La Jolla

Wayne C. Koff describes a scientific project that promises to accelerate the development of next-generation weapons in the fight against deadly infectious diseases.

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Vaccines are one of the great success stories in the history of individual and public health. They have helped rid the planet of the scourge of smallpox, are poised to eliminate polio, and each year prevent millions of deaths, reducing the suffering and costs caused by infectious diseases.

But there are still many diseases for which vaccines do not yet exist. Moreover, strategies that have previously led to the successful development of vaccines are unlikely to work against more complex bacteria or viruses, such as HIV, which have evolved multiple mechanisms to evade the immune system.

The history of vaccinology is one in which biomedical and technological advances usher in the “next generation” of vaccines. In the 1950’s, a breakthrough that enabled viruses to grow in tissue cultures led to the development of both live attenuated vaccines and inactivated vaccines for measles, polio, and other diseases. In the 1980’s, recombinant DNA technology led to the development of vaccines against hepatitis B and human papillomavirus.

Around the turn of the century, the first sequencing of the human genome led to “reverse vaccinology.” This approach, whereby computational analysis of a pathogen’s genome enables identification and screening of a great many more potential vaccine targets than was previously possible, was used in the successful development of a vaccine against meningitis B.

The past decade has already yielded major advances in structure-assisted vaccine discovery, synthetic biology, systems biology, and immune monitoring. However, successfully translating these advances into the development of next-generation vaccines continues to be impeded by gaps in our understanding of the human immune response that protects against specific bacteria, viruses, or parasites.

That is why I, along with eight fellow scientists, have proposed the establishment of a new human-immunology-based clinical-research initiative, the Human Vaccines Project. In February 2014, leading scientists and public-health specialists will gather in La Jolla, California, to craft a scientific plan to identify, prioritize, and, most important, solve the major problems currently hindering development of vaccines against diseases such as AIDS, tuberculosis, and malaria.

Such a project would represent a paradigm shift in vaccine development. The current process is long (often spanning decades from concept to licensure), has a low probability of success (because of the limitations of animal models in predicting immune response and efficacy in humans), and is costly (often requiring hundreds of millions of dollars to develop a single vaccine).

Consider this: In just the past few years, many candidate vaccines against HIV, dengue, herpes, tuberculosis, and staphylococcus aureus have failed, at a cost of more than $1 billion. Investing that amount over the next decade in a coordinated effort to address the major questions facing vaccine development would rapidly accelerate our search for effective solutions, implying a transformative impact on individual and public health.

HIV presents perhaps the greatest challenge, because the virus leverages its extensive genetic variability to hide from the immune system. Using recent advances, however, scientists have now identified highly conserved regions of this variable virus, determined their molecular structure, and begun designing next-generation vaccine candidates to elicit antibodies that target these regions to prevent HIV infection. But HIV vaccine development, like that for several other diseases, is still impeded by the limitations of what animal models can tell us about how to elicit the necessary immune responses in humans.

Two recent advances could accelerate vaccine development and reduce its costs dramatically. In synthetic biology, the rapid engineering of nucleic acid-based vaccines means more candidates move more quickly from concept to trial. In systems biology, high-throughput technologies have increased the number of genetic and immunologic parameters assessed in trials. This approach has helped predict the efficacy of potential new-generation vaccines against yellow fever and influenza within days of immunization, compared with the usual timeframe of months or years.

Vaccines already prevent the deaths of 2-3 million people every year, preempt human suffering, lighten the burden placed on health-care systems, and enable more rapid economic and social development. Models show that adding even a partly effective AIDS vaccine to the current range of prevention and treatment procedures could dramatically lower the rate of HIV infection.

As the Nobel Peace Prize laureate Desmond Tutu, one of the world’s great campaigners against HIV/AIDS, wrote recently: “We must make the most of scientific advances over the last half-century, which have made vaccines for other preventable diseases the most powerful and cost-effective health-care investment that currently exists.”

