HIV Treatment as Prevention: Natural Experiments Highlight Limits of Antiretroviral Treatment as HIV Prevention

There is growing enthusiasm for increasing coverage of antiretroviral treatment among HIV-infected people for the purposes of preventing ongoing transmission. Treatment as prevention will face a number of barriers when implemented in real world populations, which will likely lead to the effectiveness of this strategy being lower than proposed by optimistic modelling scenarios or ideal clinical trial settings. Some settings, as part of their prevention and treatment strategies, have already attained rates of HIV testing and use of antiretroviral therapy—with high levels of viral suppression—that many countries would aspire to as targets for a treatment-as-prevention strategy. This review examines a number of these “natural experiments”, namely, British Columbia, San Francisco, France, and Australia, to provide commentary on whether treatment as prevention has worked in real world populations. This review suggests that the population-level impact of this strategy is likely to be considerably less than as inferred from ideal conditions.     

HIV Treatment as Prevention: Issues in Economic Evaluation

Meyer-Rath and Over assert in another article in the July 2012 PLoS Medicine Collection, “Investigating the Impact of Treatment on New HIV Infections”, that economic evaluations of antiretroviral therapy (ART) in currently existing programs and in HIV treatment as prevention (TasP) programs should use cost functions that capture cost dependence on a number of factors, such as scale and scope of delivery, health states, ART regimens, health workers'' experience, patients'' time on treatment, and the distribution of delivery across public and private sectors. We argue that for particular evaluation purposes (e.g., to establish the social value of TasP) and from particular perspectives (e.g., national health policy makers) less detailed cost functions may be sufficient. We then extend the discussion of economic evaluation of TasP, describing why ART outcomes and costs assessed in currently existing programs are unlikely to be generalizable to TasP programs for several fundamental reasons. First, to achieve frequent, widespread HIV testing and high uptake of ART immediately following an HIV diagnosis, TasP programs will require components that are not present in current ART programs and whose costs are not included in current estimates. Second, the early initiation of ART under TasP will change not only patients'' disease courses and treatment experiences—which can affect behaviors that determine clinical treatment success, such as ART adherence and retention—but also quality of life and economic outcomes for HIV-infected individuals. Third, the preventive effects of TasP are likely to alter the composition of the HIV-infected population over time, changing its biological and behavioral characteristics and leading to different costs and outcomes for ART.     

Prevalence and Correlates of HIV Testing among Young People Enrolled in Non-Formal Education Centers in Urban Chiang Mai,Thailand: A Cross-Sectional Study

BackgroundHIV testing is the gateway to HIV prevention, treatment, and care. Despite the established vulnerability of young Thai people to HIV infection, studies examining the prevalence and correlates of HIV testing among the general population of Thai youth are still very limited. This study investigates socio-demographic, behavioral, and psychosocial factors associated with HIV testing among young Thai people enrolled in Non-formal Education Centers (NFEC) in urban Chiang Mai, Northern Thailand.MethodsThis was a cross-sectional quantitative study conducted among young unmarried Thai youth—between the ages of 15 and 24—who were enrolled in NFEC in urban Chiang Mai. Multiple logistic regressions were used to identify correlates of “ever tested for HIV” among the sexually active participants.FindingsOf the 295 sexually active participants, 27.3% reported “ever tested for HIV;” 65.4% “did not consistently use condom;” and 61.7% “had at least 2 lifetime partners.” We found that “self-efficacy” (AOR, 4.92; CI, 1.22–19.73); “perception that it is easy to find a location nearby to test for HIV” (AOR, 4.67; CI, 1.21–18.06); “having at least 2 lifetime sexual partners” (AOR, 2.05; CI, 1.09–3.85); and “ever been pregnant or made someone pregnant” (AOR, 4.06; CI, 2.69–9.15); were associated with increased odds of having ever been tested. On the other hand, “fear of HIV test results” (AOR, 0.21; CI, 0.08–0.57) was associated with lower odds of ever having been tested for HIV.ConclusionThe main finding is that a substantially high proportion of Thai youth is engaged in risky sexual behaviors—yet reports low rates of ever having been tested for HIV. This highlights an urgent need to develop appropriate interventions—based on the identified correlates of HIV testing. There is also an urgent need to enhance HIV testing and to promote safer sexual behaviors among young Thai people—particularly those who are out-of-school.     

Genomes, race and health. Racial profiling in medicine might just be a stepping stone towards personalized health care

Considering a patient''s ethnic background can make some diagnoses easier. Yet, ‘racial profiling'' is a highly controversial concept and might soon be replaced by the advent of individualized medicine.In 2005, the US Food and Drug Administration (FDA; Bethesda, MD, USA) approved BiDil—a combination of vasodilators to treat heart failure—and hailed it as the first drug to specifically treat an ethnic group. “Approval of a drug to treat severe heart failure in self-identified black population is a striking example of how a treatment can benefit some patients even if it does not help all patients,” announced Robert Temple, the FDA''s Director of Medical Policy. “The information presented to the FDA clearly showed that blacks suffering from heart failure will now have an additional safe and effective option for treating their condition” (Temple & Stockbridge, 2007). Even the National Medical Association—the African-American version of the American Medical Association—advocated the drug, which was developed by NitroMed, Inc. (Lexington, MA, USA). A new era in medicine based on racial profiling seemed to be in the offing.By January 2008, however, the ‘breakthrough'' had gone bust. NitroMed shut down its promotional campaign for BiDil—a combination of the vasodilators isosorbide dinitrate, which affects arteries and veins, and hydralazine hydrochloride, which predominantly affects arteries. In 2009, it sold its BiDil interests and was itself acquired by another pharmaceutical company.In the meantime, critics had largely discredited the efforts of NitroMed, thereby striking a blow against the drug if not the concept of racial profiling or race-based medicine. Jonathan Kahn, a historian and law professor at Hamline University (St Paul, MN, USA), described the BiDil strategy as “a leap to genetics.” He demonstrated that NitroMed, motivated to extend its US patent scheduled to expire in 2007, purported to discover an advantage for a subpopulation of self-identified black people (Kahn, 2009). He noted that NitroMed conducted a race-specific trial to gain FDA approval, but, as there were no comparisons with other populations, it never had conclusive data to show that BiDil worked in black people differently from anyone else.“If you want to understand heart failure, you look at heart failure, and if you want to understand racial disparities in conditions such as heart failure or hypertension, there is much to look at that has nothing to do with genetics,” Kahn said, adding “that jumping to race as a genetic construct is premature at best and reckless generally in practice.” The USA, he explained, has a century-old tradition of marketing to racial and ethnic groups. “BiDil brought to the fore the notion that you can have ethnic markets not only in things like cigarettes and food, but also in pharmaceuticals,” Kahn commented.“BiDil brought to the fore the notion that you can have ethnic markets not only in things like cigarettes and food, but also in pharmaceuticals”However, despite BiDil''s failure, the search for race-based therapies and diagnostics is not over. “What I have found is an increasing, almost exponential, rise in the use of racial and ethnic categories in biotechnology-related patents,” Kahn said. “A lot of these products are still in the pipeline. They''re still patent applications, they''re not out on the market yet so it''s hard to know how they''ll play out.”The growing knowledge of the human genome is also providing new opportunities to market medical products aimed at specific ethnic groups. The first bumpy steps were taken with screening for genetic risk factors for breast cancers. Myriad Genetics (Salt Lake City, UT, USA) holds broad patents in the USA for breast-cancer screening tests that are based on mutations of the BRCA1 and BRCA2 genes, but it faced challenges in Europe, where critics raised concerns about the high costs of screening.The growing knowledge of the human genome is also providing new opportunities to market medical products aimed at specific ethnic groupsThe European Patent Office initially granted Myriad patents for the BRCA1 and BRCA2-based tests in 2001, after years of debate. But it revoked the patent on BRCA1 in 2005, which was again reversed in 2009. In 2005 Myriad decided to narrow the scope of BRCA2 testing on the basis of ethnicity. The company won a patent to predict breast-cancer risk in Ashkenazi Jewish women on the basis of BRCA2 mutations, which occur in one in 100 of these women. Physicians offering the test are supposed to ask their patients whether they are in this ethnic group, and then pay a fee to Myriad.Kahn said Myriad took this approach to package the test differently in order to protect its financial interests. However, he commented, the idea of ethnic profiling by asking women whether they identify themselves as Ashkenazi Jewish and then paying extra for an ‘ethnic'' medical test did not work in Europe. “It''s ridiculous,” Kahn commented.After the preliminary sequence of the human genome was published a decade ago, experts noted that humans were almost the same genetically, implying that race was irrelevant. In fact, the validity of race as a concept in science—let alone the use of the word—has been hotly debated. “Race, inasmuch as the concept ought to be used at all, is a social concept, not a biological one. And using it as though it were a biological one is as a much an ethical problem as a scientific problem,” commented Samia Hurst, a physician and bioethicist at Geneva University Medical School in Switzerland.​Switzerland.Open in a separate window© Monalyn Gracia/CorbisCiting a popular slogan: “There is no gene for race,” she noted, “there doesn''t seem to be a single cluster of genes that fits with identification within an ethnic group, let alone with disease risks as well. We''re also in an increasingly mixed world where many people—and I count myself among them—just don''t know what to check on the box. If you start counting up your grandparents and end up with four different ethnic groups, what are you going to do? So there are an increasing number of people who just don''t fit into those categories at all.”Still, some dismiss criticism of racial profiling as political correctness that could potentially prevent patients from receiving proper care. Sally Satel, a psychiatrist in Washington, DC, USA, does not shy away from describing herself as a racially profiling physician and argues that it is good medicine. A commentator and resident scholar at the nonpartisan conservative think tank, the American Enterprise Institute (Washington, DC, USA), Satel wrote the book PC, M.D.: How Political Correctness is Corrupting Medicine. “In practicing medicine, I am not color blind. I take note of my patient''s race. So do many of my colleagues,” she wrote in a New York Times article entitled “I am a racially profiling doctor” (Satel, 2002).…some dismiss criticism of racial profiling as political correctness that could potentially prevent patients from receiving proper careSatel noted in an interview that it is an undeniable fact that black people tend to have more renal disease, Native Americans have more diabetes and white people have more cystic fibrosis. She said these differences can help doctors to decide which drugs to prescribe at which dose and could potentially lead researchers to discover new therapies on the basis of race.Satel added that the mention of race and medicine makes many people nervous. “You can dispel that worry by taking pains to specify biological lineage. Simply put, members of a group have more genes in common than members of the population at large. Some day geneticists hope to be able to conduct genomic profiles of each individual, making group identity irrelevant, but until then, race-based therapeutics has its virtues,” she said. “Denying the relationship between race and medicine flies in the face of clinical reality, and pretending that we are all at equal risk for health problems carries its own dangers.”However, Hurst contended that this approach may be good epidemiology, rather than racial profiling. Physicians therefore need to be cautious about using skin colour, genomic data and epidemiological data in decision making. “If African Americans are at a higher risk for hypertension, are you not going to check for hypertension in white people? You need to check in everyone in any case,” she commented.Hurst said European physicians, similarly to their American colleagues, deal with race and racial profiling, albeit in a different way. “The way in which we struggle with it is strongly determined by the history behind what could be called the biases that we have. If you have been a colonial power, if the past is slavery or if the past or present is immigration, it does change some things,” she said. “On the other hand, you always have the difficulty of doing fair and good medicine in a social situation that has a kind of ‘them and us'' structure. Because you''re not supposed to do medicine in a ‘them and us'' structure, you''re supposed to treat everyone according to their medical needs and not according to whether they''re part of ‘your tribe'' or ‘another tribe''.”Indeed, social factors largely determine one''s health, rather than ethnic or genetic factors. August A. White III, an African-American orthopaedic surgeon at Harvard Medical School (Boston, MA, USA) and author of the book Seeing Patients: Unconscious Bias In Health Care, noted that race is linked to disparities in health care in the USA. A similar point can be made in Europe where, for example, Romani people face discrimination in several countries.White said that although genetic research shows that race is not a scientific concept, the way people are labelled in society and how they are treated needs to be taken into account. “It''d be wonderful at some point if we can pop one''s key genetic information into a computer and get a printout of which medications are best of them and which doses are best for them,” he commented. “In the meantime though, I advocate careful operational attempts to treat everyone as human beings and to value everyone''s life, not devalue old people, or devalue women, or devalue different religious faiths, etc.”Notwithstanding the scientific denunciation, a major obstacle for the concept of racial profiling has been the fact that the word ‘race'' itself is politically loaded, as a result of, among other things, the baggage of eugenics and Nazi racism and the legacies of slavery and colonialism. Richard Tutton, a sociologist at Lancaster University in the UK, said that British scientists he interviewed for a Wellcome Trust project a few years ago prefer the term ethnicity to race. “Race is used in a legal sense in relation to inequality, but certainly otherwise, ethnicity is the preferred term, which obviously is different to the US” he said. “I remember having conversations with German academics and obviously in Germany you couldn''t use the R-word.”Jan Helge Solbakk, a physician, theologian and medical ethicist at the University of Oslo in Norway, said the use of the term race in Europe is a non-starter because it makes it impossible for the public and policy-makers to communicate. “I think in Europe it would be politically impossible to launch a project targeting racial differences on the genetic level. The challenge is to find not just a more politically correct concept, but a genetically more accurate concept and to pursue such research questions,” he said. According to Kahn, researchers therefore tend to refer to ethnicity rather than race: “They''re talking about European, Asian and African, but they''re referring to it as ethnicity instead of race because they think somehow that''s more palatable.”Regardless, race-based medicine might just be a stepping stone towards more refined and accurate methods, with the advent of personalized medicine based on genomics, according to Leroy Hood, whose work has helped to develop tools to analyse the human genome. The focus of his company—the Institute for Systems Biology (Seattle, WA, USA)—is to identify genetic variants that can inform and help patients to pioneer individualized health care.“Race as a concept is disappearing with interbreeding,” Hood said. “Race distinction is going to slowly fade away. We can use it now because we have signposts for race, which are colour, fairness, kinkiness of hair, but compared to a conglomeration of things that define a race, those are very few features. The race-defining features are going to be segregating away from one another more and more as the population becomes racially heterogeneous, so I think it''s going to become a moot point.”Hood instead advocates “4P” health care—“Predictive, Personalized, Preventive and Participatory.” “My overall feeling about the race-based correlations is that it is far more important to think about the individual and their individual unique spectra of health and wellness,” he explained. “I think we are not going to deal in the future with racial or ethnic populations, rather medicine of the future is going to be focused entirely on the individual.”Yet, Arthur Caplan, Director of the Center for Bioethics at the University of Pennsylvania (Philadelphia, PA, USA), is skeptical about the prospects for both race-based and personalized medicine. “Race-based medicine will play a minor role over the next few years in health care because race is a minor factor in health,” he said. “It''s not like we have a group of people who keel over dead at 40 who are in the same ethnic group.”Caplan also argued that establishing personalized genomic medicine in a decade is a pipe dream. “The reason I say that is it''s not just the science,” he explained. “You have to redo the whole health-care system to make that possible. You have to find manufacturers who can figure out how to profit from personalized medicine who are both in Europe and the United States. You have to have doctors that know how to prescribe them. It''s a big, big revamping. That''s not going to happen in 10 years.”Hood, however, is more optimistic and plans to advance the concept with pilot projects; he believes that Europe might be the better testing ground. “I think the European systems are much more efficient for pioneering personalized medicine than the United States because the US health-care system is utterly chaotic. We have every combination of every kind of health care and health delivery. We have no common shared vision,” he said. “In the end we may well go to Europe to persuade a country to really undertake this. The possibility of facilitating a revolution in health care is greater in Europe than in the United States.”     

