The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever

In humans, sexual dimorphism is associated with the presence of two X chromosomes in the female, whereas males possess only one X and a small and largely degenerate Y chromosome. How do men cope with having only a single X chromosome given that virtually all other chromosomal monosomies are lethal? Ironically, or even typically many might say, women and more generally female mammals contribute most to the job by shutting down one of their two X chromosomes at random. This phenomenon, called X-inactivation, was originally described some 50 years ago by Mary Lyon and has captivated an increasing number of scientists ever since. The fascination arose in part from the realisation that the inactive X corresponded to a dense heterochromatin mass called the “Barr body” whose number varied with the number of Xs within the nucleus and from the many intellectual questions that this raised: How does the cell count the X chromosomes in the nucleus and inactivate all Xs except one? What kind of molecular mechanisms are able to trigger such a profound, chromosome-wide metamorphosis? When is X-inactivation initiated? How is it transmitted to daughter cells and how is it reset during gametogenesis? This review retraces some of the crucial findings, which have led to our current understanding of a biological process that was initially considered as an exception completely distinct from conventional regulatory systems but is now viewed as a paradigm “par excellence” for epigenetic regulation.     

The A to T of historical evidence

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

Gene patents and capital investment

Will the US Supreme Court''s ruling that genes can no longer be patented in the USA boost venture capital investment into biotech and medical startup companies?Three years ago, Noubar Afeyan, managing partner and CEO of Flagship Ventures, an early-stage venture capital firm in Cambridge, Massachusetts, USA, was working with a biotech start-up company developing techniques for BRCA gene testing for breast cancer risk that avoided the patents held by Myriad Genetics, a molecular diagnostics company in Salt Lake City (Utah, USA) and the only operator in the field. However, despite the promise of the start-up''s techniques, investors were put off by Myriad''s extensive patent portfolio and fiercely defensive tactics: “A lot of investors were simply not willing to take that chance, even though our technology was superior in many ways and patentably different,” Afeyan said. The effort to launch the start-up ultimately failed.…it is also not clear how the Supreme Court''s ruling will affect the […] industry at large, now that one of the most contested patents for a human gene has been ruled invalidAfeyan believes the prospects for such start-ups improved on the morning of 13 June 2013 when the US Supreme Court ruled in an unanimous vote that Myriad''s fundamental patents on the BRCA1 and BRCA2 genes themselves are invalid, opening up the field to new competitors. The court''s ruling, however, validated Myriad''s patents for BRCA cDNA and methods-of-use.The court''s decision comes at a time when venture capital investment into the life sciences is projected to decline in the years ahead. Some believe that the court''s decision sets a precedent and could provide a boost for products, diagnostics and other tests under development that would have been legally difficult in the light of existing patents on human and other DNA sequences.The US Patent Office issued the original patents for the BRCA 1 and BRCA2 genes in 1997 and 1998 for the US National Institute of Environmental Health Services, the University of Utah and Myriad Genetics. One year earlier, Myriad had launched its first diagnostic test for breast cancer risk based on the two genes and has since aggressively defended it against both private and public competitors in court. Many universities and hospitals were originally offering the test for a lower cost, but Myriad forced them to stop and eventually monopolized BRCA-based diagnostics for breast cancer risk in the USA and several other countries.“Myriad did not create anything,” Justice Clarence Thomas wrote in the Supreme Court''s decision. “To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.” Even so, the court did uphold Myriad''s patents on the methodology of its test. Ron Rogers, a spokesman for the biotech firm, said the Supreme Court had “affirmed the patent eligibility of synthetic DNA and underscored the importance and applicability of method-of-use patents for gene-based diagnostic tests. Before the Supreme Court case we had 24 patents and 520 claims. After the Supreme Court decision, we still have 24 patents. […] [T]he number of our patent claims was reduced to 515. In the Supreme Court case itself, only nine of our 520 patent claims were at issue. Of the nine, the Supreme Court ruled that five were not patent-eligible and they ruled that four were patent-eligible. We still have strong intellectual property protection surrounding our BRCA test and the Supreme Court''s decision doesn''t change that.”Within hours of the ruling, capitalism kicked into high gear. Two companies, Ambry Genetics in Alieso Viejo, California, and Gene by Gene Ltd in Houston, Texas, USA, announced that they were launching tests for the BRCA1 and BRCA2 genes for less than the US$3,100 Myriad has been charging privately insured patients and US$2,795 for patients covered by Medicare—the government health plan for the elderly and disabled. Several other companies and universities also announced they would be offering BRCA testing.Entrepreneur Bennett Greenspan, a managing partner of Gene by Gene, explained that his company had been poised to offer BRCA testing if the Supreme Court ruled against Myriad. He said, “We had written a press release with our PR firm a month before the release of the Supreme Court with the intention that if the Supreme Court overruled the patent or invalidated the patent that we would launch right away and if they didn''t, we would just tear up the press release.” His company had previously offered BRCA gene testing in Israel based on guidelines from the European Union.Myriad Genetics has not given up defending its patents, however. On 9 and 10 July 2013, it slapped Ambry and Gene by Gene with lawsuits in the US District Court in Salt Lake City for allegedly infringing on patents covering synthetic DNA and methods-of-use related to the BRCA1 and BRCA2 genes. Rogers commented that the testing processes used by the firms “infringes 10 patents covering synthetic primers, probes and arrays, as well as methods of testing, related to the BRCA1 and BRCA2 genes.”On 6 August 2013, Ambry countersued Myriad, arguing that the company “continues a practice of using overreaching practices to wrongfully monopolize the diagnostic testing of humans'' BRCA1 and BRCA2 genes in the United States and to attempt to injure any competitor […] Due to Myriad''s anticompetitive conduct, customers must pay significantly higher prices for Myriad''s products in the relevant market, often nearly twice as high as the price of Ambry''s products and those of other competitors” [1].Just as the courts will have to clarify whether the competitors in this case infringe on Myriad''s patents, it is also not clear how the Supreme Court''s ruling will affect the biotech and diagnostics industry at large, now that one of the most contested patents for a human gene has been ruled invalid. In recent years, venture capital investment into the life sciences has been in decline. The National Venture Capital Association and the Medical Innovation & Competitiveness Coalition reported from a survey that, “An estimated funding loss of half a billion dollars over the next three years will cost America jobs at a time when we desperately need employment growth” [2]. The survey of 156 venture capital firms found that 39% of respondents said they had reduced investment in the life sciences during the previous three years, and the same proportion intended to do so in the next three years. “[US Food and Drug Administration] FDA regulatory challenges were identified as having the highest impact on these investment decisions,” the report states, adding that many investors intended to shift their focus from the US towards Europe and the Asia/Pacific region.Another report from the