How human biology can prevent drug deaths

Thousands of people die from adverse effects of medicines that have been tested on animals. There is a better way, say geneticist Kathy Archibald and pharmacologist Robert Coleman

ADVERSE drug reactions are a major cause of death, killing 197,000 people annually in the European Union and upwards of 100,000 in the US. Little coverage is given to such grim statistics by governments or pharmaceutical companies, so patients and their doctors are not primed to be as vigilant as they should be, and adverse drug reactions (ADRs) remain seriously under-recognised and under-reported.

The €5.88-million EU-ADR project, which published its final report in October, showed that it is possible to spot these reactions earlier by applying data-mining techniques to electronic health records. These techniques could, for example, have detected the cardiovascular risk signals of arthritis drug Vioxx three years before the drug was withdrawn in 2004 - saving many tens of thousands of lives. But invaluable as such systems are, it would be even better to detect risk signals before a drug reaches humans, thus saving even more lives.

Currently, 92 per cent of new drugs fail clinical trials, even though they have successfully passed animal tests. This is mostly because of toxicity, which can be serious and even fatal for the people taking part in the trials. For example, in 2006, six people enrolled in a UK trial of the drug TGN1412 were hospitalised after developing multiple organ failure. Many clinical trials are now conducted in India, where, according to India's Tribune newspaper, at least 1725 people died in drug trials between 2007 and 2011. Clearly, there is an urgent need for better methods to predict the safety of medicines for patients as well as volunteers in clinical trials.

At the patient safety charity, Safer Medicines, we believe this goal is most likely to be achieved through a greatly increased focus on human, rather than animal, biology in preclinical drugs tests. New tests based on human biology can predict many adverse reactions that animal tests fail to do, and could, for example, have detected the risk signals produced by Vioxx, which in animal studies appeared to be safe, and even beneficial to the heart.

These techniques include: human tissue created by reprogramming cells from people with the relevant disease (dubbed "patient in a dish"); "body on a chip" devices, where human tissue samples on a silicon chip are linked by a circulating blood substitute; many computer modelling approaches, such as virtual organs, virtual patients and virtual clinical trials; and microdosing studies, where tiny doses of drugs given to volunteers allow scientists to study their metabolism in humans, safely and with unsurpassed accuracy. Then there are the more humble but no less valuable studies in ethically donated "waste" tissue.

These innovations promise precious insights into the functioning of the integrated human system. Many are already commercially available, but they are not being embraced with the enthusiasm they merit.

Pharmaceutical companies would make much greater use of them if governments encouraged it, but inflexible requirements for animal tests is a major deterrent. Ever since the thalidomide birth-defects tragedy, animal testing has been enshrined in law worldwide, despite the irony that more animal testing would not have prevented the release of thalidomide, because the drug harms very few species.

So how well have animal tests protected us? Many studies have calculated the ability of animal tests to predict adverse reactions to be at or below 50 per cent. In 2008, a study in Theriogenology (vol 69, p 2) concluded: "On average, the extrapolated results from studies using tens of millions of animals fail to accurately predict human responses." And a recent study in Regulatory Toxicology and Pharmacology (vol 64, p 345) shows that animal tests missed 81 per cent of the serious side effects of 43 drugs that went on to harm patients.

It is hard to understand why governments defend a system with such a poor record, or why they are dismissive of new technologies that promise increased patient safety while decreasing the time and cost of drug development, not to mention the savings to healthcare systems from fewer adverse drug reactions. Proposals to compare human-based tests with animal-based approaches have been strongly supported by members of the UK parliament. The Early Day Motions they signed were among the most-signed of all parliamentary motions between 2005 and 2006, 2008 and 2009, and 2010 and 2012.

Safer Medicines has put these concerns to the UK Department of Health and the prime minister - to be told that "human biology-based tests are not better able to predict adverse drug reactions in humans than animal tests".

It is a tragedy that so many suffer or die through the use of inadequately tested drugs when tests based on human biology are readily available. Yet governments continue to mandate animal tests, despite the lack of a formal demonstration of fitness for purpose, and a growing global realisation among scientists that animal toxicity tests are inadequate and must be replaced.

In its 2007 report, Toxicity Testing in the 21st Century: A Vision and a Strategy, the US National Research Council called for the replacement of animal tests: "The vision for toxicity testing in the 21st century articulated here represents a paradigm shift from the use of experimental animals... toward the use of more efficient in vitro tests and computational techniques." To its credit, the US government is at least working on initiatives to hasten this. The UK government, however, still denies there is a problem. How many must die before it listens?

