Author Archives: David Cyranoski

UN climate change report marks risks of a warm future

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From shrinking glaciers to sea water becoming more acidic, climate change has already a notable imprint on Earth’s natural systems, according to a United Nations climate-science report released today. The warming projected for the 21st century poses risks — which will be severe if the rise in atmospheric concentration of heat-trapping gases continues unabated — to future food security, human well-being and wealth, says the Intergovernmental Panel on Climate Change (IPCC).

The document, which was the work of 243 lead authors, 66 editors and 436 additional experts, is the first IPCC report in seven years on the impacts of global climate change.

More frequent heat spells and drought, and more erratic precipitation, threaten to reduce freshwater water supplies and crop yields on all populated continents and particularly in countries in dry regions and the tropics. On land and in the oceans, biodiversity will decline as plants and corals die and species unable to adapt migrate or become extinct, the report concludes.

“No one on this planet will be untouched,” said  chairman Rajendra Pachauri, opening the press conference that followed a week-long meeting to finalize the report.

Chris Field, a grassland ecologist at the Carnegie Institution for Science at Stanford University in California, and co-chair of the working group that drafted the document, says that the key to the report is “how many impacts have been quantified. These are no longer projections — these are impacts,” he says.

“It’s changed the debate from one about the future to one about the present,” says Mark Howden, an agriculture expert at the Commonwealth Scientific and Industrial Research Organisation in Canberra, who was lead author on the report’s chapter on food security.

The data have helped the author–scientists to paint a picture of unprecedented clarity of some impacts of climate change. Warming linked to human activity, for example, is prompting species of marine life to migrate to higher latitudes, disturbing food chains and habitats there. This has consequences on fishery productivity in already over-fished parts of the oceans, the report warns. In tropical seas, species migration is projected to reduce the catch of economically important fish by more than 50%.

Food-crop studies also point to potentially significant drops in yield in maize (corn) and wheat as climate change proceeds, especially in tropical areas. Soy and rice — thought to be buffered from temperature extremes by the water in the paddies — are thought to be less susceptible to rising temperatures.

The report mapped spikes in grain prices resulting from climate extremes in recent years — something that Howden says shows the impact as a trend even if a causal link can’t be established in any single case.

The problem could be especially grave for farmers in the more vulnerable areas in the lower latitudes, he says. Although climate change could force a gradual restructuring of land use — for example, driving some farmers to shift to raising livestock — a more serious problem will arise when those vulnerable populations are hit by increasingly wild climate fluctuations and more frequent extremes. “Really big droughts will trash production,” says Howden. For poorer countries, especially those without proper storage infrastructure, that could spell disaster, he says.

But the data are still not easily interpreted. For example, 10% of the projections the IPCC has considered predict a 10–50% decline in global crop yields between 2030 and 2049, compared to yields in the late 20th century.  Another 10% of the studies predict a decrease in crop yields of more than 25% (up to roughly 50%) during the same period. However, almost 20% of projections project yield gains of up to 25% for the same period.

The seeming discrepancy, says Hermann Lotze-Campe, an agricultural economist at the Potsdam Institute of Climate Research in Germany, mirrors the complexity of the processes involved in photosynthesis and plant growth. Results from lab experiments and controlled free-air carbon-enrichment experiments, provide important insight but cannot simply be extrapolated to real-world changes in agriculture, as those are influenced by many other factors.  Furthermore, he says, the fertilization effect of elevated carbon dioxide concentrations on plant growth is not sufficiently well understood.

The report also brought a new level of detail to studies of the oceans. Marine ecosystems had been neglected in the past, says Field, because sea-water temperatures change more slowly than atmospheric ones and animals have more freedom to move there than they do on land. Thanks to a flood of data on the subject, ocean acidification, essentially  mentioned only in passing in the last report, in 2007, is now a central theme, says Jean-Pierre Gattuso, an oceanographer at the National Centre for Scientific Research in Villefranche-sur-Mer, France.

Ocean acidification, already apparent in large patches of the global ocean, will combine with warming and other changes, putting at risk dozens of species of warm- and cold-water corals, mollusks and crustaceans. “Meta-analyses and expert surveys have demonstrated that we know enough about the future combined impacts of ocean acidification and warming that it is critical to act now to reduce these impacts,” says Gattuso.

