Blockchain Papers

Peggy Eastman

In response to growing threats on federal funding for the National Institutes of Health (NIH), Sen. Tammy Baldwin (D-WI) and Sen. Peter Welch (D-VT) held a Senate forum on Capitol Hill with speakers, including researchers and patients. The speakers included surgical oncologist Monica Bertagnolli, MD, former Director of the NIH, former Director of the National Cancer Institute (NCI), and a cancer survivor. She stressed the dire consequences of grant freezes, disruptions in funding, staffing cuts, administrative upheaval, confusion, and a chilling effect on young investigators just beginning their scientific careers. “We are here today to sound the alarm,” Baldwin said. “This isn't efficiency; this is cruelty.” She said that “cures for Alzheimer's disease and cancer are not waste, or fraud, or abuse,” and she noted that “biomedical research can't just be turned on and off on a whim. We have heard heartbreaking stories from patients in clinical trials.” Welch noted, “It's an upside-down set of priorities; the cruelty speaks for itself. It's a lack of confidence in our nation. This is an erosion of our spirit.” Senate Minority Leader Chuck Schumer (D-NY) called cuts for NIH research “just appalling. We are going to fight this tooth and nail. The public is on our side; we must win this fight. People's lives are at stake.” The American Association for Cancer Research (AACR), which worked with Senate organizers on the forum, has reported and is fighting the freezing of new NIH grants and blockages of already approved funding; proposed the capping of indirect costs at 15 percent; canceled NIH advisory council meetings, halting final approval of peer-reviewed grants; the ordering of massive layoffs and the imposition of a hiring freeze at the NIH; and continued termination of active NIH grants despite federal court orders. The AACR is urging Americans to contact their members of Congress and tell them to reject any funding cuts to the NIH and NCI, address the instability caused by recent administrative disruptions, and preserve the progress of scientific research by ensuring that early-career scientists have the stable funding necessary to drive the next wave of medical research breakthroughs. “This is a critical time for our nation...the confusion is rampant,” Bertagnolli said. As a cancer survivor, she noted that she would not be here today without the research funded by the NIH over the past 5 decades. She termed NIH research “a great investment for the American people.” She cited the harm caused by “more than 300 grants terminated and about $1.5 billion in funding delays and barriers that are preventing the NIH's role of ensuring that funding is delivered to outstanding researchers across the nation.” Bertagnolli mentioned the case of a young researcher who trained for 16 years and could not get a job because of hiring freezes. She said this is not an isolated story and the nation is being deprived of the promising work of young investigators. Bertagnolli added there was not a day she was at the NIH that people employed there did not ask how they could make sure they were doing the most cutting-edge research. She noted that NIH research funding is the foundation for the work on which most of the new drugs that reach clinical practice are based. Scientific researchers built bridges that have allowed patients to outpace cancer, including Larry Saltzman, MD, a survivor of chronic lymphocytic leukemia diagnosed in 2010, a retired physician, and former Executive Research Director at the Leukemia & Lymphoma Society. He has been on many clinical trials and received many treatments, including CAR T-cell therapy. “Time is everything,” he said. “I am living proof of what the NIH can do. We must speak up, stand up for science,” and protect the future of medical research. Whitney Wharton, PhD, Associate Professor at Emory University and an Alzheimer's disease researcher, noted she