Kathy Archibald is director of the Safer Medicines Trust. She is a geneticist who worked in the pharmaceutical industry.

Robert Coleman is a pharmacologist with pharmaceutical industry experience. He is now a drug discovery consultant and adviser to the trust

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PM Lee congratulates Japan's Shinzo Abe on election win

SINGAPORE: Prime Minister Lee Hsien Loong has congratulated the leader of the Liberal Democratic Party of Japan, Mr Shinzo Abe, on the party's victory in the lower house elections.

In a letter, Mr Lee said he looks forward to working closely with Mr Abe to improve bilateral ties.

Mr Lee said Singapore and Japan share a longstanding and strong relationship and that bilateral relations are comprehensive, comprising deep economic links and mutually beneficial cooperation in areas such as defence, health and cultural exchanges.

He added that Singapore will continue to support Japan's recovery efforts from the Tohuku disasters last year.

PM Lee said Singapore remains committed to a peaceful and prosperous Asia, and believes that Japan has a major contribution to make in building such a region.

Singapore will work closely with Japan in ASEAN and other multilateral fora to achieve this goal.

- CNA/lp

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Apple: Top 5 events from 2012

Apple spent 2012 much like it did the year before: relentlessly pushing out new products. But that's nothing new.

Instead, tech historians will likely look back at 2012 as one of the company's most transformative years. A time where we saw some of the first pieces of a post-Jobs Apple begin to take shape.

Five key news events marked Apple's 2012, from products to company controversy.

Editor's note: This is the first in a series of stories chronicling the top five events during 2012 for a handful of major technology companies, and technology categories. In the coming days CNET will also recap major events for Google, Facebook, Microsoft, Amazon, and others.

1. Apple v. Samsung
What's more interesting than watching rivals duke it out? When they're also multibillion-dollar-a-year business partners with one another, as was the case between Apple and Samsung.

This legal war began in 2011 when Apple sued the South Korean technology giant. But 2012 was the banner year for the fight as those lawsuits went to trial in a Northern California court.

The three-week-long trial provided hours upon hours of testimony from witnesses on both sides. But what really captured the public's interest were some of the secrets unearthed along the way. That included numerous photos of Apple's iPhone and iPad prototypes as well as internal e-mails, and presentations from both sides. Samsung ended up losing considerably, as the jury sided with Apple in nearly all of its claims.

The two companies went back to court earlier this month to sort out a number of remaining details, including whether Apple can get a permanent sales ban on at least eight of Samsung's devices in the U.S., and whether Samsung can persuade a judge to grant a retrial. There's also a separate trial between the two set for 2014 concerning some of the newer devices.

Apple CEO Tim Cook visits Foxconn's Zhengzhou factory line.

(Credit:
Bowen Liu/Apple Inc. / Bloomberg)

2. Apple in China
Apple's annual supplier responsibility report made waves immediately upon its release in January. For one, the company for the first time released a full list of its suppliers. Apple also joined the Fair Labor Association, who would go on to begin auditing Apple's suppliers and production facilities.

Any positive findings were quickly overshadowed by a series of reports from The New York Times, lambasting the manufacturing side of Apple's business, something near and dear to CEO Tim Cook. While Apple's chief operating officer, Cook is credited with utilizing overseas manufacturers to very quickly produce massive numbers of computers, iPods, and now iPhones and iPads.

The reports, which weren't the first to be critical on the matter, homed in on Apple for poor labor and safety issues in its supplier facilities, as well as for using business practices that prohibited those manufacturers from making improvements. In its own annual supplier report, Apple said it found issues with working hours and compliance with environmental standards.

Cook responded to the situation in a memo to employees (which was leaked), saying the company cared about "every worker in our worldwide supply chain," and that "any suggestion that we don't care is patently false and offensive to us." Cook then made a public appearance at a technology conference put on by Goldman Sachs to reiterate those claims. He followed that with a trip to China, where he was photographed next to workers on the shop floor of Foxconn, donning some of the same protective clothing.

Actor Mike Daisey.

(Credit:
Courtesy Ursa Waz)

Alongside the issue was newfound criticism of one of Apple's staunchest labor critics, Mike Daisey, who penned his one-man show "The Agony and the Ecstasy of Steve Jobs" after traveling to Shenzhen, China. The monologue, which debuted in 2010, highlighted labor issues in Chinese factories, from underage workers to people being poisoned by industrial chemicals while producing Apple's gadgets.

