Guardian Daily: Climate science under siege

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Following a special investigation by the Guardian this week, we discuss the hacked climate change emails at the University of East Anglia, and the issue of trust in the global warming debate

Photoreceptors from skin: A photoreceptor cell (green) derived from human skin cells incorporates itself into a mouse retina (red).
Credit: Thomas Reh

Photoreceptors created from induced pluripotent stem cells

MIT Technology Review, February 3, 2010, by Janelle Weaver  —  Think twice the next time you wipe a few flecks of dandruff from your shoulder. You might be shedding cells that may someday restore human vision.

Thomas Reh and colleagues at the University of Washington, in Seattle, have generated light-sensing retinal cells, called photoreceptors, from adult human skin cells. They then transplanted the cells into a mouse retina, showing that the photoreceptors integrated normally into the surrounding tissue. This technological feat raises hopes for the development of treatments for retinal diseases, such as retinitis pigmentosa and macular degeneration, which cause visual impairment or blindness in millions of people in the U.S.

Researchers used induced pluripotent stem (iPS) cell technology, activating a handful of genes in skin cells in order to revert them to a flexible embryonic state. They then used previously developed methods to differentiate the cells into photoreceptors. While Reh’s team has done similar experiments using embryonic stem cells, iPS cells are a preferable source for cell replacement therapies because they can be derived from the patient. Skin cells are a ready source of cells that are tissue-matched to the recipient, bypassing problems associated with immune rejection of stem-cell transplants.

The cells also provide a new way to study retinal degeneration diseases and to identify drug targets. Retinitis pigmentosa, for example, is an inherited disorder in which the photoreceptors begin to die. Retinal cells derived from a patient with the disease harbor all the genetic mutations that contributed to the patient’s disease, so scientists can try to determine the molecular mechanisms that lead to cell death. They can then use the cells to screen for molecules that can slow or stop the damage.

“There are no good drugs to slow photoreceptor degeneration,” said Reh, a neurobiologist at the University of Washington. “One reason we don’t have more molecules we can test is that we don’t have good animal models for many human retinal diseases.”

Scientists will still need to overcome some serious hurdles before using the cells for transplantation therapies. The genetic flaws that led to the disease would need to be fixed before implanting the cells into the eye. And researchers need to figure out how to get large volumes of cells to integrate effectively into the retina. In the current experiments, published last month in the journal PLoS ONE, the number of cells that took root in the mouse eye was too low to restore visual sensitivity. “We need about 10,000 cells to integrate into the retina for them to restore function,” Reh said.

Future research will have to explore how well the transplanted photoreceptors connect with other cell types in the retina and function as an integrated circuit. “The work still ahead is huge,” said Robert Lanza, chief scientific officer at Advanced Cell Technology. “But this is a very important first step.”

Get connected: A new chip encourages nerve cells to grow in set patterns; it could speed up neurotoxicity testing of drugs and chemicals. Credit: University of Dortmund

 

 

Device could mean fewer animal experiments

MIT Technology Review, February 4, 2010, by Duncan Graham Rowe  —  Want to see how your brain looks on drugs? A new lab-on-a-chip device will show you.

The chip, called a network formation assay (NFA), should let researchers test compounds quicker and more reliably, making neurotoxicity tests easier and animal experiments less common. Although animal tests are still required by the FDA for drug development, improved in-vitro tests will mean that fewer toxic compounds make it to the animal-testing stage.

There is another reason researchers need better in-vitro screening techniques. Many European countries have already banned cosmetics testing on animals, while a European Union directive called REACH will require more frequent chemical tests.

“There are estimated to be around 30,000 chemicals that are not fully tested for their toxicological risk,” says Jonathan West a microengineer at the University of Dortmund in Germany, who developed the new chip with colleagues.

In-vitro neurotoxicity tests involve growing nerve cells and counting the number axons and dendrites that grow between them. This neural connectivity is a basic feature of normal brain function and underlies activities such as learning and memory. So its disruption is a reliable predictor of neurotoxicity. For example, acrylamide, a known neurotoxin, inhibits the formation of these connections. But such tests are usually time-consuming and unreliable because nerve cells end up randomly positioned, making it difficult to objectively assess the length of connections between them under a microscope.

