved around the boatRevealed: How heat sensors found the Boston terror  suspect – the cameras showed how the man moved around the boat

‘He all of a sudden comes out from under  cover and just starts walking down the street, shooting at our police officers,  trying to get closer,’ Police Chief  Edward  Deveau, of Watertown, Massachusetts, said.

‘Now, my closest officer is five to 10  feet  away, and they’re exchanging gunfire between them. And he runs out  of  ammunition — the bad guy — and so one of my police officers comes  off the  side and tackles him in the street.’

He was in the process of being  handcuffed by  two or three officers when his younger brother,  19-year-old Dzhokhar, jumped  behind the wheel of a black SUV the two  hand allegedly carjacked earlier and  barreled toward the group.

The older of the two Chechen brothers  suspected of bombing the Boston Marathon was wounded but alive following a  police gun battle when his younger brother ran him over with a car,  possibly  causing his death.

Officers who were restraining  Tamerlan  Tsarnaev got out of the way of the speeding vehicle, which  ended up driving  over the wounded suspect, the police chief told CNN.

According to Deveau, the 19-year-old suspect  dragged his sibling’s body a short distance down the street and drove off.

He later ditched the SUV and escaped on  foot.

‘I am extremely lucky that I’m not at a  funeral this morning for one of my officers,’ Deveau said in an interview on  MSNBC.

‘They were heroic, very talented, and had the  guts and glory to defend our town, our community, in a very tight  situation.’

Suspects: Tamerlan Tsarnaev, 26, left, was reportedly run over by his accomplice and younger brother Dzhokhar Tsarnaev, 19Suspects: Tamerlan Tsarnaev, 26, left, was reportedly  run over by his accomplice and younger brother Dzhokhar Tsarnaev, 19

Tamerlan Tsarnaev was pronounced dead at a  hospital a short time later.

An alleged autopsy photograph of Tamerlan  that was leaked Friday shows  multiple gunshot wounds and a massive open gash  that spans from the  center of his chest to his back.

Another smaller gash is located right below  the larger wound. His right shoulder and his face show signs of hemorrhaging.

A doctor involved in treating the Boston  Marathon bombing suspect who  died in a gunbattle with police told the  Associated Press that Tamerlan Tsarnaev  had injuries from head to toe and all  limbs intact when he arrived at the hospital.

Dr David Schoenfeld said 26-year-old  Tamerlan Tsarnaev was unconscious and had so many penetrating wounds  when he  arrived at Beth Israel Deaconess Medical Center early Friday  that it isn’t  clear which ones killed him, and a medical examiner will  have to determine the  cause of death.

The older  Tsarnaev’s clothes had been cut  off by emergency responders at the  scene, so if he had been wearing a vest with  explosives, he wasn’t by  the time he arrived at the hospital, the doctor  said.

‘From head to toe, every region of his body  had injuries,’ he said.

‘His legs and arms were intact – he  wasn’t  blown into a million pieces’ – but he lost a pulse and was in  cardiac arrest,  meaning his heart and circulation had stopped, so CPR,  or cardio-pulmonary  resuscitation, was started.

SiteSite: Investigators work around the boat where Dzhokhar  Tsarnaev was found hiding after a massive manhunt that left the Boston area  paralyzed in fear

Schoenfeld did not address the police assertion that Tsarnaev was run over by a car driven by his brother as  he fled  the gunfire.

The doctor said he couldn’t discuss specific  treatments in the case except  to say what is usually done in such  circumstances, including putting a  needle in the chest to relieve pressure that  can damage blood vessels,  and cutting open the chest and using rib-spreaders to  let doctors drain  blood in the sac around the heart that can put pressure on  the heart and keep it from beating.

‘Once you’ve done all of those things … if  they don’t respond there’s  really nothing you can do. You’ve exhausted the  playbook,’ he said.

After 15 minutes of unsuccessful treatment,  doctors pronounced him dead at  1:35am.

His body was turned over to law enforcement  for examination to  determine the source of his injuries.

‘We did everything we could’ to try to save  his life, Schoenfeld said.

‘There was some discussion in the emergency  room about who it was. That discussion ended pretty quickly,’ Schoenfeld said.

‘It really doesn’t matter who the person is.  We’re going to treat them as best we can.’

EvidenceEvidence: Investigators gather evidence on Saturday,  near the location in Watertown, Mass., where Dzhokhar Tsarnaev, 19, was  captured
ReviewReview: Investigators remained at the home in Watertown,  Mass. where the surviving suspect was located

After the early morning violence, officials  frantically searched for the suspect who remained on the loose.

The city issued a ‘shelter-in-place’ request,  telling residents of the greater Boston area while the streets were overun with  an estimated 1,000 law enforcement officers who scoured the are for the  fugitive.

Shortly before 6pm, officials announced that  though they hadn’t located the alleged  bomber, Dzhokhar Tsarnaev, they were  lifting the lockdown and urged residents to exercise extreme caution and be  vigilant.

One Watertown, Mass. resident took that  advice to heart.

After 6pm, David  Henneberry walked out to his backyard and noticed something odd about his  boat, that is stored behind his home.

‘He looked and noticed something was off  about his boat, so he got his  ladder, and he put his ladder up on the side of  the boat and climbed up, and then he saw blood on it, and he thought he saw what  was a body  laying in the boat,’ Henneberry’s neighbor, George Pizzuto told ABC  News.

‘So he got out of the boat fast and  called  police.’

How the drama in Watertwon unfolded in the early hours of Friday

Authorities then used a helicopter  equipped  with a thermal imaging device to confirm that there was a body  in the tarp  covered boat and that the person was alive.

Hovering over the area, the helicopter  spotted the heat signature of a person, confirming Henneberry’s  suspicions.

‘Our helicopter had actually detected  the  subject in the boat,’ Col. Timothy Alben of the Massachusetts State  Police told  NBC News. ‘We have what’s called a FLIR — a forward-looking  infrared device —  on that helicopter.

The chopper  monitored the body in the boat  for more than an hour before police moved in.

ATF, SWAT and  K-9 units had descended upon  67 Franklin Street and engaged Tsarnaev in a vicious gun battle – over 40 shots  rang out in the quiet suburban  neighborhood.

‘There was an exchange of gunfire,’ confirmed  Boston Police Commissioner Ed Davis at a news conference.

‘We used a robot to pull the tarp off the  boat,’ David Procopio of the  Massachusetts State Police said to CNN.

Unconfirmed reports suggest that  Tsarnaev  was shot twice by law enforcement in the gun battle which raged until his  capture at approximately 8:45pm.

Law enforcement sources have suggested that  Tsarnaev gave himself up  voluntarily after realizing continuing resistance was  fruitless.

Search Search: A light beam from a helicopter, top right, aims in the direction of  Watertown, where officials searched for a suspect on Friday

Endgame: An ambulance carries Boston Marathon Dzhokhar Tsarnaev from the scene after he was apprehended in Watertown, Massachusetts, USA on Friday
Endgame: An ambulance carries Boston Marathon Dzhokhar  Tsarnaev from the scene after he was apprehended in Watertown, Massachusetts,  USA on Friday

He was found bleeding heavily from gunshot  wounds to his neck and foot  from the shoot-out on Friday morning, which he  escaped on foot before taking up his hiding place in a Watertown backyard boat.

The blood loss  would have taken place over  more than 20 hours by the time he was found and there were reports,  which could  not be confirmed, that he may have been shot a further two  times last  night.

‘He had lost a lot of blood. He was so weak  that we were able to just go in and scoop him up,’ state police spokesman David  Procopio told the  Boston Herald adding that the suspect was in ‘serious if not  critical  condition’.

He was rushed from the scene by ambulance  and images showed apparatus being used to help him breathe.