Evolvement of uniformity and volatility in the stressed global financial village

Background

In the current era of strong worldwide market couplings the global financial village became highly prone to systemic collapses, events that can rapidly sweep throughout the entire village.

Methodology/Principal Findings

We present a new methodology to assess and quantify inter-market relations. The approach is based on the correlations between the market index, the index volatility, the market Index Cohesive Force and the meta-correlations (correlations between the intra-correlations.) We investigated the relations between six important world markets—U.S., U.K., Germany, Japan, China and India—from January 2000 until December 2010. We found that while the developed “western” markets (U.S., U.K., Germany) are highly correlated, the interdependencies between these markets and the developing “eastern” markets (India and China) are volatile and with noticeable maxima at times of global world events. The Japanese market switches “identity”—it switches between periods of high meta-correlations with the “western” markets and periods when it behaves more similarly to the “eastern” markets.

Conclusions/Significance

The methodological framework presented here provides a way to quantify the evolvement of interdependencies in the global market, evaluate a world financial network and quantify changes in the world inter market relations. Such changes can be used as precursors to the agitation of the global financial village. Hence, the new approach can help to develop a sensitive “financial seismograph” to detect early signs of global financial crises so they can be treated before they develop into worldwide events.     

The A to T of historical evidence

Geneticists and historians collaborated recently to identify the remains of King Richard III of England, found buried under a car park. Genetics has many more contributions to make to history, but scientists and historians must learn to speak each other''s languages.The remains of King Richard III (1452–1485), who was killed with sword in hand at the Battle of Bosworth Field at the end of the War of the Roses, had lain undiscovered for centuries. Earlier this year, molecular biologists, historians, archaeologists and other experts from the University of Leicester, UK, reported that they had finally found his last resting place. They compared ancient DNA extracted from a scoliotic skeleton discovered under a car park in Leicester—once the site of Greyfriars church, where Richard was rumoured to be buried, but the location of which had been lost to time—with that of a seventeenth generation nephew of King Richard: it was a match. Richard has captured the public imagination for centuries: Tudor-friendly playwright William Shakespeare (1564–1616) portrayed Richard as an evil hunchback who killed his nephews in order to ascend to the throne, whilst in succeeding years others have leapt to his defence and backed an effort to find his remains.The application of genetics to history is revealing much about the ancestry and movements of groups of humans, from the fall of the Roman Empire to ancient ChinaMolecular biologist Turi King, who led the Leicester team that extracted the DNA and tracked down a descendant of Richard''s older sister, said that Richard''s case shows how multi-disciplinary teams can join forces to answer history''s questions. “There is a lot of talk about what meaning does it have,” she said. “It tells us where Richard III was buried; that the story that he was buried in Greyfriars is true. I think there are some people who [will] try and say: “well, it''s going to change our view of him” […] It won''t, for example, tell us about his personality or if he was responsible for the killing of the Princes in the Tower.”The discovery and identification of Richard''s skeleton made headlines around the world, but he is not the main prize when it comes to collaborations between historians and molecular biologists. Although some of the work has focused on high-profile historic figures—such as Louis XVI (1754–1793), the only French king to be executed, and Vlad the Impaler, the Transylvanian royal whose patronymic name inspired Bram Stoker''s Dracula (Fig 1)—many other projects involve population studies. Application of genetics to history is revealing much about the ancestry and movements of groups of humans, from the fall of the Roman Empire to ancient China.Open in a separate windowFigure 1The use of molecular genetics to untangle history. Even when the historical record is robust, molecular biology can contribute to our understanding of important figures and their legacies and provide revealing answers to questions about ancient princes and kings.Medieval historian Michael McCormick of Harvard University, USA, commented that historians have traditionally relied on studying records written on paper, sheepskin and papyrus. However, he and other historians are now teaming up with geneticists to read the historical record written down in the human genome and expand their portfolio of evidence. “What we''re seeing happening now—because of the tremendous impact from the natural sciences and particularly the application of genomics; what some of us are calling genomic archaeology—is that we''re working back from modern genomes to past events reported in our genomes,” McCormick explained. “The boundaries between history and pre-history are beginning to dissolve. It''s a really very, very exciting time.”…in the absence of written records, DNA and archaeological records could help fill in gapsMcCormick partnered with Mark Thomas, an evolutionary geneticist at University College London, UK, to try to unravel the mystery of one million Romano-Celtic men who went missing in Britain after the fall of the Roman Empire. Between the fourth and seventh centuries, Germanic tribes of Angles, Saxons and Jutes began to settle in Britain, replacing the Romano-British culture and forcing some of the original inhabitants to migrate to other areas. “You can''t explain the predominance of the Germanic Y chromosome in England based on the population unless you imagine (a) that they killed all the male Romano-Celts or (b) there was what Mark called ‘sexual apartheid'' and the conquerors mated preferentially with the local women. [The latter] seems to be the best explanation that I can see,” McCormick said of the puzzle.Ian Barnes, a molecular palaeobiologist at Royal Holloway University of London, commented that McCormick studies an unusual period, for which both archaeological and written records exist. “I think archaeologists and historians are used to having conflicting evidence between the documentary record and the archaeological record. If we bring in DNA, the goal is to work out how to pair all the information together into the most coherent story.”Patrick Geary, Professor of Western Medieval History at the Institute for Advanced Study in Princeton, New Jersey, USA, studies the migration period of Europe: a time in the first millennium when Germanic tribes, including the Goths, Vandals, Huns and Longobards, moved across Europe as the Roman Empire was declining. “We do not have detailed written information about these migrations or invasions or whatever one wants to call them. Primarily what we have are accounts written later on, some generations later, from the contemporary record. What we tend to have are things like sermons bemoaning the faith of people because God''s wrath has brought the barbarians on them. Hardly the kind of thing that gives us an idea of exactly what is going on—are these really invasions, are they migrations, are they small military groups entering the Empire? And what are these ‘peoples'': biologically related ethnic groups, or ad hoc confederations?” he said.Geary thinks that in the absence of written records, DNA and archaeological records could help fill in the gaps. He gives the example of jewellery, belt buckles and weapons found in ancient graves in Hungary and Northern and Southern Italy, which suggest migrations rather than invasions: “If you find this kind of jewellery in one area and then you find it in a cemetery in another, does it mean that somebody was selling jewellery in these two areas? Does this mean that people in Italy—possibly because of political change—want to identify themselves, dress themselves in a new style? This is hotly debated,” Geary explained. Material goods can suggest a relationship between people but the confirmation will be found in their DNA. “These are the kinds of questions that nobody has been able to ask because until very recently, DNA analysis simply could not be done and there were so many problems with it that this was just hopeless,” he explained. Geary has already collected some ancient DNA samples and plans to collect more from burial sites north and south of the Alps dating from the sixth century, hoping to sort out kinship relations and genetic profiles of populations.King said that working with ancient DNA is a tricky business. “There are two reasons that mitochondrial DNA (mtDNA) is the DNA we wished to be able to analyse in [King] Richard. In the first instance, we had a female line relative of Richard III and mtDNA is passed through the female line. Fortunately, it''s also the most likely bit of DNA that we''d be able to retrieve from the skeletal remains, as there are so many copies of it in the cell. After death, our DNA degrades, so mtDNA is easier to retrieve simply due to the sheer number of copies in each cell.”Geary contrasted the analysis of modern and ancient DNA. He called modern DNA analysis “[…] almost an industrial thing. You send it off to a lab, you get it back, it''s very mechanical.” Meanwhile, he described ancient DNA work as artisanal, because of degeneration and contamination. “Everything that touched it, every living thing, every microbe, every worm, every archaeologist leaves DNA traces, so it''s a real mess.” He said the success rate for extracting ancient mtDNA from teeth and dense bones is only 35%. The rate for nuclear DNA is only 10%. “Five years ago, the chances would have been zero of getting any, so 10% is a great step forward. And it''s possible we would do even better because this is a field that is rapidly transforming.”But the bottleneck is not only the technical challenge to extract and analyse ancient DNA. Historians and geneticists also need to understand each other better. “That''s why historians have to learn what it is that geneticists do, what this data is, and the geneticists have to understand the kind of questions that [historians are] trying to ask, which are not the old nineteenth century questions about identity, but questions about population, about gender roles, about relationship,” Geary said.DNA analysis can help to resolve historical questions and mysteries about our ancestors, but both historians and geneticists are becoming concerned about potential abuses and frivolous applications of DNA analysis in their fields. Thomas is particularly disturbed by studies based on single historical figures. “Unless it''s a pretty damn advanced analysis, then studying individuals isn''t particularly useful for history unless you want to say something like this person had blue eyes or whatever. Population level studies are best,” he said. He conceded that the genetic analysis of Richard III''s remnants was a sound application but added that this often is not the case with other uses, which he referred to as “genetic astrology.” He was critical of researchers who come to unsubstantiated conclusions based on ancient DNA, and scientific journals that readily publish such papers.…both historians and geneticists are becoming concerned about potential abuses or frivolous applications of DNA analysis in their fieldsThomas said that it is reasonable to analyse a Y chromosome or mtDNA to estimate a certain genetic trait. “But then to look at the distribution of those, note in the tree where those types are found, and informally, interpretively make inferences—“Well this must have come from here and therefore when I find it somewhere else then that means that person must have ancestors from this original place”—[…] that''s deeply flawed. It''s the most widely used method for telling historical stories from genetic data. And yet is easily the one with the least credibility.” Thomas criticized such facile use of genetic data, which misleads the public and the media. “I suppose I can''t blame these [broadcast] guys because it''s their job to make the programme look interesting. If somebody comes along and says ‘well, I can tell you you''re descended from some Viking warlord or some Celtic princess'', then who are they to question.”Similarly, the historians have reservations about making questionable historical claims on the basis of DNA analysis. Geary said the use of mtDNA to identify Richard III was valuable because it answered a specific, factual question. However, he is turned off by other research using DNA to look at individual figures, such as a case involving a princess who was a direct descendant of the woman who posed for Leonardo Da Vinci''s Mona Lisa. “There''s some people running around trying to dig up famous people and prove the obvious. I think that''s kind of silly. There are others that I think are quite appropriate, and while is not my kind of history, I think it is fine,” he said. “The Richard III case was in the tradition of forensics.”…the cases in which historians and archaeologists work with molecular biologists are rare and remain disconnected in general from the mainstream of historical or archaeological researchNicola Di Cosmo, a historian at the Institute for Advanced Study, who is researching the impact of climate change on the thirteenth century Mongol empire, follows closely the advances in DNA and history research, but has not yet applied it to his own work. Nevertheless, he said that genetics could help to understand the period he studies because there are no historical documents, although monumental burials exist. “It is important to get a sense of where these people came from, and that''s where genetics can help,” he said. He is also concerned about geneticists who publish results without involving historians and without examining other records. He cited a genetic study of a so-called ‘Eurasian male'' in a prestige burial of the Asian Hun Xiongnu, a nomadic people who at the end of the third century B.C. formed a tribal league that dominated most of Central Asia for more than 500 years. “The conclusion the geneticists came to was that there was some sort of racial tolerance in this nomadic empire, but we have no way to even assume that they had any concept of race or tolerance.”Di Cosmo commented that the cases in which historians and archaeologists work with molecular biologists are rare and remain disconnected in general from the mainstream of historical or archaeological research. “I believe that historians, especially those working in areas for which written records are non-existent, ought to be taking seriously the evidence churned out by genetic laboratories. On the other hand, geneticists must realize that the effectiveness of their research is limited unless they access reliable historical information and understand how a historical argument may or may not explain the genetic data” [1].Notwithstanding the difficulties in collaboration between two fields, McCormick is excited about historians working with DNA. He said the intersection of history and genomics could create a new scientific discipline in the years ahead. “I don''t know what we''d call it. It would be a sort of fusion science. It certainly has the potential to produce enormous amounts of enormously interesting new evidence about our human past.”     