has had two NIH grants terminated recently. She said they have been “devastating” for her research team and the patients participating in clinical trials. Wharton stressed the importance of engendering trust in people who enroll in clinical trials and who willingly donate their time and—in many cases—samples from their bodies. “It takes a long time to become a scientist,” said Wharton, and the current concerns about the stability of a scientific career may cause some young scientists to leave research altogether. Sterling Johnson, PhD, Professor of Medicine and Associate Director of the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin-Madison, agreed. He noted that Alzheimer's disease appears years, if not decades, before the onset of symptoms, and medical research has led to the development of prescription drugs to slow the progression of the disease. He said that 6.9 million Americans have Alzheimer's disease, a number projected to double by 2050 without scientific research advances. Johnson said that, just at a time when young investigators are urgently needed, growing uncertainty is discouraging early-career scientists from entering the biomedical field. “That is stopping progress,” he said. Jessy Ybarra, a veteran living with amyotrophic lateral sclerosis (ALS) and a board member of the ALS Association, noted that veterans are twice as likely to develop ALS and research is urgently needed to make ALS “a livable disease” until a cure can be found. He played a recording from his 10-year-old son at the Senate forum in which the son pleaded for support for medical research, noting, “I am not ready to say goodbye to my best friend, my dad.” Sen. Elizabeth Warren (D-MA) stated that the NIH is the largest biomedical research institution in the world and investing in it pays off financially, as well as medically. “We cannot afford to lose a generation of scientific breakthroughs and a generation of research scientists,” she stressed. Sen. Edward Markey (D-MA) agreed. “The NIH is really the national institutes of hope,” he said. “I'm going to fight for all those young researchers.” Sen. Dick Durbin (D-IL), Democratic minority whip and longtime senator from Illinois, stressed the urgent need for a bipartisan effort to support medical research, noting that what is lacking now is “support from the other side of the aisle.” He said he remembers a time in the past when the NIH received a strong increase in congressional funding due to cooperative bipartisan support. Sen. Catherine Cortez Masto (D-NV) agreed with Durbin on the need for strong bipartisan support of NIH research. “This is about saving lives,” she said. “It is not a red state or blue state issue. It touches so many of us; that's what this is all about.” Sen. Angela Alsobrooks (D-MD) noted that the NIH is in her state's backyard and “an attack on the NIH is, in fact, an attack on the state of Maryland.” She noted she is a member of the “sandwich generation” who is raising a 19-year-old daughter and caring for a mother who has Alzheimer's disease. For women caregivers like her, she said that breakthroughs from medical research are becoming increasingly important. The AACR has vowed to continue the fight to preserve the NIH as the cornerstone of biomedical research. “The administration's ongoing disruptions of and restrictions on the NIH's ability to work in partnership with the broader scientific community are jeopardizing progress and delaying innovations and treatments that are pivotal to improving patient outcomes and saving lives,” the AACR stated. “The stakes could not be higher. The decisions made today will determine whether we accelerate the fight against cancer or allow critical momentum to be lost.” The AACR's work on the Senate forum is “part of our long-standing commitment to ensuring that policymakers understand what is at stake and that they hear directly from those on the front lines.” Peggy Eastman is a contributing writer.