As the suspect receives treatment at the Beth  Israel Deaconess Medical  Center in Boston, law enforcement officials have  revealed that he  injured his throat in the standoff with police and may not be  able to  speak, a law enforcement official toward CNN.

Massachusetts Governor Deval Patrick said on  Friday : ‘[I] hope he survives, because we have a million questions.’

Tsarnaev was captured last night in  the  culmination of a dramatic week-long police hunt and a completely  unprecedented  $333 million shutdown of Boston and its suburbs.

SceneScene: Aerial views of 67 Franklin Street, where  Dzhokhar was taken into custody
WoundedWounded: Dzhokhar Tsarnaev is seen being transported in  an ambulance after he was captured on Friday. Officials say he suffered an  injury to his throat and cannot speak

The medical facility where he is a  patient  is under heavy armed guard and federal prosecutors are standing  by at the  center for when the teenager is able to speak.

Victims who were injured in the  deadly blast  at the marathon on Monday are also among those being  treated at the medical  center, which has some families angry about the  close proximity to the alleged  mastermind.

Tsarnaev is being treated in a room  yards  from where 11 injured marathon victims are still in recovery while a specially  drawn up High-Value Detainee Interrogation Group wait  anxiously to question  him.

One Boston mother, Liz Norden’s two  sons,  Paul and J.P., were in the crowd at the race on Monday and have  both lost a leg  in the aftermath of the tragic event. Her younger son, Paul, is being  treated at Beth Israel Deaconess Medical Center.

She told NBC News that she is shocked and  angry that the suspect is so near.

‘I can’t even tell you how devastating it’s  been,’ Liz Norden told NBC News. ‘Those two [the bombers] shattered my  world.’

Harrowing scene: Bomb disposal robots searched the suspects' vehicle, with an eye witness saying a water bottle was removedHarrowing scene: Bomb disposal robots searched the  suspects’ vehicle early on Friday, with an eye witness saying a water bottle was  removed
Green accord
Scene

Violent moments: The scene of the shootout, in  which  Tamerlan Tsarnaev was killed, involving the Boston bomber suspects in Watertown,  Massachusetts

Tense night: Police with guns drawn search for a suspect in the bombing after a shootout and carjacking Tense night: Police with guns drawn search for a suspect  in the bombing after a shootout and carjacking
Foolhardy: At one point, police say Tamerlan marched down the street toward police while firing a gun at them Nothing to lose: At one point, police say Tamerlan  marched down the street toward police while firing a gun at them
Explosive: Police say the suspects opened fire on officers and lobbed makeshift bombs devices at them Explosive: Police say the suspects opened fire on  officers and lobbed makeshift bombs devices at them
Fire power: About 200 rounds were fired during the shootout in a matter of five-ten minutes Fire power: About 200 rounds were fired during the  shootout in a matter of five-ten minutes
Chaos in the streets: Gunfire erupted in a quiet suburban neighborhood, setting off a massive manhunt Chaos in the streets: Gunfire erupted in a quiet  suburban neighborhood, setting off a massive manhunt

The showdown in Watertown broke out after the  violence began in Cambridge, Mass.

Violence erupted in the early morning hours  Friday when police received reports of a robbery of a convenience store in  Kendall Square near MIT and a police officer was shot and  ended up with a gun  fight in a small suburban street as residents slept.

Sean Collier, an MIT police officer, was shot  multiple times while in his  cruiser at Main and Vassar streets, near the Stata  Center on the MIT  campus.

Officials told the Washington Post that  footage from a security camera shows the two suspects approaching the car and  speaking to the officer.

All of a sudden, one of the suspects pulled a  gun and shot Collier multiple times, including one shot to the head.

Hero: MIT Police Officer Sean Collier was shot and killed in an armed confrontation with the suspects in the Boston Marathon bombingHero: MIT Police Officer Sean Collier was shot and  killed in an armed confrontation with the suspects in the Boston Marathon  bombing

Some police have suggested that the shooting  was meant to spark a full scale confrontation with police.

‘They were looking to start something,’ one  official told the Washington Post.

The 26-year-old Collier was pronounced dead  at Massachusetts General Hospital.

A short time later, the two men carjacked a  Mercedes SUV at gunpoint.

The  hostage was then driven around for half an hour as the pair decided what their  next move would be.

As police moved in on the vehicle following  reports of a carjacking, the pair decided to dump the driver at a gas station on  Memorial Drive in Cambridge.

The search for the vehicle led to a chase  that ended in Watertown, where authorities said the suspects threw explosive  devices from the car and exchanged gunfire with police.

Richard H. Donahue, 33, a transit police  officer was seriously injured during the chase.

In Watertown, witnesses reported hearing  multiple gunshots and explosions at about 1am on Friday, when the frightening  scene occurred.

On Saturday, Boston police paid tribute to  the MIT officer who died in the line of duty.

Mr Collier’s body was transported from the  Boston medical examiner’s office to the deceased man’s hometown of  Wilmington.

Officers and local residents lined the street  to remember the slain officer as his body left the office.

His family had asked that the hearse, with a  police escort, pass through the center of hometown before  heading to a funeral  home in Stoneham.

A vigil was held in his hometown of  Wilmington on Saturday night, as residents flocked to the streets in remembrance  of the hero, who was shot multiple times  by the suspects.

The Collier family said that the 26-year-old  had always wanted to be a police officer.

‘We are heartbroken by the loss of our  wonderful and caring son and brother, Sean Collier. Our only solace is that Sean  died bravely doing what he committed his life to – serving others,’ his family  said in a statement.

Mr Obama similarly offered his condolences to  the Collier family on Friday night, after the surviving suspect was captured.

‘He died bravely in the line of duty  doing  what he committed his life to doing, serving and protecting  others,’ the  president said.

Boston StrongBoston Strong: Fans hold an American flag during  ceremonies in tribute of victims and first responders to the Boston Marathon  bombings before a baseball game between the Boston Red Sox and the Kansas City  Royals

The Red Sox paid an emotional tribute to the  people of Boston on Saturday afternoon in a moving pregame ceremony at  Fenway  Park, the first time since last Monday’s deadly terrorist attacks that killed  three and left more than 180 wounded.

Designated hitter David Ortiz exclaimed ‘this  is our f***ing city’ to rapturous  cheers, and some tears, after a moving video,  encapsulating the horror  and heroism of the past few days, played on the big  screen.

Proud Bostonians could be seen watching the  game, many of them clutching  American flags.

The city used the significant sporting event  to honor  the victims and offer gratitude to the police, firefighters and  medical  personnel as well as strangers who risked their lives to save others  after the senseless attacks.

‘All right, Boston,’ said Ortiz. ‘This jersey  that we wear today, it doesn’t say Red Sox. It says Boston.

He continued: ‘We want to thank you, Mayor  Menino, Governor Patrick, the  whole police department for the great job they  did this past week. This  is our f***ing city, and nobody is going to dictate  our freedom. Stay  strong.’

The Boston team,  rather than wearing their  traditional ‘Red Sox’ embroidered across the  chest, wore crisp white uniforms  that simply read ‘Boston,’ with a ‘B  Strong’ logo.

The team said their uniforms would be  autographed and  auctioned to raise money for the charity established to help  the  victims, called One Fund Boston.

RemembranceRemembrance: Lisa Marriott and her son, Joseph, hold a  sign and candles during a vigil for slain MIT police officer Sean Collier at the  Town Common in Wilmington, Massachusetts on Saturday

During the video, the crowd applauded when  images of the brave Carlos Arredondo appeared on the screens and  it increased  when pictures and quotations from President Obama, Governor Patrick and Mayor  Menino were shown.

It was accompanied by Jeff Buckley’s  rendition of ‘Hallelujah.’