Transitions from injection-drug-use-concentrated to self-sustaining heterosexual HIV epidemics: patterns in the international data

Background

Injecting drug use continues to be a primary driver of HIV epidemics in many parts of the world. Many people who inject drugs (PWID) are sexually active, so it is possible that high-seroprevalence HIV epidemics among PWID may initiate self-sustaining heterosexual transmission epidemics.

Methods

Fourteen countries that had experienced high seroprevalence (<20%) HIV epidemics among PWID and had reliable data for injection drug use (IDU) and heterosexual cases of HIV or AIDS were identified. Graphs of newly reported HIV or AIDS cases among PWID and heterosexuals were constructed to identify temporal relationships between the two types of epidemics. The year in which newly reported cases among heterosexuals surpassed newly reported cases among PWID, aspects of the epidemic curves, and epidemic case histories were analyzed to assess whether it was “plausible” or “highly unlikely” that the HIV epidemic among PWID might have initiated the heterosexual epidemic in each country.

Results

Transitions have occurred in 11 of the 14 countries. Two types of temporal relationships between IDU and heterosexual HIV epidemics were identified, rapid high incidence transitions vs. delayed, low incidence transitions. In six countries it appears “plausible” that the IDU epidemic initiated a heterosexual epidemic, and in five countries it appears “highly unlikely” that the IDU epidemic initiated a heterosexual epidemic. A rapid decline in incidence among PWID after the peak year of new cases and national income were the best predictors of the “highly unlikely” initiation of a heterosexual epidemic.

Discussion

Transitions from IDU concentrated epidemics to heterosexual epidemics are common in countries with high seroprevalence among PWID though there are distinct types of transitions. Interventions to immediately reduce HIV incidence among PWID may reduce the likelihood that an IDU epidemic may initiate a heterosexual epidemic.     

Evidence-based policymaking when evidence is incomplete: The case of HIV programme integration

Jan Hontelez and co-authors discuss the use of different types of evidence to inform HIV program integration.

Summary points

• Sustainable Development Goal 3 aims to “ensure healthy lives and promote well-being for all at all ages” and has set a target of achieving global universal health coverage, representing a major policy shift away from mostly disease-specific “vertical programmes”.
• While health service integration can be a promising strategy to improve healthcare coverage, health outcomes, and efficiency, the exact impact of integration in different settings is hard to predict, and policy makers need to choose from a large variety of integration strategies and opportunities with varying levels of scientific evidence.
• Using the case of health service integration for HIV in low- and middle-income countries, we outline implementation strategies for integration opportunities with lacking or scarce high-level causal evidence, based on existing frameworks and methodologies from within and beyond healthcare and implementation science.
• Proper use of scientific evidence in other contexts requires adequate and systematic assessments of the transportability of an intervention. Several methods exist that allow for judging transferability and comprehensively identifying key context-specific indicators across studies that can affect the reported impact of interventions.
• When (transferable) evidence is absent, we propose that by drawing on well-established design and implementation methodologies—underpinned by ongoing learning and iterative improvement of local service delivery strategies—countries could substantially improve decision-making even in the absence of scientific evidence.
• Reaching the goal of making the HIV response an integral part of a larger, universal, people-centred health system that meets the needs and requirements of citizens can be facilitated by applying lessons learned from implementation science and novel design methodologies.

     

Innovation in Evaluating the Impact of Integrated Service-Delivery: The Integra Indexes of HIV and Reproductive Health Integration

Background

The body of knowledge on evaluating complex interventions for integrated healthcare lacks both common definitions of ‘integrated service delivery’ and standard measures of impact. Using multiple data sources in combination with statistical modelling the aim of this study is to develop a measure of HIV-reproductive health (HIV-RH) service integration that can be used to assess the degree of service integration, and the degree to which integration may have health benefits to clients, or reduce service costs.

Methods and Findings

Data were drawn from the Integra Initiative’s client flow (8,263 clients in Swaziland and 25,539 in Kenya) and costing tools implemented between 2008–2012 in 40 clinics providing RH services in Kenya and Swaziland. We used latent variable measurement models to derive dimensions of HIV-RH integration using these data, which quantified the extent and type of integration between HIV and RH services in Kenya and Swaziland. The modelling produced two clear and uncorrelated dimensions of integration at facility level leading to the development of two sub-indexes: a Structural Integration Index (integrated physical and human resource infrastructure) and a Functional Integration Index (integrated delivery of services to clients). The findings highlight the importance of multi-dimensional assessments of integration, suggesting that structural integration is not sufficient to achieve the integrated delivery of care to clients—i.e. “functional integration”.

Conclusions

These Indexes are an important methodological contribution for evaluating complex multi-service interventions. They help address the need to broaden traditional evaluations of integrated HIV-RH care through the incorporation of a functional integration measure, to avoid misleading conclusions on its ‘impact’ on health outcomes. This is particularly important for decision-makers seeking to promote integration in resource constrained environments.     

The puzzle of sympatry. Recent evidence supports the notion of sympatric speciation--the rise of new species in the same location--but the reasons for this phenomenon remain elusive

Sympatric speciation—the rise of new species in the absence of geographical barriers—remains a puzzle for evolutionary biologists. Though the evidence for sympatric speciation itself is mounting, an underlying genetic explanation remains elusive.For centuries, the greatest puzzle in biology was how to account for the sheer variety of life. In his 1859 landmark book, On the Origin of Species, Charles Darwin (1809–1882) finally supplied an answer: his grand theory of evolution explained how the process of natural selection, acting on the substrate of genetic mutations, could gradually produce new organisms that are better adapted to their environment. It is easy to see how adaptation to a given environment can differentiate organisms that are geographically separated; different environmental conditions exert different selective pressures on organisms and, over time, the selection of mutations creates different species—a process that is known as allopatric speciation.It is more difficult to explain how new and different species can arise within the same environment. Although Darwin never used the term sympatric speciation for this process, he did describe the formation of new species in the absence of geographical separation. “I can bring a considerable catalogue of facts,” he argued, “showing that within the same area, varieties of the same animal can long remain distinct, from haunting different stations, from breeding at slightly different seasons, or from varieties of the same kind preferring to pair together” (Darwin, 1859).It is more difficult to explain how new and different species can arise within the same environmentIn the 1920s and 1930s, however, allopatric speciation and the role of geographical isolation became the focus of speciation research. Among those leading the charge was Ernst Mayr (1904–2005), a young evolutionary biologist, who would go on to influence generations of biologists with his later work in the field. William Baker, head of palm research at the Royal Botanic Gardens, Kew in Richmond, UK, described Mayr as “one of the key figures to crush sympatric speciation.” Frank Sulloway, a Darwin Scholar at the Institute of Personality and Social Research at the University of California, Berkeley, USA, similarly asserted that Mayr''s scepticism about sympatry was central to his career.The debate about sympatric and allopatric speciation has livened up since Mayr''s death…Since Mayr''s death in 2005, however, several publications have challenged the notion that sympatric speciation is a rare exception to the rule of allopatry. These papers describe examples of both plants and animals that have undergone speciation in the same location, with no apparent geographical barriers to explain their separation. In these instances, a single ancestral population has diverged to the extent that the two new species cannot produce viable offspring, despite the fact that their ranges overlap. The debate about sympatric and allopatric speciation has livened up since Mayr''s death, as Mayr''s influence over the field has waned and as new tools and technologies in molecular biology have become available.Sulloway, who studied with Mayr at Harvard University, in the late 1960s and early 1970s, notes that Mayr''s background in natural history and years of fieldwork in New Guinea and the Solomon Islands contributed to his perception that the bulk of the data supported allopatry. “Ernst''s early career was in many ways built around that argument. It wasn''t the only important idea he had, but he was one of the strong proponents of it. When an intellectual stance exists where most people seem to have gotten it wrong, there is a tendency to sort of lay down the law,” Sulloway said.Sulloway also explained that Mayr “felt that botanists had basically led Darwin astray because there is so much evidence of polyploidy in plants and Darwin turned in large part to the study of botany and geographical distribution in drawing evidence in The Origin.” Indeed, polyploidization is common in plants and can lead to ‘instantaneous'' speciation without geographical barriers.In February 2006, the journal Nature simultaneously published two papers that described sympatric speciation in animals and plants, reopening the debate. Axel Meyer, a zoologist and evolutionary biologist at the University of Konstanz, Germany, demonstrated with his colleagues that sympatric speciation has occurred in cichlid fish in Lake Apoyo, Nicaragua (Barluenga et al, 2006). The researchers claimed that the ancestral fish only seeded the crater lake once; from this, new species have evolved that are distinct and reproductively isolated. Meyer''s paper was broadly supported, even by critics of sympatric speciation, perhaps because Mayr himself endorsed sympatric speciation among the cichlids in his 2001 book What Evolution Is. “[Mayr] told me that in the case of our crater lake cichlids, the onus of showing that it''s not sympatric speciation lies with the people who strongly believe in only allopatric speciation,” Meyer said.…several scientists involved in the debate think that molecular biology could help to eventually resolve the issueThe other paper in Nature—by Vincent Savolainen, a molecular systematist at Imperial College, London, UK, and colleagues—described the sympatric speciation of Howea palms on Lord Howe Island (Fig 1), a minute Pacific island paradise (Savolainen et al, 2006a). Savolainen''s research had originally focused on plant diversity in the gesneriad family—the best known example of which is the African violet—while he was in Brazil for the Geneva Botanical Garden, Switzerland. However, he realized that he would never be able prove the occurrence of sympatry within a continent. “It might happen on a continent,” he explained, “but people will always argue that maybe they were separated and got together after. […] I had to go to an isolated piece of the world and that''s why I started to look at islands.”Open in a separate windowFigure 1Lord Howe Island. Photo: Ian Hutton.He eventually heard about Lord Howe Island, which is situated just off the east coast of Australia, has an area of 56 km² and is known for its abundance of endemic palms (Sidebar A). The palms, Savolainen said, were an ideal focus for sympatric research: “Palms are not the most diverse group of plants in the world, so we could make a phylogeny of all the related species of palms in the Indian Ocean, southeast Asia and so on.”…the next challenges will be to determine which genes are responsible for speciation, and whether sympatric speciation is common