The report has been steeped in controversy, with some scientists labelling it alarmist and others saying that it underestimates the impact of climate change. But it has tried in many ways to strike a compromise, pointing to the need to mitigate some causes of climate change while at the same time recognizing the benefits that can come from various strategies of adapting to it.  With 12,000 citations in its 30 chapters, the authors have staked a claim that it covers a suitably broad spectrum of scientific findings. “I hope the this report will reveal what we know and what we don’t know and that it will start a conversation,” says Field.

 

Call for acid-bath stem-cell paper to be retracted

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Less than 40 days after a team led by Haruko Obokata of the RIKEN Center for Developmental Biology in Kobe, Japan, presented two stunning papers claiming a method of using a simple acid-bath method to reprogramme mature mammalian cells back to an embryonic state — so called STAP cells — researchers in Japan, including one of the papers’ co-authors, are calling for them to be retracted.

Within weeks of their 30 January publication, the paper was criticized for irregularities and apparent duplicated images. Numerous scientists also had difficulty reproducing the supposedly simple method. The team responded with the promise of corrections and a list of tips to help other scientists to reproduce the results.

Over the weekend, however, two more serious problems surfaced. The Nature paper was found to contain two images apparently duplicated from Obokata’s doctoral dissertation. Her thesis also reported experiments dealing with cells that were supposedly in an embryonic state, but the cells reported in the Nature paper were said to be derived from a different process in an altogether different experiment.

The revelation has led to a flurry of calls — including some from senior scientists in Japan — for the paper to be retracted.

Perhaps the most damning comes from Teruhiko Wakayama, a cloning expert at Yamanashi University and a corresponding author on one of the papers. Interviewed by NHK news, Wakayama said: “I have lost faith in the paper. Overall there are now just too many uncertainties about it. I think we have to wait for some confirmation.” Wakayama calls for an investigation of all the laboratory notebooks and data. He continues: “To check the legitimacy of the paper, we should retract it, prepare proper data and images, and then use those to demonstrate, with confidence, that the paper is correct.” Wakayama reportedly contacted all of the authors requesting that they agree to retract the paper. RIKEN says it is still investigating the case.

 

Acid-bath stem-cell team releases tip sheet

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A group of Japanese researchers whose revolutionary method to  produce stem cells simply drew questions from other biologists has published more details of their protocol.

The authors, who developed an ‘acid-bath’ technique that others have so far been unable to reproduce, released technical tips with a press statement today and published them on Nature Protocol Exchange. The document is entitled ‘Essential technical tips for STAP cell conversion culture from somatic cells’.

In it, Haruko Obokata, Hitoshi Niwa and Yoshiki Sasai, all of the RIKEN Centre for Developmental Biology in Kobe, say that despite its “seeming simplicity”, the method requires special care. But it is “absolutely reproducible”, Niwa told Nature News.

The controversy began at the end of January when Obokata and colleagues released two papers in Nature detailing how stress — in the form of low pH or physical pressure — could trigger the reprogramming of a mouse’s cells into an embryonic state, a process they called stimulus-triggered acquisition of pluripotency (STAP).

Cells reprogrammed into this state are ideal for studying the development of disease or the effectiveness of drugs, and could also be transplanted to regenerate failing organs. Making another type of pluripotent stem cell, called induced pluripotent stem (iPS) cells, requires a complex recipe of chemical or genetic factors. Obokata’s simple technique made headlines around the world.

But after the papers were published, they came under attack for a number of reasons, including the presence of duplicated images, an apparently plagiarized passage and the abnormal presentation of certain data. This led some commenters to question the validity of the results.

Something that would resolve the controversy would be the replication of the results by another group, but so far there have only been reports of failed attempts.

Despite a media frenzy, especially in Japan, with headlines even suggesting the results are fraudulent, the authors have stood by the work. Today Niwa told Nature News that members of the team besides Obokata have replicated the bulk of the work and that others outside the laboratory have succeeded in the first crucial step, inducing Oct3/4 expression after the acid treatment.

But the authors admit that the procedure is more complicated than originally advertised, leading to the publication of the tips.

The 10-page document states: “Despite its seeming simplicity, this procedure requires special care in cell handling and culture conditions, as well as in the choice of starting cell population.” The authors also point to the importance of bringing the cells gradually to the brink of death — which kills some 80% of them after 2–3 days — to reach the “optimal level of sub-lethal stress”.