Suzanne O'Halloran

No abstract is available for this record.

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Headline INTERNATIONAL:Tesla’s bitcoin bet is not a gamechanger

Mahelia Bissassar

Transnational medical tourism is a growing sector of modern global health care, facilitated by globalism and connecting platforms like the Internet, which provides opportunities for health care to those who can afford it. Patients who can afford the steep price (and, very often, those who can't) partake in organ tourism as alternative means of seeking a needed organ, reproductive tourism as a method to treat infertility, in the form of egg donation and surrogacy, as well as stem cell tourism. During the past decade, stem cell research has skyrocketed spurring increased scientific excitement about what the future of stem cell research could hold for regenerative medicine and treatment of untreatable diseases. However, a developing market commercializing in an international setting without regulation and restriction has led to expensive pseudo medical treatments, for which there is no scientific rationale or evidence of efficacy or safety, that threaten the health of patients. Several highly publicized cases including the death of a child in the German1 stem-cell clinic XCell Center, as well as the highly publicized paralysis and cancer-like growth of American patient Jim Gass in stem-cell clinics in Mexico, China, and Argentina have prompted global outcry and a call for increased regulation and implantation of safety standards.[2,3] The prevalence of stem-cell clinics that provide untested and potentially lethal medical interventions threatens the global health and financial security of patients. Stem cell tourism, a growing industry largely advertised online, involves privately owned stem cell clinics, often managed by physicians, fraudulently advertising pseudoscientific stem-cell cures for a variety of untreatable conditions directly to health consumers. Patients looking for stem-cell treatments travel from a diverse range of locations in North America, Europe, the Middle East and Asia.[8] The clinics they travel to are located around the world, the most popular ones in countries at the forefront of medical stem-cell innovation and in nations with lax stem-cell clinic laws. Companies are located in United States, Mexico, Russia, Germany, India, and China, among several other countries.[9] They all rely on weak and subjective claims of improvement, selective anecdotes and testimonials, favorable media reports, untested scientific jargon, and links to unrelated studies to appeal to health consumers.[6] A further study on the data collected from clinics illustrates a therapeutic effect likely due only to a placebo effect.[10] No clinical data or procedures have been released from these clinics, having the most dangerous implications. No data or procedures released means that efficacy cannot be measured, so hurtful experiences are not counted and actual therapeutically valuable data cannot be used or tested for efficacy against other studies of accepted treatment.[6,11] These clinics cannot be held to clinical standards of safety or effectiveness and are not held responsible for futile treatment. This shoddy science threatens the future beneficiaries of such innovative clinical science and weakens proof that stem-cell clinics are anything but a farce. These clinics prey on the hopes and fears of their clients by appealing to a broad array of degenerative, chronic, and fatal diseases.[5,6,7] Unknown risks were withheld from patients, threatening not just their autonomy to make an informed decision about their own health but also violates the primary principle of medicine: to do no harm. Embryonic and other stem cells have tumorigenic potential and have been proposed as a source of common origin for cancer.[2] These clinics exist as an alternative to patients not eligible for clinical trials or otherwise averse to such trials in the US.[16] Patients go abroad in search of treatments unavailable at home, searching for a source of hope. Patients suffering from serious or debilitating conditions, like Alzheimer’s and multiple sclerosis, can’t be cured with modern medical treatments. Their only treatment options include palliative care, symptom management or drugs that temporarily slow the progress of the disease.[6] These situations create similar circumstances of rashness that drive organ tourism and foment human rights violations.[4] Stem-cell companies provided misleading medical information to their consumers, projecting medical authority and expertise in order to frame their stem-cell therapies as new and innovative rather than unproven.[6,13] Doing so is intentionally maleficent and puts patients in harm’s way. Stem cell tourism brings unique intricate ethical concerns where generalized medical knowledge is at odds with patients’ immediate desire to survive, pushing patients to risky treatment many would not consider. This is not simply another case of buyer beware. The potential for serious harm to vulnerable patients is at stake.