That is the idea behind the Human Vaccines Project – a concept that would have been unimaginable even a decade ago. Today, technological advances in vaccine discovery and immune monitoring allow us realistically to explore this potentially game-changing approach to disease prevention. February’s gathering in California may take us a giant step closer to a world without deadly and debilitating infectious diseases.

Anticonvulsant Promising for Alcohol Dependence.

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The anticonvulsant gabapentin, a widely prescribed anticonvulsant used to treat epilepsy and neuropathic pain, is showing promise in the treatment of alcohol dependence, new research suggests.

Results from a 12-week, randomized, placebo-controlled trial show that participants taking 1800 mg of gabapentin were twice as likely to refrain from heavy drinking and 4 times as likely to stop drinking altogether compared with participants taking placebo.

“Gabapentin’s effect on drinking outcomes is at least as large or greater than those of existing FDA-approved treatments,” lead researcher Barbara Mason, PhD, Scripps Research Institute, La Jolla, California, said in a statement.

The study was published online November 4 in JAMA Internal Medicine.

Filling a Treatment Gap

According to investigators, gabapentin has the potential to fill a large gap in the treatment of alcohol dependence. They note that of the estimated 8.5 million alcohol-dependent Americans, statistics show that only 720,000 prescriptions were filled for US Food and Drug Administration (FDA)–approved medications for alcohol dependence in 2007, most of them prescribed by psychiatrists.

Previous studies of gabapentin for alcohol-dependent persons have suggested that the drug may be safe and effective, but conclusive results have been hampered by small sample size and methodologic or dosing issues.

To provide a more definitive evaluation of the drug for alcohol dependence, the researchers conducted a 12-week, double-blind, placebo-controlled, randomized, dose-ranging trial of 150 adults with current alcohol dependence who were attending a single outpatient center.

Participants were randomly assigned to receive 900 mg/day, 1800 mg/day, or placebo. All patients received concomitant counseling.

The study’s primary outcomes included sustained abstinence and no heavy drinking, and decreases in alcohol-related insomnia, dysphoria, and craving in a dose-dependent manner.

Results showed that gabapentin significantly improved the rates of abstinence and no heavy drinking with rates of 4.1% (95% confidence interval [CI], 1.1% – 13.7%) in the placebo group, 11.1% (85% CI, 5.2% – 22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9% – 30.1%) in the 1800-mg group.

Further, the investigators report that the no-heavy-drinking rate was 22.5% (95% CI, 13.6% – 37.2%) in the placebo group, 29.6% (95% CI, 19.1% – 42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4% – 58.8%) in the 1800-mg group.

In addition, the results showed that the drug significantly reduced cravings, depression, and sleeplessness. The researchers report that gabapentin had a favorable safety profile with no reports of serious adverse events.

According to Dr. Mason, gabapentin offers several potential advantages over the 3 other FDA-approved medications for alcohol dependence. It is “the only medication shown to improve sleep and mood in people who are quitting or reducing their drinking, and it’s already widely used in primary care ― that’s an appealing combination,” she said.

Broader Access to Treatment

In an accompanying editorial,Edward V. Nunes, MD, writes that the finding that gabapentin prevents relapse in alcohol-dependent patients is “an important development.”

“This well-designed and well-powered trial replicates the positive findings of several previous smaller trials,” Dr. Nunes writes.

He notes that a large proportion of alcohol-dependent patients presenting to family physicians fall into the mild to moderate range of alcohol dependence, which further suggests “the strong potential for gabapentin in the treatment of alcohol dependence in primary care.”

Acting director of the National Institute on Alcohol Abuse and Alcoholism, Kenneth R. Warren, PhD, said, “Gabapentin adds to the list of existing medications that have shown promise in treating alcohol dependence. We will continue to pursue research to expand the menu of treatment options available for alcoholism in the hopes of reaching more people.”