The tips break down the process into three sections: collection of tissue and treatment with low-pH needed to produce STAP cells; preparing the culture needed to convert STAP cells to STAP stem cells, which behave like iPS cells or embryonic stem cells; and preparing the culture needed to turn STAP cells into “FI cells”, which can form placenta.

The document includes 28 “important” tips, which note the necessity of starting with primary cells (as opposed to cultured cells); that mice less than a week old, especially male mice, gave better results; the recommendation of using non-adhesive plates, which allow cell mobility and cluster formation; the importance of getting the cell density right in culture; the recommendation of using mice of a specific genetic lineage and many other detailed hints for using the proper culture conditions.

Martin Pera, a stem-cell researcher at the University of Melbourne in Australia, says: “The details provided in Nature Protocol Exchange will undoubtedly be helpful to those trying to repeat these findings.” But Pera, who has not tried to make STAP cells, adds: “The additional information does not seem to me to reveal any key procedural detail without which it would be impossible to duplicate the work. It appears instead to reinforce and emphasise some aspects of the technique that were disclosed originally.”

Those who are trying to replicate the method are intrigued by the publication of the tips. Jacob Hanna, at the Weizmann Institute of Science in Rehoboth, Israel, has made 10 batches of cells in an as-yet-unsuccessful effort to make STAP cells. He looks forward to trying some of the tips on culture conditions. “Some protocols can indeed be tricky and finicky and I commend the authors on making the effort to reach out to the scientific community,” he says. But he questions how the more complicated protocol would apply to another method of producing STAP cells advertised in the original article — putting pressure on the cell membranes. “I find that hard to imagine as a very complicated manipulation,” he says.

Qi Zhou, of the Institute of Zoology in Beijing, also appreciates the authors sharing all the details, as “some were overlooked” in his efforts to make STAP cells. The restrictions on the origin of the cell type to specific stage and gender “raise very interesting questions which may help to explain the underlying mechanism of STAP”, he says.

Niwa says that the original team is working on a “full protocol” that will make it easier to make STAP cells, but that won’t be available for at least a month. “We are not sure when it will happen because we are now trying to improve some point to enhance the reproducibility,” he says.

Self-confessed liar publishes more dubious stem-cell work

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Hisashi Moriguchi

Hisashi Moriguchi in a picture from 2012. {credit}AP/Press Association Images{/credit}

He’s back.

Last autumn, Hisashi Moriguchi stunned the world of stem-cell science by claiming he had become the first person to transfer induced pluripotent stem (iPS) cells into patients. In a now infamous front-page spread in the Yomiuri Shimbun — which has the largest number of subscribers of any newspaper in the world — Moriguchi said he created a type of iPS cell, differentiated them into cardiac cells and treated six patients with heart failure. One, he said, had already recovered and was living a healthy life.

But in an interview with Nature on the day the story appeared, Moriguchi’s claims quickly fell apart. Nature found that a paper that had supposedly set the foundation for the work was largely plagiarized, that Moriguchi had lied about his training, that he couldn’t name collaborators and that the facilities where the procedures supposedly took place had no record of them.

He also prevaricated about his affiliations — claiming in publications, for example, to hold a position at Harvard long after the short-term visiting fellowship he held in 1999–2000. Under fire, Moriguchi admitted to many false statements. Several papers were retracted. He maintained, however, that one procedure had taken place.

But Moriguchi has not rested on his laurels since then.

He has had three papers in the past two months in the peer-reviewed medical journal BMJ Case Reports. In one, published online on 18 April, he claims to have supercooled oocytes to preserve eggs from the ovaries of patients with cancer, so that the patients can later use them for in vitro fertilization. That paper, judging from the abstract, which has almost identical wording, seems to be a plagiarized version of a paper he retracted last autumn.

In a second paper, published online on 2 May, he again claims to have used iPS cells to defeat disease — this time, liver cancer. It is unclear from the summary whether he claims to have already accomplished the feat or just achieved a proof of principle.

In a third paper, published online on 24 May and reminiscent of last year’s controversial announcements, he claims to have transplanted iPS-cell-derived cardiac cells into a patient with heart failure.