[17] The stem cell tourism industry is a complex, extensive industry with multiple interlaced causes and contributions. One pronounced contributor is the patient frustration with the lack of treatment in their native country and their immediate healthcare needs. The overselling of stem cell treatments before they have been sufficiently validated and tested for safety has been attributed to the sensationalized attention given to stem cell research in popular media. Stem cell research is portrayed as the next new big thing in medicine, in which the promising research potential is seen as rapidly translatable to cures. With some theatricals, stem cell clinics can extend the applicability of accepted clinical treatments to swindle customers.[13] The perpetrators of the crime are the medical entrepreneurs and brokers who advertise and provide the treatments,[4] but emphasis on communicating openly with patients to understand why patients go abroad for treatment rather than on persecuting brokers and dishonest clinicians carrying out procedures, may be a more effective way of battling unsafe stem cell tourism from the root. Some researchers contribute the growth of stem cell tourism to American scientists and clinicians.[12] They argue that scientists and clinicians underestimate the relevance of hope to patients making the decisions to travel abroad for dubious treatment, proposing that, even unfounded hope is better than no hope at all in the patient’s mind.[12,18] It is imperative for discussion to reflect on why so little hope is found at home rather than just importance of allowing hope to flourish offshore.[12] The paternalistic dismissive attitude of American physicians in the face of patients considering dangerous or futile stem-cell treatment in the hope of some improvement has been argued to push patients away from established medical professionals to dubious stem-cell clinics.18 The lack of health care at home has also been identified as a contributing factor. Salter and colleagues insist that the matter at hand isn’t toning down the hype but rather domestically available health care supply.16 Patients in need don’t care about expanding medical knowledge or the benefit of future suffering patients, they care about is getting better and surviving. Demonizing stem cell tourism will never squelch this vital instinct.[20] Acceptable channels must be made available to seriously ill patients. Constraints such as the proximity of death as well as the specific burdens of a particular disease condition contribute to the stress of the limits of local treatment to impress an immediacy pointing to external care.[16,19] Recognizing the role of health consumer choices in this emerging global market will be essential to discouraging risky and exploitative healthcare decisions. Works Cited 1. Mendick, R. and Hall, A. (2011) Europe’s largest stem cell clinic shut down after death of baby, The Telegraph, 8 May. Available at www. telegraph.co.uk/news/worldnews/europe/germany/8500233/Europes-largest-stem-cell-clinic-shut-down-after-death-of-baby.html (accessed 1 May 2017) 2. Berkowitz ,Aaron L., Miller, Micheal B., Mir Saad A., Daniel Cagney Daniel, Chavakula Vamsidhar, Guleria Indira, Aizer Ayal, Ligon Keith L., Chi John H., N Engl J Med 2016; 375:196-198 3. Kolata Gina, (2016) A Cautionary Tale of ‘Stem Cell Tourism’. The New York Times, 22 June (Accessed May 1, 2017) 4. Shalev, Carmel (2010) Stem Cell Tourism—A Challenge for Trans-National Governance, The American Journal of Bioethics, 10:5, 40-42, 5. Alan Petersen, Kate Seear and Megan Munsie Sociology of Health & Illness Vol. 36 No. 5 2013 ISSN 0141-9889, pp. 670–685 6. Sipp, Douglas. The unregulated commercialization of stem cell treatments: a global perspective. Front. Med. 2011, 5(4): 348–355 7. Lau D, Ogbogu U, Taylor B, Stafinski T, Menon D, Caulfield T. Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell 2008; 3(6): 591–594. China Stem Cell News. http://www.stemcellschina.com 8. Ibid 9. ALSUntangled Group. ALSUntangled update 4: investigating the XCell-Center. Amyotroph Lateral Scler 2010; 11(3): 337–338 10. D. Lau et al., Cell Stem Cell 3, 591 (2008). 11. Devereaux, Mary and Loring, Jeanne F. (2010) Growth of an Industry: How U.S. Scientists and Clinicians Have Enabled Stem Cell Tourism, The American Journal of Bioethics, 10:5, 45-46, 12. Patra PK, Sleeboom-Faulkner M. Bionetworking: Between Guidelines and Practice in Stem Cell Therapy Enterprise in India. (2010) 7:2 SCRIPTed 295, http://www.law.ed.ac.uk/ahrc/script-ed/vol7-2/patra.asp 13. R. Alta Charo, Alta R. On the Road (to a Cure?) — Stem-Cell Tourism and Lessons for Gene Editing, N Engl J Med 2016; 374:901-903 14. Clinicaltrials.gov 15. Salter, Brian, Zhou, Yinhua ,Datta, Saheli. Making Choices: Health Consumers, Regulation and the Global Stem Cell Therapy Market. BioDrugs (2014) 28:461–464 16. Hyun, Insoo (2013) Bioethics and the Future of Stem Cell Research, Print Cambridge University Press, pg.186-204 17. Murdoch, C.E. and Scott,