When the footage moved to the manhunt for  19-year-old Dzhokar A Tsarnev in Watertown, the fans were on their feet  cheering.

At that point, law enforcement and first  responders walked onto the field and formed a line in front of the Red Sox  dugout.

Moments of silence were then held for  Marathon victims, eight-year-old Martin  Richard, Krystle Campbell and Lu Lingzi  and MIT police officer Sean  Collier, who was killed Thursday night in a  shootout between the  Tsarnaevs.

The emotional tribute came after  baseball stadiums around the U.S. erupted  into cheers last night as news that  police had captured the second Boston  bombings suspect was plastered  across the big screens.

Read more: http://www.dailymail.co.uk/news/article-2312387/Boston-bombers-Dzhokhar-Tsarnaev-Tamerlan-Tsarnaev-plant-MORE-devices.html#ixzz2RANjAwbJ Follow us: @MailOnline on Twitter | DailyMail on Facebook

Physicians’ brain scans indicate doctors can feel their patients’ pain — and their relief

Contact: Bonnie Prescott bprescot@bidmc.harvard.edu 617-667-7306 Beth Israel Deaconess Medical Center

Novel experiment illuminates the importance of the doctor-patient relationship

BOSTON – A patient’s relationship with his or her doctor has long been considered an important component of healing. Now, in a novel investigation in which physicians underwent brain scans while they believed they were actually treating patients, researchers have provided the first scientific evidence indicating that doctors truly can feel their patients’ pain – and can also experience their relief following treatment.

Led by researchers at Massachusetts General Hospital (MGH) and the Program in Placebo Studies and Therapeutic Encounter (PiPS) at Beth Israel Deaconess Medical Center/Harvard Medical School, the new findings, which appear on-line today in Molecular Psychiatry, help to illuminate one of the more intangible aspects of health care – the doctor/patient relationship.

“Our findings showed that the same brain regions that have previously been shown to be activated when patients receive placebo therapies are similarly activated in the brains of doctors when they administer what they think are effective treatments,” explains first author Karin Jensen, PhD, an investigator in the Department of Psychiatry and Martinos Center for Biomedical Imaging at MGH and member of the PiPS. Notably, she adds, the findings also showed that the physicians who reported greater ability to take things from the patients’ perspective, that is, to empathize with patients’ feelings, experienced higher satisfaction during  patients’ treatments, as reflected in the brain scans.

“By demonstrating that caring for patients involves a complex set of brain events, including deep understanding of the patient’s facial and body expressions, possibly in combination with the physician’s own expectations of relief and feelings of reward, we have been able to elucidate the neurobiology underlying caregiving,” adds senior author Ted Kaptchuk, director of the PiPS and Associate Professor of Medicine at Harvard Medical School. “Our findings provide early evidence of the importance of interacting brain networks between patients and caregivers and acknowledge the doctor/patient relationship as a valued component of health care, alongside medications and procedures.”

Previous investigations have demonstrated that a brain region associated with pain relief (right ventrolateral prefrontal cortex, VLPFC) and a region associated with reward (rostral anterior cingulate cortex, rACC) are activated when patients experience the placebo effect, which occurs when patients show improvement from treatments that contain no active ingredients. The placebo effect accounts for significant portions of clinical outcomes in many illnesses — including pain, depression and anxiety.

Although behavioral research has suggested that physicians’ expectations influence patients’ clinical outcomes and help determine patients’ placebo responses, until now little effort has been directed to understanding the biology underlying the physician component of the clinical relationship. Jensen and her colleagues hypothesized that the same brain regions that are activated during patients’ placebo responses – the VLPFC and rACC — would similarly be activated in the brains of physicians as they treated patients. They also hypothesized that a physician’s perspective-taking skills would influence the outcomes.

To test these hypotheses, the scientists developed a unique equipment arrangement that would enable them to conduct functional magnetic resonance imaging (fMRI) of the physicians’ brains while the doctors had face-to-face  interactions with patients, including observing patients as they underwent pain treatments.

The experiment included 18 physicians (all of whom had received their medical degree within the last 10 years and represented nine separate medical specialties). Two 25-year-old females played the role of “patients” and followed a rehearsed script. The experiment called for the participating physicians to  administer pain relief with what they thought was a pain-relieving electronic device, but which was actually a non-active “sham” device.

To ensure that the physicians believed that the sham device really worked, the investigators first administered a dose of “heat pain” to the physicians’ forearms to gauge pain threshold and then “treated” them with the fake machine. During the treatments, the investigators reduced the heat stimulation, to demonstrate to the participants that the therapy worked. The physicians underwent fMRI scans while they experienced the painful heat stimulation so that investigators could see exactly which brain regions were activated during first-person perception of pain.

In the second portion of the experiment,each physician was introduced to a patient and asked to perform a standardized clinical examination, which was conducted in a typical exam room for approximately 20 minutes. (The clinical exam was performed in order to establish a realistic rapport between the physician and patient before fMRI scanning took place, and was comparable to a standard U.S. doctor’s appointment.) At this point the physician also answered a questionnaire, the Interpersonal Reactivity Index, used to measure the participant’s self-reported perspective-taking skills.

During the third step, says Jensen, the physician and patient were led into the scanner room. “The physician went inside the scanner and was equipped with a remote control that could activate the ‘analgesic device’ when prompted,” she explains. Mirrors inside the scanner enabled physicians to maintain eye contact with the patient, who was seated on a chair next to the scanner’s bed and hooked up to both the thermal pain stimulator and the pain-relieving device.

Then, in a randomized order, physicians were instructed to either treat a patient’s pain or to press a control button that provided no relief. When physicians were told not to activate pain relief, the “patient” exhibited a painful facial expression while the physicians watched. When the physicians were instructed to treat the patients’ pain, they could see that the subjects’ faces were neutral and relaxed, the result of pain relief. During these doctor-patient interactions, fMRI scans measured the doctors’ brain activations.

Following the scanning session, the physicians were removed from the scanner and told exactly how the experiment had been performed, says Jensen. “If the physician did not agree with the deceptive component of the study, they were given the opportunity to withdraw their data. No one did this.”

As predicted, the authors found that while treating patients, the physicians activated the right VLPFC region of the brain, a region previously implicated in the placebo response. Furthermore, Jensen adds, the physicians’ ability to take the patients’ viewpoints correlated to brain activations and subjective ratings; physicians who reported high perspective-taking skills were more likely to show activation in the rACC brain region, which is associated with reward.

“We already know that the physician-patient relationship provides solace and can even relieve many symptoms,” adds Kaptchuk. “Now, for the first time, we’ve shown that caring for patients encompasses a unique neurobiology in physicians. Our ultimate goal is to transform the ‘art of medicine’ into the ‘science of care,’ and this research is an important first step in this process as we continue investigations to find out how patient-clinician interactions can lead to measurable clinical outcomes in patients.”

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In addition to Jensen and Kaptchuk, study coauthors include MGH and PiPS investigators Jacqueline Raicek, Alexandra Cheetham, Rosa Spaeth, Amanda Cook, Randy L. Gollub, and Jian Kong; Predrag Petrovic of the Karolinska Institute, Stockholm, Sweden;  and Irving Kirsch of the PiPS.

This study was funded, in part, by the Swedish Society for Medical Research and the Swedish Council for Working Life and Social Research, Osher Center for Integrative Medicine (Karolinska Institute) and by NIH grants from the National Center on Complementary and Alternative Medicine (K24AT004095; P01 AT003883; R21AT004497; R01AT006364; R01AT005280), the National Institute on Drug Abuse (R03AT218317); and the National Center for Research Resources (M01-RR-01066 and UL1 RR025758-01; and P41RR14075).

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of “America’s Best Hospitals.”