Sidebar A | Research in paradise

Alexander Papadopulos is no Tarzan of the Apes, but he has spent a couple months over the past two years aloft in palm trees hugging rugged mountainsides on Lord Howe Island, a Pacific island paradise and UNESCO World Heritage site.Papadopulos—who is finishing his doctorate at Imperial College London, UK—said the views are breathtaking, but the work is hard and a bit treacherous as he moves from branch to branch. “At times, it can be quite hairy. Often you''re looking over a 600-, 700-metre drop without a huge amount to hold onto,” he said. “There''s such dense vegetation on most of the steep parts of the island. You''re actually climbing between trees. There are times when you''re completely unsupported.”Papadopulos typically spends around 10 hours a day in the field, carrying a backpack and utility belt with a digital camera, a trowel to collect soil samples, a first-aid kit, a field notebook, food and water, specimen bags, tags to label specimens, a GPS device and more. After several days in the field, he spends a day working in a well-equipped field lab and sleeping in the quarters that were built by the Lord Howe governing board to accommodate the scientists who visit the island on various projects. Papadopulos is studying Lord Howe''s flora, which includes more than 200 plant species, about half of which are indigenous.Vincent Savolainen said it takes a lot of planning to get materials to Lord Howe: the two-hour flight from Sydney is on a small plane, with only about a dozen passengers on board and limited space for equipment. Extra gear—from gardening equipment to silica gel and wood for boxes in which to dry wet specimens—arrives via other flights or by boat, to serve the needs of the various scientists on the team, including botanists, evolutionary biologists and ecologists.Savolainen praised the well-stocked researcher station for visiting scientists. It is run by the island board and situated near the palm nursery. It includes one room for the lab and another with bunks. “There is electricity and even email,” he said. Papadoupulos said only in the past year has the internet service been adequate to accommodate video calls back home.Ian Hutton, a Lord Howe-based naturalist and author, who has lived on the island since 1980, said the island authorities set limits on not only the number of residents—350—but also the number of visitors at one time—400—as well as banning cats, to protect birds such as the flightless wood hen. He praised the Imperial/Kew group: “They''re world leaders in their field. And they''re what I call ‘Gentlemen Botanists''. They''re very nice people, they engage the locals here. Sometimes researchers might come here, and they''re just interested in what they''re doing and they don''t want to share what they''re doing. Not so with these people. Savolainen said his research helps the locals: “The genetics that we do on the island are not only useful to understand big questions about evolution, but we also always provide feedback to help in its conservation efforts.”Yet, in Savolainen''s opinion, Mayr''s influential views made it difficult to obtain research funding. “Mayr was a powerful figure and he dismissed sympatric speciation in textbooks. People were not too keen to put money on this,” Savolainen explained. Eventually, the Leverhulme Trust (London, UK) gave Savolainen and Baker £70,000 between 2003–2005 to get the research moving. “It was enough to do the basic genetics and to send a research assistant for six months to the island to do a lot of natural history work,” Savolainen said. Once the initial results had been processed, the project received a further £337,000 from the British Natural Environment Research Council in 2008, and €2.5 million from the European Research Council in 2009.From the data collected on Lord Howe Island, Savolainen and his team constructed a dated phylogenetic tree showing that the two endemic species of the palm Howea (Arecaceae; Fig 2) are sister taxa. From their tree, the researchers were able to establish that the two species—one with a thatch of leaves and one with curly leaves—diverged long after the island was formed 6.9 million years ago. Even where they are found in close proximity, the two species cannot interbreed as they flower at different times.Open in a separate windowFigure 2The two species of Howea palm. (A) Howea fosteriana (Kentia palm). (B) Howea belmoreana. Photos: William Baker, Royal Botanical Gardens, Kew, Richmond, UK.According to the researchers, the palm speciation probably occurred owing to the different soil types in which the plants grow. Baker explained that there are two soil types on Lord Howe—the older volcanic soil and the younger calcareous soils. The Kentia palm grows in both, whereas the curly variety is restricted to the volcanic soil. These soil types are closely intercalated—fingers and lenses of calcareous soils intrude into the volcanic soils in lowland Lord Howe Island. “You can step over a geological boundary and the palms in the forest can change completely, but they remain extremely close to each other,” Baker said. “What''s more, the palms are wind-pollinated, producing vast amounts of pollen that blows all over the place during the flowering season—people even get pollen allergies there because there is so much of the stuff.” According to Savolainen, that the two species have different flowering times is a “way of having isolation so that they don''t reproduce with each other […] this is a mechanism that evolved to allow other species to diverge in situ on a few square kilometres.”According to Baker, the absence of a causative link has not been demonstrated between the different soils and the altered flowering times, “but we have suggested that at the time of speciation, perhaps when calcareous soils first appeared, an environmental effect may have altered the flowering time of palms colonising the new soil, potentially causing non-random mating and kicking off speciation. This is just a hypothesis—we need to do a lot more fieldwork to get to the bottom of this,” he said. What is clear is that this is not allopatric speciation, as “the micro-scale differentiation in geology and soil type cannot create geographical isolation”, said Baker.…although molecular data will add to the debate, it will not settle it aloneThe results of the palm research caused something of a splash in evolutionary biology, although the study was not without its critics. Tod Stuessy, Chair of the Department of Systematic and Evolutionary Botany at the University of Vienna, Austria, has dealt with similar issues of divergence on Chile''s Juan Fernández Islands—also known as the Robinson Crusoe Islands—in the South Pacific. From his research, he points out that on old islands, large ecological areas that once separated species—and caused allopatric speciation—could have since disappeared, diluting the argument for sympatry. “There are a lot of cases [in the Juan Fernández Islands] where you have closely related species occurring in the same place on an island, even in the same valley. We never considered that they had sympatric origins because we were always impressed by how much the island had been modified through time,” Stuessy said. “What [the Lord Howe researchers] really didn''t consider was that Lord Howe Island could have changed a lot over time since the origins of the species in question.” It has also been argued that one of the palm species on Lord Howe Island might have evolved allopatrically on a now-sunken island in the same oceanic region.In their response to a letter from Stuessy, Savolainen and colleagues argued that erosion on the island has been mainly coastal and equal from all sides. “Consequently, Quaternary calcarenite deposits, which created divergent ecological selection pressures conducive to Howea species divergence, have formed evenly around the island; these are so closely intercalated with volcanic rocks that allopatric speciation due to ecogeographic isolation, as Stuessy proposes, is unrealistic” (Savolainen et al, 2006b). Their rebuttal has found support in the field. Evolutionary biologist Loren Rieseberg at the University of British Columbia in Vancouver, Canada, said: “Basically, you have two sister species found on a very small island in the middle of the ocean. It''s hard to see how one could argue anything other than they evolved there. To me, it would be hard to come up with a better case.”Whatever the reality, several scientists involved in the debate think that molecular biology could help to eventually resolve the issue. Savolainen said that the next challenges will be to determine which genes are responsible for speciation, and whether sympatric speciation is common. New sequencing techniques should enable the team to obtain a complete genomic sequence for the palms. Savolainen said that next-generation sequencing is “a total revolution.” By using sequencing, he explained that the team, “want to basically dissect exactly what genes are involved and what has happened […] Is it very special on Lord Howe and for this palm, or is [sympatric speciation] a more general phenomenon? This is a big question now. I think now we''ve found places like Lord Howe and [have] tools like the next-gen sequencing, we can actually get the answer.”Determining whether sympatric speciation occurs in animal species will prove equally challenging, according to Meyer. His own lab, among others, is already looking for ‘speciation genes'', but this remains a tricky challenge. “Genetic models […] argue that two traits (one for ecological specialisation and another for mate choice, based on those ecological differences) need to become tightly linked on one chromosome (so that they don''t get separated, often by segregation or crossing over). The problem is that the genetic basis for most ecologically relevant traits are not known, so it would be very hard to look for them,” Meyer explained. “But, that is about to change […] because of next-generation sequencing and genomics more generally.”Many researchers who knew Mayr personally think he would have enjoyed the challenge to his viewsOthers are more cautious. “In some situations, such as on isolated oceanic islands, or in crater lakes, molecular phylogenetic information can provide strong evidence of sympatric speciation. It also is possible, in theory, to use molecular data to estimate the timing of gene flow, which could help settle the debate,” Rieseberg said. However, he cautioned that although molecular data will add to the debate, it will not settle it alone. “We will still need information from historical biogeography, natural history, phylogeny, and theory, etc. to move things forward.”Many researchers who knew Mayr personally think he would have enjoyed the challenge to his views. “I can only imagine that it would''ve been great fun to engage directly with him [on sympatry on Lord Howe],” Baker said. “It''s a shame that he wasn''t alive to comment on [our paper].” In fact, Mayr was not really as opposed to sympatric speciation as some think. “If one is of the opinion that Mayr opposed all forms of sympatric speciation, well then this looks like a big swing back the other way,” Sulloway commented. “But if one reads Mayr carefully, one sees that he was actually interested in potential exceptions and, as best he could, chronicled which ones he thought were the best candidates.”Mayr''s opinions aside, many biologists today have stronger feelings against sympatric speciation than he did himself in his later years, Meyer added. “I think that Ernst was more open to the idea of sympatric speciation later in his life. He got ‘softer'' on this during the last two of his ten decades of life that I knew him. I was close to him personally and I think that he was much less dogmatic than he is often made out to be […] So, I don''t think that he is spinning in his grave.” Mayr once told Sulloway that he liked to take strong stances, precisely so that other researchers would be motivated to try to prove him wrong. “If they eventually succeeded in doing so, Mayr felt that science was all the better for it.”? Open in a separate windowAlex Papadopulos and Ian Hutton doing fieldwork on a very precarious ridge on top of Mt. Gower. Photo: William Baker, Royal Botanical Gardens, Kew, Richmond, UK.     