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Headline INTERNATIONAL: Coinrail hack underlines deterrents

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Headline INTERNATIONAL: NSA surveillance may undermine bitcoin

Fred Powledge

Climate change—fears of it; predictions about it; proposed reactions to it; and in some cases, denials of it—is a momentous issue for humanity, and it promises to become even more important. However, despite its importance—and mountains of scientific research on the topic—real progress by those with the means to address climate change has been slow in coming. The warming climate, with its accompanying intense weather, rising seas, and wrenching changes in agriculture, human health, and ecosystems in general, is not a recent discovery. Scientists and policymakers have been talking about it for decades. Climate scientists have produced reams of information about the change that is upon us—some showing that the shift is well under way, some offering ideas about how to cope with it by mitigating its effects or by adapting to it. Scientists are starting to develop the tools necessary to discover links between global change and specific local events, such as floods and droughts. Much of the US-based research is directed at people who make political decisions: members of Congress, the president, state legislators, municipal officials. But whereas the flow of information from scientists has been copious, the response from policymakers, including those at the topmost positions in government, has been minuscule. Interest in preparing for climate change seems to have been superseded by concerns about the economy. But the problems of a changed climate march on (see National Research Council definitions box), and at some point, policymakers will have to deal with them. As far back as 1978, Congress passed the National Climate Program Act in response to a need “to assist in the understanding and response to natural and man-induced climate processes and their implications.” The legislation stated that “Congress finds and declares” that “an ability to anticipate natural and man-induced changes in climate would contribute to the soundness of policy decisions in the public and private sectors,” and that “the United States lacks a well-defined and coordinated program in climate-related research, monitoring, assessment of effects, and information utilization.” Today, after dozens of data-heavy reports on climate change, bolstered by the work of the Intergovernmental Panel on Climate Change (IPCC), the crisis remains unaddressed, in large part because the issue has become a partisan arguing point—increasingly so as a presidential election looms. In April 2011, the House of Representatives considered action stating that “Congress accepts the scientific findings… that climate change is occurring, is caused largely by human activities, and poses significant risks for public health and welfare.” The national legislators voted the proposition down 240 to 184, largely along party lines. Scientists who study climate change, then, are left with the following question: How do we communicate in a meaningful way with policymakers? Climate change, in the United States and elsewhere, covers most areas of the human experience. A report from the US National Research Council lists the following areas of concern: changes in the climate system; sea-level rise and its effects on the coastal environment; freshwater resources; ecosystems, ecosystem services, and biodiversity; agriculture and aquaculture; public health; cities and the “built environment”; transportation systems; energy systems; solar radiation management; national and human security; and climate policy. First of all, says Pamela A. Matson, an interdisciplinary earth scientist at Stanford University, scientists should not tell policymakers what to do. Matson chaired one of four expert panels charged by the US National Academies in 2009 with studying climate change and recommending responses to it. The panels—Limiting the Magnitude of Future Climate Change, Adapting to the Impacts of Climate Change, Informing an Effective Response to Climate Change, and Advancing the Science of Climate Change—each produced extensive reports. Together, these reports and a summary volume form a solid tutorial on the challenges facing the nation (see For more information). Matson headed the Advancing the Science of Climate Change panel. “We can't do much about politics,” said Matson in an interview, “other than to keep reminding people that there is a huge amount of evidence about climate change, its causes, and the risks associated with it. Decisionmakers of all sorts will need to decide if they want to take the risks and expose future generations to even greater risks, but scientists can do our best to provide the best and most clear information about those risks and uncertainties. We can also help by providing viable options for reducing those risks—options that make sense from social, economic, technical, and environmental perspectives. The Advancing report calls for more research designed to develop such options and thus support decisionmakers who want to respond to the risks of climate change by limiting it and adapting to it.” In practically all of the heavyweight studies of climate change, including those in the National Academies quartet, the panelists assumed that the federal government is the logical leader in climate policymaking, if only because climate does not respect local boundaries (or international ones either). But there are scant signs of leadership from federal officials, and there is active opposition to any climate action (or even the notion that climate change exists) among some national legislators. Progress at the federal level, says Peter Raven, cochair of the National Academies panel Informing Decisions and Actions, is missing. His panel recommended that the federal government create “comprehensive, robust, and credible information systems to inform climate choices and evaluate their effectiveness.” “My impression,” said Raven recently, “is that it hasn't happened. The United States is the only nation in the world where serious doubt is expressed about the scientific conclusion that the climate is warming rapidly and that human beings are the principal underlying factor. That kind of anti-intellectualism can only hurt as we try to maintain our standing in science and technology against some very stiff competition internationally.” Robert Fri, visiting scholar at Resources for the Future, chaired the Limiting the Magnitude