Study suggests too much risk associated with SSRI usage and pregnancy: Elevated risk of miscarriage, preterm birth, neonatal health complications and possible longer term neurobehavioral abnormalities, including autism

Contact: Kelly Lawman klawman@bidmc.harvard.edu 617-667-7305 Beth Israel Deaconess Medical Center

Antidepressants should only be prescribed with great caution

BOSTON – Elevated risk of miscarriage, preterm birth, neonatal health complications and possible longer term neurobehavioral abnormalities, including autism, suggest that a class of antidepressants known as selective serotonin reuptake inhibitors (SSRI) should only be prescribed with great caution and with full counseling for women experiencing depression and attempting to get pregnant, say researchers at Beth Israel Deaconess Medical Center, Tufts Medical Center and MetroWest Medical Center.

“Depression and infertility are two complicated conditions that more often than not go hand in hand. And there are no definitive guidelines for treatment,” says lead author Alice Domar, Ph.D, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Executive Director of the Domar Center for Mind/Body Health at Boston IVF. “We hope to provide a useful analysis of available data to better inform decisions made by women and the providers who care for them.”

Domar and colleagues conducted a review of published studies evaluating women with depressive symptoms who took antidepressants while pregnant. The results appear online October 31 in the journal Human Reproduction.

“There are three main points that stand out from our review of the scientific studies on this topic,” says senior author Adam Urato, MD, Chairman of Obstetrics and Gynecology at MetroWest Medical Center and a Maternal-Fetal Medicine specialist at Tufts Medical Center. “First, there is clear and concerning evidence of risk with the use of the SSRI antidepressants by pregnant women, evidence that these drugs lead to worsened pregnancy outcomes. Second, there is no evidence of benefit, no evidence that these drugs lead to better outcomes for moms and babies. And third, we feel strongly that patients, obstetrical providers, and the public need to be fully aware of this information.”

Over the last 20 years antidepressant usage has increased 400 percent. Antidepressants are now the most commonly prescribed medication in the United States for people between 18 and 44 years of age, the childbearing years for most women. And as women enter their late 30s and early 40s they are more likely to experience infertility.

“According to the Centers for Disease Control, more than 1 percent of the babies born in the USA each year are the result of an IVF cycle,” write the authors. “And most women will report symptoms of depression during infertility treatment, especially following unsuccessful treatment cycles.”

As many as 11 percent of women undergoing fertility treatment report taking an SSRI to combat depressive symptoms, but Domar and colleagues found no evidence of improved pregnancy outcomes with antidepressant usage, and in fact, found the opposite. They also found plenty of controversy around SSRI efficacy. Many studies found SSRIs to be no more effective or only slightly more effective than placebos in treating depression. “More broadly, there is little evidence of benefit from the antidepressants prescribed for the majority of women of childbearing age–and there is ample evidence of risk,” the authors write.

For starters, there is mounting evidence that SSRIs may decrease pregnancy rates for women undergoing fertility treatment. Additionally, studies consistently show that women using antidepressants experience increased rates of miscarriage. There is also a strong signal of congenital abnormalities, the most noted of which is the association between the use of the antidepressant, Paxil, and cardiac defects. In 2005, this association prompted the FDA to ask Paxil’s manufacturer, GlaxoSmithKline to change Paxil’s risk factor from a C to a D, where a D rating indicates a demonstrated risk to the fetus.

“Preterm birth is, perhaps, the most pressing obstetrical complication,” write the authors. In more than 30 studies, the evidence overwhelmingly points to increased risk for early delivery in women who are taking antidepressants. “This is a significant finding because we know that babies born before 37 weeks are at risk for many short and long-term health problems,” says Urato. “Caring for premature babies adds up to billions of dollars in healthcare expenditures.”

Available data also suggests that antidepressant usage, especially if it extends beyond the first trimester, leads to an increased risk of pregnancy-induced hypertension and preeclampsia. “Given the importance of the hypertensive disorders of pregnancy in terms of maternal and newborn morbidity and mortality, and the widespread use of antidepressants during pregnancy, further investigation into this area will be essential,” write the authors.

Similarly, long-term exposure to SSRIs appears to correspond to an increased incidence of birth weight falling below the 10th percentile, coupled with increased rates of respiratory distress.

The health complications associated with antidepressant usage can be carried into infancy and beyond. A 2006 study showed that infants exposed to antidepressants in utero had a 30 percent risk of Newborn Behavioral Syndrome, most commonly associated with persistent crying, jitteriness and difficulty feeding. In more rare instances the syndrome can produce seizures and breathing difficulties leading to the need for intubation. Studies have also shown delayed motor development in babies and toddlers. And a Kaiser Permanente study showed a “two-fold increased risk of autism spectrum disorders associated with maternal treatment with SSRI antidepressants during the pregnancy, with the strongest effect associated with treatment during the first trimester.”

“There is enough evidence to strongly recommend that great caution be exercised before prescribing SSRI antidepressants to women who are pregnant or who are attempting to get pregnant, whether or not they are undergoing infertility treatment,” says Domar. “We want to stress that depressive symptoms should be taken seriously and should not go untreated prior to or during pregnancy, but there are other options out there that may be as effective, or more effective than SSRIs without all the attendant risks.”

Domar and team looked at studies assessing different treatment modalities for depression in the general population, including psychotherapy, exercise, relaxation training, yoga, acupuncture and nutritional supplements. While many of these options were shown to provide some benefit, psychotherapy, specifically cognitive behavioral therapy (CBT) showed the most promise. “There is overwhelming evidence that CBT is equivalent to antidepressant medication in the treatment of mild to moderate depression and more recent research indicates that it is effective in the treatment of severe depression as well,” write the authors.

A 2008 study showed impressive results for CBT in depressed women undergoing infertility treatments. The results showed that 79 percent of women who received CBT reported a significant decrease in symptoms, compared with 50 percent of women in the medication group.

“These alternative treatment options may not be appropriate for everyone, still we think it’s important for women on an antidepressant who are considering becoming pregnant to have a conversation with their physician about the risks and benefits of continuing to take their medication,” says Domar. “Because at this point in time, with no data to indicate an advantage to taking an SSRI during pregnancy, the research all points to increased risk.”

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In addition to Domar and Urato, other co-authors include: Vasiliki A. Moragianni, MD, MS and David A. Ryley, MD of Beth Israel Deaconess Medical Center and Boston IVF.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

MetroWest Medical Center is a full-service community teaching hospital system dedicated to meeting the health care needs of the MetroWest region of Massachusetts by providing advanced care with a community touch. The 269-bed health care system — the largest between Worcester and Boston — includes Framingham Union Hospital, Leonard Morse Hospital in Natick, MetroWest HomeCare and Hospice, and The MetroWest Wellness Center, an outpatient diagnostic imaging and rehabilitation center.

Tufts Medical Center is an exceptional, not-for-profit, 415-bed academic medical center that is home to both a full-service hospital for adults and Floating Hospital for Children. Conveniently located in downtown Boston, the Medical Center is the principal teaching hospital for Tufts University School of Medicine. Floating Hospital for Children is the full-service children’s hospital of Tufts Medical Center and the principal pediatric teaching hospital of Tufts University School of Medicine. Tufts Medical Center is affiliated with seven community hospitals and with New England Quality Care Alliance, its community physicians’ network. For more information, please visit www.tuftsmedicalcenter.org.

Glutamine supplements show promise in treating stomach ulcers

2009 study posted for filing

Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center

Amino acid helps offset stomach damage caused by H. pylori bacteria; animal study suggests popular supplement could also reduce risk of gastric cancers

BOSTON – Nearly 20 years ago, it was discovered that bacteria known as Helicobacter pylori were responsible for stomach ulcers. Since then, antibiotics have become the primary therapy used to combat the H. pylori infection, which affects approximately six percent of the world population and is also a primary cause of stomach cancer. But today the bacteria is growing increasingly resistant to antibiotics.