same groups explains how public policy involving the FDA and other players in “the medical innovation ecosystem”—including the US patent system, public agencies, tax policy, securities regulation, immigration laws and private groups such as insurers—affect the decisions of investors to commit to funding medical innovation [3].Some investors think that the court decision about the patentability of human DNA will increase confidence and help to attract investors back to the life sciencesSome investors think that the court decision about the patentability of human DNA will increase confidence and help to attract investors back to the life sciences. “The clarity is helpful because for the longest time people didn''t do things because of ambiguity about whether those patents would be enforceable,” Afeyan said. “It''s one thing to not do something because of a patent, it''s another to not do something because you know that they have patents but you''re not sure what it''s going to stop you from doing because it hasn''t been really fully fleshed out. Now I think it is reasonably well fleshed out and I think you will see more innovation in the space.”Others also appreciate the clarification from the Supreme Court about what is a patentable invention in regard to human genes and DNA. “The Myriad decision was a very solid reading of the underlying purpose of our patent law, which is to reward novel invention,” commented Patrick Chung, a partner with New Enterprise Associates, a venture capital firm in Menlo Park, California, which invested in 23andMe, a personal genomics company based in Mountain View (California, USA), and who serves on the 23andMe board.But not everyone agrees that the Supreme Court''s decision has provided clarity. “You could spin it and say that it was beneficial to create some certainty, but at the end of the day, what the Court did was reduce the scope of what you''re allowed to get patent claims on,” said Michael Schuster, a patent lawyer and Intellectual Property Partner and Co-Chair of the Life Sciences Group at Fenwick & West LLP in San Francisco, California, USA. “It''s going to be a continuing dance between companies, smart patent lawyers, and the courts to try to minimize the impact of this decision.”Kevin Noonan, a molecular biologist and patent lawyer with McDonnell Boehnen Hulbert & Berghoff LLP in Chicago, Illinois, USA, commented that he does not expect the Supreme Court decision will have much of an impact on venture investments or anything else. “This case comes at a time fortunately when biotechnology is mature enough so that the more pernicious effects of the decision are not going to be quite as harmful as they would if this had happened ten, 15 or 20 years ago,” he said. “We''re now in the ‘post-genomic'' era; since the late ‘90s and turn of the century, the genomic and genetic data from the Human Genome Project have been on publicly available databases. As a consequence, if a company didn''t apply for a patent before the gene was disclosed publicly, it certainly is not able to apply for a patent now. The days of obtaining these sequences and trying to patent them are behind us.”Noonan also noted that the Myriad Genetics patents were due to expire in 2014–2015 anyway. “Patents are meaningless if you can''t enforce them. And when they expire, you can no longer enforce them. So it really isn''t an impediment to genetic testing now,” he explained. “What the case illustrates is a disconnect between scientists and lawyers. That''s an old battle.”George Church, professor of genetics at Harvard Medical School (Boston, Massachusetts, USA) and Director of the Personal Genome Project, maintains that the Supreme Court decision will have minimal influence on the involvement of venture capitalists in biotech. “I think it''s a non-issue. It''s basically addressing something that was already dead. That particular method of patenting or trying to patent components of nature without modification was never really a viable strategy and in a particular case of genes, most of the patents in the realm of bio-technology have added value to genes and that''s what they depend on to protect their patent portfolio—not the concept of the gene itself,” he said. “I don''t know of any investor who is freaked out by this at all. Presumably there are some, because the stock oscillates. But you can get stock to oscillate with all kinds of nonsense. But I think the sober, long-term investors who create companies that keep innovating are not impacted.”Church suggests that the biggest concern for Myriad now is whole-gene sequencing, rather than the Supreme Court''s decision. “Myriad should be worrying about the new technology, and I''m sure they''ve already considered this. The new technology allows you to sequence hundreds of genes or the whole genome for basically the price they''ve been charging all along for two genes. And from what I understand, they are expanding their collection to many genes, taking advantage of next generation sequencing as other companies have already,” he said.Whatever its consequences in the US, the Supreme Court''s decision will have little impact on other parts of the world, notably Europe, where Myriad also holds patents on the BRCA genes in several countries. Gert Matthijs, Head of the Laboratory for Molecular Diagnostics at the Centre for Human Genetics in Leuven, Belgium, says that even though the US Supreme Court has invalidated the principle of patenting genes in America, the concept remains in Europe and is supported by the European Parliament and the European Patent Convention. “Legally, nothing has changed in Europe,” he commented. “But there is some authority from the US Supreme Court even if it''s not legal authority in Europe. Much of what has been used as arguments in the Supreme Court discussions has been written down by the genetics community in Europe back in 2008 in the recommendations on behalf of the European Society for Human Genetics. The Supreme Court decision is something that most of us in Europe would agree upon only because people have been pushing towards protecting the biotech industry that the pendulum was so way out in Europe.”Benjamin Jackson, Senior Director of legal affairs at Myriad Genetics, commented that Myriad holds several patents in Europe that are not likely to be affected by the Supreme Court''s ruling. “The patent situation both generally and for Myriad is a lot clearer in Europe. The European Union Biotech Directive very clearly says that isolated DNA is patentable even if it shares the same sequence as natural DNA,” he said. “Right now, it''s pretty uncontroversial, or at least it''s well settled law basically in Europe that isolated DNA is patentable.” However, while the Directive states that “biological material which is isolated from its natural environment or produced by means of a technical process” might be patentable “even if it previously occurred in nature”, the European Patent Office (EPO) in Munich, Germany, requires that the subject matter is an inventive step and not just an obvious development of existing technology and that the industrial application and usefulness must be disclosed in the application.Myriad has opened a headquarters in Zurich and a lab in Munich during the past year, hoping to make inroads in Europe. In some EU countries, Myriad offers its BRCA test as part of cancer diagnosis. In other countries, BRCA testing is conducted at a fraction of what Myriad charges in the USA, either because institutions ignore the patents that are not enforced in their jurisdictions, or because these countries, such as Belgium, were not included in the patent granted by the European Patent Office. Moreover, in various countries BRCA testing is only available through the healthcare system and only as part of a more extensive diagnosis of cancer risk. In addition, as Matthijs commented, “[t]he healthcare system in Europe is very heterogeneous and that''s also of course a big impediment for a big laboratory to try and conquer Europe because you have to go through different reimbursement policies in different countries and that''s not easy.”Ultimately, it seems the Supreme Court''s decision might turn out to have little impact on biotech firms in either the USA or Europe. Technological advances, in particular new sequencing technologies, might render the issue of patenting individual genes increasingly irrelevant.     