In all three papers, he is the corresponding author. In all three, the other author is Joren Madson, whose affiliation is given as Reprogramming, Inc. in Boston, Massachusetts.

Nature has not been able to confirm the existence of a Reprogramming, Inc., in Boston or of a researcher named Joren Madson.

Nature has also not been able to confirm the existence of a company called Reprogramming, Inc., in Chiba, Japan, where Moriguchi claims to have an affiliation. Moriguchi’s e-mail address as the corresponding author is provided by the University Hospital Medical Information Network (UMIN) Center, an organization that acts as a clearing house for clinical-trial data. But a UMIN representative says that Moriguchi does not have a position there. E-mail addresses are given out to anyone who registers on the site.

In an e-mail, Moriguchi responded to Nature’s request for more information:

“Thank you very much for your interest. This week including today is difficult as I am in hospital. In another days (next weeks, etc), I appreciate if I can discuss about the issue via e-mail. I look forward to hearing from you via e-mail.”

Nature alerted BMJ Case Reports to the articles yesterday (13 June); a press officer says that the journal is looking into the matter.

 

China’s stealthy bird flu spreads

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Chinese health authorities are urging calm as the circle of people infected with an elusive influenza virus widens.

Over the past two days, Zhejiang province reported its first three cases — a 67-year-old retiree from Hangzhou, a 64-year-old man from Huzhou and a 38-year-old chef. The 38-year-old chef worked in neighboring Jiangsu province, where four cases had already been reported, and died on 27 March. As of 4 April, ten people, all in the Shanghai region, have been infected. Three have died, and the rest are listed in critical condition.

Health authorities are working under the assumption that poultry is to blame, and the government has warned people not to slaughter chickens. The warning is timely: some families in southern China sacrifice chickens as part of a ritual during tomb-sweeping holidays, which start today.

But the source of the virus is still a mystery. A few of those infected had direct contact with poultry, but others did not. According to official state media, tests have failed to find the virus in poultry or pigs. Shanghai tested 34 of the some 16,000 carcasses recently found floating nearby in the Huangpu River following concern that they could have carried the disease. So far, no infections in animals have been confirmed.

If it is birds that are carrying the virus, they do not seem to suffer symptoms. This makes it difficult to implement what has been the most effective tool against H5N1 and other avian flu viruses — culling of sick birds.

Although the virus clearly can be pathogenic in humans, it does not seem to be passing easily from human to human. Among hundreds of people who have been in contact with those who fell sick, none have been found to be infected.

At present, there is no vaccine.  ‘Candidate’ vaccines against other H7 viruses are available, but none target the various strains of H7N9.

Chinese central and local governments seem to be acting relatively quickly to track new cases and prepare health centres to deal with them. The health ministry distributed reagents for detecting H7N9 to the country’s 31 administrative districts. Jiangsu province, which accounts for four of the nine cases, has implemented emergency measures including strengthening of networks to report unexplained cases of pneumonia and communication with agriculture departments to expand epidemiological studies.

But health authorities have still come under criticism for delays in reporting cases and apprising families of the extent of the problem. The uncle of one victim said he thought that his son had died from pneumonia until he saw the news about H7N9 on television. He says that the hospital failed to recognize the seriousness of his nephew’s condition.

 

Novartis blockbuster linked to retracted papers

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Japanese media are reporting some uncomfortable ties between Novartis and some suspicious Japanese research linked to valsartan (Diovan), a lucrative blood-pressure drug.

Sales of the drug hit ¥119.2 billion (US$1.3 billion) in 2011, making it the top-selling drug for Novartis’s Japanese subsidiary and the third-best-selling drug in Japan. The boom in sales followed reports that it not only lowered blood pressure but also reduced the risk of stroke and heart attack. Novartis used the results in advertisements.

But then Hiroaki Matsubara, the professor at the Kyoto Prefectural University of Medicine who was heading the group that published those results, ran into trouble. In December 2012, the Japanese Circulation Society retracted two of Matsubara’s papers, citing “serious errors in data analysis” in both. A 2012 paper claimed that the drug helped diabetics to avoid heart disease. The other, published in 2011, claimed benefits for high-risk hypertensive patients. Matsubara stood by his conclusions, saying that the errors were accidental. A university committee in January found no signs of misconduct.