Now a study led by scientists at Beth Israel Deaconess Medical Center (BIDMC) and the Massachusetts Institute of Technology demonstrates that the amino acid glutamine, found in many foods as well as in dietary supplements, may prove beneficial in offsetting gastric damage caused by H. pylori infection. Reported in the May 2009 issue of the Journal of Nutrition., the findings offer the possibility of an alternative to antibiotics for the treatment of stomach ulcers.

“Our findings suggest that extra glutamine in the diet could protect against gastric damage caused by H. pylori,” says senior author Susan Hagen, PhD, Associate Director of Research in the Department of Surgery at BIDMC and Associate Professor of Surgery at Harvard Medical School. “Gastric damage develops when the bacteria weakens the stomach’s protective mucous coating, damages cells and elicits a robust immune response that is ineffective at ridding the infection.” Eventually, she notes, years of infection result in a combination of persistent gastritis, cell damage and an environment conducive to cancer development.

Glutamine is a nonessential amino acid naturally found in certain foods, including beef, chicken, fish, eggs, dairy products and some fruits and vegetables. L-glutamine – the biologically active isomer of glutamine – is widely used as a dietary supplement by body builders to increase muscle mass.

Hagen and her coauthors had previously shown that glutamine protects against cell death from H. pylori-produced ammonia. “Our work demonstrated that the damaging effects of ammonia on gastric cells could be reversed completely by the administration of L-glutamine,” explains Hagen. “The amino acid stimulated ammonia detoxification in the stomach – as it does in the liver – so that the effective concentration of ammonia was reduced, thereby blocking cell damage.”

She and her coauthors, therefore, hypothesized that a similar mechanism might be at work in the intact stomach infected with H. pylori. To test this hypothesis, the investigators divided 105 mice into two groups, which were fed either a standardized diet (containing 1.9 percent glutamine) or the same diet with supplemental L-glutamine (containing 6.9 percent glutamine) replacing carbohydrates for five percent of the total calories. After two weeks, the mice were subdivided into two more groups, with one group receiving a sham (fake) dose and the other group receiving a real dose containing H. pylori. (This resulted in four separate mouse groups: an uninfected control group; an uninfected glutamine group; an infected control group; and an infected glutamine group.)

The mice were then followed for a 20-week period, during which time samples of blood and stomach tissue were removed. Blood was analyzed for antibodies to specific types of T-helper immune cells, which mediate the body’s response to H. pylori infection. Stomach tissues were examined for evidence of damage and cancer progression and also chemically analyzed for cytokines (inflammatory substances) which are produced by T-helper cells.

Their results showed that at six-weeks-post infection, the animals exhibited increased expression of three cytokines – interleukin 4, interleukin 10 and transforming growth factor-alpha mRNA. “These all play an important role in the stomach’s ability to protect against damaging effects resulting from other responses to H. pylori infection,” explains Hagen.

Of even greater significance, by week 20, the study results showed that, among the H. pylori-infected animals, the mice that were fed the L-glutamine diet exhibited lower levels of inflammation than did the mice that received the standard control diet.

“Because many of the stomach pathologies during H. pylori infection [including cancer progression] are linked to high levels of inflammation, this result provides us with preliminary evidence that glutamine supplementation may be an alternative therapy for reducing the severity of infection,” explains Hagen, adding that studies in human subjects will be the next step to determine the relevance of this finding in the clinical setting.

H. pylori bacteria infect more than half of the world’s population and were recently identified as a Group 1 carcinogen by the World Health Organization,” she adds. “Approximately 5.5 percent of the entire global cancer burden is attributed to H. pylori infection and, worldwide, over 900,000 new cases of gastric cancer develop each year. The possibility that an inexpensive, easy-to-use treatment could be used to modify the damaging effects of H. pylori infection warrants further study in clinical trials.”

 

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Study coauthors include MIT investigators James Fox, Nancy Taylor and Barry Rickman and BIDMC investigators Jin-Rong Zhou and George Blackburn.

This study was supported by grants from the National Institutes of Health.

BIDMC is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit

Diverse intestinal viruses may play a role in AIDS progression

Contact: Elisabeth Lyons
elyons@cell.com
617-386-2121
Cell Press

In monkeys and humans with AIDS, damage to the gastrointestinal tract is common, contributing to activation of the immune system, progressive immune deficiency, and ultimately advanced AIDS. How this gastric damage occurs has remained a mystery, but now researchers reporting in the Cell Press journal Cell provide new clues, implicating the presence of potentially pathogenic virus species other than the main virus that causes AIDS. The findings could provide an opportunity to explain and eventually intervene in the processes that lead to AIDS progression.

To investigate what causes gastrointestinal damage in monkeys and humans with AIDS, researchers used a sequencing method that allows them to obtain genetic sequences of all of the bacterial, viral, and other organisms residing in the gastrointestinal tract. Using this technique, they examined the feces of monkeys with SIV-induced AIDS, monkeys without SIV infection, and monkeys infected with SIV strains that do not cause AIDS. (SIV is the monkey counterpart to HIV.)

“We found that the gastrointestinal tract of the animals with AIDS contained a large number of previously undescribed viruses—including potential pathogens, but we did not see any obvious changes in the bacteria. This means that previously unrecognized viruses may contribute to AIDS disease progression in monkeys,” explains co-author Dr. Dan Barouch, of Harvard Medical School and the Beth Israel Deaconess Medical Center, in Boston. It’s not clear why monkeys with AIDS have more intestinal viruses, but it may be related to their compromised immune system.

The researchers also noted that some of the viruses in the feces of monkeys with AIDS were also found circulating in the animals’ blood. In addition, many were RNA viruses, meaning that their genetic material is made up of RNA rather than DNA. “This is the first time anyone has looked at both DNA- and RNA-based organisms in the fecal matter in association with AIDS. The striking finding of so many RNA viruses to go along with DNA viruses opens up the broader issue of whether we need to rethink how we study the genomes of microorganisms that may affect disease,” says senior author Dr. Herbert Virgin, of the Washington University School of Medicine, in Saint Louis.

In addition to providing new information on how AIDS advances, and therefore how to potentially intervene to slow it down, the results indicate that the viruses found in AIDS patients’ intestines could indicate how progressive their disease will be.

 

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Handley et al.: “Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome.”

Intestinal bacteria promote — and prevent — inflammatory bowel disease

2008 – re-post for filing

Contact: David Cameron
david_cameron@hms.harvard.edu
617-432-0441
Harvard Medical School

BOSTON, Mass. (May 28, 2008)—Scientists search for drug candidates in some very unlikely places. Not only do they churn out synthetic compounds in industrial-scale laboratories, but they also scour coral reefs and scrape tree bark in the hope of stumbling upon an unsuspecting molecule that just might turn into next year’s big block buster. But one region that scientists have not been searching is their guts. Literally.

Now, a team of researchers at Harvard Medical School, Brigham and Women’s Hospital, and the California Institute of Technology have demonstrated that a molecule produced by bacteria in the gut’s intestinal microflora can eliminate symptoms of inflammatory bowel disease (IBD), a condition that includes Crohn’s disease and ulcerative colitis, in animal models.

“Given the sheer number of bacteria in the gut, the potential for discovering new molecules that can treat a whole range of these diseases is promising,” says Dennis Kasper, co-lead author on the study, professor of medicine and microbiology and molecular genetics at Harvard Medical School, and director of the Channing Laboratory at Brigham and Women’s Hospital.

The study will appear as the cover story in the May 29 issue of Nature.