of Future Climate Change panel, which recommended “a framework of national goals and policies” to limit greenhouse gases. Asked about the report's reception, he replied, “Policy attention has been focused on the economy recently. Not much has happened on the climate front as a result.” So the search for leadership has turned elsewhere—to local, state, and regional governments and private organizations. Several states have undertaken serious studies of climate change problems, many of them as a result of gubernatorial executive orders issued a few years ago, when climate change was considered less controversial. Some went a step further and set up commissions to recommend legislative action. The results of those efforts have been mixed; the economic crisis has sapped much of the climate change energy of local, as well as national, politicians. Arizona's Policy on Climate Change, instituted on 2 February 2010, under Governor Jan Brewer, seeks to reduce greenhouse gas emissions “while maintaining Arizona's economic growth and competitiveness.” Yet in the same executive order that established the policy, Brewer pulled her state out of a promising regional effort, the Western Climate Initiative, to limit the gases. The 15-member commission created by Brewer's executive order included representatives of electric power, manufacturing, and mining companies, but no scientists. Arctic sea ice reaches its annual minimum in September. The satellite images above show September Arctic sea ice in 1979 (upper panel), the first year these data were available, and in 2007 (lower panel). Source: US Global Change Research Program (www.globalchange.gov). For a free download of the National Academies 2009 expert panel reports and a summary volume, among other reports on climate, go to www.nap.edu. A 1990 law created the National Climate Assessment, which evaluates federal global research programs. The most recent assessment was in 2009; to see an outline of the forthcoming 2013 report, visit http://globalchange.gov/what-we-do/assessment. Information on climate research may be found through the US Global Change Research Program Web site, at http://globalchange.gov/. The Pew Center on Global Climate Change publishes the “Climate Change 101” series, available at www.pewclimate.org/globalwarming-basics/climate_change_101. For detailed state reports on plans and recommendations for adaptation, see Massachusetts's at www.mass.gov/eea/docs/eea/energy/cca/eea-climate-adaptation-report.pdf. For a critical look at America's willingness to adapt to climate change, see Robert Repetto's 2008 report for the Yale School of Forestry and Environmental Studies at http://environment.yale.edu/publication-series/climate_change/5790. The Colorado Climate Project created a blue-ribbon action panel in 2007 that, a year later, produced 70 recommendations for reducing greenhouse gas emissions and preparing for the coming changes. The panel's efforts appear to have been received favorably by policymakers. Texas, beset by wildfires in 2011 that some experts linked to climate change, has no state adaptation plan, according to a survey by the Pew Center on Global Climate Change. Texas leads the states in carbon dioxide emissions. In Connecticut, the Governor's Steering Committee on Climate Change says that it is “working with stakeholders” and “assessing the impacts of climate change.” However, the committee's Web site devotes approximately half of its space to thanking the company that designed its logo. Massachusetts has made a more strenuous effort. In September 2011, the state sent a report to its legislature in which the expected impacts were analyzed and suggestions were made for reactions to them. The proof of the pudding in Massachusetts, as in the nation as a whole, lies in what happens after the recommendations go to the policymakers. In the Bay State, that would include the office of Frank I. Smizik, the chair of the House Committee on Climate Change. Smizik believes that climate change is going to affect “every corner of our lives,” is already creating problems, and is “one of the most complex and interrelated problems we face. And that makes it even more of a challenge to confront.” In an interview, the legislator praised the state's framework report both for its “long-term and far-reaching strategies” and for the “small, incremental improvements we can make at little or no cost. This aspect of the report makes the necessary task of climate adaptation seem more feasible.” Does this mean that Massachusetts's policymakers will rush to enact laws to deal with the well-documented menace? “Ideally, the need to adapt to climate change will be taken seriously, and these strategies will be swiftly transformed into reality in Massachusetts,” said Smizik. “Realistically, it won't be that easy. My job as the Chair of the House Committee on Global Warming and Climate Change is to advocate for the strategies that I think are not only most effective but also the most politically feasible at this time. I could see some of the more short-term, cost-effective strategies making progress in the State House as legislative packages. Meanwhile, some strategies will be directly implemented by state agencies. “I feel these issues are very pressing and they warrant our immediate attention. But… the legislating and governing process takes time, with good reason. The release of this adaptation report is an important step for our state, but it's hard to say how quickly or slowly these adaptation measures will become law. The economic climate is such that legislators are very focused on job creation and the like, and environmental issues are often pushed to the back burner in this situation.” The state of Washington is another place where policymakers take climate change seriously. Hedia Adelsman is the director of the state's Department of Ecology. Her predecessor in that job was Christine Gregoire, who went on to become the state's attorney general and then governor. Adelsman credits Gregoire with helping move climate awareness into action. Also, the University of Washington produced an exhaustive examination of climate change and ways to react to it that has served as a vital resource for legislators and other policymakers. Within 50–100 years, 2400 miles of major roadway are projected to be inundated by sea-level rise in the Gulf Coast region. The map shows roadways at risk in the event of a sea-level rise of about 4 feet, which is within the range of projections for this region in this century under medium- and high-emissions scenarios. In total, 