Eat More, Weigh Less: Worm Study Provides Clues to Better Fat-Loss Therapies for Humans

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Scientists at The Scripps Research Institute (TSRI) have discovered key details of a brain-to-body signaling circuit that enables roundworms to lose weight independently of food intake. The weight-loss circuit is activated by combined signals from the worm versions of the neurotransmitters serotonin and adrenaline, and there are reasons to suspect that it exists in a similar form in humans and other mammals.

“Boosting serotonin signaling has been seen as a viable strategy for weight loss in people, but our results hint that boosting serotonin plus adrenaline should produce more potent effects—and there is already some evidence that that’s the case,” said TSRI Assistant Professor Supriya Srinivasan, who was principal investigator for the study, published online before print on October 10, 2013 by the journal Cell Metabolism.

Serotonin signaling, which can be increased artificially by some diet and antidepressant drugs, has long been known to reduce weight. Until recently, scientists assumed that it does so largely by suppressing appetite and food intake. However, Srinivasan reported in 2008—while she was a postdoctoral fellow at the University of California, San Francisco—that serotonin changes food intake and fat levels via separate signaling pathways. “We could make the animals we studied lose fat even as they ate more,” she said. Her experiments were conducted on C. elegansroundworms, whose short lifespans and well-characterized nervous systems make them a preferred species for quick-turnaround lab studies. Indeed, other researchers soon found that serotonin’s food-intake-suppressing and weight-loss effects are separable in mammals, too.

Now with her own laboratory at TSRI, Srinivasan has been examining the C. elegans weight loss circuitry in more detail. In the new study, Srinivasan and her colleagues, first author Research Assistant Tallie Noble and graduate student Jonathan Stieglitz, used a series of gene-blocking experiments to identify some of the circuit’s key elements.

Their most surprising discovery was that serotonin isn’t the sole driver of this weight-loss pathway, but works in concert with another neurotransmitter, octopamine—the C. elegans version of adrenaline (also called epinephrine) in mammals. “That was a very interesting finding, especially since other studies suggest that these two neurotransmitters tend to oppose each other’s functions,” said Noble.

The team mapped out a self-reinforcing network of serotonin and octopamine-producing neurons in the worms that send the lose-weight signal to the body. This network includes a set of serotonin-sensitive neurons known as URX neurons, which have access to the worm circulatory system and apparently release a still-to-be-identified signaling molecule. The downstream result of this signal, the researchers found, is a boost in the production of a key enzyme in the worm intestine. The enzyme, known as adipocyte triglyceride lipase 1 (ATGL-1), literally cuts fat molecules in a way that leads to their further metabolic breakdown. ATGL-1 also has a very similar counterpart in mammals.

Srinivasan and her colleagues plan in future work to identify the long-range molecular signal that boosts ATGL-1 production and to better delineate the serotonin-octopamine network that produces the signal. Eventually, they would like to map out the corresponding fat-loss network in a closer evolutionary relative of humans, such as the mouse.

However, Srinivasan noted that the human experience with weight-loss drugs already hints that mammals may have such a fat-loss circuit. Serotonin-plus-adrenaline boosting therapies, the most prominent of which was fenfluramine-phentermine (“fen-phen”), have tended to do better at cutting weight than serotonin-boosting therapies alone. Unfortunately, the serotonin-boosting elements of these compounds have often been blamed for cardiovascular side effects—fenfluramine, for example, was banned by the FDA in 1997—but in principle, future combination therapies could be designed to avoid producing such side effects.

“We wonder if boosting not just serotonin but serotonin plus a little bit of adrenaline is the real key to more potent weight loss,” Srinivasan said.

Scripps Research Institute Scientists Invent a Better Way to Make Antibody-Guided Therapies

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Chemists at The Scripps Research Institute (TSRI) have devised a new technique for connecting drug molecules to antibodies to make advanced therapies.

Antibody-drug conjugates, as they’re called, are the basis of new therapies on the market that use the target-recognizing ability of antibodies to deliver drug payloads to specific cell types—for example, to deliver toxic chemotherapy drugs to cancer cells while sparing most healthy cells. The new technique allows drug developers to forge more stable conjugates than are possible with current methods.