Scientists have known for many decades that the mammalian gut is an ecosystem teeming with approximately 1,000 different species of bacteria, species as distinct from the host as a single-cell amoeba in pond scum. Rather than causing disease, these bacteria are responsible for protecting against infection and aiding digestion. An increasing number of scientists also suspect that recent increases in asthma and even certain food allergies are caused by disruptions in the delicate balance of this intestinal ecosystem.

In 2005, Kasper and Sarkis Mazmanian, then a postdoc in Kasper’s lab and now an assistant professor of biology at the California Institute of Technology, discovered that a species of intestinal bacteria called Bacteroides fragilis could restore immune system balance in mice that were bred to lack intestinal bacteria. A particular product of B. fragilis, a sugar molecule called polysaccharide A (PSA), recovered the equilibrium of a certain subclass of immune system cells (called Th1 and Th2) whose levels became skewed when bacteria in the gut were absent. The researchers referred to PSA as a “symbiosis factor,” one that established a beneficial link between bacteria and mammals. This was the first study in which such a link was demonstrated.

Interestingly, when the study was completed, Kasper and Mazmanian found in these mice an abundance of immune system cells that were known to protect against colitis and Crohn’s disease. In the current report, the groups decided to expand these findings and explore potential links between PSA and inflammatory bowel disease.

When immunocompromised mice with a specific pathogen-free microbiota were given an intestinal bacterium called Helicobacter hepaticus, they soon developed “rip roaring” IBD, according to Kasper. However, when Helicobacter was combined with B. fragilis, the mice were fine. Further experiments revealed that PSA—the special sugar molecule—was the key factor in preventing IBD. In fact, when mice were given Helicobacter combined with PSA purified from B. fragilis bacteria, they showed no symptoms of IBD.

“But then the key question was, if PSA was essential for preventing these animals from coming down with either colitis or Crohn’s, how did it do it”” says Kasper. “What was the mechanism””

The answer came by studying a subset of interleukins, that is, molecules secreted by immune cells.

Previous studies had shown that two particular interleukins, called IL-17 and IL-23, promote intestinal inflammation and are present at high levels in IBD patients. Here, while the researchers found IL-17 and IL-23 in the guts of animals who had received Heliobacter alone, these interleukins were absent from animals who had also received both PSA-producing B. fragilis and purified PSA.

“We realized that something in PSA must be preventing the inflammation that causes colitis and Crohn’s, which would explain the reduction in IL-17 and IL-23,” says Kasper.

This hunch brought the researchers to consider a third interleukin, IL-10. The opposite of IL-17 and IL-23, IL-10 is anti-inflammatory and had previously been shown to protect against experimental colitis.

The researchers once again administered Helicobacter and PSA-active B. fragilis (the combination that had previously led to healthy mice), only this time they included an antibody that blocked IL-10. As a result, the mice all came down with IBD.

“This demonstrated for us the mechanism by which PSA protects against IBD,” says Kasper.

Indeed, the researchers deduced that PSA prompts immune system cells to secrete IL-10, which in turn suppresses the inflammation caused by IBD. In other words, PSA is an anti-inflammatory.

This research should encourage people (including many scientists) to consider the vast potential for beneficial contributions to human health by “good” bacteria. And what’s more, “This is the first time that a beneficial molecule produced by intestinal bacteria has been shown to work therapeutically in an animal model,” says Mazmanian.

The researchers caution that these findings do not promise any near-term treatments for IBD. “PSA might do the same thing in humans, and it might not,” says Kasper.

However, the mechanism that they’ve discovered should persuade scientists and drug manufacturers to consider new sources for expanding the drug pipeline.

“There is currently no effort to develop molecules that are naturally made by bacteria to use therapeutically,” continues Mazmanian. “This study opens up that possibility.”

 

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Full citation:
Nature, May 29, 2008, 453 (7195), 620-624
“A microbial symbiosis factor prevents intestinal inflammatory disease”
Sarkis K. Mazmanian(1), June L. Round(1) & Dennis L. Kasper(2,3)

1-Division of Biology, California Institute of Technology, Pasadena, California.
2-Channing Laboratory, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
3-Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts

Harvard Medical School (http://hms.harvard.edu/hms/home.asp) has more than 7,500 full-time faculty working in 11 academic departments located at the School’s Boston campus or in one of 47 hospital-based clinical departments at 18 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Cambridge Health Alliance, Children’s Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Immune Disease Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.

Brigham and Women’s Hospital (http://www.brighamandwomens.org/) is a 747-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 860 physician-investigators and renowned biomedical scientists and faculty supported by more than $416 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses’ and Physicians’ Health Studies and the Women’s Health Initiative.

Study targets key molecule to reverse kidney damage in mice

Test likely to proceed to clinical trials

BOSTON — In findings that may lead to clinical trials of a promising new drug for kidney disease, researchers at Beth Israel Deaconess Medical Center (BIDMC) and their colleagues have identified a key molecular player and shown how a targeted experimental drug can reverse kidney damage in mouse models of diabetes, high blood pressure, genetic kidney disease, and other kidney injuries.

The study builds on a discovery that, in mice, a key protein can repair and reverse renal fibrosis, the critical damage caused by different kidney diseases in humans. The new paper details 10 years of methodical follow-up experiments to understand, verify and harness the protective molecular process with a new drug that can be tested in people. The paper appears in the March 2012 issue of Nature Medicine.

“This paper reports the discovery of one of the first targeted drugs specifically developed to reverse fibrosis and regenerate the kidney,” said senior author Raghu Kalluri, MD, PhD, Chief of the Division of Matrix Biology at BIDMC and Professor of Medicine at Harvard Medical School (HMS). “We’re optimistic about the benefits, but the real proof will come from clinical testing.”

Chronic kidney disease is becoming a major public health problem, partly due to the increase in obesity, diabetes, hypertension and an aging population. It affects one out of every 10 people older than 20, and is most prevalent in those over 60. Most people with impaired kidney function are in the early stages and have no symptoms, but deteriorating kidneys significantly raise the risk of death by cardiovascular disease. Those who survive heart attacks and strokes can progress to end-stage renal disease, which requires dialysis in most cases or transplants when donor kidneys are available.

“The field is desperate for new interventions that can halt or slow the progression of renal failure,” said nephrologist Qais Al-Awqati, MB, ChB, a professor of medicine and physiology at Columbia University and immediate past editor of the journal Kidney International. Al-Awqati, who was not involved in the study, notes that kidney disease is the third leading cause of death in the U.S.

In the kidneys and other organs, fibrosis develops from normal repair mechanisms that do not stop. Scar tissue slowly builds up and replaces the working cells of the organ. In 2003, Kalluri’s lab reported that the destructive fibrosis in mice can be countered by the human protein BMP-7, originally named for its ability to spur bone growth. A manmade version of BMP-7 is approved by the U.S. Food & Drug Administration (FDA) to help repair long bones and vertebrate disks. However, the large protein needs to be injected or surgically implanted and, therefore, is not useful for long-term treatment protocols.

Kalluri and his colleagues continued their studies, seeking a smaller molecule that could be taken by mouth in a pill form in order to more specifically exert its protective effect on the kidney. Probing deeper into the biology of the kidney, they identified the protein Alk3, which is not the protein’s primary partner in bone.

Soon after the BIDMC team identified the key receptor Alk3 in the lab, they collaborated with a Canadian biotechnology company, Thrasos Therapeutics, interested in developing targeted therapies for the prevention and treatment of severe organ failure, especially kidney disease. Based on the details about the molecular interaction between the BMP protein and the ALK receptor, company scientists developed a class of small functional peptides, including THR-123, which then underwent further testing.