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.”     

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.”     

Forming and Interpreting Gradients in the Early Xenopus Embryo

The amphibian embryo provides a powerful model system to study morphogen gradients because of the ease with which it is possible to manipulate the early embryo. In particular, it is possible to introduce exogenous sources of morphogen, to follow the progression of the signal, to monitor the cellular response to induction, and to up- or down-regulate molecules that are involved in all aspects of long-range signaling. In this article, I discuss the evidence that gradients exist in the early amphibian embryo, the way in which morphogens might traverse a field of cells, and the way in which different concentrations of morphogens might be interpreted to activate the expression of different genes.The idea that a morphogen gradient activates the expression of different genes at different concentrations was perhaps stated most clearly by Wolpert''s French flag model, in which a graded signal activates the expression of “blue,” “white,” and “red” genes at high, intermediate, and low concentrations (Wolpert 1969). Since that original work, great progress has been made in identifying morphogens and their target genes and it is now clear that the spatial pattern of gene expression in the developing embryo is frequently established by graded signals of this sort. But many questions remain, and in particular little is known about how gradients are established in the embryo with the necessary precision and how cells interpret different concentrations of morphogen to activate different genes. I discuss these issues with respect to mesoderm induction in the developing amphibian embryo.     

Systems Biology and Genomics of Breast Cancer

It is now accepted that breast cancer is not a single disease, but instead it is composed of a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Gene expression profiling using DNA microarrays has contributed significantly to our understanding of the molecular heterogeneity of breast tumor formation, progression, and recurrence. For example, at least two clinical diagnostic assays exist (i.e., OncotypeDX RS and Mammaprint®) that are able to predict outcome in patients using patterns of gene expression and predetermined mathematical algorithms. In addition, a new molecular taxonomy based upon the inherent, or “intrinsic,” biology of breast tumors has been developed; this taxonomy is called the “intrinsic subtypes of breast cancer,” which now identifies five distinct tumor types and a normal breast-like group. Importantly, the intrinsic subtypes of breast cancer predict patient relapse, overall survival, and response to endocrine and chemotherapy regimens. Thus, most of the clinical behavior of a breast tumor is already written in its subtype profile. Here, we describe the discovery and basic biology of the intrinsic subtypes of breast cancer, and detail how this interacts with underlying genetic alternations, response to therapy, and the metastatic process.     