24 percent of interstate highway miles and 28 percent of secondary road miles in the Gulf Coast region are at elevations below 4 feet. Source: US Global Change Research Program (www.globalchange.gov). Even though Washington is more environmentally conscious than most other states, economic troubles have hampered action on the climate front. “The conversation is not as active as it used to be,” said Adelsman in an interview, “[for] a couple of reasons: One of them—no surprise—is all the budget problems that the state is facing. And when you talk about the impact of climate change, people really see it as in the future. And right now we have all these urgent problems facing us. Some of the impacts that would be due to climate change… people don't see as something that's happening now. They see it as happening a little bit more in the future. So they feel like they can get back to it later… But the communication continues. “It all depends on how you describe it,” she said. “If you are describing the problem as a water-availability issue—if we are going to face a major issue with water available for irrigation; for municipal, for our fish, the salmon—you get people to listen. If you talk about it as global warming, it's immediately, ‘go away.’ “It's kind of sad to not call it by what it is, but it's much easier to communicate with the public and with the policymaker if you put it in these terms.” Some, including the authors of the National Research Council's panel Advancing the Science of Climate Change, think that a likely source of federal leadership can come, with a few modifications, from an existing organization: the US Global Change Research Program (USGCRP), which was created in 1989 as a presidential initiative by George H. W. Bush. USGCRP coordinates and integrates the global change work of 13 agencies, from the US Department of Agriculture to the US Department of Defense to the US Environmental Protection Agency and the Smithsonian Institution. Thomas Armstrong, of the White House Office of Science and Technology Policy, is USGCRP's executive director. In an interview, he said that he certainly agreed with the panels' findings. “But the real challenge comes not when you recommend strategic changes but when you get down to the nuts and bolts of implementing programs.” One potential obstacle, he said, could come if 13 agencies, which together receive $2.8 billion in global change research funds, are asked not only to funnel their work through a single office—his—but are made to redirect their agencies' funding as well. “If we were to take this level of enterprise and now say that it is no longer just coordinated but actually run out of my office, with all the resources coming to my office, that would be a big change in our collective way of doing to say the said is the 13 agencies, and the 13 are The of 13 them and a of leadership of this I would be that in their we would be the and of 13 federal who their research and to 13 agencies' In we would be the USGCRP out of what makes this program so the Science in climate information to policymakers. one is the climate change who can of all science in the of some is the of of scientific which scientists by their as does the in of such as very out of out of very than out of and so deal with communication such as these and many there has a of or for a can be government agencies, such as the that produced the state action or state such as Hedia in and federal such as the USGCRP they can be such as the regional Climate Science that were established in 2009 by the US Department of the The are by the US and by one or more significant of communication is by private and the Pew Center on Global Climate Change, which has been to and information on climate Climate an of and a for natural systems in the face of climate change.” The which a large of for for adaptation, dozens of studies from The appear to be some in scientific information into the of those who already want to it in their program director at the Climate for the part of a regional program run by the National and says that it that are more with decisionmakers much to the in of decisions that may be to scientific for something more to We certainly people who are out scientific information to make decisions that help them deal with of these decisions to the that has the region for years and are vital to policymakers who deal with water does a of its when public and private including a to a are also for scientific about adaptation and a then, is on the that climate change is important. are who for one or climate or climate change as something they really need to more about into their it's because a to attention to of the US Department of the have been under orders now to make climate change part of their it's because an like their is to the impacts of climate, and they want to more so they can to address this it's because an or government has a climate impact that them into The is an of as is in the United States and for how are projected to become more A so that it is years would other year or more by the of the century under the Source: US Global Change Research Program (www.globalchange.gov). But on many other the science of climate change has a much was one of states that active in the issue of climate change State and a the on Global Climate Change and it with the problems of global warming, as well as with into ways to the and with the potential of carbon The commission for years and up with the of that time, the legislature to the commission to its State who was cochair of the now says that the effort. in the way of the scientific evidence and any for doing about a she said in an “We a from the with the of so They all up and to recommend of We a very large and it was so it was to Even with she said, that make it out of her at the As the climate that are to Source: US Global Change Research Program (www.globalchange.gov). says that opposition to progress from and such as the and who of the US are major of and “It was she said. “I could get an passed that that our state the impact of climate change and make recommendations as to policy changes and other even any to deal with I that we would be that climate change is an issue in will see little to no to address climate change the leadership is in This is we are the most in the to sea-level she said. In the state is for and has also and said, “We are one of the of greenhouse at in the than many that the state has to a of and has its carbon The for those measures was For climate change legislation to on its she said, “I we will need federal

