KSR Int'l Co. v. Teleflex, Inc.: no obvious changes for the biotechnology market

With the advent of molecular biology, genomics, and proteomics, the intersection between science and law has become increasingly significant. In addition to the ethical and legal concerns surrounding the collection, storage, and use of genomic data, patent disputes for new biotechnologies are quickly becoming part of mainstream business discussions. Under current patent law, new technologies cannot be patented if they are “obvious” changes to an existing patent. The definition of “obvious,” therefore, has a huge impact on determining whether a patent is granted. For example, are modifications to microarray protocols, popular in diagnostic medicine, considered “obvious” improvements of previous products? Also, inventions that are readily apparent now may not have been obvious when discovered. Polymerase chain reaction, or PCR, is now a common component of every biologist’s toolbox and seems like an obvious invention, though it clearly was not in 1983. Thus, there is also a temporal component that complicates the interpretation of an invention’s obviousness. The following article discusses how a recent Supreme Court decision has altered the definition of “obviousness” in patent disputes. By examining how the obviousness standard has changed, the article illuminates how legal definitions that seem wholly unrelated to biology or medicine could still potentially have enormous effects on these fieldsJust what is obvious or not is a question that has provoked substantial litigation in the Federal Circuit, the appellate court with special jurisdiction over patent law disputes. Under U.S. patent law, an inventor may not obtain a patent, which protects his invention from infringement by others, if the differences between the subject matter sought to be patented and the prior art are such that “the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill” in the patent’s subject matter area [1]. However, what was “obvious” at the time of invention to a person of ordinary skill is hardly clear and is, in effect, a legal fiction designed to approximate objectivity. As illustrated by Chief Justice John Roberts of the Supreme Court in a moment of levity, “Who do you get to ... tell you something’s not obvious … the least insightful person you can find?” [2] Despite the apparent objectivity provided by a “person of ordinary skill” obviousness standard, the difficulty lies in that such a standard is still susceptible to multiple interpretations, depending on the point of view and knowledge ascribed to the “ordinary person.” As such, how obviousness is defined and interpreted by the courts will have important implications on biotechnology patents and the biotechnology business.The issue of obviousness arose in April 2007 when the Supreme Court handed down its decision in KSR Int’l Co. v. Teleflex, Inc. [3] The facts of the case were anything but glamorous; in the suit, Teleflex, a manufacturer of adjustable pedal systems for automobiles, sued KSR, its rival, for infringement of its patent, which “describe[d] a mechanism for combining an electronic sensor with an adjustable automobile pedal so that the pedal’s position can be transmitted to a computer that controls the throttle in the vehicle’s engine.” [4] Teleflex believed that KSR’s new pedal design was too similar to its own patented design and therefore infringed upon it [5]. In defense, KSR argued that Teleflex’s patent was merely the obvious combination of two pre-existing elements and, thus, the patent, upon which Teleflex’s infringement claim was based, was invalid.Patent law relies on the concept of obviousness to distinguish whether new inventions are worthy of being protected by a patent. If a new invention is too obvious, it is not granted a patent and is therefore not a legally protected property interest. However, if an invention is deemed not obvious and has met the other patentability requirements, a patent will be granted, thereby conferring exclusive use of the invention to the patent holder. This exclusive right prohibits others from making, using, selling, offering to sell, or importing into the United States the patented invention [6]. Essentially, the definition of obviousness sets the balance between rewarding new inventions with exclusive property rights and respecting old inventions by not treating minor variations of existing patents as new patents. In this manner, the law seeks to provide economic incentives for the creation of new inventions by ensuring that the property right conferred by the patent will be protected against insignificant variations. The importance of where the line for obviousness is drawn and how clearly it is drawn is especially important in the biotechnology industry. Studies have shown that the development of a new pharmaceutical therapy can take up to 14 years with costs exceeding $800 million [7]. Such an enormous investment of time and money would not be practical if it did not predictably result in a legally enforceable property right.The standard for what constitutes a patentable discovery has evolved over the last 150 years. In 1851, the Supreme Court held in Hotchkiss v. Greenwood that a patentable discovery required a level of ingenuity above that possessed by an ordinary person [8]. Lower courts treated the Hotchkiss standard as a subjective standard, whereby courts sought to determine “what constitute[d] an invention” [9] and a “flash of creative genius” [10]. However, the attempts at imposing the Hotchkiss standard proved unworkable, and in 1952, Congress overrode the case law with the Patent Act, “mandat[ing] that patentability be governed by an objective nonobviousness standard.” [11] This new statutory standard moved the courts away from subjective determinations and toward a more workable, objective obviousness standard.While the Patent Act laid the foundation for the current obviousness standard, the Supreme Court in Graham v. John Deere Co. interpreted the statutory language in an attempt to provide greater clarity as to what exactly “obvious” meant [12]. The Supreme Court determined that the objective analysis would require “the scope and content of the prior art ... to be determined; differences between the prior art and the claims at issue ... to be ascertained; and the level of ordinary skill in the pertinent art resolved.” [13] In addition to analysis under this three-part framework, the Supreme Court called for several secondary considerations to be weighed, including “commercial success, long felt but unresolved needs, [and the] failure of others [to solve the problem addressed].” [13]Unsurprisingly, lower courts were unsatisfied with the Supreme Court’s attempts to clarify the obviousness standard and sought to provide “more uniformity and consistency” to their evaluation of obviousness than the Supreme Court’s jumble of factors provided [14]. In search of consistency, the Federal Circuit created the “teaching, suggestion, or motivation” test (TSM test) “under which a patent is only proved obvious if ‘some motivation or suggestion to combine prior art teachings’ can be found in the prior art, the nature of the problem, or the knowledge of a person having ordinary skill in the art.” [14] Through implementation of the TSM test, the Federal Circuit sought to maintain the flexibility envisioned by the Supreme Court in Graham, while at the same time providing more certainty and predictability to obviousness determinations.The issue before the Supreme Court in KSR Int’l Co. v. Teleflex, Inc. was whether the Federal Circuit’s elaboration on the statutory language of the Patent Act, the TSM test, was consistent with the terms of the Patent Act itself and the Supreme Court’s own analysis in Graham. The Supreme Court determined that while the TSM test was, on its terms, consistent with the framework set out in Graham, the rigid manner in which the Federal Circuit had taken to applying that standard was inconsistent with the flexible approach established by Graham [15]. More generally, it appears the Supreme Court was mainly interested in restoring a more rounded, thorough inquiry to the evaluation of obviousness: “Graham set forth a broad inquiry and invited courts, where appropriate, to look at any secondary considerations that would prove instructive.” [16] As stated by the Supreme Court, “[r]igid preventative rules that deny factfinders recourse to common sense, however, are neither necessary under our case law nor consistent with it.” [17] As such, the Supreme Court reversed the findings of the Federal Circuit, which had found the Teleflex patent valid, and remanded the case back to the lower court with directions to analyze, without rigid adherence to the TSM test, whether the Teleflex patent was obvious [18].The Supreme Court’s ruling in KSR Int’l Co. v. Teleflex, Inc. that the Federal Circuit apply its TSM test less rigidly may have implications for those seeking biotechnology patents in the future. As discussed above, the large investments necessary to develop a marketable biotechnology product demand that entrepreneurs making those investments be reasonably assured that they can predict any future legal hurdles in patenting their invention and in ultimately protecting their patent. As explained by the Biotechnology Industry Organization in its amicus curiae brief in KSR Int’l Co. v. Teleflex, Inc., “[i]nvestment thus is predicated on an expected return on investment in the form of products or services that are protected by patents whose validity can be fairly determined.” [19] Therefore, the Supreme Court’s insistence that the Federal Circuit no longer rigidly rely on the TSM test could increase uncertainty in the grant of future patents. However, the Supreme Court’s refusal to completely dismiss the TSM test, while in fact endorsing its continued use, albeit on a less rigid basis, has to be viewed as a profound victory for an industry with a significant stake in maintaining the status quo. Moreover, it is unclear how much the Supreme Court’s holding in KSR Int’l Co. v. Teleflex, Inc. will truly change the legal analysis of the lower courts, given the evidence that lower courts already were independently shifting away from rigid adherence to the TSM test before the Supreme Court’s ruling [20].More importantly, several aspects of the Supreme Court’s reasoning in KSR Int’l Co. v. Teleflex, Inc. seem to directly address relevant concerns of the biotechnology market in favorable ways. First, the Supreme Court made clear that though a product is the result of a combination of elements that were “obvious to try,” it is not necessarily “obvious” under the Patent Act. Retaining the possibility that “obvious to try” inventions still may be patentable is extremely important to the biotechnology industry in particular because “many patentable inventions in biotechnology spring from known components and methodologies found in [the] prior art.” [21] Rather than foreclosing all “obvious to try” inventions as being obvious, and therefore not patentable, the Supreme Court instead explained that where there is “a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions,” it is more likely that a person of ordinary skill would find it obvious to pursue “known options.” [22] Thus, the proper inquiry, as stated by the Supreme Court, is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” [23] While this reasoning may prevent some “obvious to try” inventions from being patented, it is unlikely to have a substantial effect on inventions in the biotechnology market because “most advances in biotechnology are only won through great effort and expense, and with only a low probability of success in achieving the claimed invention at the outset.” [24] In other words, it would be hard to characterize the use of prior art in the biotechnology context as predictable based on the inherent unpredictability of obtaining favorable results. As such, most biotechnology inventions would presumably fall outside the Supreme Court’s “obvious to try” reasoning due to the very nature of the industry, meaning they would remain patentable under the Supreme Court’s KSR Int’l Co. v. Teleflex, Inc. decision.Second, the Supreme Court recognized the “distortion caused by hindsight bias” and the importance of avoiding “arguments reliant upon ex post reasoning,” though it lessened the Federal Circuit’s rigid protection against hindsight bias [24]. Hindsight bias requires that obviousness be viewed at the time the invention was made, because what may seem revolutionary at the time of invention may, upon the passage of time, seem “obvious.” Cognizance of hindsight bias is crucial for biotechnology patents because “there often is a long ‘passage of time between patent application filing and litigation with biotechnology inventions [that] can exacerbate the problem’ of hindsight bias.” [25] The problem is further exacerbated by the “significantly longer durations of commercial utility” biotechnology inventions enjoy as compared to those in other fields [25]. The more time between the filing of a patent and the subsequent litigation over its validity, the greater the risk that “reliable accounts of [the] context” in which the discovery is made will no longer exist [26]. As such, inventions that were not obvious when they were created will be inescapably colored by the passage of time and by new knowledge and discoveries; the likelihood of this occurrence is higher the further removed the litigation is from the patent filing date. Once again, however, it seems clear that despite the Supreme Court’s abandonment of the TSM test’s rigidity, strong protections against hindsight bias still were emphasized in the Supreme Court’s KSR Int’l Co. v. Teleflex, Inc. decision. In fact, lower courts applying KSR Int’l Co. v. Teleflex, Inc. acknowledge they are “cautious” to avoid “using hindsight” in biotechnology obviousness determinations [27].Finally, the Supreme Court seems to believe that the imposition of a more flexible approach will be more likely to benefit markets not directly at issue in KSR Int’l Co. v. Teleflex, Inc. The Supreme Court asserted, “[t]he diversity of inventive pursuits and of modern technology counsels against limiting the analysis” to the rigid TSM test of the Federal Circuit [28]. This language suggests that the Supreme Court expects lower courts to take into consideration the special considerations facing unique markets, such as the biotechnology market. As such, the specific concerns of the biotechnology market discussed above may receive more attention under the flexible framework asserted by the Supreme Court in KSR Int’l Co. v. Teleflex, Inc.Leading up to the oral argument in KSR Int’l Co. v. Teleflex, Inc., there was widespread speculation that the case could result in a watershed moment, significantly altering the definition of obviousness in patent law. For many, including those in the biotechnology industry, there was ample reason to be concerned. Any change in the definition of obviousness would effectively shift property rights from new patent holders to old, or vice versa. However, the Supreme Court acted with restraint. While the decision purports to make substantial changes by doing away with the Federal Circuit’s TSM test, the opinion seems more like a mild-mannered rebuke of lower courts that had become too complacent in the implementation of their beloved test. If anything, the Supreme Court’s insistence on a more flexible formula is simply a call for lower courts to employ common sense, in addition to considering the factors from Graham and the TSM test. Accordingly, the Supreme Court’s opinion in KSR Int’l Co. v. Teleflex, Inc. is unlikely to have a pronounced effect on the biotechnology market, despite the widespread concern generated before the actual decision was handed down.     