Is Primatology an Equal-Opportunity Discipline?

The proportion of women occupying academic positions in biological sciences has increased in the past few decades, but women are still under-represented in senior academic ranks compared to their male colleagues. Primatology has been often singled out as a model of “equal-opportunity” discipline because of the common perception that women are more represented in Primatology than in similar fields. But is this indeed true? Here we show that, although in the past 15 years the proportion of female primatologists increased from the 38% of the early 1990s to the 57% of 2008, Primatology is far from being an “equal-opportunity” discipline, and suffers the phenomenon of “glass ceiling” as all the other scientific disciplines examined so far. In fact, even if Primatology does attract more female students than males, at the full professor level male members significantly outnumber females. Moreover, regardless of position, IPS male members publish significantly more than their female colleagues. Furthermore, when analyzing gender difference in scientific productivity in relation to the name order in the publications, it emerged that the scientific achievements of female primatologists (in terms of number and type of publications) do not always match their professional achievements (in terms of academic position). However, the gender difference in the IPS members'' number of publications does not correspond to a similar difference in their scientific impact (as measured by their H index), which may indicate that female primatologists'' fewer articles are of higher impact than those of their male colleagues.     

A new era for plant biotechnology. A combination of pharmaceutical applications, technologies and safety measures could lead to new applications for genetically modified plants