Vaccine outlooks

After negative publicity and a series of setbacks over HIV/AIDS and influenza, the prospects for research on new vaccines are improvingVaccine research is at a crossroads between renewed optimism created by fundamental scientific advances, and pessimism from a series of scientific and publicity setbacks over the past decade. Early successes in the field against acute viral diseases, such as smallpox and polio, raised hopes that more serious infectious diseases could be controlled or even eradicated by vaccination, just as it was once thought that penicillin would eradicate major bacterial diseases such as tuberculosis and leprosy....it became clear that many viruses were much tougher nuts to crack in terms of vaccine development...However, it became clear that many viruses were much tougher nuts to crack in terms of vaccine development than had been thought, and it also emerged that not all vaccines were equally safe. Indeed, mounting concerns over the safety of vaccines culminated in the infamous Wakefield paper published in the Lancet in 1998 that associated the MMR vaccine—against measles, mumps and rubella—with autism and inflammatory bowel disease in children. After several studies failed to reproduce these results, the Lancet eventually retracted this paper in 2010, but not before considerable damage had been done to public confidence in vaccination as a whole. Other factors have also sapped confidence in the field—notably the continuing failure to develop an effective vaccine against HIV/AIDS, 15 years after the first hopeful reports that a breakthrough might be imminent (Gorse et al, 1995).Researchers have since developed a string of HIV/AIDS vaccine candidates, some of which have entered clinical trials, but none of which have been sufficiently efficient and safe. The gloom has deepened further after the failure of a vaccine candidate developed by the pharmaceutical company Merck in 2007, that had high hopes for success. This vaccine, called V520, used a weakened adenovirus that carries three HIV genes, to stimulate host production of T cells that it was hoped would kill HIV-infected cells. Early small trials had detected cellular immune responses, but these largely failed to materialize in a subsequent phase II clinical trial. The recombinant vaccine triggered a rapid immune response against itself that actually impaired the T-cell response against the HIV antigens. As a result, the trial was halted in September 2007 (Anon, 2007).Controversially, it has since been suggested that V520 rendered some individuals more liable to subsequent infection, although views on this finding are polarized. According to Steven Patterson, a research fellow specializing in HIV at Imperial College, London, “there was a greater incidence of infection in those individuals who had immunity to adenovirus type 5 before vaccination. Some scientists argue that the numbers [of people who suffered infection during the trial] are relatively low, the results represent a statistical anomaly and that the effect gradually disappeared, suggesting that it was not a real effect. Others, including ourselves, think that in adenovirus type 5-immune individuals the vector activated pre-existing memory CD4 cells migrate to mucosal tissue. Then, because the virus preferentially replicates in activated CD4 T cells and the number of HIV susceptible cells is increased at the site of HIV infection, there is an increase in the number of infections. With time the activated cells return to a resting state which would explain why the effect of adenovirus vaccination gradually disappeared.”Whatever the truth in this case, it highlighted the setbacks in HIV/AIDS research and increased negative sentiments both among the public and, more crucially, funding agencies. “The devastating impact of HIV and its lethality have placed research on vaccines and other preventative measures under an unfamiliar spotlight,” said Colonel Jerome Kim, HIV vaccines product manager for the US Army from the Walter Reed Army Institute of Research. “This has tended to exaggerate both the incremental successes and failures of HIV-1 vaccine research.”The devastating impact of HIV and its lethality have placed research on vaccines and other preventative measures under an unfamiliar spotlightThis might have contributed to a decline in public funding that has been combined with a continuing lack of investment from the private sector (AVERT, 2010). More worryingly, there have been signs that governments are withdrawing funding from vaccine research (Médecins Sans Frontières, 2009). In fact, the US government—through the National Institutes of Health—and the Bill and Melinda Gates Foundation—the charitable trust established in 1994 by Microsoft founder Bill Gates—accounted for 79% of the world''s US$868 million funding for HIV/AIDS vaccine research in 2008 (HIV Vaccines and Microbicides Resource Tracking Working Group, 2010).Other areas of vaccination research have also contributed to negative sentiments towards the field. A universal vaccine against influenza has proved similarly elusive, given the mutability of the virus. The recent swine flu pandemic—the severity of which fell short of many pessimistic expectations—left many governments having spent huge sums on vaccines that they never needed. Furthermore, had swine flu become as virulent as it might have, these vaccine stockpiles might still have been only partially effective.More worryingly, there have been signs that governments are withdrawing funding from vaccine researchAll of these factors are fuelling groups who are opposed to vaccine research for various reasons, according to Joachim Hombach, at the World Health Organization''s Initiative for Vaccine Research in Geneva. “There are certain groups, particularly in the industrialised world, that have an anti-vaccine attitude, and these kinds of cases find very fertile ground there,” he said, referring in particular to the Lancet MMR article. “There is also a different story relating to general attitudes towards acceptance of absolutely no risk associated with vaccines or other medical interventions.” This risk-averse culture exposes vaccines to public scrutiny when side effects occur during trials or afterwards, and has even been spreading to developing countries. “This creates a challenging climate for vaccine research,” said Hombach.There are still strong grounds for optimism, as huge strides have been made in understanding the relationship between viruses and the immune response, which is more subtle and diverse than has been previously appreciated. In a sense, diseases such as polio represent the low-hanging fruit in the orchard of infectious disease; early successes in vaccine development have perhaps created a false sense of optimism. “Diseases that are more chronic, where you have a very delicate balance between the pathogen and the immune response, are very difficult to prevent with vaccines,” Hombach said. “HIV is not the only one and there is also TB for instance, which is quite difficult. It is much easier to develop vaccines against acute diseases.”There is accordingly a need to educate the public about these difficulties, commented Tomáš Hanke, Nuffield professor of medicine specializing in HIV research at Oxford University. “Public confidence is a matter of public education and understanding of the process of scientific discovery,” he said. “The more challenging the aim is, the more explaining the public needs.”Researchers disagree about the major problems hindering the development of new vaccines. In the case of HIV, Kim identified the elimination of CD4⁺ helper T cells by the virus as one of the major problems, because these cells are at the centre of immune control and influence the activities of other cells. It is this disabling of helper T cells that weakens the immune response to other diseases in those who have AIDS.Patterson believes that the greatest problem is the virus''s mutability. “The ability of the virus to quickly mutate and escape from responses that are mounted against specific domains of the virus that are recognized by the immune system is, I think, the major hurdle that we need to overcome,” he said. This is one reason why the traditional strategy of inducing protective antibodies by administering an attenuated virus has not worked for HIV.There are two further problems. First, important regions of the HIV virus are shielded by sugars and second, although antibodies that disable a broad range of HIV viruses have been identified, these tend to be produced too late in the immune response, when infection is already well established. For this reason, there has been increased focus on T-cell vaccines that can recognize and kill infected cells, rather than on efforts to prevent infection in the first place. Crucially though, as Patterson pointed out, this approach still faces the problem of mutation, because this can enable the virus to escape recognition by T cells.This, in turn, suggests that vaccines must target regions of the virus that are well conserved. “A normal T cell immune response tends to be against a small number of so-called dominant epitopes and in the case of HIV these are often against the more variable regions the virus can afford to mutate without any cost to itself,” Patterson explained. “To avoid immune escape, we probably need to induce a T cell response against a number of conserved virus epitopes that the virus could not afford to mutate without severely impairing its replication capacity. I believe this aim is achievable.”While the battle against HIV/AIDS has been catching most of the headlines, a lesser known viral disease, dengue, has been rising quickly up the research agendaMore fundamental research at the molecular level is needed to achieve this goal. Robin Weiss, professor of viral oncology at University College London, leads one team who are trying to identify antigens or targets that might one day become useful in vaccine design. Weiss does not claim to be near an imminent breakthrough, but he believes that a major step might be made soon towards developing a broad-spectrum vaccine that could prevent HIV infection in the first place. The problem, as Weiss pointed out, is not that individuals with HIV fail to produce antibodies, but that HIV elicits too many different ones, nearly all of which are ineffective. Only a few HIV-infected individuals produce potent antibodies and even then, these are often in insufficient concentrations. Now that the crystal structure of the potent antibodies has been defined, this vital molecular information could be used to design new vaccines that elicit production of these antibodies in the host.Valuable information has also come from a US Army sponsored clinical trial in Thailand that studied more than 16,000 healthy individuals between 2003 and 2006. A vaccine containing genetically engineered versions of three HIV genes was used, with an inert form of the bird virus canary pox as the vector. In December 2009, the sponsors reported that the rate of HIV infection among volunteers who received the experimental vaccine was 31% lower than among those who received a placebo (Rerks-Ngarm et al, 2009). “[The trial] showed, for the first time, that a vaccine is able to reduce the risk of HIV infection in humans,” said Kim. “Although our results were modest, they are providing a great deal of information to inform the field. For example, the protection appeared highest at 6–12 months based on post-hoc analysis. If we can sustain or increase this effect, that would be a great accomplishment.”While the battle against HIV/AIDS has been catching most of the headlines, a lesser known viral disease, dengue fever, has been rising quickly up the research agenda. Dengue fever is caused by four related strains of flavivirus that are transmitted by mosquitoes. The disease affects 50–100 million people annually, mostly in urban tropical areas, where an estimated 2.5 billion are at risk (Webster et al, 2009), largely because of growing urban populations. Attempts to develop a vaccine have been inhibited by the host immune response to the vaccine, according to Sarah Rowland-Jones, professor of immunology at the Weatherall Institute of Molecular Medicine in Oxford, UK. “It is a tough target for vaccine development principally because of the possibility that immune mechanisms contribute to pathogenesis, so researchers have to be particularly careful that a dengue vaccine does not make disease more likely because of the kind of immune response it stimulates, rather than leading to protection from infection,” she said.The fact that there are four viruses is another problem, especially as a vaccine protecting against one might actually prime individuals for another serotype. “The best hypothesis for severe dengue is that following a first infection, an individual gains immunity against that serotype but becomes more prone to a second infection with a different serotype,” said Jeremy Farrar, Director of the Wellcome Unit in Vietnam and a professor of tropical medicine at Oxford University. “With that second infection against another serotype, more severe disease develops. Obviously this makes vaccine development difficult as one worries individuals will be ‘primed'' by the vaccine and, when they get a natural infection will have more severe disease.”...the effect of each nucleotide change on virus activity is very small, but the cumulative impact of hundreds of such changes causes strong attenuationHowever, Farrar believes this problem has been fixed with the new generation of ‘chimeric vaccines'' that offer protection against all four serotypes. These are based on an exisiting vaccine against the related disease yellow fever, incorporating a part of the dengue virus that triggers an immune response. This chimeric approach has the potential to be extended to develop vaccines against other diseases.This begs the question of why a dengue virus vaccine has not been developed already, given that the related yellow fever vaccine has been available for years. Part of the reason is that dengue is a tougher target, involving four serotypes, but it is also because its mortality is much lower than the 50% rate of yellow fever. “Dengue hasn''t been top of the agenda because it hasn''t caused so much mortality, but there is a lot of morbidity, and it puts a lot of stress on health authorities and has an epidemic potential,” Hombach said. For this reason it has received more funding recently, with phase III clinical trials likely to begin soon, according to Farrar.An entirely different approach for engineering vaccines might also be emerging. Traditional vaccines use mutated virus strains with limited replication abilities, in order to stimulate the immune system. The main drawback of this approach is that many attenuated strains fail to elicit adequate immunity, and it takes a long time to develop such strains. However, Eckard Wimmer and colleagues at Stony Brook University in New York, have developed a computer-aided approach to create attenuated strains without changing the composition and amino-acid sequence of the virus''s proteins (Mueller et al, 2010).They exploit the redundancy of the genetic code; 64 codons code for just 20 amino acids. As most amino acids are coded for by several codons, it is possible to introduce single-nucleotide changes without altering which proteins are expressed, thereby retaining all antigens that might generate an adaptive immune response. Crucially, however, this alters the expression of some genes, which reduces the ability of the virus to replicate. As Wimmer pointed out, the effect of each nucleotide change on virus activity is very small, but the cumulative impact of hundreds of such changes causes strong attenuation. “We call this ‘death by a thousand cuts'',” he said.Moreover, subsequent natural mutations will probably change only one or two of these nucleotide substitutions back to the original, so the chance that the virus will regain its former virulence is very small. The greatest advantage of this approach, however, is speed. “Clearly, such recoded genomes can only be produced by chemical synthesis,” said Wimmer. “They can be designed rapidly—much faster than any other live vaccine that was isolated after long trials of selection.” This, argues Wimmer, makes the approach ideal for countering emerging pandemics when time is short, especially those caused by influenza. Indeed, Wimmer has demonstrated his approach by designing an influenza vaccine (Mueller et al, 2010).Even if this synthetic approach can generate new vaccine candidates more quickly, it will still require development time and clinical trials to assess their efficacy and safety—as is the case for other emerging techniques. New knowledge and new technologies are filtering through to vaccine development; while the disappointments of the past have provided valuable lessons.     

Universal definition of loss to follow-up in HIV treatment programs: a statistical analysis of 111 facilities in Africa, Asia, and Latin America

Background

Although patient attrition is recognized as a threat to the long-term success of antiretroviral therapy programs worldwide, there is no universal definition for classifying patients as lost to follow-up (LTFU). We analyzed data from health facilities across Africa, Asia, and Latin America to empirically determine a standard LTFU definition.

Methods and Findings

At a set “status classification” date, patients were categorized as either “active” or “LTFU” according to different intervals from time of last clinic encounter. For each threshold, we looked forward 365 d to assess the performance and accuracy of this initial classification. The best-performing definition for LTFU had the lowest proportion of patients misclassified as active or LTFU. Observational data from 111 health facilities—representing 180,718 patients from 19 countries—were included in this study. In the primary analysis, for which data from all facilities were pooled, an interval of 180 d (95% confidence interval [CI]: 173–181 d) since last patient encounter resulted in the fewest misclassifications (7.7%, 95% CI: 7.6%–7.8%). A secondary analysis that gave equal weight to cohorts and to regions generated a similar result (175 d); however, an alternate approach that used inverse weighting for cohorts based on variance and equal weighting for regions produced a slightly lower summary measure (150 d). When examined at the facility level, the best-performing definition varied from 58 to 383 d (mean = 150 d), but when a standard definition of 180 d was applied to each facility, only slight increases in misclassification (mean = 1.2%, 95% CI: 1.0%–1.5%) were observed. Using this definition, the proportion of patients classified as LTFU by facility ranged from 3.1% to 45.1% (mean = 19.9%, 95% CI: 19.1%–21.7%).

Conclusions

Based on this evaluation, we recommend the adoption of ≥180 d since the last clinic visit as a standard LTFU definition. Such standardization is an important step to understanding the reasons that underlie patient attrition and establishing more reliable and comparable program evaluation worldwide. Please see later in the article for the Editors'' Summary     

Testing time for telomeres

Our knowledge of the importance of telomeres to health and ageing continues to grow. Some scientists are therefore commercializing their research, whereas others believe we need an even deeper understanding before we can interpret the results.After 30 years of research, the analysis of telomere length is emerging as a commercial biomarker for ageing and disease, as well as a tool in the search for new medications. Several companies offer tests for telomere length, and more are due to launch their products shortly. Even so, and despite the commercial enthusiasm, interpreting precisely what an individual''s telomeres mean for their health and longevity remains challenging. As a result, there is some division within the research community between those who are pushing ahead with ventures to offer tests to the public, and those who feel that telomere testing is not yet ready for prime time.Peter Lansdorp, a scientist at the British Columbia Cancer Agency and a professor at the University of British Columbia (Vancouver, Canada), founded his company, Repeat Diagnostics, in response to the number of questions and requests he received from physicians for tests for telomere length. The company became the first to offer commercial telomere testing in 2005 and now mainly serves medical researchers, although it makes its test available to the public through their physicians for C $400. Nevertheless, Lansdorp thinks that testing is of limited use for the public. “Testing [...] outside the context of research studies is in my view premature. Unfortunately I think some scientists are exploiting it,” he said. “At this point, I would discourage people from getting their telomeres tested unless there are symptoms in the family that may point to a telomere problem, or a disease related to a telomere problem. I don''t see why on Earth you would want to do that for normal individuals.”“Testing [...] outside the context of research studies is in my view premature. Unfortunately I think some scientists are exploiting it”Others are more convinced of the general utility of telomere tests, when used in combination with other diagnostic tools. Elizabeth Blackburn, Professor of Biology and Physiology at the University of California (San Francisco, USA), was a co-recipient of the Nobel Prize for Physiology or Medicine in 2009 for her part in the discovery of telomerase, the enzyme that replenishes telomeres (Sidebar A). She stressed that the point of telomere testing is to obtain an overall picture “using a marker that integrates many inputs, and produces a robust statistical association with [...] disease risks. It is not a specific diagnostic.” Telome Health, Inc. (Menlo Park, California, USA)—the company that Blackburn helped found and that she now advises in a scientific capacity—plans to begin selling its own US $200 telomere test later this year. “The science has been emerging at a rapid pace recently [...] for those who are familiar with the wealth of the evidence and the accumulated data, the overwhelming pattern is that there are clear associations with telomere maintenance, including longitudinal patterns, and health measures that have had well-tested clinical relevance,” she explained.