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.”     

Twin Town in South Brazil: A Nazi's Experiment or a Genetic Founder Effect?

Cândido Godói (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the “Twins'' Town” due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the “Nazi''s experiment” and of the “founder effect” hypotheses. We surveyed a total of 6,262 baptism records from 1959–2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the “Nazi''s experiment hypothesis”, there is no spurt in twinning between the years (1964–1968) when Mengele allegedly was in CG (P = 0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (P = 0.351), and no difference in twinning among CG districts considering two different periods: 1927–1958 and 1959–2008 (P = 0.638). On the other hand, the “founder effect hypothesis” is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, P = 0.019). In summary, our results show no evidence for the “Nazi''s experiment hypothesis” and strongly suggest that the “founder effect hypothesis” is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified.     

Stem-cell battles. Stem-cell research in the USA is facing new legal and political challenges

The US still leads the world in stem-cell research, yet US scientists are facing yet another political and legal battle for federal funding to support research using human embryonic stem cells.Disputes over stem-cell research have been standard operating procedure since James Thompson and John Gearhart created the first human embryonic cell (hESC) lines. Their work triggered an intense and ongoing debate about the morality, legality and politics of using hESCs for biomedical research. “Stem-cell policy has caused craziness all over the world. It is a never-ending, irresolvable battle about the moral status [of embryos],” commented Timothy Caulfield, research director of the Health Law Institute at the University of Alberta in Edmonton, Canada. “We''re getting to an interesting time in history where science is playing a bigger and bigger part in our lives, and it''s becoming more controversial because it''s becoming more powerful. We need to make some interesting choices about how we decide what kind of scientific inquiry can go forward and what can''t go forward.”“Stem-cell policy has caused craziness all over the world…[i]t is a never-ending, irresolvable battle about the moral status [of embryos]”The most contested battleground for stem-cell research has been the USA, since President George W. Bush banned federal funding for research that uses hESCs. His successor, Barack Obama, eventually reversed the ban, but a pending lawsuit and the November congressional elections have once again thrown the field into jeopardy.Three days after the election, the deans of US medical schools, chiefs of US hospitals and heads of leading scientific organizations sent letters to both the House of Representatives and the Senate urging them to pass the Stem Cell Research Advancement Act when they come back into session. The implication was to pass legislation now, while the Democrats were still the majority. Republicans, boosted in the election by the emerging fiscally conservative Tea Party movement, will be the majority in the House from January, changing the political climate. The Republicans also cut into the Democratic majority in the Senate.Policies and laws to regulate stem-cell research vary between countries. Italy, for example, does not allow the destruction of an embryo to generate stem-cell lines, but it does allow research on such cells if they are imported. Nevertheless, the Italian government deliberately excluded funding for projects using hESCs from its 2009 call for proposals for stem-cell research. In the face of legislative vacuums, this October, Science Foundation Ireland and the Health Research Board in Ireland decided to not consider grant applications for projects involving hESC lines. The UK is at the other end of the scale; it has legalized both research with and the generation of stem-cell lines, albeit under the strict regulation by the independent Human Fertility and Embryology Authority. As Caulfield commented, the UK is “ironically viewed as one of the most permissive [on stem-cell policy], but is perceived as one of the most bureaucratic.”Somewhere in the middle is Germany, where scientists are allowed to use several approved cell lines, but any research that leads to the destruction of an embryo is illegal. Josephine Johnston, director of research operations at the Hastings Center in Garrison, NY, USA—a bioethics centre—said: “In Germany you can do research on embryonic stem-cells, but you can''t take the cells out of the embryo. So, they import their cells from outside of Germany and to me, that''s basically outsourcing the bit that you find difficult as a nation. It doesn''t make a lot of sense ethically.”Despite the public debates and lack of federal support, Johnson noted that the USA continues to lead the world in the field. “[Opposition] hasn''t killed stem-cell research in the United States, but it definitely is a headache,” she said. In October, physicians at the Shepherd Center, a spinal cord and brain injury rehabilitation hospital and clinical research centre in Atlanta, GA, USA, began to treat the first patient with hESCs. This is part of a clinical trial to test a stem-cell-based therapy for spinal cord injury, which was developed by the US biotechnology company Geron from surplus embryos from in vitro fertilization.Nevertheless, the debate in the USA, where various branches of government—executive, legislative and legal—weigh in on the legal system, is becoming confusing. “We''re never going to have consensus [on the moral status of fetuses] and any time that stem-cell research becomes tied to that debate, there''s going to be policy uncertainty,” Caulfield said. “That''s what''s happened again in the United States.”Johnson commented that what makes the USA different is the rules about federally funded and non-federally funded research. “It isn''t much discussed within the United States, but it''s a really dramatic difference to an outsider,” she said. She pointed out that, by contrast, in other countries the rules for stem-cell research apply across the board.The election of Barack Obama as US President triggered the latest bout of uncertainty. The science community welcomed him with open arms; after all, he supports doubling the budget of the National Institutes of Health (NIH) over the next ten years and dismantled the policies of his predecessor that barred it from funding projects beyond the 60 extant hESC lines—only 21 of which were viable. Obama also called on Congress to provide legal backing and funding for the research.The executive order had unforeseen consequences for researchers working with embryonic or adult stem cells. Sean Morrison, Director of the University of Michigan''s Centre for Stem Cell Biology (Ann Arbor, MI, USA), said he thought that Obama''s executive order had swung open the door on federal support forever. “Everybody had that impression,” he said.Leonard I. Zon, Director of the Stem Cell Program at Children''s Hospital Boston (MA, USA), was so confident in Obama''s political will that his laboratory stopped its practice of labelling liquid nitrogen containers as P (Presidential) and NP (non-Presidential) to avoid legal hassles. His lab also stopped purchasing and storing separate pipettes and culture dishes funded by the NIH and private sources such as the Howard Hughes Medical Institute (HHMI; Chevy Chase, MD, USA).But some researchers who focused on adult cells felt that the NIH was now biased in favour of embryonic cells. Backed by pro-life and religious groups, two scientists—James Sherley of the Boston Biomedical Research Institute and Theresa Deisher of AVM Biotechnology (Seattle, WA)—questioned the legality of the new NIH rules and filed a lawsuit against the Department of Health and Human Services (HHS) Secretary, Kathleen Sebelius. Deisher had founded her company to “[w]ork to provide safe, effective and affordable alternative vaccines and stem-cell therapies that are not tainted by embryonic or electively aborted fetal materials” (www.avmbiotech.com).…the debate in the USA, where various branches of government—executive, legislative and legal—weigh in on the legal system, is becoming confusingSherley argued in an Australian newspaper in October 2006 that the science behind embryonic stem-cell research is flawed and rejected arguments that the research will make available new cures for terrible diseases (Sherley, 2006). In court, the researchers also argued that they were irreparably disadvantaged in competing for government grants by their work on adult stem cells.Judge Royce C. Lamberth of the District Court of the District of Columbia initially ruled that the plaintiffs had no grounds on which to sue. However, the US District Court of Appeals for the District of Columbia overturned his decision and found that “[b]ecause the Guidelines have intensified the competition for a share in a fixed amount” of NIH funding. With the case back in his court, Lamberth reversed his decision on August 23 this year, granting a preliminary injunction to block the new NIH guidelines on embryonic stem-cell work. This injunction is detailed in the 1995 Dickey-Wicker Amendment, an appropriation bill rider, which prohibits the HHS from funding “research in which a human embryo or embryos are destroyed, discarded or knowingly subjected to risk of injury or death.” By allowing the destruction of embryos, Lamberth argued, the NIH rules violate the law.This triggered another wave of uncertainty as dozens of labs faced a freeze of federal funding. Morrison commented that an abrupt end to funding does not normally occur in biomedical research in the USA. “We normally have years of warning when grants are going to end so we can make a plan about how we can have smooth transitions from one funding source to another,” he said. Morrison—whose team has been researching Hirschsprung disease, a congenital enlargement of the colon—said his lab potentially faced a loss of US$ 250,000 overnight. “I e-mailed the people in my