“A more stable linkage between the drug molecule and the antibody means a better therapy—the toxic drug is less likely to fall off the antibody before it’s delivered to the target,” said Carlos F. Barbas III, the Janet and Keith Kellogg II Chair at TSRI.

Barbas and two members of his laboratory, Research Associates Narihiro Toda and Shigehiro Asano, report the finding in the chemistry journal Angewandte Chemie, where their paper was published recently online ahead of print and selected as a “hot” contribution.

A Popular Approach with Limitations

The new method for making more stable antibody-drug conjugates comes as the first generation of these powerful therapies are entering the market. Two such conjugates are now in clinical use. Brentuximab vedotin (Adcetris®), approved by the FDA in 2011, has shown powerful effects in clinical trials against otherwise treatment-resistant lymphomas. It uses an antibody to deliver the cell-killing compound monomethyl auristatin E to cells that bear the CD30 receptor, a major marker of lymphoma. The other conjugate, ado-trastuzumab emtansine (Kadcyla®), approved just this year for metastatic breast cancer, delivers the toxic compound mertansine to breast cancer cells that express the receptor HER2.

The success of these antibody-drug conjugates and the broad potential of the technology have made them popular with drug companies, particularly those trying to develop new anticancer medicines. “The current development pipeline is full of antibody-drug conjugates,” says Barbas.

Yet the chemical method that has been used to make these conjugates has significant limitations. The method involves the use of compounds derived from maleimide, which can be easily added to small drug molecules. The maleimide molecule acts as a linker or bridge, making strong bonds with cysteine amino acids that can be engineered into an antibody protein. In this way, a single antibody protein can be tagged with one or more maleimide-containing drug molecules. The main problem is that these maleimide-to-cysteine linkages are susceptible to several forms of degradation in the bloodstream. When such a cut occurs, the disconnected “payload” drug-molecule—typically a highly toxic compound—is liable to cause unwanted collateral damage to the body, like a “smart bomb” gone astray. This instability of current maleimide-based conjugates probably accounts for at least some of their considerable toxicity.

A more stable linkage would mean less toxicity and higher efficacy for antibody-drug conjugates, and for the past several years research chemistry laboratories around the world have been looking for a way to achieve this.

Improved Linkages

Now Barbas and his colleagues appear to have found one in the form of a novel Thiol-Click reaction. In their new paper, they have described a way to make improved linkages using compounds based on methylsulfonyl-substituted heterocycles instead of maleimides. “This method turns out to enable more stable linkages to an antibody protein, as well as more specific linkages, so the drug attaches to the right place on the right protein,” said Barbas.

Coincident with the report of the new linking compounds in Angewandte Chemie, the chemical supplier Sigma-Aldrich Corporation will begin selling the compounds, so that pharmaceutical companies can start working with them to make more stable antibody-drug conjugates. Under a recent agreement (see http://www.scripps.edu/news/press/2013/20130718sigma.html), Sigma-Aldrich markets new chemical reagents from Barbas’s and several other TSRI laboratories as soon as the papers describing them are released.

“Improved antibody–drug conjugate technologies are a top-priority research area in the pharmaceutical industry and exactly the type of fundamental research issue that our partnership with Scripps will continue to address,” said Amanda Halford, vice president of academic research at Sigma-Aldrich.

Although linking drug molecules to target-homing antibodies is the best-known therapeutic application of the new method, Barbas emphasized its broad relevance. “It should be useful for many types of protein conjugation,” he said. These include the conjugation of proteins to fluorescent beacon molecules for laboratory experiments, as well as the linkage of drug compounds to polyethylene glycol molecules—“pegylation”—to slow their clearance from the body and thus keep them working longer.

New tools automatically match patients with clinical trials.