West and colleagues Christoph van Thriel, Jan Hengstler, and Marcel Leist from the University of Konstanz, also in Germany, found a way to standardize the neurotoxicity test by fixing neurons in place at set distances from each other.

The new NFA chip is covered with a thin layer of a hydrophobic polymer–polydimethylsiloxane (PDMS)–etched with a hexagonal array of points where the underlying substrate is visible, says West. The PDMS is repulsive to extracellular matrix proteins, which cells normally use to bind to a surface. So cells automatically position themselves in the hexagonal array, where they can reach the substrate. This lets testers quickly assess if connections have formed between cells and precisely measure the length of these connections.

“It’s very clever,” says Kelly Bérubé, a cell biologist at the University of Cardiff, in Wales, and scientific advisor to the U.K. charity Safer Medicines Trust.

It normally takes about 10 hours to test a single compound–thirty times for 10 different doses. Using the new chip, West says, the process takes only a few hours.

“Companies are looking for something like this so they can quickly find molecules that are least toxic before moving on to animal tests,” says Bérubé. “You would save lots and lots of animals. This has to be the way to go.”

“I think this is very interesting,” says Dominic Wells, head of cellular and molecular neuroscience at Imperial College London. “There’s always been a problem of screening toxicological compounds, and this has the potential to be automated.”

West’s group is now looking at developing chips for testing other types of cells, including stem cells. Their research is published in the latest edition of the journal Lab on a Chip.

WINSTON-SALEM, N.C., Feb. 4 /PRNewswire-USNewswire/ — The Regenerative Medicine Foundation today announced the first annual Translational Regenerative Medicine Forum to be held April 6-8, 2010 at the Benton Convention Center in Winston-Salem.

The forum seeks to advance the field of regenerative medicine and health care innovation through the sharing of scientific discoveries, clinical and corporate best practices and business models. Keynote speakers and panelists will provide a domestic and international perspective, including critical areas such as clinical advances, trial design, venture funding and obtaining regulatory approval.

“The Translational Regenerative Medicine Forum is designed to be the premiere international event for leaders in regenerative medicine translation, representing academic and clinical research, health care policy, venture investment and biotechnology industry interests,” said Anthony Atala, M.D., director, Wake Forest Institute for Regenerative Medicine, and a forum speaker. “The body’s natural capacity for healing has been known for generations, and the field of regenerative medicine exists to harness this natural healing process. It takes a collaborative approach to address the challenges of delivering regenerative medicine therapies to patients in a timely and cost-effective manner, and it is our expectation that this forum will bring together all the elements and fulfill the promise of the research.”

Keynote speakers and plenary panelists include Steven Bauer, Ph.D., chief of the Cell and Tissue Therapy Branch, FDA Center for Biologics Evaluation and Research; Richard Caruso, Ph.D., founder and chairman of the board, Integra; Juan Enriquez, managing director, Excel Venture Management; Robert Klein, chairman, California Institute for Regenerative Medicine; Robert Lanza, M.D., chief scientific officer, Advanced Cell Technology; Lesa Mitchell, vice president, Kauffman Foundation; Sherrill Neff, founding partner, Quaker BioVentures; and Teruo Okano, Ph.D., professor and director of the Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University.

Also, Buddy Ratner, Ph.D., professor of bioengineering and chemical engineering, University of Washington; and Camillo Ricordi, M.D., Diabetes Research Institute, University of Miami Miller School of Medicine; Lt. Gen. Eric Schoomaker, M.D., Ph.D., surgeon general/commander, U.S. Army Medical Command; Andrew von Eschenbach, M.D., former U.S. Food and Drug Administration Commissioner who is now senior advisor with Greenleaf Health and the Center for Health Transformation; John Walker, CEO, iPierian; and Jay Watkins, managing director, DeNovo Ventures.

Translational Forum attendees will include executives from biotechnology, pharmaceutical and medical device, and regenerative medicine companies; patient advocacy groups and medical research foundations; institutional investors from private equity and venture capital firms; academic researchers, clinical researchers and physicians; and those interested in health care innovation and personalized medicine.

To foster interaction between investors and entrepreneurs, the forum will showcase 15 regenerative medicine companies presenting in front of an audience of venture capitalists and corporate venture executives.