lab and said, ‘We may have just lost this funding and if so, then the project is over''”.Morrison explained that the positions of two people in his lab were affected by the cut, along with a third person whose job was partly funded by the grant. “Even though it''s only somewhere between 10–15% of the funding in my lab, it''s still a lot of money,” he said. “It''s not like we have hundreds of thousands of dollars of discretionary funds lying around in case a problem like that comes up.” Zon noted that his lab, which experienced an increase in the pace of discovery since Obama had signed his order, reverted to its Bush-era practices.On September 27 this year, a federal appeals court for the District of Columbia extended Lamberth''s stay to enable the government to pursue its appeal. The NIH was allowed to distribute US$78 million earmarked for 44 scientists during the appeal. The court said the matter should be expedited, but it could, over the years ahead, make its way to the US Supreme Court.The White House welcomed the decision of the appeals court in favour of the NIH. “President Obama made expansion of stem-cell research and the pursuit of groundbreaking treatments and cures a top priority when he took office. We''re heartened that the court will allow [the] NIH and their grantees to continue moving forward while the appeal is resolved,” said White House press secretary Robert Gibbs. The White House might have been glad of some good news, while it wrestles with the worst economic downturn since the Great Depression and the rise of the Tea Party movement.Even without a formal position on the matter, the Tea Party has had an impact on stem-cell research through its electoral victoriesTimothy Kamp, whose lab at the University of Wisconsin (Madison, WI, USA) researches embryonic stem-cell-derived cardiomyocytes, said that he finds the Tea Party movement confusing. “It''s hard for me to know what a uniform platform is for the Tea Party. I''ve heard a few comments from folks in the Tea Party who have opposed stem-cell research,” he said.However, the position of the Tea Party on the topic of stem-cell research could prove to be of vital importance. The Tea Party took its name from the Boston Tea Party—a famous protest in 1773 in which American colonists protested against the passing of the British Tea Act, for its attempt to extract yet more taxes from the new colony. Protesters dressed up as Native Americans and threw tea into the Boston harbour. Contemporary Tea Party members tend to have a longer list of complaints, but generally want to reduce the size of government and cut taxes. Their increasing popularity in the USA and the success of many Tea Party-backed Republican candidates for the upcoming congressional election could jeopardize Obama''s plans to pass new laws to regulate federal funding for stem-cell research.Even without a formal position on the matter, the Tea Party has had an impact on stem-cell research through its electoral victories. Perhaps their most high-profile candidate was the telegenic Christine O''Donnell, a Republican Senatorial candidate from Delaware. The Susan B. Anthony List, a pro-life women''s group, has described O''Donnell as one of “the brightest new stars” opposing abortion (www.lifenews.com/state5255.html). Although O''Donnell was eventually defeated in the 2 November congressional election, by winning the Republican primary in August, she knocked out nine-term Congressman and former Delaware governor Mike Castle, a moderate Republican known for his willingness to work with Democrats to pass legislation to protect stem-cell research.In the past, Castle and Diane DeGette, a Democratic representative from Colorado, co-sponsored the Stem Cell Research Advancement Act to expand federal funding of embryonic stem-cell research. They aimed to support Obama''s executive order and “ensure a lasting ethical framework overseeing stem cell research at the National Institutes of Health”.Morrison described Castle as “one of the great public servants in this country—no matter what political affiliation you have. For him to lose to somebody with such a chequered background and such shaky positions on things like evolution and other issues is a tragedy for the country.” Another stem-cell research advocate, Pennsylvania Senator Arlen Specter, a Republican-turned-Democrat, was also defeated in the primary. He had introduced legislation in September to codify Obama''s order. Specter, a cancer survivor, said his legislation is aimed at removing the “great uncertainty in the research community”.According to Sarah Binder, a political scientist at George Washington University in Washington, DC, the chances of passing legislation to codify the Obama executive order are decreasing: “As the Republican Party becomes more conservative and as moderates can''t get nominated in that party, it does lead you to wonder whether it''s possible to make anything happen [with the new Congress] in January.”There are a variety of opinions about how the outcome of the November elections will influence stem-cell policies. Binder said that a number of prominent Republicans have strongly promoted stem-cell research, including the Reagan family. “This hasn''t been a purely Democratic initiative,” she said. “The question is whether the Republican party has moved sufficiently to the right to preclude action on stem cells.” Historically there was “massive” Republican support for funding bills in 2006 and 2007 that were ultimately vetoed by Bush, she noted.…the debate about public funding for stem-cell research is only part of the picture, given the role of private business and states“Rightward shifts in the House and Senate do not bode well for legislative efforts to entrench federal support for stem-cell research,” Binder said. “First, if a large number of Republicans continue to oppose such funding, a conservative House majority is unlikely to pursue the issue. Second, Republican campaign commitments to reduce federal spending could hit the NIH and its support for stem-cell research hard.”Binder added that “a lingering unknown” is how the topic will be framed: “If it gets framed as a pro-choice versus pro-life initiative, that''s quite difficult for Congress to overcome in a bipartisan way. If it is framed as a question of medical research and medical breakthroughs and scientific advancement, it won''t fall purely on partisan lines. If members of Congress talk about their personal experiences, such as having a parent affected by Parkinson''s, then you could see even pro-life members voting in favour of a more expansive interpretation of stem-cell funding.”Johnson said that Congress could alter the wording of the Dickey-Wicker Amendment when passing the NIH budget for 2011 to remove the conflict. “You don''t have to get rid of the amendment completely, but you could rephrase it,” she said. She also commented that the public essentially supports embryonic stem-cell research. “The polls and surveys show the American public is morally behind there being some limited form of embryonic stem-cell research funded by federal money. They don''t favour cloning. There is not a huge amount of support for creating embryos from scratch for research. But there seems to be pretty wide support among the general public for the kind of embryonic stem-cell research that the NIH is currently funding.”In the end, however, the debate about public funding for stem-cell research is only part of the picture, given the role of private business and states. Glenn McGee, a professor at the Center for Practical Bioethics in Kansas City, MO, USA, and editor of the American Journal of Bioethics, commented that perhaps too much emphasis is being put on federal funding. He said that funding from states such as California and from industry—which are not restricted—has become a more important force than NIH funding. “We''re a little bit delusional if we think that this is a moment where the country is making a big decision about what''s going to happen with stem cells,” he said. “I think that ship has sailed.”     

Opposition to Myriad Genetics patents and their total or partial revocation in Europe: early conclusions

The proceedings instituted against three European patents held by the US company Myriad Genetics, on the BRCA1 gene and the breast cancer diagnosis gene, resulted in the total or partial revocation of these patents. These decisions put an end to the legal monopoly claimed by Myriad Genetics on the BRCA1 gene and on breast cancer gene tests, and left the field open to European geneticists to develop and implement their test methods within the framework of a clinical not-for-profit organization. The opposition procedure, through which any actor is allowed to challenge European patents, was used by geneticists doctors in Europe to refuse the emergence of an industrial monopoly on a medical service offered in a clinical context. The decision to revoke or strongly limit these patents was based on the European Patent Office's refusal to establish an invention priority on a sequence that had errors at the time the application was filed by the patent holder, in September 1994. The patent holder was granted an invention priority only on 24 March 1995, when it filed an application for a corrected sequence of the gene. But by then the BRCA1 gene sequence had already been divulged in a public data base, Genbank, from October 1994, notably by Myriad. Myriad Genetics' patents were thus victims of the patent race that prompted the firm to file multiple patent applications on insufficiently validated sequences, and of the conflict between diffusion in the public domain and the novelty requirement. Opposition to the patents, undertaken by a coalition of medical institutions, human genetic societies, two States, Holland and Austria, an environmental protection organization (Greenpeace), and the Swiss Labour Party, made it possible to preserve and develop the clinical economy of genetic tests in Europe. It resulted in amendments to intellectual property laws in France and thus extended the possibility of using compulsory licences for public health purposes to in vitro diagnosis.     