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The majority of Americans—72%—say they would take part in a clinical trial recommended by their doctor, according to a survey released last month by the Alexandria, Virginia-based science advocacy group Research!America. Despite that enthusiasm, though, there’s a shortage of enrollment. According to US government estimates, only about 3% of patients with advanced cancer enroll in phase 1 trials. Part of the problem, experts believe, comes down to a lack of awareness: the general public doesn’t know about investigational trials, and few physicians discuss the option with their patients.

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New tools unveiled this year that automatically prescreen patients for trials based on their electronic medical records and email matches to doctors could help solve the problem. “We’ve needed these kinds of tools for a long time,” says Eric Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, California. “Physicians are really busy, and there are so many clinical trials that no human could track them all.”

The US federal registry, ClinicalTrials.gov, currently lists more than 145,000 trials in all 50 states, as well as 184 foreign countries. Wading through those listings is a daunting task for individuals interested in signing up for a study, assuming that they know of the resource to begin with. Ultimately, problems with patient recruitment delay clinical trials by 4.6 months, on average, according to the Center for Information and Study on Clinical Trial Research Participation, a nonprofit organization in Boston. That holdup means it takes longer for treatments to reach the market.

To increase enrollment, some patient-advocacy groups have started playing matchmaker. A year ago, the Michael J. Fox Foundation for Parkinson’s Research launched the Fox Trial Finder, a web portal designed to help pair people with Parkinson’s with clinical studies (see Nat. Med. 18, 837,2012). The Alzheimer’s Association’s TrialMatch, meanwhile, has been up and running since 2010. Anyone can register online or by phone and see if he or she—or a patient or loved one—is a good fit for any of the 153 trials in 621 locations. To date, there have been 11,166 referrals, says Heather Snyder, the Chicago-based association’s director of medical and scientific operations.

In addition to the Fox Trial Finder and TrialMatch, for-profit companies have unveiled web portals to link people with studies. New York’s EmergingMed helps connect individuals with cancer trials, and in late May, Michigan-based CureLauncher unveiled a clinical-trial-matching service for a range of disorders. But tools such as these rely on the gumption of patients and doctors to wade through web listings. A new wave is emerging of automated tools that do away with the need for patients or physicians to manually enter information.

On alerts

Earlier this year, the Virginia Commonwealth University’s Massey Cancer Center in Richmond unveiled two new tools that work with its Clinical Trials Eligibility Database, which stores information about patients and clinical trials at the center. Since February, its MD Alert Notification System has automatically prescreened the list of scheduled patients each morning and emailed physicians when it finds that one of those individuals is eligible for one or more of 75 open trials at the center.

“If the patient is interested, one click by the physician refers them to the research nurse associated with that trial,” says Lynne Penberthy, director of the Massey Cancer Center’s informatics core who oversees the tracking and matching tools. Another new computer application there, the Automated Matching Tool, has been available since January. It screens all patients in the system on a scheduled basis, not just those coming in for a visit.

An algorithm known as Trial Prospector offers even greater automation for clinical trial enrollment. In a pilot study presented at last month’s American Society of Clinical Oncology meeting in Chicago, the program reached into the medical records of 60 people with gastrointestinal cancer who had scheduled appointments at the University Hospitals Seidman Cancer Center of the Case Comprehensive Cancer Center in Cleveland, Ohio. It pulled out 15 pieces of information—including age, diagnosis and blood count—that it compared to eligibility criteria of the 300-plus trials in Cases’s database. It then emailed doctors lists of any matches, and it also shows the studies for which the patient didn’t qualify and explains why; for example, some factors, such as low red blood cell count, might be easily fixed with a transfusion. The algorithm was 100% accurate, and 11% of the patients ended up enrolling in a trial suggested to the doctor by the algorithm.

“In theory this could be readily adapted anywhere, but we’ve still got a long way to go,” says Neal Meropol, associate director for clinical research at the Case Comprehensive Cancer Center. His team plans to refine Trial Prospector over the next 6 to 12 months, expand it to other cancers, and test it in a community-practice setting, where physicians aren’t highly specialized and may not have as much knowledge of open trials.