In March, popular radio program This American Life issued a retraction of a show it ran featuring a large portion of Daisey's monologue, followed by an indepth report by host Ira glass and American Public Media's China correspondent, Rob Schmitz, refuting a number of the claims made by Daisey.

Concerns about overseas manufacturing, and Apple's involvement persist. A report from the Students and Scholars Against Corporate Misbehavior said in September that those in a key Foxconn factory in China that produces iPhones still faced "deplorably harsh working conditions," among other violations of Chinese law. Foxconn said the report did not represent the 192,000 employees who worked at the facility. Just three days later, 2,000 workers at a Foxconn factory in a different part of the country erupted in a riot, reportedly over a spat between a worker and a guard. The plant, which employed 79,000 employees at the time, was closed and reopened a day later.

More recently, an investigative report from French TV program Envoyé Spécial claimed there were still some major worker rights issues, including workers living in unfinished buildings without water or electricity. The report made use of hidden-camera footage captured at Foxconn's campus in Zhengzhou.

Scott Forstall, senior VP of iOS Software set to depart Apple next year.

(Credit:
James Martin/CNET)

3. Executive shakeup
While the East Coast of the U.S. was reeling from Hurricane Sandy, Apple quietly announced the departure of two of its top executives, including one who was thought to be a future candidate for CEO.

Apple said iOS chief Scott Forstall would be leaving the company next year, while retail chief John Browett was out immediately. Picking up the remaining responsibilities were top execs Jony Ive, Eddy Cue, and Craig Federighi, who Apple said would stay on with expanded roles. Hardware chief Bob Mansfield also took on a new position heading up a division that focuses on semiconductors and cellular technologies.

The change was the first major shift in top management since the death of Steve Jobs. While Tim Cook promoted several key players to greater positions within the company's executive team shortly after he became CEO, Apple positioned the newer change as something that would improve collaboration.

In the aftermath, what caught everyone's attention were numerous reports painting Forstall as a divisive player among Apple's top brass. A report from The Wall Street Journal, for instance, claimed that Forstall refused to sign Apple's apology over the quality of its new maps software, instead leaving it up to Cook -- something that ultimately led to his firing. Meanwhile, Browett's departure (which was also said to be a firing), left the company searching for a new boss of its retail operations, a role that is expected to be filled sometime next year.

4. Stock highs, lows, and a dividend
Apple's stock soared to new heights in 2012, reaching an all-time high of $702 on September 21, the same day the
iPhone 5 went on sale. But from there, it became a different story. The focus turned from Apple's quick and steady growth to an equally speedy decline, as shares fell nearly 20 percent in the course of a month. Some analyst firms like Merrill Lynch, Jefferies, Evercore, and Nomura Equity Research reduced their price targets, but maintained recommendations to buy.

In March, Apple announced plans to pay a dividend to investors as well as buy back $10 billion worth of its stock, answering what had become a frequent question at investor meetings and quarterly conference calls with analysts about how and when Apple would use some of its massive cash hoard.

All told, the plan involves spending $45 billion over its first three years. But the real takeaway is that it set up Apple to become more attractive to a new group of investors who eye dividends for long-term security over big jumps in the sale price.

Apple executive Phil Schiller showing off the iPad Mini for the first time at the company's event in October.

(Credit:
James Martin/CNET)

5. iPad Mini
To be sure, the
iPad Mini was the product everyone was expecting. Rumors in the months and weeks ahead of its release nailed down every specific detail, right down to the buttons, screen resolution, and price.

So why include it on this list you might be asking? The Mini is Apple's first expansion of the iPad line with a completely new model, and one that promises to get more people in the door with a lower price tag. Some even believe that the Mini will quickly become Apple's main iPad, with more consumers choosing to buy it over the larger, more expensive version.

Estimates from some analysts suggest Apple will sell at least 30 million of the smaller
tablets next year, well over the number of iPads Apple sold during the original product's first year. That makes it a product introduction that's hard to ignore.

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Space Pictures This Week: Frosty Mars, Mini Nile, More

Photograph by Mike Theiss, National Geographic

The aurora borealis, also known as the northern lights, illuminates the Arctic sky in a recent picture by National Geographic photographer Mike Theiss.

A storm chaser by trade, Theiss is in the Arctic Circle on an expedition to photograph auroras, which result from collisions between charged particles released from the sun's atmosphere and gaseous particles in Earth's atmosphere.

After one particularly amazing show, he wrote on YouTube, "The lights were dancing, rolling, and twisting, and at times looked like they were close enough to touch!" (Watch his time-lapse video of the northern lights.)