Exploring the world of phospholipids and their interactions with proteins: the work of William Dowhan

The Gene Encoding the Phosphatidylinositol Transfer Protein Is Essential for Cell Growth (Aitken, J. F., van Heusden, G. P., Temkin, M., and Dowhan, W. (1990) J. Biol. Chem. 265, 4711–4717)A Phospholipid Acts as a Chaperone in Assembly of a Membrane Transport Protein (Bogdanov, M., Sun, J., Kaback, H. R., and Dowhan, W. (1996) J. Biol. Chem. 271, 11615–11618)William Dowhan''s curiosity about the connections between phospholipids and proteins associated with them goes back as far as his days as a graduate student with Esmond Snell at the University of California, Berkeley. In these two JBC Classics, his group''s ability to manipulate biochemical and molecular genetics tools to answer fundamental questions about lipid biology shines through. “William Dowhan and his research group have made many contributions to the biochemistry of phospholipid metabolism and membrane biogenesis,” says Robert Simoni at Stanford University.Open in a separate windowBill Dowhan (right) is shown here with the late Chris Raetz (left), who was a longtime collaborator and friend, and his former postdoctoral advisor, the late Gene Kennedy, on the occasion of Kennedy''s 90th birthday in 2009 (photo courtesy of William Dowhan).The first paper, published in 1990, documented the importance of phosphatidylinositol/phosphatidylcholine transfer proteins in vivo. Dowhan''s group, which has been based at the University of Texas Medical School since 1972, used a combination of biochemistry and genetics to clone the protein''s gene. Dowhan had first heard of phospholipid transfer proteins in 1969, when he began his postdoctoral training with Eugene (Gene) Kennedy at Harvard Medical School. At his very first Kennedy lab meeting, the discussion centered around a publication that had just come out (1). The paper described “one of the first observations of proteins in the soluble phase that transferred lipids between bilayers,” recalls Dowhan. “No one could figure out what these proteins really did in vivo, but they knew the proteins had this function” of transferring lipids between membranes.As he moved through his career, Dowhan focused on cloning and characterizing genes and purifying enzymes responsible for phospholipid metabolism in Escherichia coli. Then came a sabbatical in 1983 with Gottfried (Jeff) Schatz at the Biozentrum of the University of Basel in Switzerland, that expanded Dowhan''s research directions into yeast genetics. He says the opportunity to work with Schatz “got me into the possibility of looking for this phosphatidylinositol/phosphatidylcholine transfer protein (PI-TP) in yeast, which I probably would have never done if I hadn''t taken this sabbatical.”Fresh from his sabbatical, Dowhan started tracking down the protein and its gene in vivo. “I submitted a grant at that time with some preliminary data that we had begun to purify to homogeneity the PI-TP from yeast, which had never been done before. Fortunately, we got the grant,” he says.The Dowhan group managed to purify PI-TP from yeast. “The most important part was using basic biochemistry and understanding how to purify proteins before the advent of genetically tagging proteins for affinity chromatography,” explains Dowhan.For the next step in the process of finding the gene for the protein, Dowhan and colleagues had to apply reverse genetics because the yeast genome was not available in the late 1980s. They sequenced the amino terminus of the protein, made the corresponding oligonucleotide probes, tested yeast cDNA libraries with those probes, and pulled out the gene. “We still didn''t know the role PI-TP played in cell function. But now we had the sequence of the gene and the knock-out mutant was not viable,” notes Dowhan. “So we published” the findings.At the same time, Vytas Bankaitis, now at the University of North Carolina, had been working on cloning the SEC14 gene in yeast, which is necessary for vesicular transport. “It turns out we had missed the DNA sequence,” Dowhan says. From Bankaitis'' work, it was obvious that “PI-TP was the product of the SEC14 gene. It all came together in a joint report in Nature. Now we had a function associated with the SEC14 gene, which we didn''t have before,” Dowhan explains (2). “We had a phenotype of a mutant lacking this phospholipid transfer protein, which then stopped vesicular transport.”This initial link between phospholipid metabolism and vesicular transport opened up the field to characterization of the Sec14 protein superfamily in a broad range of biological systems. These proteins contain lipid-binding domains, which sense membrane lipid composition and integrate lipid metabolism and lipid-mediated signaling with an array of cellular processes.The second JBC Classic focused on a different feature of phospholipids: their role in protein folding. Dowhan was fascinated by membrane proteins ever since he was a graduate student and had gone to the Kennedy laboratory as a postdoctoral fellow, intending to purify the membrane component expressed by the lac operon for lactose transport in E. coli. He was unsuccessful because, at that time, the necessary detergents were not available. Once the lactose permease was purified (3), Dowhan noticed in the literature that other researchers mentioned that when the protein was reconstituted in liposomes missing phosphatidylethanolamine, the protein was defective in energy-dependent uphill transport. Dowhan recalls that he wondered, “Was that an artifact of the liposome system or was that also true in vivo?”To get to the bottom of this observation, Dowhan''s group used E. coli to generate null mutants of what were considered to be absolutely essential genes for phospholipid synthesis and cell viability. They created a null mutant of the pssA gene, which encodes the committed step to the synthesis of the major phospholipid, phosphatidylethanolamine. By establishing conditions in which bacterial cells lacking phosphatidylethanolamine remained viable, the investigators were able to identify and characterize different cell phenotypes caused by the missing phospholipid both in vivo and in vitro. In collaboration with Ronald Kaback at UCLA, Dowhan''s group showed that phosphatidylethanolamine was essential for the proper folding of an epitope of lactose permease that was also necessary to support the energy-dependent uphill transport of lactose. “Studies by others have since shown a similar chaperone role for lipids in other bacteria, plants and mammalian cells,” notes Simoni.To obtain their data, the investigators developed a new technique, the Eastern-Western blot. In this method, membrane proteins were delipidated and partially denatured by SDS. The proteins underwent gel electrophoresis and then were transferred to a solid support by Western blotting. A series of individual lipids were then laid over the proteins at a 90° angle so that the investigators could see, after incubating with conformation-specific antibodies, which lipids helped which membrane proteins regain proper conformation.This technique was used to establish that phosphatidylethanolamine was necessary in a late step of folding of lactose permease, but was not necessary to maintain the final folded state. This observation suggested that lipids act as molecular chaperones in helping protein maturation. “This paper set the stage for understanding how lipids affect the topological organization of wild-type proteins in the membrane,” notes Dowhan.Dowhan and his collaborator Mikhail Bogdanov have continued using bacterial mutants in phospholipid metabolism to systematically manipulate the native membrane lipid compositions during the cell cycle. They have analyzed the transmembrane domain orientation of membrane proteins to establish the molecular basis for lipid-dependent organization of lactose permease and other secondary transporters (4).Dowhan says his work has two take-home messages. One is that “Lipids aren''t just glorified biological detergents,” he says. “They have specific roles” in the cell. The other message is in the power of numbers. Dowhan says the more techniques applied to solve a biological mystery, the more likely the mystery will be successfully solved.     

Patents Associated with High-Cost Drugs in Australia

Australia, like most countries, faces high and rapidly-rising drug costs. There are longstanding concerns about pharmaceutical companies inappropriately extending their monopoly position by “evergreening” blockbuster drugs, through misuse of the patent system. There is, however, very little empirical information about this behaviour. We fill the gap by analysing all of the patents associated with 15 of the costliest drugs in Australia over the last 20 years. Specifically, we search the patent register to identify all the granted patents that cover the active pharmaceutical ingredient of the high-cost drugs. Then, we classify the patents by type, and identify their owners. We find a mean of 49 patents associated with each drug. Three-quarters of these patents are owned by companies other than the drug''s originator. Surprisingly, the majority of all patents are owned by companies that do not have a record of developing top-selling drugs. Our findings show that a multitude of players seek monopoly control over innovations to blockbuster drugs. Consequently, attempts to control drug costs by mitigating misuse of the patent system are likely to miss the mark if they focus only on the patenting activities of originators.     

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.     

BRCA1/2 Mutations Appear Embryo-Lethal Unless Rescued by Low (CGG n<26) FMR1 Sub-Genotypes: Explanation for the “BRCA Paradox”?

BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG _n<26) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG _n<26) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called “BRCA paradox” by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated.     

European stem cell research in legal shackles

Advances in stem cell biology have raised legal challenges to the patentability of stem cells and any derived technologies and processes. In 1999, Oliver Brüstle was granted a patent for the generation and therapeutic use of neural cells derived from human embryonic stem cells (hESCs). The patent was challenged and put before the European Court of Justice, which ruled that inventions involving the prior destruction of human embryos cannot be patented. The legal maneuvering around this case demonstrates that the future of stem cell‐based patents in Europe remains unsettled. Furthermore, owing to the European Court's broad definition of hESC as ‘any cell that is capable of commencing development into a human being,’ novel technologies that could eliminate the need for hESCs, such as induced pluripotent stem cells (iPSCs), are at risk of being included under the same ruling. Advances in the in vitro development of germ cells from pluripotent stem cells may one day provide a direct developmental path from iPSC to oocyte and sperm, and, according to the European Court's reasoning, legally equate iPSCs with human embryos. In this review, we will briefly discuss the Brüstle v Greenpeace case and the implications of the European Court of Justice's ruling. We will identify potential risks for stem cell research and future therapeutics resulting from the broad legal definition of the human embryo. Finally, we will broach the current legal landscape, as this broad definition has also created great uncertainty about the status of human iPSCs.     

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.     