Penberthy similarly sees automated trial matching tools as a way to reach a more diverse set of participants. “We’re hoping that this is going help increase the equity,” she says. “It may help to increase minority patients enrolled in clinical trials,” an underrepresented population.

Topol, who isn’t involved with the programs, says that although automated matching programs are in their infancy, “eventually they could build something that’s extraordinary.”

Source: Nature

 

Nuking Dangerous Asteroids Might Be the Best Protection, Expert Says.

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If a dangerous asteroid appears to be on a collision course for Earth, one option is to send a spacecraft to destroy it with a nuclear warhead. Such a mission, which would cost about $1 billion, could be developed from work NASA is already funding, a prominent asteroid defense expert says.

Bong Wie, director of the Asteroid Deflection Research Center at Iowa State University, described the system his team is developing to attendees at the International Space Development Conference in La Jolla, Calif., on May 23. The annual National Space Society gathering attracted hundreds from the space industry around the world.

An anti-asteroid spacecraft would deliver a nuclear warhead to destroy an incoming threat before it could reach Earth, Wie said. The two-section spacecraft would consist of a kinetic energy impactor that would separate before arrival and blast a crater in the asteroid. The other half of the spacecraft would carry the nuclear weapon, which would then explode inside the crater after the vehicle impacted.

The goal would be to fragment the asteroid into many pieces, which would then disperse along separate trajectories. Wie believes that up to 99 percent or more of the asteroid pieces could end up missing the Earth, greatly limiting the impact on the planet. Of those that do reach our world, many would burn up in the atmosphere and pose no threat.

Wie’s study has focused on providing the capability to respond to a threatening asteroid on short notices of a year or so. The plan would be to have two spacecraft on standby — one primary, the other backup — that could be launched on Delta 4 rockets. If the first spacecraft failed on launch or didn’t fragment the asteroid, the second would be sent aloft to finish the job.

 

 

Bong Wie, director of the Asteroid Deflection Research Center at Iowa State University, described the system his team is developing to attendees at the International Space Development Conference in La Jolla, Calif., on May 23. The annual National Space Society gathering attracted hundreds from the space industry around the world.

An anti-asteroid spacecraft would deliver a nuclear warhead to destroy an incoming threat before it could reach Earth, Wie said. The two-section spacecraft would consist of a kinetic energy impactor that would separate before arrival and blast a crater in the asteroid. The other half of the spacecraft would carry the nuclear weapon, which would then explode inside the crater after the vehicle impacted. [Gallery: Potentially Dangerous Asteroids]

The goal would be to fragment the asteroid into many pieces, which would then disperse along separate trajectories. Wie believes that up to 99 percent or more of the asteroid pieces could end up missing the Earth, greatly limiting the impact on the planet. Of those that do reach our world, many would burn up in the atmosphere and pose no threat.

Wie’s study has focused on providing the capability to respond to a threatening asteroid on short notices of a year or so. The plan would be to have two spacecraft on standby — one primary, the other backup — that could be launched on Delta 4 rockets. If the first spacecraft failed on launch or didn’t fragment the asteroid, the second would be sent aloft to finish the job.

Political fallout

Wie admitted that sending nuclear weapons into space would be politically controversial. However, he said there are a number of safety features that could be built into the spacecraft to prevent the nuclear warhead from detonating in the event of a launch failure.

A nuclear weapon is the only thing that would work against an asteroid on short notice, Wie added. Other systems designed to divert an asteroid such as tugboats, gravity tractors, solar sails and mass drivers would require 10 or 20 years of advance notice.

Much of the technology for the mission has already been successfully demonstrated in flight, Wie said. NASA’s Deep Impact spacecraft sent a kinetic impactor to collide with Comet Tempel 1 on July 4, 2005. Four years later, the space agency sent a Centaur upper stage crashing into the moon during theLCROSS mission (Lunar Crater Observation and Sensing Satellite), followed by a sub-satellite that photographed the impact before crashing into the surface itself.