New applications and technologies, and more rigorous safety measures could herald a new era for genetically modified crops with improved traits, for use in agriculture and the pharmaceutical industry.The imminent prospect of the first approval of a plant-made pharmaceutical (PMP) for human use could herald a new era for applied plant science, after a decade of public backlash against genetically modified crops, particularly in Europe. Yet, the general resistance to genetically modified organisms might have done plant biotechnology a favour in the long run, by forcing it to adopt more-rigorous procedures for efficacy and safety in line with the pharmaceutical industry. This could, in turn, lead to renewed vigour for plant science, with the promise of developing not only food crops that deliver benefits to consumers and producers, but also a wide range of new pharmaceuticals.This is certainly the view of David Aviezer, CEO of Protalix, an Israeli company that has developed what could become the first recombinant therapeutic protein from plants to treat Gaucher disease. The protein is called taliglucerase alpha; it is a recombinant human form of the enzyme glucocerebrosidase that is produced in genetically engineered carrot cells. This enzyme has a crucial role in the breakdown of glycolipids in the cell membrane and is either used to provide energy or for cellular recognition. Deficiency of this enzyme causes accumulation of lipids with a variety of effects including premature death.“My feeling is that there is a dramatic change in this area with a shift away from the direction where a decade ago biotech companies like Monsanto and Dow went with growing transgenic plants in an open field, and instead moving this process into a more regulatory well-defined process inside a clean room,” Aviezer said. “Now the process is taking place in confined conditions and is very highly regulated as in the pharmaceutical industry.”…resistance to genetically modified organisms might have done plant biotechnology a favour […] forcing it to adopt more-rigorous procedures for efficacy and safety…He argues that this is ushering in a new era for plant biotechnology that could lead to greater public acceptance, although he denies that the move to clean-room development has been driven purely by the environmental backlash against genetically modified organisms in the late 1990s and early 2000s. “That was one aspect, but I think the move has been coming more from an appreciation that biopharmaceuticals require a more regulatory defined setting than is achieved at the moment with transgenic plants.”Interest in deriving pharmaceuticals from plants, known colloquially as ‘pharming'', first took off in the 1990s after researchers showed that monoclonal antibodies could be made in tobacco plants (Hiatt et al, 1989). This led to genetic engineering of plants to produce vaccines, antibodies and proteins for therapeutics, but none gained regulatory approval, mostly because of safety concerns. Moreover, the plants were grown in open fields, therefore attracting the same criticisms as transgenic food crops. In fact, a recent study showed that the views of the public on pharming depended on the product and the means to produce it; the researchers found increasing acceptance if the plants were used to produce therapeutics against severe diseases and grown in containment (Pardo et al, 2009).However, it was the technical challenges involved in purification and the associated regulatory issues that really delayed the PMP field, according to George Lomonossoff, project leader in biological chemistry at the John Innes Centre for plant research in Norwich in the UK, part of the Biotechnology and Biological Sciences Research Council (BBSRC). “Extraction from plants required the development of systems which are not clogged by the large amounts of fibrous material, mainly cellulose, and the development of GMP [good manufacturing practice; quality and testing guidelines for pharmaceutical manufacture] compliant methods of purification which are distinct from those required from, say, mammalian cells,” said Lomonossoff. “All this is very time consuming.”“Secondly there was no regulatory framework in place to assess the risks associated with proteins produced in plants, and determining how equivalent they are to mammalian-cell-produced material and what kind of contaminants you might have to guard against,” Lomonossoff added. “Again, attempting to address all possible concerns is a lengthy and expensive process.” Yet recent work by Protalix and a few other companies, such as Dow Agrosciences, has given grounds for optimism that purification and GMP-compliant methods of production have finally been established, Lomonossoff added.…a recent study showed that the views of the public on pharming depended on the product and the means to produce it…The first important breakthrough for PMPs came in 2006, when Dow Agrosciences gained regulatory approval from the US Department of Agriculture for a vaccine against Newcastle disease, a contagious bird infection caused by paramyxovirus PMV-1. “Though the vaccine, produced in tobacco-suspension culture cells, was never deployed commercially, it showed that regulatory approval for a plant-made pharmaceutical can be obtained, albeit for veterinary use in this case,” Lomonossoff said.As approval is imminent for taliglucerase alpha for human use, it is natural to ask why plants, as opposed to micro-organisms and animals, are worth the effort as sources of vaccines, antibiotics or hormones. There are three reasons: first, plants can manufacture some existing drugs more cheaply; second, they can do it more quickly; and third, and perhaps most significantly, they will be able to manufacture more complex proteins that cannot be produced with sufficient yield in any other way.An important example in the first category is insulin, which is being manufactured in increasing quantities to treat type 1 diabetes and some cases of type 2 diabetes. Until the arrival of recombinant DNA technology, replacement insulin was derived from the pancreases of animals in abattoirs, mostly cattle and pigs, but it is now more often produced from transgenic Escherichia coli, or sometimes yeast. Recently, there has been growing interest in using plants rather than bacteria as sources of insulin (Davidson, 2004; Molony et al, 2005). SemBioSys, a plant biotechnology company based in Calgary, Canada, is now developing systems to produce insulin and other therapeutic proteins in the seeds of safflower, an oilseed crop (Boothe et al, 2009).