But the situation has spiraled since then. In February, the European Society of Cardiology retracted a similar 2009 paper on valsartan by Matsubara. The notice raised the level of alarm: “Critical problems existed with some of the data reported in the above paper.”

Since then the Japanese Circulation Society has requested another investigation by Matsubara’s university. On 28 February, he resigned. A day later, the university began an investigation.

Novartis has maintained its distance from the research. When it was revealed that a scientist working for Novartis co-authored an earlier study (also on valsartan) with the group but used an Osaka City University affiliation, Novartis responded by saying that its employee has an adjunct position at the university and, “being famous in the statistician community, merely gave advice on what type of statistical analysis to use”. Yesterday, The Mainichi newspaper also reported that Novartis invested ¥100 million in the group’s research.

 

Japan’s new leadership to boost science

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Japan’s Liberal Democratic Party (LDP), which regained power in a 16 December election, finalized a proposal for a ¥10.3-trillion (US$115 billion) supplementary budget on Friday. The supplementary budget, the second largest in the country’s history, reverses the path of austerity followed by the LDP’s predecessor, the Democratic Party of Japan, which decreased funding for some research projects and lowered many scientists’ salaries. Expected to be approved by parliament in mid-February, the supplementary budget aims to decrease energy consumption, encourage environment-friendly industry and give a significant boost to some research fields.

The industry ministry hopes to spur the economy and lower carbon dioxide emissions. To expand the use of electric vehicles (EVs), the ministry will use ¥100 billion to increase the number of EV battery quick-charging stations across the country from the current 1,400 to 35,000.  Another ¥200 billion will give support to companies that reduce energy consumption through co-generation and other measures. The environment agency will put ¥1 billion into the introduction of LED lights on roads.

The development of alternative materials to rare-earth minerals will also receive a boost. With Japan and China at loggerheads over islands both countries claim, China has restricted access to its near monopoly of such minerals.

Of ¥570 billion requested by the science and education ministry, ¥180 billion will encourage universities to commercialize basic research and another 20 billion for induced pluripotent stem (iPS) cell research. That will increase the amount of money earmarked for iPS cell research over the next ten years to ¥110 billion.

Vegetative patient free of pain

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A man thought to have been in a vegetative state for twelve years told doctors he is not in pain.

The patient communicated through a question-and-answer technique using fMRI imaging developed by University of Western Ontario’s Adrian Owen.

Owen developed the technique by asking patients diagnosed as vegetative to imagine doing certain common activities, such as playing tennis or walking through a house. These tasks produce distinct brain scans in healthy subjects, and the patients were shown to be produce the same results.  Owen uses their ability to produce those distinct brain scans to ask them questions: for example, imagine playing tennis as a proxy for yes, walking through your house for no.

He confirmed the method by asking would-be vegetative state patients factual questions. Many were able to get them right.

Reports emerging today–of Scott Routley, a 39-year-old Canadian who had shown no signs of meaningful communication since a car accident 12 years ago–is the first example in which doctors used the technique to ask patients substantive questions about their own condition.

If the reports convince the medical community, it will be a triumph of the diagnostic technique over conventional clinical examination. It will also help in the care of such patients, since they could indicate pain levels or even convey what kind of music they wanted to hear.  Lurking in the background is the question that Owen still won’t ask, for lack of moral consensus: Do you want to die? But in the meantime, some families, like  Routley’s, will be happily vindicated in their belief that their loved one is “still there.”

Texas stem-cell provider under FDA gun

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Last September, Nature predicted a stem-cell showdown in Texas, between the US Food and Drug Administration (FDA) and a company providing unproven stem-cell treatments, and that seems to be happening.

In a severe “warning letter” posted on the agency’s website this week (but dated 24 September 2012), the FDA told Celltex Therapeutics of Sugar Land, Texas, that its stem-cell products fall under FDA regulation and need to be approved before use in patients. The company lacks such approval but has been providing them to physicians who then inject them to paying patients for pricey, unproven clinical treatments.

The FDA’s reasoning is that Celltex stem-cell preparations constitute drugs and do not meet the exemption requirements that would allow such cellular products to be used at the discretion of doctors. The FDA argues that the cells are more than “minimally manipulated” because the “processing … alters the original relevant characteristics of the adipose tissue” from which the cells were derived. The warning letter also states that injection of the cells does not meet the exemption requirement that they be applied for “homologous” use. (Although the explanation in the document is redacted, this is presumably because cells,  originally part of adipose or fat tissue, are being injected for treatment of neurological and other non-homologous uses.)