Sidebar A | Telomeres and telomerase

Telomeres are regions of repetitive DNA sequence that prevent the DNA replication process or damage from degrading the ends of chromosomes, essentially acting as buffers and protecting the genes closest to the chromosome ends. Russian biologist Alexei Olovnikov first hypothesized in the early 1970s that chromosomes could not completely replicate their ends, and that such losses could ultimately lead to the end of cell division (Olovnikov, 1973). Some years later, Elizabeth Blackburn, then a postdoctoral fellow in Joseph Gall''s lab at Yale University (New Haven, Connecticut, USA), and her colleagues published work suggesting that telomere shortening was linked with ageing at the cellular level, affected lifespan and could lead to cancer (Blackburn & Gall, 1978; Szostak & Blackburn, 1982). In 1984, Carol Greider, working as a postdoc in Blackburn''s lab at the University of California (Berkeley, USA), discovered telomerase, the enzyme that replenishes telomeres. Blackburn and Greider, together with Jack Szostak, were awarded the 2009 Nobel Prize in Physiology or Medicine for “the discovery of how chromosomes are protected by telomeres and the enzyme telomerase” (http://nobelprize.org/nobel_prizes/medicine/laureates/2009/).María Blasco, Director of the Centro Nacional de Investigaciones Oncológicas (CNIO; Spanish National Cancer Research Centre; Madrid, Spain), is similarly optimistic about the prospect of telomere testing becoming a routine health test. “As an analogy, telomere length testing could be similar to what has occurred with cholesterol tests, which went in [the] early 80s from being an expensive test for which no direct drug treatment was available to being a routine test in general health check-ups,” she said.Carol Greider, Professor and Director of Molecular Biology and Genetics at Johns Hopkins University (Baltimore, Maryland, USA) and co-recipient of the 2009 Nobel Prize with Blackburn, however, does not believe that testing is ready for widespread use, although she agreed that telomere length can reveal a lot about disease and is an important subject for research. “Certainly, right now, I think it''s very premature to be offering this kind of testing to the public. I don''t think that the research has yet told us about the risks, what we can actually say statistically with high confidence, so it''s unclear to me if there is any real value to the general public to testing telomeres,” she said.Blasco is Chief Scientific Advisor to Life Length, a CNIO spin-off company that launched its test last year to a storm of media attention. “For some scientists, there is always a question that needs to be solved or has not been sufficiently evaluated,” she said. “We have lots of information showing that telomere length is important for understanding ageing and certain diseases [...] New technologies have been developed that allow us now to measure telomere length in a large scale using a simple blood sample or a spit sample. The fact that the technology is here and the science is here makes this a good moment to market this testing.”“We have lots of information showing that telomere length is important for understanding ageing and certain diseases [...] the technology is here and the science is here”Apart from discussion of the science, companies that offer telomere testing are also encountering scepticism from ethicists and other scientists about the value of telomere-length testing for normal healthy people.Lansdorp, who is a medical doctor by training, thinks that practitioners are not yet ready to use and interpret the tests. “It''s a new field and there are good clinical papers out there, but the irony is that our work [that] has highlighted the value of these tests for specific clinical conditions [is] now being used [...] to make the point that it''s really important to have your telomeres tested, but the dots are not connected by a straight line,” he said.Jonathan Stein, Director of Science and Research at SpectraCell Laboratories (Houston, Texas, USA)—which offers its US $250 telomere test as an extension of its nutritional product line that is sold to family physicians, chiropractors and naturopaths—said that there has only really been demand for the telomere test from his company among physicians and their spouses, but not for use in the clinic. “Doctors are incredibly curious about [the test] and then when we do follow-ups in general, they tell us it''s interesting and they know it''s valuable, but they''re not entirely sure what it means to people. Where we go from the bench to bedside, there seems to be a real sticking point,” he said, adding that he thinks demand will increase as the public becomes increasingly educated about telomeres and health.Arthur Caplan, Professor of Bioethics and Director of the Center for Bioethics at the University of Pennsylvania (Philadelphia, USA), is not clear that even an educated public will be interested in what the test can tell them. “We don''t have any great reason to think that people will be interested in knowing facts about themselves [...] if they can''t do anything about it. I think most people would say ''I''m not going to spend money on this until you tell me if there''s something I can do to slow this process or expand my life''.” As such, he thinks that companies that are getting in early to ''cash in'' on the novelty of telomere testing are unlikely to see huge success, partly because the science is not yet settled.Calvin Harley, President and Chief Science Officer at Telome Health, disagrees. He thinks that two things will drive demand for telomere testing: the growing number of clinical studies validating the utility of the test, and the growing interest in lifestyle changes and interventions that help to maintain telomeres....two things will drive demand for telomere testing: the growing number of clinical studies [...] and [...] interest in lifestyle changes and interventions that help maintain telomeresBut these are early days. Jerry Shay, Professor of Cell Biology and Neuroscience at the University of Texas Southwestern Medical Center (Dallas, USA) and an adviser to the company Life Length, said that early adopters are likely to be the health conscious and the curious. “Some people will say, ''Well, look, I had my telomeres measured: I''m a 60 year old with 50-year-old telomeres'',” he explained. “It will have ''My telomeres are longer than your telomeres'' type of cocktail talk appeal. That''s fine. I have no problem with that as long as we can follow this sort of population and individuals over decades.”“It will have ''My telomeres are longer than your telomeres'' type of cocktail talk appeal [...] I have no problem with that as long as we can follow this sort of population and individuals...”Shay''s last point is the key—research and data collection. Even those commercializing telomere-length tests agree that our understanding of telomere biology, although extensive, is incomplete and that we have yet to unpick fully the links between telomeres and disease. Stefan Kiechl, a telomere researcher in the Department of Neurology at Innsbruck Medical University (Austria), published an article last year on telomere length and cancer (Willeit et al, 2010). “The appealing thing with telomere length measurements is that they allow the estimation of the biological—in contrast to the chronological—age of an organism. This was previously not possible. Moreover, long telomere length has been linked with a low risk of advanced atherosclerosis, cardiovascular disease and cancer, and, vice versa, short telomere length is associated with a higher risk of these diseases.”But, he said that problems remain to be resolved, such as whether telomere length can only be measured in cells that are readily available, such as leukocytes, and whether telomere length in leukocytes varies substantially from telomere length in other tissues and cells. “Moreover, there is still insufficient knowledge on which lifestyle behaviours and other factors affect telomere length,” he concluded.This might be a bumpy road. When Life Length announced its launch in May, newspapers carried headlines such as ''The £400 test that tells you how long you''ll live'', reporting: “A blood test that can show how fast someone is ageing—and offers the tantalizing possibility of estimating how long they have left to live—is to go on sale to the general public in Britain later this year” (Connor, 2011).The story was catchy, but Life Length officials are determined to explain that, despite the name of the company, its tests do not predict longevity for individuals. Blasco said that the word ''life'' in the name is meant as an analogy between telomeres and life. “A British newspaper chose to use this headline, but the company name has no intention to predict longevity,” she said. Instead, the name refers to extensive research correlating the shortened chromosome tips with the risk for certain diseases and personal habits, such as smoking, obesity, lack of exercise and stress, Blasco explained.Life Length''s test measures the abundance of short telomeres, as they claim that there is genetic evidence that short telomeres are the ones that are relevant to disease. “The preliminary results are exciting: we are observing that the percent of short telomeres with increasing age is more divergent between individuals than average telomere length for the same group of individuals,” Blasco explained. “This is exactly what you would expect from a parameter [abundance of short telomeres] that reflects the effects of environmental factors and lifestyle on people''s telomeres.” She noted that being in a lower quartile of average telomere length and the higher quartile of abundance of short telomeres would indicate that telomeres are shorter than normal for a given age, which has been correlated with a higher risk of developing certain diseases.So, what can be done about an abundance of short telomeres? Lansdorp said that, as a physician, he would be hard pressed to know what to tell patients to do about it. “The best measure of someone''s age and life expectancy is the date on their birth certificate. Telomere length, as a biomarker, shows a clear correlation with age at the population level. For an individual the value of telomere length is very limited,” he said. “I suspect there''s going to be a lot of false alarms based on biological variation as well as measurement errors using these less accurate tests.”“The best measure of someone''s age and life expectancy is the date on their birth certificate. [...] For an individual the value of telomere length is very limited”Harley, however, said that if telomere length were perfectly correlated with age, it would be a useless biomarker, except for in forensic work. “The differences in telomere length between individuals at any given age is where the utility lies [...] people with shorter telomeres are at higher risk for morbidity and mortality. In addition, there is emerging data suggesting that people with shorter telomeres respond differently to certain drugs than people with longer telomeres. This fits into the paradigm of personalized medicine,” he said....if telomere length were perfectly correlated with age, it would be a useless biomarker, except for in forensic workWhile he was at Geron Corporation, Harley was the lead discoverer of telomerase activators purified from the root of Astragalus membranaceus. Harley, Blasco and colleagues have published two peer-reviewed papers on one of those molecules, TA-65—one in humans and the other in mice (de Jesus et al, 2011; Harley et al, 2011). Both showed positive effects on certain health measures, and Blasco''s lab found that mice treated with TA-65 had improved health status compared with those given a placebo. “However, we did not see significant effects on longevity,” Blasco said.In the meantime, researchers are squabbling about the techniques used by the testing companies. Greider maintains that Flow-FISH (fluorescence in situ hybridization), which was developed by Lansdorp, is the gold standard used by clinical researchers and that it is the most reliable technique. Harley argues that the quantitative real-time (qRT)-PCR assay developed by the Blackburn lab is just as reliable, and easier to scale-up for commercial use. Blasco pointed out that, similarly to its rivals, the qFISH used by Life Length offers measurements of average telomere length, but that it is the only company to report the percentage of short telomeres in individual cells. In the end, Lansdorp suggested that the errors inherent in the tests, along with biological variations and cost, should give healthy people pause for thought about being tested.Ultimately, whichever test for telomere length is used and whatever the results can tell us about longevity and health, it is unlikely that manipulating telomere length will unlock the fountain of youth, à la Spanish explorer Juan Ponce de León y Figueroa (1474–1521). Nevertheless, telomere testing could become a key diagnostic tool for getting a few more years out of life, and it could motivate people to follow healthier lifestyles. As Kiechl pointed out, “[t]here is convincing evidence that calculation of an individual''s risk of cardiovascular disease [...] substantially enhances compliance for taking medicines and the willingness to change lifestyle. Knowing one''s biological age may well have similar favourable effects.”     