从Myriad案谈基因专利的正当性及美国对基因专利授权实质性要件分析

按照专利制度构建的本质,基因专利的作用在于激励产业创新,促进基因研究的发展。但基因专利从产生以来就一直存在着争议。2011年美国Myriad案对分离DNA序列的可专利性具有不同的观点,从Myriad I案认为分离的DNA是不可专利的客体,到Myriad II上诉案中联邦巡回上诉法院推翻地方法院的观点,认为分离的DNA具有不同的化学结构,满足专利客体的适格性,但同时也反射出了对DNA序列可专利性的怀疑。Myriad案引起了美国、欧洲和澳大利亚司法审判中就基因专利适格性问题的较大争议。本文结合美国Myriad案来分析DNA序列作为专利客体的适格性以及目前美国对基因专利授权的实质性条件。     

Crop shortages

A lack of breeders to apply the knowledge from plant science is jeopardizing public breeding programmes and the training of future plant scientistsIn the midst of an economic downturn, many college and university students in the USA face an uncertain future. There is one crop of graduates, though, who need not worry about unemployment: plant breeders. “Our students start with six-digit salaries once they leave and they have three or four offers. We have people coming to molecular biology and they can''t find jobs. People coming to plant breeding, they have as many jobs as they want,” said Edward Buckler, a geneticist with the US Department of Agriculture''s Agricultural Research Service Institute for Genomic Diversity at Cornell University (Ithaca, NY, USA).The lure of Big Ag depletes universities and research institutes of plant breeders […] and jeopardizes the training of future generations of plant scientists and breedersThe secret behind the success of qualified breeders on the job market is that they can join ‘Big Ag''—big agriculture—that is, major seed companies. Roger Boerma, coordinator of academic research for the Center for Applied Genetic Technologies at the University of Georgia (Athens, GA, USA), said that most of his graduate and postdoctoral students find jobs at companies such as Pioneer, Monsanto and Syngenta, rather than working in the orchards and fields of academic research. According to Todd Wehner, a professor and cucurbit breeder at the Department of Horticultural Science, North Carolina State University (Raleigh, NC, USA), the best-paying jobs—US$100,000 plus good benefits and research conditions—are at seed companies that deal with the main crops (Guner & Wehner, 2003). By contrast, university positions typically start at US$75,000 and tenure track.As a result, Wehner said, public crop breeding in the USA has begun to disappear. “To be clear, there is no shortage of plant breeders,” he said. “There is a shortage of plant breeders in the public sector.” The lure of Big Ag depletes universities and research institutes of plant breeders—who, after all, are the ones who create new plant varieties for agriculture—and jeopardizes the training of future generations of plant scientists and breeders. Moreover, there is an increasing demand for breeders to address the challenge of creating environmentally sustainable ways to grow more food for an increasing human population on Earth.At the same time, basic plant research is making rapid progress. The genomes of most of the main crop plants and many vegetables have been sequenced, which has enabled researchers to better understand the molecular details of how plants fend off pests and pathogens, or withstand drought and flooding. This research has also generated molecular markers—short regions of DNA that are linked to, for example, better resistance to fungi or other pathogens. So-called marker-assisted breeding based on this information is now able to create new plant varieties more effectively than would be possible with the classical strategy of crossing, selection and backcrossing.However, applying the genomic knowledge requires both breeders and plant scientists with a better understanding of each other''s expertise. As David Baulcombe, professor of botany at the University of Cambridge, UK, commented, “I think the important gap is actually in making sure that the fundamental scientists working on genomics understand breeding, and equally that those people doing breeding understand the potential of genomics. This is part of the translational gap. There''s incomplete understanding on both sides.”…applying the genomic knowledge requires both breeders and plant scientists with a better understanding of each other''s expertiseIn the genomic age, plant breeding has an image problem: like other hands-on agricultural work, it is dirty and unglamorous. “A research project in agriculture in the twenty-first century resembles agriculture for farmers in the eighteenth century,” Wehner said. “Harvesting in the fields in the summer might be considered one of the worst jobs, but not to me. I''m harvesting cucumbers just like everybody else. I don''t mind working at 105 degrees, with 95% humidity and insects biting my ankles. I actually like that. I like that better than office work.”For most students, however, genomics is the more appealing option as a cutting-edge and glamorous research field. “The exciting photographs that you always see are people holding up glass test tubes and working in front of big computer screens,” Wehner explained.In addition, Wehner said that federal and state governments have given greater priority and funding to molecular genetics than to plant breeding. “The reason we''ve gone away from plant breeding of course is that faculty can get competitive grants for large amounts of money to do things that are more in the area of molecular genetics,” he explained. “Plant breeders have switched over to molecular genetics because they can get money there and they can''t get money in plant breeding.”“The frontiers of science shifted from agriculture to genetics, especially the genetics of corn, wheat and rice,” agreed Richard Flavell, former Director of the John Innes Centre (Norwich, UK) and now Chief Scientific Officer of Ceres (Thousand Oaks, CA, USA). “As university departments have chased their money, chased the bright students, they have [focused on] programmes that pull in research dollars on the frontiers, and plant breeding has been left behind as something of a Cinderella subject.”In the genomic age, plant breeding has an image problem: like other hands-on agricultural work, it is dirty and unglamorousIn a sense, public plant breeding has become a victim of its own success. Wehner explained that over the past century, the protection of intellectual property has created a profitable market for private corporations to the detriment of public programmes. “It started out where they could protect seed-propagated crops,” he said. “The companies began to hire plant breeders and develop their own varieties. And that started the whole agricultural business, which is now huge.”As a result, Wehner said, the private sector can now outmanoeuvre public breeders at will. “[Seed companies] have huge teams that can go much faster than I can go. They have winter nurseries and big greenhouses and lots of pathologists and molecular geneticists and they have large databases and seed technologists and sales reps and catalogue artists and all those things. They can do much faster cucumber breeding than I can. They can beat me in any area that they choose to focus on.”He said that seed corporations turn only to public breeders when they are looking for rare seeds obtained on expeditions around the world or special knowledge. These crops and the breeders and other scientists who work on them receive far less financial support from government than do the more profitable crops, such as corn and soybean. In effect, these crops are in an analogous position to orphan drugs that receive little attention because the patients who need them represent a small economic market.The dwindling support for public breeding programmes is also a result of larger political developments. Since the 1980s, when British Prime Minister Margaret Thatcher and US President Ronald Regan championed the private sector in all things, government has consistently withdrawn support for public research programmes wherever the private sector can profit. “Plant breeding programmes are expensive. My programme costs about US$500,000 a year to run for my crops, watermelon and cucumber. Universities don''t want to spend that money if they don''t have to, especially if it''s already being done by the private sector,” Wehner said.“Over the last 30 years or so, food supplies and food security have fallen off the agenda of policymakers”…“Over the last 30 years or so, food supplies and food security have fallen off the agenda of policymakers,” Baulcombe explained. “Applied research in academic institutions is disappearing, and so the opportunities for linking the achievements of basic research with applications, at least in the public sector, are disappearing. You''ve got these two areas of the work going in opposite directions.”There''s another problem for plant breeding in the publish-or-perish world of academia. According to Ian Graham, Director of the Centre for Novel Agricultural Products at York University in the UK, potential academics in the plant sciences are turned off by plant breeding as a discipline because it is difficult to publish the research in high-impact journals.Graham, who is funded by the Bill & Melinda Gates Foundation to breed new varieties of Artemisia—the plant that produces the anti-malarial compound artemisinin—said this could change. “Now with the new [genomic] technologies, the whole subject of plant breeding has come back into the limelight. We can start thinking seriously about not just the conventional crops […] but all the marginal crops as well that we can really start employing these technologies on and doing exciting science and linking phenotypes to genes and phenotypes to the underlying biology,” he said. “It takes us back again closer to the science. That will bring more people into plant breeding.”…potential academics in the plant sciences are turned off by plant breeding as a discipline because it is difficult to publish the research in high-impact journalsBuckler, who specializes in functional genomic approaches to dissect complex traits in maize, wheat and Arabidopsis, said that public breeding still moves at a slower pace. “The seed companies are trying to figure out how to move genomics from gene discovery all the way to the breeding side. And it''s moving forward,” he said. “There have been some real intellectual questions that people are trying to overcome as to how fast to integrate genomics. I think it''s starting to occur also with a lot of the public breeders. A lot of it has been that the cost of genotyping, especially for specialty crops, was too high to develop marker systems that would really accelerate breeding.”Things might be about to change on the cost side as well. Buckler said that decreasing costs for sequencing and genotyping will give public breeding a boost. Using today''s genomic tools, researchers and plant breeders could match the achievements of the last century in maize breeding within three years. He said that comparable gains could be made in specialty crops, the forte of public breeding. “Right now, most of the simulations suggest that we can accelerate it about threefold,” Buckler said. “Maybe as our knowledge increases, maybe we can approach a 15-fold rate increase.”Indeed, the increasing knowledge from basic research could well contribute to significant advances in the coming years. “We''ve messed around with genes in a rather blind, sort of non-predictive process,” said Scott Jackson, a plant genomics expert at Purdue University (West Lafayette, IN, USA), who headed the team that decoded the soybean genome (Schmutz et al, 2010). “Having a full genome sequence, having all the genes underlying all the traits in whatever plant organism you''re looking at, makes it less blind. You can determine which genes affect the trait and it has the potential to make it a more predictive process where you can take specific genes in combinations and you can predict what the outcome might be. I think that''s where the real revolution in plant breeding is going to come.”Nevertheless, the main problem that could hold back this revolution is a lack of trained people in academia and the private sector. Ted Crosbie, Head of Plant Breeding at Monsanto (St Louis, MO, USA), commented at the national Plant Breeding Coordinating Committee meeting in 2008 that “[w]e, in the plant breeding industry, face a number of challenges. More plant breeders are reaching retirement age at a time when the need for plant breeders has never been greater […] We need to renew our nation''s capacity for plant breeding.”“…with the new [genomic] technologies, the whole subject of plant breeding has come back into the limelight”Dry bean breeder James Kelly, a professor of crop and soil sciences at Michigan State University (East Lansing, MI, USA), said while there has been a disconnect between public breeders and genomics researchers, new federal grants are designed to increase collaboration.In the meantime, developing countries such as India and China have been filling the gap. “China is putting a huge amount of effort into agriculture. They actually know the importance of food. They have plant breeders all over the place,” Wehner said. “The US is starting to fall behind. And now, agricultural companies are looking around wondering—where are we going to get our plant breeders?”To address the problem, major agriculture companies have begun to fund fellowships to train new plant breeders. Thus far, Buckler said, these efforts have had only a small impact. He noted that 500 new PhDs a year are needed just in maize breeding. “It''s not uncommon for the big companies like Monsanto, Pioneer and Syngenta to spend money on training, on endowing chairs at universities,” Flavell said. “It''s good PR, but they''re serious about the need for breeders.”The US government has also taken some measures to alleviate the problem. Congress decided to establish the US National Institute of Food and Agriculture (Washington, DC, USA) under the auspices of the US Department of Agriculture to make more efficient use of research money, advance the application of plant science and attract new students to plant breeding (see the interview with Roger Beachy in this issue, pp 504–507). Another approach is to use distance education to train breeders, such as technicians who want to advance their careers, in certificate programmes rather than master''s or doctorate programmes.“If [breeding] is not done in universities in the public sector, where is it done?”…“If [breeding] is not done in universities in the public sector, where is it done?” Flavell asked about the future of public breeding. “I can wax lyrical and perhaps be perceived as being over the top, but if we''re going to manage this planet on getting more food out of less land, this has to be almost one of the highest things that has got to be taken care of by government.” Wehner added, “The public in the developed world thinks food magically appears in grocery stores. There is no civilization without agriculture. Without plant breeders to work on improving our crops, civilization is at risk.”     