For more information and to register, go to www.rmconferences.org

About the Regenerative Medicine Foundation

The Regenerative Medicine Foundation (www.regenerativemedicinefoundation.org) is an internationally focused, not-for-profit organization created to enable the advancement of new treatments and therapies based on regenerative medicine, and ultimately, to realize the goals of personalized medicine.

Launched in 2005, the Foundation hosted one of the first regulatory meetings with the U.S. Food and Drug Administration (FDA) on the topic of regenerative medicine, and was instrumental in the formation of STRAC, the Soldier Treatment and Regeneration Consortium, a precursor to the Armed Forces Institute of Regenerative Medicine (AFIRM), and the Washington, DC-based Alliance for Regenerative Medicine.

Through educational programs, translational conferences and public policy initiatives, the Foundation advocates for increased medical research, promotes the training and education of scientists, and facilitates the translation of therapies to patients.

SOURCE Regenerative Medicine Foundation

RELATED LINKS
http://www.regenerativemedicinefoundation.org
http://www.rmconferences.org

Injury prevention: A helmet with separate outer and inner shells could one day help prevent neck injuries. In the top image, an outer shell (blue) remains in place, while the inner shell (white) rotates on impact. In the lower image a locking mechanism (red) connects the helmet’s two shells. Credit: The University of British Columbia

Engineers are designing a helmet that could protect the spine from serious injury.

MIT Technology Review, February 4, 2010, by Lauren Gravitz  —  Helmets for everything from football and hockey to motorcycle riding are built to protect the head from impact. Each successive generation of design is better at dissipating force and protecting against concussions and other knocks to the skull. But current helmets can still do little to prevent the spinal injuries that cause paralysis.

Now researchers at the University of British Columbia in Vancouver are working on a design that could protect the spine during a head-on collision. When a person’s head hits a flat object straight on, the impact normally causes the neck to crumple as it absorbs the brunt of the force. If a broken vertebra dissects or otherwise damages the delicate spinal cord, the result can be permanent paralysis. If the head hits an object at an angle, it can glance off without much damage–that’s why football players are taught to tackle opponents with their heads raised.

“I became interested in whether there was a way to convert the impact against a flat object into an impact against an angled object,” says Peter Cripton, the mechanical engineer and biomechanics specialist at UBC who led the project. He and his colleagues developed the “Pro-Neck-Tor” helmet, which consists of an outer shell that looks like most helmets on the market today, a rotating inner shell that hugs the head, and a mechanism that connects the two.

“The main purpose of helmets, whether in sports or transportation, is always to prevent brain injuries. We’re trying to do something quite different,” Cripton says. “We’re working toward a helmet with the same ability to prevent concussion, but also with the ability to prevent neck injuries.” During normal, day-to-day use, the inner shell remains immobile. But when the helmet hits something with enough force, the inner mechanism releases, and the inner shell rotates, guiding the head as if it were hitting an angled surface instead of a flat one.

“Just putting more padding on your head isn’t going to solve the neck injury problem, and it may even make it worse,” says injury biomechanics expert John Melvin, an adjunct professor at Wayne State University in Michigan who’s been studying the problem since 1968. “It’s a tough problem, but they’re taking a unique approach, and I think it has potential. It’ll have to be evaluated in many, many ways to make sure it’s safe–you don’t want to end up causing serious brain injury while preventing a serious neck injury.”

Revamping helmets is a tricky business, especially when there’s no good way to field-test them without living, breathing human beings. (Crash test dummies won’t work, and cadavers don’t have the necessary neck strength and position.) But in simulation testing, 3-D prototypes of the helmets reduced force to the neck by about 50 percent. Once the researchers perfect the design, they’ll individualize the helmets for different sports–football, hockey, and bicycling, for instance, which tend to result in different kinds of impacts.

The Pro-Neck-Tor project just received $150,000 in a new round of funding from the Canadian Institutes of Health Research to help enable commercialization of the technology. Cripton and his colleagues hope to have a helmet ready for market in about three years.