…plants can in principle be engineered to produce any protein, including animal ones…“We have developed technology that combines the high-capacity, low-cost production of therapeutic proteins in seeds with a novel technology that simplifies downstream purification,” said Joseph Boothe, vice president of research and development at SemBioSys. “The target proteins are engineered to associate with small, oil-containing structures within the seed known as oilbodies,” Boothe explained. “When extracted from the seed these oilbodies and associated proteins can be separated from other components by simple centrifugation. As a result, much of the heavy lifting around the initial purification is accomplished without chromatography, providing for substantial cost savings.”The second potential advantage of PMPs is their speed to market, which could prove most significant for the production of vaccines, either against emerging diseases or seasonal influenza, for which immunological changes in the virus mean that newly formulated vaccines are required each year. “In terms of a vaccine, I think influenza is very promising particularly as speed is of the essence in combating new strains,” Lomonossoff said. “Using transient expression methods, you can go from sequence to expressed protein in two weeks.” Transient gene expression involves injection of genes into a cell to produce a target protein, rather than permanently incorporating the gene into a host genome. This is emerging as a less technically difficult and faster alternative to developing stable cell lines for expressing bioengineered proteins. The process of injecting the desired gene into the target genome, known as transfection, can be effected not only by viruses, but also by non-viral agents including various lipids, polyethylenine and calcium phosphate.The last of the three advantages of plants for pharmaceutical production—the ability to manufacture proteins not available by other means—is creating perhaps the greatest excitement. The Protalix taliglucerase alpha protein falls into this category, and is likely to be followed by other candidates for treating disorders that require enzymes or complex molecules beyond the scope of bacteria, according to Aviezer. “I would say that for simpler proteins, bacteria will still be the method of choice for a while,” Aviezer said. “But for more complex proteins currently made via mammalian cells, I think we can offer a very attractive alternative using plant cells.”Indeed, plants can in principle be engineered to produce any protein, including animal ones, as Boothe pointed out. “In some cases this may require additional genetic engineering to enable the plant to perform certain types of protein modification that differ between plants and animals,” he said. “The classic example of this is glycosylation. With recent advances in the field it is now possible to engineer plants to glycosylate proteins in a manner similar to that of mammalian cells.” Glycosylation is a site-directed process that adds mono- or polysaccharides to organic molecules, and plays a vital role in folding and conferring stability on the finished molecule or macromolecule. Although plants can be engineered to perform it, bacteria generally cannot, which is a major advantage of plant systems over micro-organisms for pharmaceutical manufacture, according to Aviezer. “This enables plant systems to do complex folding and so make proteins for enzyme replacement or antibodies,” Aviezer said.Genomic-assisted breeding is being used either as a substitute for, or a complement to, genetic-modification techniques…In addition to plants themselves, their viruses also have therapeutic potential, either to display epitopes—the protein, sugar or lipid components of antigens on the surface of an infectious agent—so as to trigger an immune response or, alternatively, to deliver a drug directly into a cell. However, as Lomonossoff pointed out, regulatory authorities remain reluctant to approve any compound containing foreign nucleic acids for human use because of the risk of infection as a side effect. “I hope the empty particle technology [viruses without DNA] we have recently developed will revive this aspect,” Lomonossoff said. “The empty particles can also be used as nano-containers for targeted drug delivery and we are actively exploring this.”As pharmaceutical production is emerging as a new field for plant biology, there is a small revolution going on in plant breeding, with the emergence of genomic techniques that allow simultaneous selection across several traits. Although genetic modification can, by importing a foreign gene, provide instant expression of a desired trait, such as drought tolerance, protein content or pesticide resistance, the new field of genomics-assisted breeding has just as great potential through selection of unique variants within the existing gene pool of a plant, according to Douwe de Boer, managing director of the Netherlands biotech group Genetwister. “With this technology it will be possible to breed faster and more efficiently, especially for complex traits that involve multiple genes,” he said. “By using markers it is possible to combine many different traits in one cultivar, variety, or line in a pre-planned manner and as such breed superior crops.”“The application of genomics technologies and next generation sequencing will surely revolutionize plant breeding and will eventually allow this to be achieved with clinical precision”Genomic-assisted breeding is being used either as a substitute for, or a complement to, genetic-modification techniques, both for food crops to bolt on traits such as nutrient value or drought resistance, and for pharmaceutical products, for example to increase the yield of a desired compound or reduce unwanted side effects. Yet, there is more research required to make genomic-assisted breeding as widely used as established genetic-modification techniques. “The challenge in our research is to find markers for each trait and as such we extensively make use of bio-informatics for data storage, analysis and visualization,” de Boer said.The rewards are potentially enormous, according to Alisdair Fernie, a group leader from the Max-Planck-Institute for Molecular Plant Physiology in Potsdam, Germany. “Smart breeding will certainly have a massive impact in the future,” Fernie said. “The application of genomics technologies and next generation sequencing will surely revolutionize plant breeding and will eventually allow this to be achieved with clinical precision.” The promise of such genomic technologies in plants extends beyond food and pharmaceuticals to energy and new materials or products such as lubricants; the potential of plants is that they are not just able to produce the desired compound, but can often do so more quickly, efficiently and cheaply than competing biotechnological methods.     