Researchers in the Kalluri lab used the experimental compound to document the role of the receptor in reversing the fibrosis and allowing normal tissue to regenerate in one mouse model after another. “This receptor must be present for the new molecule to function,” said Kalluri. Working through the receptor, the molecule suppressed inflammation, cell death and fibrosis formation, as well as reversing established fibrosis and allowing kidneys to regenerate functional cells, he adds.

Further experiments showed that the test drug worked even better in the mice when given in combination with ACE inhibitors, the anti-hypertensive drugs now considered a standard therapy for chronic kidney disease which work by targeting another molecular process.

“Targeting the receptor not only stops fibrosis, it removes established fibrosis, and it works in combination with an existing drug used in patients,” Kalluri notes. “The next step is to test this molecule in the clinic.”

The mice studies are “a good first step,” said Al-Awqati. “It will be interesting to pin down the role of the BMP-7 pathway in kidney fibrosis in people.”

Going forward, Kalluri’s group will continue to study these molecular players and their roles in fibrosis in other organs, including the liver, lung, intestine and heart in the hopes of expanding the experimental-drug pipeline. “If you don’t have a pipeline of experimental drugs, how will you succeed in coming up with new drugs?” he asks.

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This study was supported by several project and training grants from the National Institutes of Health, and the Else Kroner-Memorial-Stipend. Kalluri discloses that in the past he has held stock options (subsequently returned to the company unexercised) and received de minimus payments for consulting for Thrasos Therapeutics, Inc.

Study coauthors include BIDMC investigators Hikaru Sugimoto, Valerie S. LeBleu, Gangadhar Taduri, Wibke Bechtel, Hirokazu Okada, Keizo Kanasaki and Michael Zeisberg; Thrasos Therapeutic investigators Dattatreyamurty Basukonda, and Peter Keck; William Carlson Jr. of Thrasos Therapeutics and Massachusetts General Hospital; Mary Rusckowski of the University of Massachusetts Medical College; and Bjorn Tampe and Desiree Tampe of Goettingen University Medical Center, Goettingen, Germany.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

New study demonstrates bone protein can reverse kidney failure

Contact: Bonnie Prescott bprescot@bidmc.harvard.edu 617-667-7306 Beth Israel Deaconess Medical Center

BOSTON – A new study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has shown that a protein used to heal fractured bones is effective in repairing and reversing chronic renal disease, a leading cause of morbidity and mortality throughout the U.S.

These findings, which are reported in the July 2003 issue of Nature Medicine, could help lead to the development of a therapeutic alternative for the nearly 300,000 kidney disease patients who are currently undergoing dialysis.

“Dialysis is not really a treatment, it’s just a means of survival until an opportunity for a transplant opens up,” notes the study’s senior author Raghu Kalluri, Ph.D., director of the Center for Matrix Biology at BIDMC and Associate Professor of Medicine at Harvard Medical School. “This is a very tedious way of living life,” he adds, explaining that the process of mechanically filtering blood through a machine to remove waste products must be performed several times a week for a period of three to four hours per visit, posing risks of infection and other side effects. Furthermore, the procedure is extremely costly.

The kidneys function as a filtration system, keeping the body’s blood supply healthy by removing excess fluids and wastes, as well as by producing hormones.  When kidneys “fail” – as can result from complications associated with diabetes, lupus or several other diseases – harmful wastes accumulate in the bloodstream, excess fluids build up in the body, and red blood cell production is impeded. Once chronic kidney disease develops, it cannot be reversed or repaired; when the organs cease to function, patients have no alternative but to undergo dialysis while awaiting a kidney transplant.

This new study looked at the role of a molecule called bone morphogenic protein (BMP)- 7 which, in its recombinant form, has been approved by the U.S. Food and Drug Administration for the treatment of bone fractures. Earlier studies had revealed that BMP-7 is highly expressed in the kidneys of healthy individuals. “We wanted to learn if this protein was somehow offering protection against kidney injury,” explains Kalluri.

The investigators used mouse models of chronic renal injury, characterized by the presence of scar tissue known as renal fibrosis; once kidney disease was well-established in the animals, they administered human recombinant BMP-7.

“We found that in the kidneys, BMP-7 reverses a process known as epithelial-to-mesenchymal transition, which generates scar-causing cells known as fibroblasts,” says Kalluri, explaining that BMP-7 first reduces the number of the fibroblast cells, and then replaces the damaged areas of the kidney tubules with healthy epithelial cells. “In effect,” he adds, “BMP-7 is decreasing the bad cells [in this context, fibroblasts] and converting them into good cells [in this context, epithelial cells].”

Although therapies exist to slow progression of kidney disease, once it has developed it becomes intractable, eventually leaving patients no alternative but to undergo dialysis. “The possibility of creating a cost-effective drug that would actually reverse renal injury could significantly reduce the need for dialysis and significantly improve the quality of life for these patients,” says Kalluri.

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Study co-authors include BIDMC investigators Michael Zeisberg, M.D., Jun-ichi Hanai, M.D., Hikaru Sugimoto, M.D., Ph.D., Tadanori Mammoto, Ph.D., David Charytan, M.D., and Frank Strutz, M.D.

This study was funded by grants from the National Institutes of Health, Deutsche Forschungsgemeinschaft, and support from the Center for Matrix Biology, BIDMC. Ortho Biotech Products, L.P., is the exclusive licensee of BMP-7.

Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical School, and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a founding member of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox

* Requested Repost

The Cancer “Breakthroughs” that Cost Too Much and Do Too Little

Author

Laura Beil, Newsweek

Aug 27, 2012 1:00 AM EDT

‘Death panels’ are a bad idea. But asking hard questions about health care is not.

In his more than 35 years of practice, Dr. Lowell Schnipper has seen a lot of women die from breast cancer. A patient’s options start to dwindle by the time tumor cells set up outposts in the bones, lungs, and other organs, defying all attempts to keep them under control. But in June, when the government approved Perjeta, Schnipper had something new to offer. The drug is one of an innovative class of drugs known as “targeted therapies.”

As the chief of oncology at Beth Israel Deaconess Medical Center in Boston, Schnipper knew Perjeta was not a cure: added to a standard treatment with Herceptin—another targeted therapy that was hailed as a breakthrough in 1998—Perjeta gives the average woman only about six months more of calm before her disease starts to stir again. Given the limited benefit, the price was startling. For most women, a full course of the drug combination will cost $188,000—enough, he says, “to give anybody a cold sweat.”

Americans spent more than $23 billion last year for cancer drugs, more than we paid for prescriptions to treat anything else. But many oncologists are starting to question what we are getting in return for that bill, whether the war on cancer has become too much of a race to produce the next blockbuster. “In general, progress for cancer has been halting and slow,” says David Howard of the Department of Health Policy and Management at Emory University. So far, most new drugs offer only marginal extensions of life and few cures. Howard says new so-called breakthroughs “overpromise and underdeliver.” Consider the popularity of Avastin, a targeted drug approved for metastatic colon cancer in 2004. A recent study found that almost 70 percent of patients on chemotherapy were receiving Avastin within a year of its release. In clinical trials, the drug increased survival by about five months. The cost? About $10,000 a month.

Treating cancer has never been cheap, but today, the price of each new treatment seems to outpace the one before, with little bearing on its efficacy. According to figures from insurer United Healthcare, a standard cocktail of drugs for treating lung cancer used to run about $1,000 a month. Today’s regimens cost from more than $6,000 to almost $10,000—for about two more months of life. “There is no such thing as a cancer drug coming on the market that is some sort of regular drug price,” says Dr. Peter Bach of Memorial Sloan-Kettering Cancer Center in New York, who studies the impact of cancer costs on U.S. health care. “They’re all priced at spectacularly high levels.” Which leads to an unsettling question: how much is a little more time worth? Would you spend $50,000 for four more months? How about $15,000 for two weeks?