Coming clean: A micrograph shows the surface of a light-activated catalyst that disinfects water even in the dark. Palladium nanoparticles on the surface of a nitrogen-doped titanium oxide help to extend the catalyst’s disinfection power up to 24 hours.
Credit: Shang, et al. University of Illinois at Urbana-Champaign

New light-activated catalyst keeps on working even after the lights go out

MIT Technology Review, February 4, 2010, by Corrinna Wu  —  Getting access to clean drinking water is an ongoing problem for people in developing countries. And even cities that have good water-treatment systems are looking for better ways to deliver safer, cleaner water. Now an international research team has developed a photocatalyst that promises quick, effective water disinfection using sunlight or artificial light. What’s more, the photocatalyst keeps working after the light is turned off, disinfecting water even in the dark.

It has long been known that irradiating water with high-intensity ultraviolet light kills bacteria. Some water filters made for campers and hikers, for example, use this technology. Researchers have been working to enhance the method’s effectiveness by adding a photocatalyst that gets activated by UV light and generates reactive chemical compounds that break down microbes into carbon dioxide and water.

The new photocatalyst improves on that by using visible, rather than UV, light. Synthesized by Jian-Ku Shang, professor of materials science and engineering at the University of Illinois, Urbana-Champaign, and his colleagues, the photocatalyst works with light in the visible spectrum–wavelengths between 400 and 550 nanometers. It consists of fibers of titanium oxide–a common material used as a white pigment–doped with nitrogen to make it absorb visible light. Alone, the nitrogen-doped titanium oxide kills bacteria, though not efficiently. The researchers added nanoparticles of palladium to the surface of the fibers, greatly increasing the efficiency of the disinfection. He and his colleagues at the Shenyang National Laboratory for Materials Sciences in China published their work online in the Journal of Materials Chemistry.

“It would be very nice to shift activity of the traditional [photocatalyst] materials, which were only activated by ultraviolet radiation, to visible,” says Alexander Orlov, assistant professor of materials science and engineering at Stony Brook University in New York. “If you look at the solar spectra, it contains only 5 percent ultraviolet and around 46 of visible.” Such photocatalysts would allow solar energy to be used more efficiently as well as used indoors, since fluorescent lighting contains very little ultraviolet light.

Shang and his colleagues tested the photocatalyst by placing it in a solution containing a high concentration of E. coli bacteria and then shining a halogen desk lamp on the solution for varying lengths of time. After an hour, the concentration of bacteria dropped from 10 million cells per liter to just one cell per 10,000 liters.

The researchers also tested the photocatalyst’s ability to disinfect in the dark. They shined light on the fibers for 10 hours to simulate exposure to daylight and then stored them in the dark for various times. Even after 24 hours, the photocatalyst still killed bacteria. In fact, just a few minutes of illumination was enough to keep the photocatalyst activated for up to that length of time.

“Typically, when you have a photocatalyst, the activity will stop almost instantaneously when the light is switched off,” Shang says. “The chemical species you generate will only last a few nanoseconds. This is an intrinsic drawback of a photocatalytic system, since you require light activation essentially all the time.”

The palladium nanoparticles boost the photocatalyst’s power in two ways. When photons hit the material, they create pairs of positive and negative charges–holes and electrons. The positively charged holes on the surface of the nitrogen-doped titanium oxide react with water to produce hydroxyl radicals, which then attack bacteria. “What palladium nanoparticles do is they grab electrons away so most of the holes you produce will be able to survive without being neutralized by electrons,” says Shang.

As soon as they grab the electrons, the nanoparticles enter a different chemical state and store the negative charges. “When the light is switched off, that charge gets slowly released, and that slow release is what gives us that memory effect,” Shang says. “That charge can react with water molecules to produce oxidizing agents again.” He says nanoparticles of other transition metals, like silver, also enhance the photocatalyst’s effectiveness.

The photocatalyst offers the ability to disinfect at full power during the day and then keep working at night or during power outages. Also, because the disinfection happens quickly, systems could be designed to clean large volumes of water by exposing it to light as the water flows through pipes, Shang says.

China’s plan to cover all 1.3 billion people with basic health insurance brings challenges, benefits, problems, and opportunities in equal measure

The-Scientist.com, February 3, 2010, by Zhu Shen  Traditionally, Chinese seniors have relied on their adult children to care for them when they become too old or too sick to look after themselves. Now, the government is planning to augment family-based care with a social safety net. The centerpiece of the policy is the provision of healthcare coverage for every one of China’s 1.3 billion citizens by 2020.