Published December 14, 2012

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'We Can't Tolerate This Anymore,' Obama Says

President Barack Obama said at an interfaith prayer service in this mourning community this evening that the country is "left with some hard questions" if it is to curb a rising trend in gun violence, such as the shooting spree Friday at Newtown's Sandy Hook Elementary School.

After consoling victims' families in classrooms at Newtown High School, the president said he would do everything in his power to "engage" a dialogue with Americans, including law enforcement and mental health professionals, because "we can't tolerate this anymore. These tragedies must end. And to end them we must change."

Mandel Ngan/AFP/Getty Images

President Obama: 'Newtown You Are Not Alone' Watch Video

Sandy Hook Elementary Shooting: Remembering the Victims Watch Video

The president was not specific about what he thought would be necessary and did not even use the word "gun" in his remarks, but his speech was widely perceived as prelude to a call for more regulations and restrictions on the availability of firearms.

The grieving small town hosted the memorial service this evening as the the nation pieces together the circumstances that led to a gunman taking 26 lives Friday at the community's Sandy Hook Elementary School, most first graders.

"Someone once described the joy and anxiety of parenthood as the equivalent of having your heart outside your body all of the time, walking around," he said, speaking of the joys and fears of raising children.

"So it comes as a shock at a certain point when you realize no matter how much you love these kids you can't do it by yourself," he continued. "That this job of protecting kids and teaching them well is something we can only do together, with the help of friends and neighbors, with the help of a community, and the help of a nation."

CLICK HERE for Full Coverage of the Tragedy at Sandy Hook

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Zebrafish made to grow pre-hands instead of fins

PERHAPS the little fish embryo shown here is dancing a jig because it has just discovered that it has legs instead of fins. Fossils show that limbs evolved from fins, but a new study shows how it may have happened, live in the lab.

Fernando Casares of the Spanish National Research Council and his colleagues injected zebrafish with the hoxd13 gene from a mouse. The protein that the gene codes for controls the development of autopods, a precursor to hands, feet and paws.

Zebrafish naturally carry hoxd13 but produce less of the protein than tetrapods - all four-limbed vertebrates and birds - do. Casares and his colleagues hoped that by injecting extra copies of the gene into the zebrafish embryos, some of their cells would make more of the protein.

One full day later, all of those fish whose cells had taken up the gene began to develop autopods instead of fins. They carried on growing for four days but then died (Cell, DOI: 10.1016/j.devcel.2012.10.015).

"Of course, we haven't been able to grow hands," says Casares. He speculates that hundreds of millions of years ago, the ancestors of tetrapods began expressing more hoxd13 for some reason and that this could have allowed them to evolve autopods.

If you would like to reuse any content from New Scientist, either in print or online, please contact the syndication department first for permission. New Scientist does not own rights to photos, but there are a variety of licensing options available for use of articles and graphics we own the copyright to.

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S'pore offers condolences to victims of US school shooting

SINGAPORE: Foreign Affairs Minister K Shanmugam offered his condolences to the victims and families of the Connecticut shooting which left more than 20 dead, including young children.

In his Facebook post, Mr Shanmugam said the news is "heartbreaking".

"Children are innocent, full of life and promise. Cut down in a hail of bullets by a person with a rifle," he said.

He noted there have been so many shootings in the US over the years, that the public is no longer surprised when something like this happens.

He cited a report which indicated that since 2005, there have been multiple-victim shooting every 5.9 days, in the US.

He said reports from the Washington Post and others, put the number of mass shootings this year alone, at between 13 and 20.

Mr Shanmugam said "in no other developed country does this happen so regularly".

He added Singapore can only offer its thoughts and prayers for the victims and their families.

- CNA/xq

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Google will alter search to end FTC antitrust inquiry, says report

The Federal Trade Commission may bring its two-year antitrust investigation of Google to a close by allowing the company to make voluntary changes to its search business, according to a report.

The search giant is said to be readying an announcement about changes to its use of "snippets," bits of text culled from sites such as Yelp and TripAdvisor and displayed in search results, Politico reports, citing unnamed sources. Yelp and others had charged Google with using their content without permission.

Google will also makes tweaks that will allow for easier porting of search-ad campaigns from Google to rival search services, Politico's sources said.

Politico suggested on Tuesday that the FTC may leave the search-related case to the European Commission, which has mounted an investigation of its own. Reuters reported on Tuesday that some Google competitors, sensing a possible defeat, are taking the case to the Justice Department.