An Empirical Analysis of Primary and Secondary Pharmaceutical Patents in Chile

We analyze the patent filing strategies of foreign pharmaceutical companies in Chile distinguishing between “primary” (active ingredient) and “secondary” patents (patents on modified compounds, formulations, dosages, particular medical uses, etc.). There is prior evidence that secondary patents are used by pharmaceutical originator companies in the U.S. and Europe to extend patent protection on drugs in length and breadth. Using a novel dataset that comprises all drugs registered in Chile between 1991 and 2010 as well as the corresponding patents and trademarks, we find evidence that foreign originator companies pursue similar strategies in Chile. We find a primary to secondary patents ratio of 1:4 at the drug-level, which is comparable to the available evidence for Europe; most secondary patents are filed over several years following the original primary patent and after the protected active ingredient has obtained market approval in Chile. This points toward effective patent term extensions through secondary patents. Secondary patents dominate “older” therapeutic classes like anti-ulcer and anti-depressants. In contrast, newer areas like anti-virals and anti-neoplastics (anti-cancer) have a much larger share of primary patents.     

BRCA1 and BRCA2 germline mutations in Malaysian women with early-onset breast cancer without a family history

Background

In Asia, breast cancer is characterised by an early age of onset: In Malaysia, approximately 50% of cases occur in women under the age of 50 years. A proportion of these cases may be attributable, at least in part, to genetic components, but to date, the contribution of genetic components to breast cancer in many of Malaysia''s ethnic groups has not been well-characterised.

Methodology

Given that hereditary breast carcinoma is primarily due to germline mutations in one of two breast cancer susceptibility genes, BRCA1 and BRCA2, we have characterised the spectrum of BRCA mutations in a cohort of 37 individuals with early-onset disease (≤40 years) and no reported family history. Mutational analysis of BRCA1 and BRCA2 was conducted by full sequencing of all exons and intron-exon junctions.

Conclusions

Here, we report a total of 14 BRCA1 and 17 BRCA2 sequence alterations, of which eight are novel (3 BRCA1 and 5 BRCA2). One deleterious BRCA1 mutation and 2 deleterious BRCA2 mutations, all of which are novel mutations, were identified in 3 of 37 individuals. This represents a prevalence of 2.7% and 5.4% respectively, which is consistent with other studies in other Asian ethnic groups (4–9%).     

Will we wake up to biodiversity?: The International Year of Biodiversity has failed to raise awareness or halt decline as economic crises and political interests have sidelined the environment