More than a blog

Blogging is circumventing traditional communication channels and levelling the playing field of science communication. It helps scientists, journalists and interested laypeople to make their voices heard.Last December, astrobiologists reported in the journal Science that they had discovered the first known microorganism on Earth capable of growing and reproducing by using arsenic (Wolfe-Simon et al, 2010). While media coverage went wild, the paper was met with a resounding public silence from the scientific community. That is, until a new breed of critic, science bloggers, weighed in. Leading the pack was Rosie Redfield, who runs a microbiology research lab in the Life Sciences Centre at the University of British Columbia in Vancouver, Canada. She posted a critique of the research to her blog, RRResearch (rrresearch.fieldofscience.com), which went viral. Redfield said that her site, which is typically a quiet window on activities in her lab got 100,000 hits in a week.Redfield said that her site, which is typically a quiet window on activities in her lab got 100,000 hits in a weekThis incident, like a handful before it and probably more to come, has raised the profile of science blogging and the freedom that the Internet offers to express an opinion and reach a broad audience. Yet it also raises questions about the validity of unfettered opinion and personal bias, and the ability to publish online with little editorial oversight and few checks and balances.Redfield certainly did not hold back in her criticism of the paper. Her post said of the arsenic study: “Lots of flim-flam, but very little reliable information. [...] If this data was presented by a PhD student at their committee meeting, I''d send them back to the bench to do more clean-up and controls.” She also opined on why the article was published: “I don''t know whether the authors are just bad scientists or whether they''re unscrupulously pushing NASA''s ''There''s life in outer space!'' agenda. I hesitate to blame the reviewers, as their objections are likely to have been overruled by Science''s editors in their eagerness to score such a high-impact publication.”Despite the fervor and immediacy of the blogosphere, it took Science and Felisa Wolfe-Simon, the lead author on the paper, nearly six months to respond in print. Eventually, eight letters appeared in Science covering various aspects of the controversy, including one from Redfield, who is now studying the bacteria in her lab. Bruce Alberts, editor-in-chief of Science, downplayed the role that blogging played in drumming up interest in the controversial study. “I am sure that the number of letters sent to us via our website reflected a response to the great publicity the article received, some of it misleading [...] This number was also likely expanded by the blogging activity, but it was not directly connected to the blogs in any way that I can detect,” he explained.Bloggers, of course, have a different take on the matter, arguing that it was another example of a growing number of cases of ''refutation by blog''. The blogging community heralds Redfield as a hero to science and science blogging. By now, more traditional science media outlets have also joined the bloggers in their skepticism over the paper''s claims, with many repeating the points Redfield made in her original blog response.Jerry Coyne, an evolutionary geneticist at the University of Chicago in the USA, writes the blog Why Evolution is True (whyevolutionistrue.wordpress.com), which is a spinoff from his book of the same name. He said that bloggers, both professional scientists and journalists, have been gaining a new legitimacy in recent years as a result of things such as the arsenic bacteria case, as well as from shooting holes in the 2009 claims that the fossil of the extinct primate Darwinius masillae from the Messel Pit in Germany was a ''missing link'' between two primate species (Franzen et al, 2009). “[Blogging has] really affected the pace of how science is done. One of the good things about science blogging, certainly as a professional, is you''re able to pass judgment on papers instantly. You don''t have to write a letter to the editor and have it reviewed. [Redfield] is a good example of the value of science blogging. Claims that are sort of outlandish and strong can be discredited or at least addressed instantaneously instead of waiting weeks and weeks like you''d otherwise have to do,” he said.“... you''re able to pass judgment on papers instantly. You don''t have to write a letter to the editor and have it reviewed”Perhaps because of the increasingly public profile of popular science bloggers, as well as the professional and social value that is becoming attached to their blogs, science blogging is gaining in both popularity and validity. The content in science blogs covers a wide spectrum from genuine science news to simply describing training or running a lab, to opinionated rants about science and its social impact. The authorship is no less diverse than the content with science professionals, science journalists and enthusiastic amateurs all contributing to the melting pot, which also has an impact on the quality.Carl Zimmer is a freelance science journalist, who writes primarily for the New York Times and Discover Magazine, and blogs at The Loom (blogs.discovermagazine.com/loom). “Most scientists have not been trained how to write, so they are working at a disadvantage,” he said. “[Writing for them] would be like me trying to find a dinosaur. I wouldn''t do a very good job because I don''t really know how to do that. There are certainly some scientists who have a real knack for writing and blogs have been a fantastic opportunity for them because they can just start typing away and all of a sudden have thousands of people who want to read what they write every day.”Bora Zivkovic, who is a former online community manager at Public Library of Science, focusing mainly on PLoS ONE, is one of those scientists. A native of Belgrade, he started commenting in the mid-1990s about the Balkan wars on Usenet, an Internet discussion network. He began blogging about science and politics in 2004 and later about his interest in chronobiology, which stems from his degree in the topic from North Carolina State University. He still combines these interests in his latest blog, Blog Around the Clock (blogs.scientificamerican.com/a-blog-around-the-clock). Last year, Scientific American named Zivkovic its blog editor and he set up a blogging network for the publication. “There isn''t really a definition of what is appropriate,” he said. “The number one rule in the blogosphere is you never tell a blogger what to blog about. Those bloggers who started on their own who are scientists treasure their independence more than anything, so networks that give completely free reign and no editorial control are the only ones that can attract interesting bloggers with their own voices.”“The number one rule in the blogosphere is you never tell a blogger what to blog about”Daniel McArthur, an Australian scientist now based in the UK, who blogs about the genetic and evolutionary basis of human variation at Genetic Future (www.wired.com/wiredscience/geneticfuture), and about personal genomics at Genomes Unzipped (www.genomesunzipped.org), said that it is difficult to define a science blog. “I think it''s semantics. There are people like me who spend some time writing about science and some time writing about industry and gossiping about things in the industrial world. Then there are the people who write about the process of doing science. There are many, many blogs where [...] the content is much more about [the blogger''s] personal voyage as a scientist rather than the science that they do. Then there are people who use science blogging as an extra thing that they do and the primary purpose of their blog is to add political advocacy. I think it''s very hard to draw a line between the different categories. My feeling is that science bloggers should write about whatever it is they want to write about .”The ability to distribute your opinion, scientific or otherwise, online and in public is raising difficult questions about standards and the difference between journalism and opinion. Sean Carroll, who writes for the physics group blog Cosmic Variance (blogs.discovermagazine.com/cosmicvariance), is a senior research associate in the Department of Physics at the California Institute of Technology in the USA. “Some blogging is indistinguishable from what you would ordinarily call journalism. Some blogging is very easily distinguishable from what you would ordinarily call journalism,” he said. “I think that whether we like it or not, the effect of the Internet is that readers need to be a little bit more aware of the status of what they are looking at. Is this something reputable? Anyone can have a blog and say anything, so that one fact is both good and bad. It''s bad because there is a tremendous amount of rubbish on the Internet [...] and people who have trouble telling the rubbish from the good stuff will get confused. But it''s also good because it used to be the case that only a very small number of voices were represented in major media.”Zimmer contrasts the independence of blogging with traditional journalism. “You really get to set your own rules. You''re not working with any editor and you''re not trying to satisfy them. You''re just trying to satisfy yourself. In terms of the style of what I do, I will tend to write more—I think of [my blog posts] as short essays, as opposed to an article in the New York Times where I''ll be writing about interviewing someone or describing them on a visit I paid to them. One of the great things about a blog is that it''s a way of making a connection with people who are your readers and people who are following you for a long time.”One of the world''s most popular scientist bloggers is Paul Zachary Myers, known as PZ, a biology professor at the University of Minnesota in the USA. He blogs at Pharyngula (scienceblogs.com/pharyngula), a site named for a particular stage in development shared by all vertebrate embryos. “Passion is an important part of this. If you can communicate a love of the science that you''re talking about, then you''re a natural for blogging,” he explained. “[Pharyngula] is a blog where I have chosen just to express myself, so self-expression is the goal and what I write about are things that annoy me or interest me.”“Passion is an important part of this. If you can communicate a love of the science that you''re talking about, then you''re a natural for blogging”Myers'' blog, which is driven by a mix of opinion, colourful science writing, campaigning against creationism and an unflinching approach to topics about which he is passionate, draws about 3 million visitors a month. He said his blog attracts more traffic than other blogs because it is not purely about science. “I do a lot of very diverse things such as controversial religious stuff and politics, and whatever I feel like. So I tap into a lot of interest groups and that builds up my rank quite a bit. I''d say there are quite a few other science blogs out there that are pure science blogs, but pure science blogs—where they just talk about science and nothing but science—cannot get quite as much traffic as a more broadly based blog.”In an example of his sometimes-incendiary posting, Myers recently took on the Journal of Cosmology regarding an article on the discovery of bacteria fossils in a meteorite. He said that the counterattack got personal, but that he usually enjoys “the push back” from readers. “That''s part of the argument. I would say that everyone has an equal right to make their case on the web. That''s sometimes daunting for some people, but I think it''s part of the give and take of free speech. It''s good. It''s actually kind of fun to get into these arguments.”Beyond the circus that can surround blogs such as Pharyngula, scientist bloggers are debating whether their blogging counts as a professional activity. Redfield said that blogging can be taken into account among the outreach some governments now require from researchers who receive public funds. She said that some researchers now list their blogging activity in their efforts to communicate science to the public.Coyne, however, does not share his interest in blogging with other senior faculty at the University of Chicago, because he does not believe they value it as a professional activity. Still, he said that he recognizes the names of famous scientists among his blog readers and argues that scientists should consider blogging to hone their writing skills. “Blogging gives you outreach potential that you really should have if you''re grant funded, and it''s fun. It opens doors for you that wouldn''t have opened if you just were in your laboratory. So I would recommend it. It takes a certain amount of guts to put yourself out there like that, but I find it immensely rewarding,” he said. In fact, Coyne has had lecture and print publishing opportunities arise from his blogs.“It opens doors for you that wouldn''t have opened if you just were in your laboratory [...] It takes a certain amount of guts to put yourself out there like that...”Redfield said she finds blogging—even if no one reads her posts—a valuable way to focus her thoughts. “Writing online is valuable at all levels for people who choose to do it. Certainly, by far the best science writing happening is in the community of writers who are considered bloggers,” she said.In terms of pay, science blogging usually remains in the ''hobby zone'', with pay varying widely from nothing at all to small amounts from advertising and web traffic. ''GrrlScientist'', an American-trained molecular evolutionary biologist based in Germany, who prefers to go by her nom de blog, has been blogging for seven years. She writes the popular Punctuated Equilibrium blog (www.guardian.co.uk/science/punctuated-equilibrium) for The Guardian newspaper in the UK, as well as Maniraptora (blogs.nature.com/grrlscientist) for the Nature Network, and is co-author of This Scientific Life (scientopia.org/blogs/thisscientificlife) for the science writing community Scientopia. She said she earns a small amount from ad impressions downloaded when her blog is viewed at The Guardian. On the other end of the scale is Myers, who declined to disclose his income from blogging. “It''s a respectable amount. It''s a nice supplement to my income, but I''m not quitting my day job,” he said.Yet bloggers tend not to do it for the money. “I know that when I go to give talks, the fact that I have the blog is one of the first things that people mention, and lots of students in particular say that they really enjoy the blog and that they''re encouraged by it,” Carroll explained. “Part of what we do is not only talk about science, but we act as examples of what it means to be scientist. We are human beings. We care about the world. We have outside interests. We like our jobs. We try to be positive role models for people who are deciding whether or not this is something that they might want to get into themselves one day.”The rise of the science blogosphere has not all been plain sailing. Although the Internet has been hailed as a brave new world of writing where bloggers can express themselves without interference from editors or commercial interests, it has still seen its share of controversy. The blogging portal ScienceBlogs was the launchpad for some of the best and most popular writers of the new generation of science bloggers, including Myers and Zivkovic. But an incident at ScienceBlogs shook up the paradise and raised journalistic ethical quandaries.In July 2010, a new site, Food Frontiers (foodfrontiers.pepsicoblogs.com), appeared on ScienceBlog, sponsored by PepsiCo, the makers of the popular drink. The blog featured posts written by the beverage maker''s representatives and was blended in with the other blog content on the portal. “Pepsi''s blog looked like my blog or PZ''s blog,” Zivkovic explained, “with no warning that this was paid for and written by Pepsi''s R&D or PR people [...] talking about nutrition from a Pepsi perspective, which is a breach in the wall between advertorial and editorial. The moment the Pepsi blog went live, about 10 bloggers immediately left.” He said that the journalist-bloggers in particular pointed to a break of trust that would sully the reputation of ScienceBlogs writers and confuse readers.In his final blog at the site, titled ''A Farewell to Scienceblogs: the Changing Science Blogging Ecosystem'', Zivkovic nailed the danger of the ''Pepsigate'' incident to the validity of the blogosphere. He wrote: “What is relevant is that this event severely undermined the reputation of all of us. Who can trust anything we say in the future? Even if you already know me and trust me, can people arriving here by random searches trust me? Once they look around the site and see that Pepsi has a blog here, why would they believe I am not exactly the same, some kind of shill for some kind of industry?” (scienceblogs.com/clock/2010/07/scienceblogs_and_me_and_the_ch.php). Myers, who at the time was responsible for more than 40% of the traffic at ScienceBlogs, went ''on strike'' to protest. In the aftermath, the Pepsi blog was pulled.Redfield raises another interesting word of caution. “Most scientists are extensively worried about being scooped, so they''re scared to say anything about what''s actually going on in their lab for fear that one of their competitors will steal their ideas,” she said. In this context, social networking sites such as ResearchGate (www.researchgate.net; Sidebar A) might be a more appropriate avenue for securely sharing ideas and exchanging tips and information because it enables users to control who has access to their missives.“... they''re scared to say anything about what''s actually going on in their lab for fear that one of their competitors will steal their ideas”