Google and the FTC also look to be close to a settlement in a case involving so-called frand -- or standard essential -- patents owned by Google.

Politico said the FTC declined to comment on today's report about the search tweaks, and it said Google would provide only the following statement: "We continue to work cooperatively with the Federal Trade Commission and are happy to answer any questions they may have."

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Space Pictures This Week: Frosty Mars, Mini Nile, More

Photograph by Mike Theiss, National Geographic

The aurora borealis, also known as the northern lights, illuminates the Arctic sky in a recent picture by National Geographic photographer Mike Theiss.

A storm chaser by trade, Theiss is in the Arctic Circle on an expedition to photograph auroras, which result from collisions between charged particles released from the sun's atmosphere and gaseous particles in Earth's atmosphere.

After one particularly amazing show, he wrote on YouTube, "The lights were dancing, rolling, and twisting, and at times looked like they were close enough to touch!" (Watch his time-lapse video of the northern lights.)

Published December 14, 2012

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Conn. Victim's Father Remembers 'Loving' Daughter

(Image credit: Emilie Parker Fund/Facebook)

Emilie Parker, the little girl with the blond hair and bright blue eyes, would have been one of the first to comfort her classmates at Sandy Hook Elementary School, had a gunman’s bullets not claimed her life, her father said.

“My daughter Emilie would be one of the first ones to be standing and giving support to all the victims because that’s the kind of kid she is,” her father, Robbie Parker said as he fought back tears, telling the world about his “bright, creative and loving” daughter who was one of the 20 young victims in the Newtown, Conn., shooting.

“She always had something kind to say about anybody,” her father said.  ”We find comfort reflecting on the incredible person Emilie was and how many lives she was able to touch.”

Emilie, 6, was helping teach her younger sisters to read and make things, and she was the little girls would go to for comfort, he said.

“They looked up to her,” Parker said.

READ: Complete List of Sandy Hook Victims

Parker moved his wife and three daughters to Newtown eight months ago after accepting a job as  a physician’s assistant at Danbury Hospital. He said Emilie, his oldest daughter, seemed to have adjusted well to her new school, and he was very happy with the school, too.

“I love the people at the school. I love Emilie’s teacher and the classmates we were able to get to know,” he said.

      (Image Credit: Alex von Kleydorff/AP Photo)

The family dealt with another tragic loss in October when Emilie lost her grandfather in an accident.

“[This] has been a topic that has been discussed in our family in the past couple of  months,” Parker said. “[My daughters ages 3 and 4] seem to get the idea that there’s somebody who they will miss very much.”

Emilie, a budding artist who carried her markers and pencils everywhere, paid tribute to her grandfather by slipping a special card she had drawn into his casket, Parker said.  It was something she frequently did to lift the spirits of others.

“I can’t count the number of times Emilie would find someone feeling sad or frustrated and would make people a card,” Parker said. “She was an exceptional artist.”

The girl who was remembered as “always willing to try new things, other than food” was learning Portuguese from her father, who speaks the language.

(Image Credit: Emilie Parker Fund/Facebook)

On Friday morning, Emilie woke up before her father left for his job and exchanged a few sentences with him in the language.

“She told me good morning and asked how I was doing,” Parker said. “She said she loved me, I gave her a kiss and I was out the door.”

Parker found out about the shooting while on lockdown in Danbury Hospital and found a television for the latest news.

“I didn’t think it was that big of deal at first,” he said. “With the first reports coming in, it didn’t sound like it was going to be as tragic as it was. That’s kind of what it was like for us.”

CLICK HERE for full coverage of the Sandy Hook shooting.

Parker said he knows that God can’t take away free will and would have been unable to stop the Sandy Hook shooting. While gunman Adam Lanza used his free agency to take innocent lives, Parker said he plans to use his in a positive way.

“I’m not mad because I have my  [free] agency to use this event to do whatever I can to make sure my family and my wife and my daughters are taken care [of],” he said. “And if there’s anything I can do to help to anyone at any time at anywhere, I’m free to do that.”

(Image credit: Emilie Parker Fund/Facebook)

Friday night, hours after he learned of his daughter’s death, Parker said he spoke at his church.

“I don’t know how to get through something like this. My wife and I don’t understand how to process all of this,” he said today. “We find strength in our religion and in our faith and in our family. ”

“It’s a horrific tragedy and I want everyone to know our hearts and prayers go out to them. This includes the family of the shooter. I can’t imagine how hard this experience must be for you and I want you to know our family … love and support goes out to you as well.”

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