Looking back on the International Year of Biodiversity, some conservationists hope that it has raised awareness, if nothing else. Even so, many scientists remain pessimistic about our efforts to halt biodiversity decline.The United Nations'' (UN) International Year of Biodiversity in 2010 was supposed to see the adoption of measures that would slow global environmental decline and the continuing loss of endangered species and habitats. Even before, in 2002, most UN members had committed to halting the decline in biodiversity, which is a measure of the health of ecosystems. But the results of these international efforts have been funereal. Moreover, the current global economic crisis, coupled with growing anti-science attitudes in the USA, are adding to the concern of scientists about whether there is the political will to address the loss of biodiversity and whether habitat loss and extinction rates are reaching a point of no return.“There is not a single report received last year that claimed to have stopped or reduced the loss of biodiversity”Ahmed Djoghlaf, Executive Secretary of the Convention on Biological Diversity under the UN Environment Programme based in Montreal, Canada, said that of the 175 national reports submitted as part of the International Year of Biodiversity to his agency last year, none reported any progress. “There is not a single report received last year that claimed to have stopped or reduced the loss of biodiversity,” he said. “These reports confirm that the rate of loss of biodiversity today is unprecedented and the rate is 1,000 higher than the rate of natural extinction on species, and [his agency''s Global Biodiversity Outlook 2010; UN, 2010a] predicts that if business is allowed to continue then major ecosystems, the ocean, the fish, the forests, will reach the tipping point, meaning that there will be irreversible and irreparable damage done to the ecosystems.”The UN campaign traces its roots to the European Union (EU) commitment in 2001 to halt the loss of biodiversity by 2010. The 2010 goal was incorporated into the UN Millennium Development Goals because of the severe impact of biodiversity loss on human well-being. However, the EU last year conceded in a report that it missed its 2010 target, too. The EU''s Biodiversity Action Plan, launched in 2006, shows that Europe''s biodiversity “remains under severe threat from the excessive demands we are making on our environment, such as changes in land use, pollution, invasive species and climate change.” Yet, EU Environment Commissioner Janez Potočnik has seen some positive signs: “We have learned some very important lessons and managed to raise biodiversity to the top of the political agenda. But we need everyone on board and not just in Europe. The threat around the world is even greater than in the EU,” he wrote last year (EC, 2010).Despite the initiative''s poor report card, Djoghlaf was upbeat about the International Year of Biodiversity. “It was a success because it was celebrated everywhere,” he said. “In Switzerland, they conducted a survey before and after the International Year of Biodiversity and they concluded that at the end of the year, 67% of all the Swiss people are now aware of biodiversity. When the year started it was 40%. People are more and more aware. In addition, biodiversity has entered the top of the political agenda.”In October 2010, delegates from 193 countries attended the UN Convention on Biodiversity in Nagoya, Japan, and adopted 20 strategic goals to be achieved by 2020 (UN, 2010b). The so-called Aichi Biodiversity Targets include increased public awareness of the values of biodiversity and the steps that individuals can take to conserve and act sustainably; the halving or halting of the rate of loss of all natural habitats, including forests; and the conservation of 17% of terrestrial and inland water, and 10% of coastal and marine areas through effective and equitable management, resulting in ecologically representative and well-connected systems. By contrast, 13% of land areas and 1% of marine areas were protected in 2010.However, the Convention on Biological Diversity is not enforceable. Anne Larigauderie, Executive Director of DIVERSITAS (Paris, France), which promotes research on biodiversity science, said that it is up to the individual countries to adopt enforceable legislation. “In principle, countries have committed. Now it depends on what individual countries are going to do with the agreement,” she said. “I would say that things are generally going in the right direction and it''s too early to tell whether or not it''s going to have an impact in terms of responding and in terms of the biodiversity itself.”Researchers, however, have been disappointed by The International Year of Biodiversity. Conservation biologist Stuart Butchart, of Birdlife International in Cambridge, UK—a partnership of non-governmental environmental organizations and colleagues from other environmental groups—compiled a list of 31 indicators to measure progress towards the 2010 goal of the International Year of Biodiversity. He and his collaborators reported in Science (Butchart et al, 2010) that these indicators, including species population trends, extinction risks and habitat conditions, showed declines with no significant rate reductions. At the same time, indicators of pressure on biodiversity, such as resource consumption, invasive alien species, nitrogen pollution, over-exploitation and climate change impacts showed increases. “Despite some local successes and increasing responses (including extent and biodiversity coverage of protected areas, sustainable forest management, policy responses to invasive alien species and biodiversity-related aid), the rate of biodiversity loss does not appear to be slowing,” the researchers wrote.​wrote.Open in a separate window© Thomas Kitchin & Victoria Hurst/Wave/CorbisButchart pointed out that even if the International Year of Biodiversity had an impact on raising awareness and reducing biodiversity loss, detecting the change would take time. He said that the International Year of Biodiversity fell short of increasing awareness in parts of government not dealing with the environment, including ministries of transport, tourism, treasury and finance. It also seems probable that the campaign had little impact on the business sector, which affects development projects with a direct impact on biodiversity. “People can''t even seem to get together on global climate change, which is a whole lot more obvious and right there,” Peter Raven, president emeritus of the Missouri Botanical Gardens in St Louis, USA, explained. “Biodiversity always seems to be a sort of mysterious background thing that isn''t quite there.”“People can''t even seem to get together on global climate change, which is a whole lot more obvious and right there…”Illka Hanski, a professor in the Department of Ecology and Evolutionary Biology at the University of Helsinki in Finland, said that studies such as Butchart''s “indicate that nothing really happened in 2010. Biodiversity decline continued and has been declining over the past 10 years.”Other researchers are more positive, although with reservations. Conservation biologist Thomas Eugene Lovejoy III, Heinz Center Biodiversity Chair and former president of the Center in Washington, DC, USA—a non-partisan, non-profit organization dedicated to advancing sound environmental policy—said that economic trends affect biodiversity and that biodiversity efforts might actually be benefiting from the current global economic crisis. For example, the decline in the housing markets in the USA and Europe has reduced the demand on lumber for new construction and has led to a reduction in deforestation. “Generally speaking, when there is an economic downturn, some of the things that are pressuring biodiversity actually abate somewhat. That''s the good news. The bad news is that the ability to marshal resources to do some things proactively gets harder,” he said.Chris Thomas, a conservation biologist at the University of York in the UK, who studies ecosystems and species in the context of climate change, said that economic depressions do slow the rate of damage to the environment. “But it also takes eyes off the ball of environmental issues. It''s not clear whether these downturns, when you look over a period of a decade, make much difference or not.” Hanski agreed: “[B]ecause there is less economic activity, there may be less use of resources and such. But I don''t think this is a way to solve our problems. It won''t lead to any stable situation. It just leads to a situation where economic policies become more and more dependent on measures that try actually just to increase the growth as soon as possible.”…biodiversity efforts might actually be benefiting from the current global economic crisisRaven said that in bad times, major interests such as those involved in raising cattle, growing soybeans and clearing habitat for oil palms have reduced political clout because there is less money available for investment. But he said economic downturns do not slow poor people scrounging for sustenance in natural habitats.To overcome this attitude of neglect, Lovejoy thinks there ought to be a new type of ‘economics'' that demonstrates the benefits of biodiversity and brings the “natural world into the normal calculus.” Researchers are already making progress in this direction. Thomas said that the valuation of nature is one of the most active areas of research. “People have very different opinions as to how much of it can be truly valued. But it is a rapidly developing field,” he said. “Once you''ve decided how much something is worth, then you''ve got to ask what are the financial or other mechanisms by which the true value of this resource can be appreciated.”Hanski said that the main problem is the short-term view of economic forecasts. “Rapid use of natural resources because of short-term calculation may actually lead to a sort of exploitation rather than conservation or preservation.” He added that the emphasis on economic growth in rich societies in North America and Europe is frustrating. “We have become much richer than in 1970 when there actually was talk of zero growth in serious terms. So now we are richer and we are becoming more and more dependent on continued growth, the opposite of what we should be aiming at. It''s a problem with our society and economics clearly, but I can''t be very optimistic about the biodiversity or other environmental issues in this kind of situation.” He added that biodiversity is still taking a backseat to economics: “There is a very long way to go right now with the economic situation in Europe, it''s clear that these sorts of [biodiversity] issues are not the ones which are currently being debated by the heads of states.”The economic downturn, which has led to reduced government and private funding and declines in endowments, has also hurt organizations dedicated to preserving biodiversity. Butchart said that some of the main US conservation organizations, including the Nature Conservancy and the World Wildlife Federation, have experienced staff cuts up to 30%. “Organizations have had to tighten their belts and reign in programmes just to stay afloat, so it''s definitely impacted the degree to which we could work effectively,” he said. “Most of the big international conservation organizations have had to lay off large numbers of staff.”…a new type of ‘economics'' that demonstrates the benefits of biodiversity and brings the “natural world into the normal calculus”Cary Fowler, Executive Director of the Global Crop Diversity Trust in Rome, Italy, a public–private partnership to fund key crop collections for food security, also feels the extra challenges of the global economic crisis. “We invest our money conservatively like a foundation would in order to generate income that can reliably pay the bills in these seed banks year after year. So I''m always nervous and I have the computer on at the moment looking at what''s happening with the sovereign debt crisis here in Europe. It''s not good,” he said. “Governments are not being very generous with contributions to this area. Donors will rarely give a reason [for cutting funding].”The political situation in the USA, the world''s largest economy, is also not boding well for conservation of and research into biodiversity. The political extremism of the Republican Party during the run up to the 2012 presidential election has worried many involved in biodiversity issues. Republican contender Texas Governor Rick Perry has been described as ‘anti-science'' for his denial of man-made climate change, a switch from the position of 2008 Republican candidate John McCain. Perry was also reported to describe evolution as a “theory that''s out there, and it''s got some gaps in it” at a campaign event in New Hampshire earlier in the year.“Most of the big international conservation organizations have had to lay off large numbers of staff”Raven said this attitude is putting the USA at a disadvantage. “It drives us to an anti-intellectualism and a lack of real verification for anything which is really serious in terms of our general level of scientific education and our ability to act intelligently,” he said.Still, Larigauderie said that although the USA has not signed the conventions on biodiversity, she has seen US observers attend the meetings, especially under the Obama administration. “They just can''t speak,” she said. Meanwhile, Lovejoy said that biodiversity could get lost in the “unbelievable polarisation affecting US politics. I have worked out of Washington for 36 years now—I''ve never seen anything like this: an unwillingness to actually listen to the other side.”Raven said it is vital for the USA to commit to preserving biodiversity nationally and internationally. “It''s extremely important because our progress towards sustainability for the future will depend on our ability to handle biodiversity in large part. We''re already using about half of all the total photosynthetic productivity on land worldwide and that in turn means we''re cutting our options back badly. The US is syphoning money by selling debt and of course promoting instability all over the world,” he explained. “It''s clear that there is no solution to it other than a level population, more moderate consumption levels and new technologies altogether.”The EU and the UN have also changed the time horizon for halting the decline in biodiversity. As part of the Nagoya meeting, the UN announced the UN Decade for Biodiversity. The strategic objectives include a supporting framework for the implementation of the Biodiversity Strategic Plan 2011–2020 and the Aichi Biodiversity Targets, as well as guidance to regional and international organizations, and more public awareness of biodiversity issues.But Butchart remains sceptical. “I suspect ‘decades of whatever'' have even less impact than years,” he said. “2008 was the International Year of the Potato. I don''t know how much impact that had on your life and awareness. I think there is greater awareness and greater potential to make significant progress in addressing biodiversity loss now than there was 10 years ago, but the scale of the challenge is still immense.”“…our progress towards sustainability for the future will depend on our ability to handle biodiversity in large part”Hanski has similar doubts. “I believe it''s inevitable that a very large fraction of the species on Earth will go extinct in the next hundred years. I can''t see any change to that.” But he is optimistic that some positive change can be made. “Being pessimistic doesn''t help. The nations still can make a difference.” He said he has observed ecotourism playing a role in saving some species in Madagascar, where he does some of his research.“We''re not going to fundamentally be able to wipe life off the planet,” Thomas said. “We will wipe ourselves off the planet virtually certainly before we wipe life out on Earth. However, from the point of view of humanity as a culture, and in terms of the resources we might be able to get from biodiversity indirectly or directly, if we start losing things then it takes things millions of years to ‘re-evolve'' something that does an equivalent job. From a human perspective, when we wipe lots of things out, they''re effectively permanently lost. Of course it would be fascinating and I would love to be able to come back to the planet in 10 million years and see what it looks like, assuming humans are not here and other stuff will be.”Djoghlaf, by contrast, is more optimistic about our chances: “I believe in the human survival aspect. When humankind realises that the current pattern of production and consumption and the current way that it is dealing with nature is unsustainable, we will wake up.”     