It’s a move that puts the current U.S. obsession with healthcare access, fairness, efficiency, cost, and quality into context. In particular, for the 820 million-sized rural population who will see their basic coverage go from virtually zero to 100 percent, it is an amazing advance. The annual premium per person across the country will be 120 RMB, less than US$20, in 2010.

But this plan isn’t driven solely by the desire to improve health. In part, it’s a response to economic pressure. China’s previously unstoppable growth has been interrupted by the economic recession, which has caused the global demand for Chinese goods to collapse. To bridge the financial deficit, the government is anxious to stimulate domestic consumption. In a country where the savings rate is 50 percent of GDP (compared to 10 percent of GDP in the U.S.; consumption in China is about 37 percent of GDP, compared with 70 percent in the US), the potential contribution to the economy of more personal spending is enormous.

However, to overcome prudent and cautious instincts, the causes of low domestic consumption and high savings have to be tackled. One of the main drivers is the lack of social safety net and basic healthcare for much of the rural population, which makes up about 80 percent of the population. Their desire to save instead of spend is borne out of real concern for “rainy days.” The government anticipates that a strengthening of the social safety net will encourage people to spend more and save less.

From a manufacturer’s viewpoint, the key to Chinese healthcare reform is the Essential Drug List, the bible of medicines supported by the healthcare program. The first version, released by the Ministry of Health (MoH) on August 18, 2009 and effective from early September, includes 307 drugs (205 Western drugs and 102 traditional Chinese medicines (TCMs)) that have prioritized prescription and reimbursement, in line with the WHO list of 340 essential drugs. This first part of a two-part list of essential medicines includes common antibiotics, pain relievers, and medicines for colds, high blood pressure, gastric ulcer, diabetes (insulin and three oral anti-diabetic generics), and even one cholesterol-lowering drug, simvastatin. Sixty to eighty percent of the most common ailments are covered by medicines on the list. The Essential Drug List will be adjusted every three years, reflecting changes in health demands.

Given the competing demands, the Development and Reform Commission (NDRC), which is the Chinese governing body that sets drug prices for every item on the Essential Drug List, faces a delicate balancing act. It must not set prices too high, to ensure that drugs are affordable, but not too low so that drug manufacturers would rather stop making the products altogether. In the drug pricing in Part I of the EDL released by NDRC on October 2, 2009, about half of the EDL products retained the existing “reference retail price,” 45 percent are reduced, by an average by 12 percent, and 6 percent modestly increased, according to a research report from Susquehanna Financial Group. “The rationale for EDL pricing is based on average cost of goods, market demand and competition, and affordability of the society,” remarked Ding Ding, a senior analyst from Susquehanna who authored the report.

In the future, the Chinese government is expected to gradually remove the price premium enjoyed by the off-patent originator drugs. The periodic and seemingly arbitrary price cuts for drugs will be gradually replaced by a systematic price review aimed at incentivizing innovation.

“Essential medicines do not mean cheap medicines,” commented Liu Xinming, director general of the department of policy and regulations of the Ministry of Health. “They were selected with due regard to disease prevalence, evidence on efficacy and safety, and comparative cost-effectiveness”, he said. According to the plan, by the end of this year, about 30 percent of state-owned grassroots health institutions will be equipped with all the medicines on the list and will be expected to give priorities to using them when treating patients.

From a manufacturer’s viewpoint, the key to Chinese healthcare reform is the Essential Drug List, the bible of medicines supported by the healthcare program.

According to inside sources, there was intense lobbying by various international and domestic drug companies fighting over whose products got on the list, leading to many revisions before the final table was determined. Some Western pharmaceutical companies are positioning themselves to take advantage of the transformative healthcare reform. Those who got their drugs on the essential list are aiming to gain greater access and volume in the rural market, which stands to gain the most from the reform. Others are focusing more on innovative, higher-priced drugs such as novel oncology drugs, and will continue to develop the high-end market beyond the essential drug list.

To satisfy the needs of mid-to top-tier hospitals in metropolitan cities, the second half of the EDL is expected to be released soon. “We estimate that another 200 to 300 drugs will be on the EDL part II which will include more specialized therapeutic areas such as anesthesia and oncology. More affluent regions could potentially increase the number of EDL drugs beyond the official list,” said Ding Ding of Susquehanna.