Reading the tea leaves of Congress. With a new Republican majority in the House of Representatives, scientific research in the USA might face budget cuts

The increasing influence of the Tea Party in Congress and politics has potential repercussions for public funding of scientific research in the USAIn 2009, Barack Obama became the 44th President of the USA, amid hopes that he would fix the problems created or left unresolved by his predecessor. However, despite his positive mantra, “Yes we can,” the situation was going to get worse: the country was spiralling towards an economic recession, a collapsing residential real-estate market and the loss of millions of jobs. Now, the deficit lingers around US$14 trillion (US Department of the Treasury, 2011). In response to these hardships and the presence of a perceived ‘socialist'' president in office, a new political movement started brewing that would challenge both the Democrats and the Republicans—the two parties that have dominated US politics for generations. Known as the Tea Party, this movement has been gaining national momentum in its denouncement of the status quo of the government, especially in relation to federal spending, including the support of scientific research.The name is a play on the Boston Tea Party, at which more than 100 American colonists dumped 45 tonnes of tea into Boston Harbour (Massachusetts, USA) in 1773 to protest against the British taxation of imported tea. Whereas the 18th century Boston Tea Party formed to protest against a specific tax, the Tea Party of the 21st century protests against taxes and ‘big'' government in general.Many view Tea Party followers as modern muckrakers, but supporters claim their movement is fundamentally about upholding the US Constitution. Tea Party Patriots, a non-partisan organization, considers itself to be the official home of the Tea Party movement. Fuelled by the values of fiscal responsibility, limited government and free markets, Tea Party Patriots believe, these three principles are granted by the Constitution, although not necessarily upheld by the administration.“If you read the Constitution, the limits of government involvement in society [are] pretty well-defined and our government has gone farther and farther beyond the specific limits of the Constitution,” said Mark Meckler, one of the co-founders of Tea Party Patriots. “Our Constitution is not designed as an empowering document, but as a limiting document… [and] was intended to be used as a weapon by the people against the government to keep it in the box.” Tea Partiers tend to be especially critical when it comes to spending tax dollars on bank bailouts and health care, but anything goes when it comes to cutting back on public spending—even science. “We believe everything needs to be on the table since the government is virtually bankrupt,” Meckler said. “We need to cut the waste, cut the abuse [and] get rid of the departments that shouldn''t exist.”Tea Partiers tend to be especially critical when it comes to spending tax dollars on bank bailouts and health care, but anything goes when […]cutting […] public spending—even scienceOn 19 February 2011, the US House of Representatives, which is currently controlled by the Republicans, passed a federal-spending bill for the remainder of the 2011 fiscal year budget. Among other cuts, the bill called for billions of dollars to be slashed from the budgets of federal science agencies. If the bill is signed into law, the National Institutes of Health (NIH) will have $1.6 billion cut from its budget—a 5.2% decrease—and the Department of Energy (DOE) will experience an 18% cut in funding for its Office of Science. Other agencies targeted include the Environmental Protection Agency (EPA), the National Aeronautics and Space Administration (NASA), the National Institute of Standards and Technology (NIST) and the National Science Foundation (NSF; Anon, 2011; Cho, 2011). Although the US Senate, which has a Democratic majority, must consider the bill before any definite amendments to the budget are made, it is likely that there will be some cuts to science funding.Although the House is in favour of science-related cuts, President Obama supports spending more on science education, basic research and clean-energy research. He has also proposed an 11.8% increase in the budget of the DOE, as well as an 8% increase in the NSF budget (Office of Management and Budget, 2011).The House is in favour of science-related cuts, but President Obama is in favour of spending more on science education, basic science and clean-energy researchJoann Roskoski, acting assistant director of the Biology Directorate at the NSF, said her institute is strongly in favour of President Obama''s budget proposal. “President Obama is a very strong supporter of fundamental research and STEM [science, technology, engineering and mathematics] education because he perceives it as investing in the future of the country,” she said. “These are just difficult budgetary times and we''ll just have to wait and see what happens. As they say, the president proposes and Congress disposes.”Karl Scheidt, a professor of chemistry at Northwestern University (Evanston, Illinois, USA), has four grants from federal agencies. “A couple of my grants expire this year, which is happening at the worst, worst possible time,” explained Scheidt, whose grants are funded by the NIH and the NSF. He added that although many politicians either do not understand or believe in the fundamentals of science, they still preach to the masses about what they ‘think'' they know. “I think it''s an absolute travesty that many people don''t understand science and that many of the Republicans who don''t fully understand science perpetuate incorrect assumptions and scientific falsehoods when speaking in public,” he said. “It makes the US less competitive and puts us collectively at a disadvantage relative to other nations if we don''t succeed in scientific education and innovative research in the future.”Although the Tea Party is not technically associated with the Republican Party, all Tea-Party representatives and senators ran as Republican candidates in the last election. While only one-third of seats in the Senate are on the ballot every two years for a six-year term, all House seats are for a two-year term. In the most recent Senatorial election, 50% of Tea Party-backed candidates won; 10 in total. 140 candidates for seats in the House of Representatives were backed by the Tea Party—all of whom were Republicans—but only 40 won. Nevertheless, with around 100 new Republicans in office, a House controlled by a Republican majority and most Congress-based Republicans in agreement with Tea Party ideals, the Tea Party actually has a lot of sway on the voting floor.Of course, as a fundamentally grass-roots movement, their influence is not limited to the halls of power. Since just before the November election last year, Tea Party-backed politicians have received more scrutiny and media exposure, meaning more people have listened to their arguments against spending on science. In fact, Republican politicians associated with the Tea Party have made critical and sometimes erroneous comments about science. Representative Michelle Bachman, for example, claimed that because carbon dioxide is a natural gas, it is not harmful to our atmosphere (Johnson, 2009). Representative Jack Kingston denounced the theory of evolution and stated that he did not come from a monkey (The Huffington Post, 2011). When asked how old he believes the Earth to be, Senator Rand Paul refused to answer (Binckes, 2010). He also introduced a bill to cut the NSF budget by 62%, and targeted the budget of the Center for Disease Control and Prevention.Scheidt believes part of the challenge is that many scientists do not properly articulate the importance of their work to the public, and there is limited representation on behalf of science in Washington. “It''s difficult sometimes to advocate for and explain the critical importance of basic research and for the most part, Congress may not always appreciate the basic fundamental mission of organizations like the NIH,” Scheidt said. “Arlen Specter was one of the few people who could form coalitions with his colleagues on both sides of the aisle and communicate why scientific research is critical. Why discovering new ways to perform transplants and creating new medicines are so important to everyone.”