Sidebar A | ResearchGate—social media goes pro

Whenever she is looking for ideas for a research project, biologist Anne-Laure Prunier, who works in the Department of Cellular Biology and Infection at the Institut Pasteur in Paris, has recently turned to ResearchGate (www.researchgate.net), the scientists'' version of the social networking site Facebook. “Every time I have used ResearchGate, I found it really useful,” she commented.ResearchGate, based in Berlin, Germany and Cambridge, USA, is a free service that launched in January 2009. It was co-founded by Ijad Madisch, who earned his MD and PhD from the University of Hannover''s medical school in Germany and is a former research fellow at Harvard Medical School. He explained that his goal in starting the network was to make research more efficient. “During my research in Boston, I noticed that science is very inefficient, especially if you''re doing an experiment and trying to get feedback from people working on the same problem. You don''t have any platforms, online networks where you can go and ask questions or if you''re trying to find someone with a specific skill set. So I decided to do that on my own.”As a result, the site offers researchers functionality similar to Facebook—the modern template for social networking. Through ResearchGate, members can follow colleagues, be followed by those interested in their research, share their conference attendance and recent papers—their own or those that interest them—and most importantly, perhaps, ask and answer questions about science and scientific techniques.“You can get in touch with a lot of different people with a lot of different backgrounds,” Prunier explained. “When I have a very precise technical question for which I don''t find an answer in my institute, I turn to ResearchGate and I ask this question to the community. I have done it three times and every time I have gotten a lot of answers and comments, and I was able to exchange information with a lot of different people which I found really useful.”By May 2011, ResearchGate had reached one million members across 192 countries. The largest numbers of registrations come from the USA, the UK, Germany and India. Biologists, who are second only to medical doctors on the site, make up more than 20% of members. In addition to blogging, ResearchGate is just one example of how the Internet—originally invented to allow physicists to share data with one another—is changing the way that scientists communicate and share information with each other and the public.Carroll, on the other hand, who has been blogging since 2004, said that physicists are very comfortable about publicly sharing research papers with colleagues online. “The whole discussion gets very heated and very deep in some places about open access publishing. Physicists look on uncomprehendingly in fact because they put everything for free on line. That''s what we''ve been doing for years. It works.” But he said they are more cautious about blogging for a general audience. By contrast, he believes biology is especially well-suited to being blogged. “[Biologists are] actually more comfortable with talking to a wider audience because biology, whether it is through medicine or through debates about creationism or life on other planets or whatever, gets involved with public debate quite often.”Zivkovic agrees: “PZ [Myers] and me and a number of others are interested in reaching a broad lay audience, showing how science is fun and cool and interesting and important in various ways. Connecting science to other areas of life, from art to politics and showing the lay audience how relevant science is to everyday life”. Even so, he pointed out that although blogging is popularizing science with the public, there is a less-mainstream sphere serving professional scientists as a forum for surviving the cut and thrust of modern science. “There is a strong subset of the science blogosphere that discusses a life in science, career choices, how to succeed in academia [...] A lot of these are written by people who [...] believe that if their real names were out there it could jeopardize their jobs. They''re not interested in talking to lay audiences. They are discussing survival techniques in today''s science with each other and providing a forum for other young people coming into science.”Ultimately, whether you read popular science blogs, trawl deeper for survival tips, or write your own, the science blogosphere is expanding rapidly and is likely to do so for years to come.     

The psycho gene

While the idea of a ‘criminal gene'' is nonsense, there is growing evidence that some psychopathic behaviour might indeed be grounded in genesThe notion that genes play an important role in many diseases has been widely accepted, but many find it much harder to acknowledge a similar link with particular behaviour or even predisposition to crime. Partly for this reason, the study of behavioural genetics remains a controversial topic, with disagreement not just over the science itself, but even more so about the therapeutic, societal and legal implications.Too much might have been made too soon of early findings that made correlations between alleles of certain genes and tendencies to antisocial or criminal behaviour. Indeed, most researchers in the field were appalled by the decision of an Italian appeal court in 2009 to cut the sentence of a convicted murderer by one year on the grounds that he had a version of the MAOA gene, which has been linked to aggression and violence (Feresin, 2009). There is equal dismay over some US courts that went the other way and accepted genetic factors as evidence for the prosecution, leading to higher sentences on the basis that people with particular alleles cannot be cured and will remain a risk to society for longer.“Taking genetic factors into account when sentencing is plain stupid, unless we are talking about something like Down''s syndrome or some other syndrome that drastically reduces intelligence and executive functioning,” insisted Anthony Walsh from the Criminal Justice Department at Boise State University in Idaho, USA. “This is the kind of “genetic determinism” that liberals have worried themselves silly over. They just have to take one or two neuroscience and genetic classes to dispense with their ‘my genes/neurons'' made me do it. Nothing relieves one of the obligation to behave civilized.”Nonetheless, the case against specific alleles has been accumulating, notably for the low-expression variant of MAOA, known as MAOA-L, which has been linked in various studies with increased risk of violent and aggressive behaviour. The gene MAOA encodes monoamine oxidase A, an enzyme that degrades amine neurotransmitters, such as dopamine, noradrenalin and serotonin. A rare genetic disorder caused by an MAOA mutation leads to MAOA deficiency and in turn an excess of monoamine transmitters, causing excessive impulsive behaviour including hypersexuality, sleep disorder and extreme mood swings as well as a tendency to violence, which is known as Brunner syndrome.…the study of behavioural genetics remains a controversial topic, with disagreement not just over the science itself, but even more so about the therapeutic, societal and legal implicationsBut while Brunner''s syndrome is rare, having only been identified in five males of one extended family, the MAOA-L variant is extremely common and occurs in about 40% of the population. Clearly, most of these people are peaceable and have never committed a crime, and yet a study involving researchers from Austria, Italy and the USA—headed by Andreas Meyer-Lindenberg, Director of the Central Institute of Mental Health in Mannheim, Germany—has discovered that at least males with this variant had neurobiological structural factors that would predispose them to violence (Meyer et al, 2006).Using structural MRI scanning, the study identified that people with MAOA-L were more likely to have a smaller limbic system—the hippocampus, amygdala, anterior thalamic nuclei and limbic cortex—which participates in emotion, behaviour and long-term memory. The team then applied functional MRI, which measures changes in blood flow, and discovered that the MAOA-L group also showed hyperresponsiveness of the amygdala during tasks such as copying facial expressions. The amygdala is associated with emotional processing and the MAOA-L group was less able to inhibit strong emotional impulses.But some trigger is still needed to tip MAOA-L people towards violence. An earlier study suggested that this trigger could be persistent maltreatment during childhood (Caspi et al, 2002). At first sight, this suggests that nearly half the human population are predisposed to violence given these triggers, but the situation is not quite that bad—it is merely nearly half of men. Women are protected in two ways: the MAOA gene is linked to the X chromosome so that women with the MAOA-L variety on one chromosome usually have a normal allele on the other; and there is circumstantial evidence that women are also protected by other genes from being disposed to violence.In any case, caution is needed to interpret the findings of Mayer-Lindenberg''s group about the MAOA-L allele, according to Ahmad Hariri, Investigator at the Institute for Genome Sciences & Policy at Duke University (Durham, NC, USA). “This is a significant basic science finding linking genes to brain to behaviour,” he said. “But it is not a significant clinical finding in and of itself. Only in as much as this very, very, very subtle bias in the brain tips the balance toward an aggressive response to provocation is this finding even remotely clinically relevant.” In fact, as Meyer-Lindenberg himself has commented, the MAOA-L allele is just one of several genes—most of which are still not identified—that increase risk of violent or antisocial behaviour.But the whole story takes a rather different turn in the case of psychopathy, which is now widely regarded as a congenital state characterized by lack of empathy or moral compass and defined at least partly by genes, in contrast to other forms of sociopathy or antisocial personality disorder (APD), in which environmental factors make a major contribution (Fontaine & Viding, 2008).“Taking genetic factors into account when sentencing is plain stupid…”“…it is useful to think of psychopathy as mainly the product of genes and sociopathy as more subject to environmental influences”“Psychopathy does seem to be heritable, and appears to have its basis at least in part in “biological” factors linked to basic emotional systems, so that the mature psychopath never develops a complete set of pro-social emotions like empathy, guilt, and the ability to truly care about and for others,” said Richard Wiebe, who specializes in the link between psychology and criminology at Fitchburg State College in Fitchburg, MA, USA. Wiebe added though that the heritability of underlying genetic factors had yet to be conclusively established. “In other words, we know that the dependent variable, that is psychopathy, is heritable, but not enough about its causes to say that they are heritable. Nevertheless it is useful to think of psychopathy as mainly the product of genes and sociopathy as more subject to environmental influences.”Environmental factors do play a part in the behaviour of psychopaths, but in a different way than in other people who develop antisocial tendencies. The condition is more common than was once thought and affects about 0.6% of the population, according to a recent study conducted in the UK (Coid et al, 2009). Obviously, psychopathy does not always lead to crime or extreme violent behaviour; indeed its occurrence in the population used to be significantly underestimated because it was diagnosed only in people who had already shown extreme behaviour when many psychopaths do not.As there is no genetic or clinical test as yet, psychopathy is still diagnosed in terms of behaviour, but taking account of various factors in combination. Robert Hare, who led the UK study and is now at the Department of Psychology of the University of British Columbia in Vancouver, Canada, has designed a test known as the ‘Psychopathy Checklist—Revised'' of about 20 symptoms that he uses to diagnose psychopathy. These include pathological lying, superficial charm, lack of empathy and guilt, proneness to boredom and sexual promiscuity.Although it is not part of the Hare checklist, psychopaths can also be detected by their lack of a “startle reflex”, which means failure of their nervous system to respond to images or events that frighten or shock other people, such as pictures of a decapitated corpse. These tests work just as well for psychopaths who have never indulged in violence and apparently lead normal lives. They can also be used to identify psychopathy in children, who exhibit the same symptoms, in particular pathological lying, lack of empathy, tendency to violence, and lack of startle reflex—in fact, several studies have found evidence of inherited psychopathy in quite young children (Viding et al, 2005).It also appears that psychopathy is more common in men than women. This supports the theory that psychopathy might be an adaptive personality trait that gives men a reproductive advantage through greater tendency and ability to form numerous relationships and so have more children. This is unproven, but it is certainly true that male psychopaths tend to form large numbers of short-term relationships and can have an almost seductive charm.However, the trait would lose its advantage if it became too common in the population. A particular trait tends only to be advantageous in certain environmental conditions as was pointed out in the context of psychopathy by Essi Viding, Co-Director of the Developmental Risk and Resilience Unit at the Department of Psychology at University College London, UK. “I think that the simple game of evolution is to ensure survival of the species under different environmental conditions,” she said. “In some conditions it may be adaptive to be anxious and cooperative, in other conditions it may be good to exploit and be antisocial. This of course is effectively contrasting alleles that have very different effects. Hence, the same allele may serve an individual very well (and in a socially acceptable manner) in one situation, but not in another.”…psychopathy might be an adaptive personality trait that gives men a reproductive advantage through greater tendency and ability to form numerous relationships and so have more childrenThis leads back to the observation that psychopathy seems to be more common in men than women, which could have two possible explanations. First, it might be true at the genetic and neurological level, in particular if some of the relevant genes are linked to the X chromosome. Yet, this is speculative as few genes have been identified that contribute specifically to psychopathy, with most of the evidence for its heritability being statistical. There is the case of the X-linked MAOA gene, but that has only been associated with general antisocial tendencies.…irrespective of where future research leads, genes should not influence sentencing decisions one way or the other because they can never be deemed responsible for behaviourThere is in any case an alternative explanation for the apparent gender difference in psychopathic prevalence. Alice Jones, specialist in childhood and adolescent psychopathy and antisocial behaviour at Goldsmiths College, University of London, UK, suggests that the condition could be much more common among women than studies suggest. It might be that women will, in many cases, fail to register on the Hare Psychopathy Checklist—Revised because the more extreme traits are cushioned by other female factors. “There is some evidence to support this idea,” said Jones, citing work by Randy Salekin at the University of Alabama, in the USA (Salekin et al, 1997) who found that just as many women as men pass the Hare test in terms of their lack of empathy, but not on the more violent and impulsive criteria. “So, while the interpersonal aspects of psychopathy seem to be present and similar in males and females, the behavioural aspects of psychopathy are very much male-heavy,” said Jones.This comes back to the question of treatment and sentencing. Viding argues that irrespective of where future research leads, genes should not influence sentencing decisions one way or the other because they can never be deemed responsible for behaviour. “Any gene alone will be neither necessary, nor sufficient to predispose someone to high levels of psychopathic traits and as such, the responsibility for choosing to offend still resides with an individual,” she said. “Most ‘risk genes'' are common in the population and yet do not cause the majority of the individuals carrying them to offend.”But the situation is different when it comes to treatment—the appropriate therapy will depend on underlying personality tendencies. Psychopaths tend not to respond well to punishment because they cannot associate it with acts they do not consider in any way morally wrong, according to Jones. But they are more likely to respond to reward. “One example of this is currently underway at a school in Buckinghamshire (UK) for primary aged children with Emotional and Behavioural Difficulties,” said Jones. “There have been very encouraging reports from teachers so far. The intervention is largely reward based, and the pupils gain rewards by working toward reaching their behavioural targets each week. Pupils can ‘cash-in'' their rewards daily, or they can save them up for a more substantial reward later in the week.”Whether this will help these children to lead constructive adult lives remains to be seen. It does provide further evidence though that while it might not be possible to cure psychopaths, it may be possible to direct their selfish tendencies away from crime and violence towards more positive and creative activities.