Funding the mission

Wie’s work has been funded under the NASA Innovative Advanced Concepts (NIAC) program. He received a $100,000 Phase I grant for 2011-2012 and then a Phase II grant worth $500,000 for 2012-2014.

NIAC doesn’t provide any additional funding after Phase II, so Wie will have to convince some agency — whether it be NASA or the Department of Defense — to fund the program through completion. This could be a difficult issue because there is no one agency in charge of planetary defense, he said.

The first step would be a $500 million flight validation mission that would target an asteroid approximately 50 meters in size. A nuclear weapon probably would not be required to destroy a body of that size, Wie said.

The point would be to demonstrate the capability to accurately target an asteroid that small, something that neither Deep Impact nor LCROSS accomplished. Accurately hitting a larger, more threatening asteroid would be easier.

Source: SPACE.com

 

Sally Ride, the first US woman in space, dies aged 61.

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Sally Ride, the first US woman to travel into space, has died aged 61, 17 months after she was diagnosed with pancreatic cancer, her foundation says.

“Sally’s historic flight into space captured the nation’s imagination and made her a household name,” Sally Ride Science said in a statement.

She blasted off in the US space shuttle Challenger in June 1983.

Ride was not the first woman in space – that was Soviet cosmonaut Valentina Tereshkova in June 1963.

Since her first mission in 1983, more than 45 women from the US and other countries have flown in space, including two as shuttle commander.

Ride died on Monday in La Jolla, California.

Once an aspiring tennis player, she went on to earn no fewer than four university degrees including a doctorate in physics.

National hero

In a statement, US President Barack Obama said he was “deeply saddened” to hear about her death.

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Her star will always shine brightly”

Charles Bolden Nasa administrator

“As the first American woman to travel into space, Sally was a national hero and a powerful role model,” he said in a statement.

Ride was born and grew up in Los Angeles, California, attending Stanford University for master’s and doctorate degrees in physics.

According to her foundation, Ride applied to Nasa after seeing an ad in the Stanford student newspaper, calling for scientists and engineers, including women to apply to the astronaut corps.

She joined Nasa in 1978 – one of 35 people selected as astronauts from a field of more than 8,000 who applied.

Ride went on her first space shuttle mission on board Challenger in 1983.

As well as being the first American woman in space, she was also – at the age of 32 – the youngest person in America at the time to go into orbit.

Great expectations

As part of that mission she used a robotic arm – which she had helped develop – to retrieve a satellite.

She reached orbit again the following year, and was scheduled for a third trip when the Challenger space shuttle broke apart during lift-off in 1986.

The disaster occurred just over a minute into the mission, killing all seven crew members, and prompting an almost three-year hiatus in the American space programme.

Following the disaster, she served as a member of the presidential commission that investigated the causes of the fatal accident. She also sat on a similar board following the Columbia space shuttle, which broke apart during its re-entry to Earth in 2003.

“Sally Ride broke barriers with grace and professionalism – and literally changed the face of America’s space program,” Nasa administrator Charles Bolden said in a statement. “She will be missed, but her star will always shine brightly.”

Ms Ride’s former husband Steve Hawley said in a statement: “Sally was a very private person who found herself a very public persona. It was a role in which she was never fully comfortable.”

The former astronaut, who was married to Ride from 1982 until 1987, added: “I was privileged to be a part of her life and be in a position to support her as she became the first American woman to fly in space.”

After leaving Nasa, Ride became a professor at University of California, San Diego, and served as a science fellow at Stanford University.

She launched Sally Ride Science, which created science programmes and publications for young students, in 2001. She also wrote five children’s science books.

“The fact that I was going to be the first American woman to go into space carried huge expectations along with it,” Ride said in a 2008 interview.

“I didn’t really think about it that much at the time – but I came to appreciate what an honour it was to be selected,” she said.

Ride is survived by her mother Carol and her partner of 27 years Tam O’Shaughnessy.

Source: BBC