Even before the universal healthcare plans come into effect, the total value of pharmaceutical products has skyrocketed, from about 10 billion RMB (US$1.45 billion) in 1985 to more than 446 billion RMB (US$64.84 billion) in 2005. Many industry watchers believe that it is only a matter of time before China takes over from the U.S. (worth US$340 billion in 2005) as the top pharmaceutical market. China’s forecasted economic growth is 8 percent per annum for the next decade and demands for healthcare are expected to increase substantially from its 1.3 billion people, many of whom have seen their disposable income grow dramatically in the past three decades.

At a personal level, however, the numbers are not so palatable. While the disposable income of China’s urban and rural residents grew by nearly 20 fold in the last two decades, their average medical costs soared by more than 130 fold in the same period. “The [healthcare] system would help safeguard people’s basic rights in using drugs, and promote the integration of drug manufacturers and distributors,” said Chen Zhu, China’s Health Minister.

For extensive medical coverage, citizens can take out additional insurance. Minister of Health Chen Zhu told China Central Television (CCTV) in March 2009 that a new healthcare insurance policy will be launched soon in which “the top limit for health insurance will be raised to six times the average urban income.” The current limit is set at four times.

Patterns of illness are in flux and are contributing enormously to the growth of the market. One aspect of this is the aging population, which has expanded substantially in past decades. People 65 and older now account for 8.2 percent of the population, and will grow to 11.2 percent in 2020, and 22 percent in 2040. And the steady rise in income, less healthy diets, and lack of exercise mean that diseases of affluence have become epidemic in China. The diabetes rate more than tripled between 1993 to 2003, with about 26 million patients estimated to have diabetes in 2003 (although three out of every four are undiagnosed, indicative of a lack of standard population-based screening programs as well as of the recent increases in new cases, according to a 2003 Pfizer/Tulane University study). Hypertension and other heart diseases have also seen alarming increases. The Chinese government is concerned about these mounting public health problems and is devising a strategy to involve healthcare professionals and local communities in the attempt to slow down the epidemic by emphasizing preventive measures and promoting healthy lifestyles.

One aspect of this effort is the reallocation of healthcare delivery resources and financing, shifting primary care from current tertiary care providers to community health centers that would treat mostly outpatients for small ailments and prevention. According to the MoH, the number of community health centers and stations more than doubled between 2003 and 2008 to reach 29,127 by the end of 2008, covering 98 percent of all townships. This represents a 28 percent annual growth rate, while major hospitals only grew at 2.8 percent annually in the same period. By the consulting firm IMS’s estimate, the number of community health centers will exceed 50,000 by 2012.

Over the past decade, multinational pharmaceutical companies have changed their China strategies. Previously, they focused on building manufacturing capability. Now they are establishing sizable R&D centers, forming strategic alliances with Chinese CROs to cut costs and streamline the R&D process, investing capital via new China-focused corporate venture funds, and signing M&A, licensing and development deals with Chinese companies.

According to inside sources, there was intense lobbying by various international and domestic drug companies fighting over whose products got on the list, leading to many revisions before the final table was determined.

Bayer China, for example, has acquired three over-the-counter (OTC) brands from local company Topsun for about US$158 million in 2007. Novartis acquired a manufacturing plant from Grunenthal, Germany in Guangdong province to expand its OTC market, and GSK entered a joint venture with Chinese drug distribution and biologics company Neptunus in June 2009 to specialize in flu vaccine manufacturing, sales, and distribution. Future M&As in the areas of OTC, manufacturing, drug distribution, and pharmaceutical R&D are likely to expand as multinationals try to differentiate themselves and gain market share in the dynamic Chinese market.

IMS analysts predict that the mash-up is likely to continue: Multinational and domestic pharma companies will cross boundaries beyond each other’s usual areas of focus, with multinationals expanding into OTC and TCM markets; generics manufacturers will license innovative products and promote branded generics such as ethical drugs, and OTC and TCM firms will explore generics market through M&A.

These trends, combined with changing demographics and a price control environment, and the overhaul of the Chinese healthcare system, will make China the most fascinating pharmaceutical market to watch in the years to come. This is a high-stakes game with winners yet to emerge. Perhaps there will be valuable lessons for other countries in the process.