…part of the challenge is that many scientists do not properly articulate the importance of their work to the public, and there is limited representation on behalf of science in WashingtonSpecter, a former senator, was Republican until 2009 when he decided to switch political parties. During the last Democratic primary, he lost the Pennsylvania Senate nomination after serving in Congress for more than four decades. The Democratic nominee, Joe Sestak, eventually lost the coveted seat to Pat Toomey, a Tea Party Republican who sponsored an amendment denying NIH funding for some grants while he was a House member. Toomey is also against funding climate science and clean-energy research with federal dollars.Specter was considered a strong supporter of biomedical research, especially cancer research. He was the catalyst that pushed through a great deal of pro-science legislation, such as adding approximately $10 billion to NIH funding as part of the stimulus package in 2009, and doubling NIH funding in the 1990s. As scientific research was so important to him, he served on the US Senate Committee on Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies and on the Senate Committee on Environment and Public Works. Specter was a popular political champion of science not only because of all he had accomplished, but also because so few scientists are elected to office.Among those Democrats who lost their seats to Tea Party Republicans was Congressman Bill Foster. Foster, who once worked for the Fermi National Accelerator Laboratory (Fermilab)—which is funded by the DOE—represented Batavia, Ilinois, which is also where Fermilab has its headquarters. “The new representative in the district where Fermilab resides is Randy Hultgren, a Republican, who has been very supportive of the laboratory since he''s been elected,” said Cindy Conger, Chief Financial Officer at Fermilab. “He''s very interested in us and very interested […] in us having adequate funding.”However, Fermilab is suffering financially. “We will […] have some level of layoffs,” Conger said. “Inadequate federal funding could result in more layoffs or not being able to run our machines for part of the year. These are the things we are contemplating doing in the event of a significant budget cut. Nothing is off the table [but] we will do everything we can to run the [Tevatron] accelerator.”But Fermilab''s desperate appeal for $35 million per year for the next three fiscal years was denied by the Obama administration and not included in the 2012 White House budget request. As a result, the most powerful proton–antiproton accelerator in the USA, the Tevatron, is shutting down indefinitely near the end of this year.Another pro-science Republican is former Congressman John Porter, who studied at the Massachusetts Institute of Technology. He encouraged the federal funding of science while serving as chair of the House Subcommittee on Labor, Health and Human Services, and Education, as well as on the House Committee on Appropriations and Related Agencies. Like Scheidt, Porter said a problem is that not many members of Congress really understand science or what goes into scientific research.“Many members of Congress don''t realize that the money appropriated for the funding of scientific research through NIH, NSF […] is sent out to research institutes in their districts and states where the research is conducted,” said Porter, who retired from Congress in 2001 after serving for more than 20 years. “They simply haven''t been exposed to it and that''s the fault of the science community, which has a great responsibility to educate about the mechanisms on how we fund scientific research.”Today, Porter is vice-chair of the Foundation for the NIH and also chairs Research!America, a non-profit organization which aims to further medical, health and scientific research as higher national priorities. He also noted that industry would not fund scientific research in the way the government does because there would essentially be no profits. Therefore, federal funding remains essential.“Let''s take away the phones, iPads and everything else [those against the federal funding of science] depend on and see what''s left,” Porter said. “The US is the world leader in science, technology and research and the way we got there and the way we have created the technology that makes life easier […] is a result of making investments in that area.”For now, Scheidt said the best approach is to educate as many people as possible to understand that scientific research is a necessity, not a luxury. “We unfortunately have a very uneducated population in regard to science and it''s not 100% their fault,” he said. “However, if people took a real interest in science and paid as much attention to stem-cell or drug-discovery research as they did to the Grammy Awards or People magazine I think they would appreciate what''s going on in the science world.”…the best approach is to educate as many people as possible to understand that scientific research is a necessity, not a luxuryInstead, the USA is lagging behind its competitors when it comes to STEM education. According to the 2009 Program for International Student Assessment (PISA), the USA is ranked 17th on science and 25th on maths out of 34 countries (US Department of Education, 2010). “We''re in a cluster now, we''re no longer the leading country,” said D. Martin Watterson, a molecular biologist who sits on NIH peer-review committees to evaluate grant proposals. The reason, according to Watterson, is that the first things to be cut after a budget decrease are training grants for continuing education efforts. Moreover, the USA already lacks highly trained workers in the field of science. “In some disciplines, employers now look to other places in Europe and Asia to find those trained personnel,” Watterson said.Ultimately, most people at least want a final budget to be passed so that there is sufficient time to plan ahead. However, Georgetown University political science professor Clyde Wilcox thinks that a compromise is not so simple. “The problem is that it''s a three-way poker game. People are going to sit down and they''re going to be bargaining, negotiating and bluffing each other,” he said. “The House Republicans just want to cut the programs that they don''t like, so they''re not cutting any Republican programs for the most part.”As a result, institutions such as the EPA find themselves being targeted by the Republicans. Although there is not a filibuster-proof majority of Democrats in the Senate, they still are a majority and will try to preserve science funding. Wilcox said that it is not necessarily a good thing to continue negotiating if nothing gets done and the country is dependent on continuing resolutions.Although there is not a filibuster-proof majority of Democrats in the Senate, they still are a majority and will try to preserve science funding“What the real problem is, when push comes to shove, someone has to blink,” he said. “I don''t think there will be deep cuts in science for a number of reasons, one is science is consistent with the Democratic ideology of education and the Republican ideology of investment. And then, we don''t really spend that much on science anyway so you couldn''t come remotely close to balancing the budget even if you eliminated everything.”Although during his time in Congress representatives of both parties were not as polarized as they are today, Porter believes the reason they are now is because of the political climate. “The president has made [science] a very important issue on his agenda and unfortunately, there are many Republicans today that say if he''s for it, I''m against it,” Porter said. In fact, several government officials ignored repeated requests or declined to comment for this article.“It''s time for everybody from both parties to stand up for the country, put the party aside and find solutions to our problems,” Porter commented. “The American people didn''t just elect us to yell at each other, they elected us to do a job. You have to choose priorities and to me the most important priority is to have our children lead better lives, to have all human beings live longer, healthier, happier lives and to have our economy grow and prosper and our standard of living maintained—the only way to do that is to invest where we lead the world and that''s in science.”