Of three frontiers in cancer treatment, targeted therapies like Perjeta are widely seen as the best hope for a cure. Traditional chemotherapy is notorious for side effects because it wields destruction indiscriminately throughout the body. Targeted therapies are designed to hit cancer cells only. Perjeta, for example, targets a protein produced in excess amounts in some breast cancers; Avastin hinders the ability of a tumor to form new blood vessels to feed itself.

Dan Dunkley / Gallerystock.com

Doctors envision the day when every patient will have therapy precisely matched to the genetic bull’s-eyes of their own cancers. The holdup has been that cancer has proven to be more genetically crafty than researchers once imagined. Scientists may build a drug to hit one target, but a tumor may also employ lots of yet-undiscovered genetic tricks to keep itself alive. Instead of a magic bullet, scientists now know that any particular tumor may need lots of magic bullets. With so many targets unknown, a lot of patients end up getting drugs that barely touch their cancers, which is why the effectiveness of many new drugs remains underwhelming.

Not that this keeps a drug from becoming a blockbuster. Patients with advanced cancer, and their physicians, are hungry for progress. As a result, almost all of the 10 bestselling cancer drugs are targeted therapies, many less than a decade old. All came on the market at thousands of dollars a month, a trend that continues today with gusto. The drug Afinitor, a daily pill, was approved in July for patients with breast cancer. It costs more than $200 a tablet. But price rarely matters to patients or even doctors, says Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans. “People have already been told there is no cure for their disease,” he says. “Every increment, every improvement, gives hope, and when options are extremely limited, we all focus on the positive possibilities.”

In addition to targeted therapies, drugs have come on the market that can spur the body’s own immune cells to lead the charge. Significant hurdles have hindered this kind of treatment for years. But they are finally being overcome. The prostate cancer drug Provenge, which came on the market in 2010, was the first immune-therapy drug to gain governmental approval. It was followed the next year by Yervoy, when approved the only drug ever shown to extend survival in advanced melanoma. Men with a common kind of advanced prostate cancer who used Provenge lived an average of four months longer than the comparison group; patients on Yervoy got an average of 3.6 months. The gains are modest, but not the cost. When Sartor learned Provenge would run $93,000 per patient, “I was stunned,” he says. And even that was cheaper than Yervoy, which appeared the following year at $120,000 for four injections. He predicts the pricing of immune therapies may be seen as “a watershed moment” in the debate over health-care costs.

The third area of touted breakthroughs has been in radiation, most recently by using protons instead of traditional X-rays to kill cancer cells. It’s a controversial undertaking: many doctors believe that protons offer better precision, able to get rid of tumors without collateral damage to nearby healthy tissues. But whether protons can treat with fewer side effects than traditional radiation is, to date, a matter of debate for almost all but pediatric and certain neurological tumors.

As with new drugs, proton-beam radiation is expensive—it can run roughly twice as much as the current state-of-the-art form of radiation that uses X-rays. In the case of proton beams, much of the cost has to do with building a cyclotron to harvest the protons—a construction project that can cost upwards of $150 million. In 2001 just three centers in the country offered proton treatment, but that number is now up to 10, with a half dozen more planned. About three quarters of the proton patient population covered by Medicare are men with prostate cancer, which, because of the length of their therapy, are the most lucrative to treat.

Why do new drugs cost so much? Pharmaceutical companies say it’s payment for scientific creativity, that high prices are necessary to recover the expense of developing and manufacturing their products and to encourage more research. A spokeswoman for Bristol-Myers Squibb, which makes Yervoy, says the cost of drugs is “based on a number of factors, including the value they deliver to patients, the scientific innovation they represent, and the cost to develop them.” Part of the price is also an investment in drug discovery. “We look at not only the past research and development, but development in the future,” says Krysta Pellegrino, a spokeswoman for Genentech, which developed Perjeta.

That said, many cancer experts remain skeptical of the notion that drug companies are simply passing along the cost of doing business and funding the incubation of new drugs. In 2004 researchers tried to test the relationship between a drug’s development and its final asking price. In the Journal of Clinical Oncology, the scientists concluded “that the drug companies are not pricing their drugs to recuperate losses associated with research and development, marketing, and operating prices, but rather [the average wholesale price] depends on what the market itself can bear.”

“It’s a marketplace where the seller has all of the control,” says Bach, from Memorial Sloan-Kettering, because private insurance companies and Medicare—the largest purchasers of drugs—are powerless to bargain for a less expensive deal. “Prices are high because they can be,” Bach says. As one doctor observed, “we are always paying for a Ferrari but often getting a Ford.” The occasional Ferrari does exist. The targeted drug Gleevec, which treats certain forms of leukemia and intestinal tumors, has allowed patients to live for years with their cancer in check.

But while the track record for some new treatments is expected to improve, Dr. Otis Brawley, chief medical and scientific officer of the American Cancer Society, says that in most cases, “new cancer treatments cost an awful lot of money, and there is usually a very small incremental benefit.” Brawley, author of How We Do Harm: A Doctor Breaks Ranks About Being Sick in America, likes to cite the case of Tarceva, a targeted therapy approved for pancreatic cancer in 2005 to piggyback on the traditional drug gemcitabine. “The median survival of Tarceva and gemcitabine compared to gemcita-bine alone was 14 to 16 days greater. Seven months versus seven and a half months.” A 2007 analysis in the Journal of Clinical Oncology determined that those extra days add around $15,000 to the cost of care. “Instead of talking about rationing care,” Brawley says, “we need to talk about rational use of care.”

If new cancer treatments continue to push the boundaries of affordability, Americans will eventually be forced into dilemmas we have largely postponed. Innovative cancer treatments, says Emory’s Howard, “really symbolize the tradeoff that we face between improving health and saving money. At some point, society—including employers, the government, patients, and clinicians—have to make a tradeoff. I think if these drugs cured the disease, which none of them do, then no one would be questioning these prices. But we are seeing very high cost for relatively little return in patient benefit and survival.”

Other countries already consider a treatment’s effectiveness in national discussions about whether to pay for it. For example, this summer in Israel, a panel of radiation oncologists advised the Israeli Ministry of Health that, because of the unproven benefits, spending public money on proton-beam treatment is not yet warranted. “We can’t say it is a justifiable expense,” says Dr. Abraham Kuten, director of oncology at Rambam Medical Center in Haifa. The United Kingdom affirmed in July, for the second time, that it will not cover Avastin for advanced breast cancer. Australia, which has one of the world’s highest incidences of melanoma, decided in March that the benefits of Yervoy are not worth the cost to the country’s national health-care system; it based its decision on an independent government advisory committee, which cited the questionable benefit to patients and the drug’s “uncertain clinical place in therapy.”

Then there is the United States, where wider access to drugs may be one of the reasons our cancer survival times rank among the highest worldwide. But the question is how long we can afford what we’re getting. “I think we are the only industrialized country that doesn’t look at the cost balanced somehow with effectiveness in making decisions about drugs,” says Dr. Thomas Smith of the Sidney Kimmel Comprehensive Cancer Center in Baltimore. “What we have now are a bunch of blockbuster-ette drugs that give a little bit of benefit. If you’re that person, it could be a really big benefit to have three extra months before your disease starts growing again, but as a society we simply can’t pay for that for everybody.”

Yet aside from academics and insurance-company executives, few Americans are willing to consider the price of time, says Dr. Lee Newcomer, senior vice president for oncology at United Healthcare. This means that the government sinks further into debt, and insurance companies keep raising premiums to keep up. “If we’re going to continue to have a sustainable health system, we have to talk about that as a society. In 15 years, you will have to earn the equivalent of a year’s salary today to pay your health-insurance premiums,” he says. “We’re going to have to have the discussion.”

Laura Beil is an independent journalist based in Dallas