Women and telomeres

Last year''s Nobel Prizes for Carol Greider and Elizabeth Blackburn should be encouraging for all female scientists with childrenCarol Greider, a molecular biologist at Johns Hopkins University (Baltimore, MD, USA), recalled that when she received a phone call from the Nobel Foundation early in October last year, she was staring down a large pile of laundry. The caller informed her that she had won the 2009 Nobel Prize in Physiology or Medicine along with Elizabeth Blackburn, her mentor and co-discoverer of the enzyme telomerase, and Jack Szostak. The Prize was not only the ultimate reward for her own achievements, but it also highlighted a research field in biology that, unlike most others, is renowned for attracting a significant number of women.Indeed, the 2009 awards stood out in particular, as five women received Nobel prizes. In addition to the Prize for Greider and Blackburn, Ada E. Yonath received one in chemistry, Elinor Ostrom became the first female Prize-winner in economics, and Herta Müller won for literature (Fig 1).Open in a separate windowFigure 1The 2009 Nobel Laureates assembled for a photo during their visit to the Nobel Foundation on 12 December 2009. Back row, left to right: Nobel Laureates in Chemistry Ada E. Yonath and Venkatraman Ramakrishnan, Nobel Laureates in Physiology or Medicine Jack W. Szostak and Carol W. Greider, Nobel Laureate in Chemistry Thomas A. Steitz, Nobel Laureate in Physiology or Medicine Elizabeth H. Blackburn, and Nobel Laureate in Physics George E. Smith. Front row, left to right: Nobel Laureate in Physics Willard S. Boyle, Nobel Laureate in Economic Sciences Elinor Ostrom, Nobel Laureate in Literature Herta Müller, and Nobel Laureate in Economic Sciences Oliver E. Williamson. © The Nobel Foundation 2009. Photo: Orasis.Greider, the daughter of scientists, has overcome many obstacles during her career. She had dyslexia that placed her in remedial classes; “I thought I was stupid,” she told The New York Times (Dreifus, 2009). Yet, by far the biggest challenge she has tackled is being a woman with children in a man''s world. When she attended a press conference at Johns Hopkins to announce the Prize, she brought her children Gwendolyn and Charles with her (Fig 2). “How many men have won the Nobel in the last few years, and they have kids the same age as mine, and their kids aren''t in the picture? That''s a big difference, right? And that makes a statement,” she said.The Prize […] highlighted a research field in biology that, unlike most others, is renowned for attracting a significant number of womenOpen in a separate windowFigure 2Mother, scientist and Nobel Prize-winner: Carol Greider is greeted by her lab and her children. © Johns Hopkins Medicine 2009. Photo: Keith Weller.Marie Curie (1867–1934), the Polish–French physicist and chemist, was the first woman to win the Prize in 1903 for physics, together with her husband Pierre, and again for chemistry in 1911—the only woman to twice achieve such recognition. Curie''s daughter Irène Joliot-Curie (1897–1956), a French chemist, also won the Prize with her husband Frédéric in 1935. Since Curie''s 1911 prize, 347 Nobel Prizes in Physiology or Medicine and Chemistry (the fields in which biologists are recognized) have been awarded, but only 14—just 4%—have gone to women, with 9 of these awarded since 1979. That is a far cry from women holding up half the sky.Yet, despite the dominance of men in biology and the other natural sciences, telomere research has a reputation as a field dominated by women. Daniela Rhodes, a structural biologist and senior scientist at the MRC Laboratory of Molecular Biology (Cambridge, UK) recalls joining the field in 1993. “When I went to my first meeting, my world changed because I was used to being one of the few female speakers,” she said. “Most of the speakers there were female.” She estimated that 80% of the speakers at meetings at Cold Spring Harbour Laboratory in those early days were women, while the ratio in the audience was more balanced.Since Curie''s 1911 prize, 347 Nobel Prizes in Physiology or Medicine and Chemistry […] have been awarded, but only 14—just 4%—have gone to women…“There''s nothing particularly interesting about telomeres to women,” Rhodes explained. “[The] field covers some people like me who do structural biology, to cell biology, to people interested in cancers […] It could be any other field in biology. I think it''s [a result of] having women start it and [including] other women.” Greider comes to a similar conclusion: “I really see it as a founder effect. It started with Joe Gall [who originally recruited Blackburn to work in his lab].”Gall, a cell biologist, […] welcomed women to his lab at a time when the overall situation for women in science was “reasonably glum”…Gall, a cell biologist, earned a reputation for being gender neutral while working at Yale University in the 1950s and 1960s; he welcomed women to his lab at a time when the overall situation for women in science was “reasonably glum,” as he put it. “It wasn''t that women were not accepted into PhD programs. It''s just that the opportunities for them afterwards were pretty slim,” he explained.“Very early on he was very supportive to a number of women who went on and then had their own labs and […] many of those women [went] out in the world [to] train other women,” Greider commented. “A whole tree that then grows up that in the end there are many more women in that particular field simply because of that historical event.Thomas Cech, who won the Nobel Prize for Chemistry in 1989 and who worked in Gall''s lab with Blackburn, agreed: “In biochemistry and metabolism, we talk about positive feedback loops. This was a positive feedback loop. Joe Gall''s lab at Yale was an environment that was free of bias against women, and it was scientifically supportive.”Gall, now 81 and working at the Carnegie Institution of Washington (Baltimore, MD, USA), is somewhat dismissive about his positive role. “It never occurred to me that I was doing anything unusual. It literally, really did not. And it''s only been in the last 10 or 20 years that anyone made much of it,” he said. “If you look back, […] my laboratory [was] very close to [half] men and [half] women.”During the 1970s and 1980s; “[w]hen I entered graduate school,” Greider recalled, “it was a time when the number of graduate students [who] were women was about 50%. And it wasn''t unusual at all.” What has changed, though, is the number of women choosing to pursue a scientific career further. According to the US National Science Foundation (Arlington, VA, USA), women received 51.8% of doctorates in the life sciences in 2006, compared with 43.8% in 1996, 34.6% in 1986, 20.7% in 1976 and 11.9% in 1966 (www.nsf.gov/statistics).In fact, Gall suspects that biology tends to attract more women than the other sciences. “I think if you look in biology departments that you would find a higher percentage [of women] than you would in physics and chemistry,” he said. “I think […] it''s hard to dissociate societal effects from specific effects, but probably fewer women are inclined to go into chemistry [or] physics. Certainly, there is no lack of women going into biology.” However, the representation of women falls off at each level, from postdoc to assistant professor and tenured professor. Cech estimated that only about 20% of the biology faculty in the USA are women.“[It] is a leaky pipeline,” Greider explained. “People exit the system. Women exit at a much higher proportion than do men. I don''t see it as a [supply] pipeline issue at all, getting the trainees in, because for 25 years there have been a great number of women trainees.“We all thought that with civil rights and affirmative action you''d open the doors and women would come in and everything would just follow. And it turned out that was not true.”Nancy Hopkins, a molecular biologist and long-time advocate on issues affecting women faculty members at the Massachusetts Institute of Technology (Cambridge, MA, USA), said that the situation in the USA has improved because of civil rights laws and affirmative action. “I was hired—almost every woman of my generation was hired—as a result of affirmative action. Without it, there wouldn''t have been any women on the faculty,” she said, but added that: “We all thought that with civil rights and affirmative action you''d open the doors and women would come in and everything would just follow. And it turned out that was not true.”Indeed, in a speech at an academic conference in 2005, Harvard President Lawrence Summers said that innate differences between males and females might be one reason why fewer women than men succeeded in science and mathematics. The economist, who served as Secretary of Treasury under President William Clinton, told The Boston Globe that “[r]esearch in behavioural genetics is showing that things people previously attributed to socialization weren''t [due to socialization after all]” (Bombardieri, 2005).Some attendees of the meeting were angered by Summers''s remarks that women do not have the same ‘innate ability'' as men in some fields. Hopkins said she left the meeting as a protest and in “a state of shock and rage”. “It isn''t a question of political correctness, it''s about making unscientific, unfounded and damaging comments. It''s what discrimination is,” she said, adding that Summers''s views reflect the problems women face in moving up the ladder in academia. “To have the president of Harvard say that the second most important reason for their not being equal was really their intrinsic genetic inferiority is so shocking that no matter how many times I think back to his comments, I''m still shocked. These women were not asking to be considered better or special. They were just asking to have their gender be invisible.”Nonetheless, women are making inroads into academia, despite lingering prejudice and discrimination. One field of biology that counts a relatively high number of successful women among its upper ranks is developmental biology. Christiane Nüsslein-Volhard, for example, is Director of the Max Planck Institute for Developmental Biology in Tübingen, Germany, and won the Nobel Prize for Physiology or Medicine in 1995 for her work on the development of Drosophila embryos. She estimated that about 30% of speakers at conferences in her field are women.…for many women, the recent Nobel Prize for Greider […] and Blackburn […] therefore comes as much needed reassurance that it is possible to combine family life and a career in scienceHowever, she also noted that women have never been the majority in her own lab owing to the social constraints of German society. She explained that in Germany, Switzerland and Austria, family issues pose barriers for many women who want to have children and advance professionally because the pressure for women to not use day care is extremely strong. As such, “[w]omen want to stay home because they want to be an ideal mother, and then at the same time they want to go to work and do an ideal job and somehow this is really very difficult,” she said. “I don''t know a single case where the husband stays at home and takes care of the kids and the household. This doesn''t happen. So women are now in an unequal situation because if they want to do the job, they cannot; they don''t have a chance to find someone to do the work for them. […] The wives need wives.” In response to this situation, Nüsslein-Volhard has established the CNV Foundation to financially support young women scientists with children in Germany, to help pay for assistance with household chores and child care.Rhodes, an Italian native who grew up in Sweden, agreed with Nüsslein-Volhard''s assessment of the situation for many European female scientists with children. “Some European countries are very old-fashioned. If you look at the Protestant countries like Holland, women still do not really go out and have a career. It tends to be the man,” she said. “What I find depressing is [that in] a country like Sweden where I grew up, which is a very liberated country, there has been equality between men and women for a couple of generations, and if you look at the percentage of female professors at the universities, it''s still only 10%.” In fact, studies both from Europe and the USA show that academic science is not a welcoming environment for women with children; less so than for childless women and fathers, who are more likely to succeed in academic research (Ledin et al, 2007; Martinez et al, 2007).For Hopkins, her divorce at the age of 30 made a choice between children or a career unavoidable. Offered a position at MIT, she recalled that she very deliberately chose science. She said that she thought to herself: “Okay, I''m going to take the job, not have children and not even get married again because I couldn''t imagine combining that career with any kind of decent family life.” As such, for many women, the recent Nobel Prize for Greider, who raised two children, and Blackburn (Fig 3), who raised one, therefore comes as much needed reassurance that it is possible to combine family life and a career in science. Hopkins said the appearance of Greider and her children at the press conference sent “the message to young women that they can do it, even though very few women in my generation could do it. The ways in which some women are managing to do it are going to become the role models for the women who follow them.”Open in a separate windowFigure 3Elizabeth Blackburn greets colleagues and the media at a reception held in Genentech Hall at UCSF Mission Bay to celebrate her award of the Nobel Prize in Physiology or Medicine. © University of California, San Francisco 2009. Photo: Susan Merrell.