Altogether the letter points to 29 “significant objectionable conditions”  with Celltex’ operations, including the failure to ensure that procedures for guaranteeing safe and quality cells are being followed. The letter points out that Celltex has failed, in response to a previous chiding about quality-control procedures,  to “provide sufficient detail to fully assess the adequacy of your corrective actions”.

The letter is a challenge to new regulations that the Texas Medical Board put in place in April, which had made FDA approval an option, not a requirement. Those regulations state that doctors injecting stem cells into patients need FDA approval or the approval of a local institutional review board (IRB). The warning letter makes clear that the FDA expects its approval to be mandatory — effectively replacing the “or” with an “and”. Continue reading →

Self-proclaimed iPS pioneer admits lies but maintains pathbreaking procedure

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The story keeps getting odder for Hisashi Moriguchi, the visiting scholar at the University of Tokyo who last week claimed a clinical breakthrough in using induced pluripotent stem (iPS) cells.

Moriguchi said that he injected cells derived from iPS cells into six patients with heart failure, with positive therapeutic effect. But the story was so full of holes, and his scientific publications were so problematic, that it was hard to believe he had done any of it.

In a press conference in New York on Saturday, Moriguchi admitted that for five of the six patients, he was discussing “planned” procedures rather than ones that had actually taken place. “I guess I got a little bit high. That was wrong,” he explained. “I admit that I lied.”

But Moriguchi has not completely given up. He maintains that the first surgery did take place — but not in February 2012 at Harvard, as he had originally claimed. At the press conference, he explained that he did it last June at a Boston hospital whose name he could not produce. As evidence, he produced a stamp in his passport showing that he had entered the United States at that time. He says he has notes on the procedure at his home in Chiba, a prefecture neighbouring Tokyo.

He also has stuck to his story that in 2010 he used iPS cells to treat a patient with hepatitis C. In April of that year, Moriguchi contacted the Nihon Keizai Shimbun to tell them about it. In June 2010 the newspaper wrote about it. On Friday (12 October), the Tokyo Medical and Dental University, which Moriguchi named as a collaborating institution on the procedures, said that no such procedures took place. Moriguchi then changed the story to say that the clinical experiment took place in the United States.

There are more problems for his published reports. Susan McGreevey, of the public affairs department at the Massachusetts General Hospital in Boston, contacted me to say that the hospital’s Raymond Chung “was stunned to see” his name listed as one of Moriguchi’s co-authors in the first reference of a Nature article. “Dr. Chung knew nothing about this paper before seeing your article.” Chung has “assisted Dr. Moriguchi with the preparation and editing of several other papers” but “he did not participate in preparing the referenced paper in any way and did not give permission for his name to be cited as a co-author.” (Nature had tried e-mail and phone to contact Chung before publishing that story.)

Four others named by Moriguchi at the press conference as collaborators in the heart-failure procedures have distanced themselves from any of the clinical work with Moriguchi. One, Kyorin University public-health specialist Takamoto Uemura, said that he hadn’t had any contact with Moriguchi for more than three years. “He just arbitrarily used my name. It’s very annoying.”

Moriguchi also, like so many fraudulent scientists before him, has image problems. The first figure in his paper about the cryopreservation of ovaries appears to be identical to the bottom figure used on the website of the Advanced Fertility Center of Chicago in Illinois. (To be fair, I have yet to call and confirm with that Chicago clinic — there’s always the possibility, quite slim I think, that they got the image from Moriguchi’s publication.) (Thanks Hiromitsu Nakauchi for drawing this to my attention.)

Likewise, in Moriguchi’s paper about making iPS cells from liver cells, Figure 2  appears to be the same as Figure 1D of Shinya Yamanaka’s 2007 paper, with the contrast changed and a little stretching of the axes. (Thanks to Noemi Fusaki for drawing my attention to that.)

Until the end of Saturday’s press conference, however, Moriguchi stuck to his guns about the one iPS cell procedure that supposedly took place at an unnamed Boston hospital. “That one was real. I really did it,” he said. He admitted, however, that his “career as a researcher is probably over.”