Jeff Greene, Dennis Purcell, Brian Edelman, Doug Giordano · 9 authors

In a roundtable published in this journal a year ago, there was a clear consensus that the R&D function in big pharma was inefficient and in need of major restructuring, possibly through increased investments by venture capital and private equity firms. In this discussion, an accomplished group of industry practitioners begins by looking at the prospects for both venture capital and private equity to play meaningful roles in financing early‐ and mid‐stage drug development. In so doing, they explore questions like the following: Are there ways for big pharma and biotech to reduce “science risk” and make R&D funding more profitable and attractive to venture capital and private equity—and perhaps even hedge funds? What roles do you see for specialty PE firms like Symphony Capital and Paul Capital, which are now bundling mid‐stage development assets and securitizing royalties? Then the panelists turn to the broader life sciences industry and consider the outlook for leveraged private equity transactions involving marketed products, late‐stage development, and services. Here they consider issues like the following: Will PE be attracted to less‐R&D‐intensive activities like medtech and generics? Have the recent consolidation through mergers and reorganization of big pharma into decentralized business units created opportunities for carve‐outs of certain businesses? For big pharma and life sciences companies in general, the answers to such questions point to greater specialization and focus achieved partly through strategic alliances with venture capital, private equity, and even hedge funds, and involving marketed products and services as well as early‐stage drug development.

Carrie Printz

Many cancer centers reach out to their elected officials by meeting with them on Capitol Hill and inviting them to tour their institutions. But few go as far as the Ohio State University Comprehensive Cancer Center (OSUCCC). At this National Cancer Institute-designated center based in Columbus, Ohio, elected officials and their staffs take on the roles of patients, researchers, or healthcare providers to gain a more personalized understanding of the importance of translational research and its impact on patient care. “At the end of their visit, we have roundtable discussions, and the feedback is always, ‘we never knew how complex cancer care and research is’,” says Jennifer Carlson, director of government relations for OSUCCC. As further proof of the program's success, legislators discussing cancer-related legislation at government hearings have referred to their participation in Project Cancer Education and the knowledge they gained from it, Carlson notes. “This hands-on program literally takes policymakers from the bench to the bedside and helps them understand some of the challenges we face,” she says, adding that it also helps illustrate some of the lost opportunities that can occur with lack of government investment or support of medical research and care. Because Project Cancer Education has been so successful in Ohio, OSUCCC Director Michael Caligiuri, MD, who was recently elected president of the Association of American Cancer Institutes (AACI), proposed making it available to member centers across the country. The program is “the cornerstone of our advocacy efforts this year,” he notes. “We have had amazing success in seeing important anticancer legislation move forward in Ohio because of the impact Project Cancer Education has had on our elected officials,” Dr. Caligiuri says. “We are asking the community of American cancer centers through the AACI to implement this best practice at their centers because it will help to justify the greater investment in cancer research and make our elected officials and staff aware of why our cause is such an urgent one.” Participants in Project Cancer Education learn about the challenges of cancer care through role-playing scenarios. Carlson is chairing the committee within the AACI that is developing a toolkit based on her center's existing collateral materials for all member centers to refine and adopt to fit their specific needs. They plan to have the materials available this spring. Additionally, they are working with the National Cancer Institute to roll out a similar program for congressional committee staffers who are based in Washington, DC. The toolkits will include different “tracks,” such as a patient scenario or a researcher scenario. The program can range from 2 hours, geared mainly toward the elected officials, to a half-day or full day, which is designed for their staff members. Participants also receive graduation certificates and pose for a photograph, which is later E-mailed to them to reinforce the program's messages. The program that supported your research has been eliminated because of federal budget cuts. Your second- and third-year budgets have been zeroed out. The institutional review board determined that you did not plan to have enough research nurses for your proposed phase 1 study. Wait 6 months and try again. Due to cuts in federal funding line for your grant, your budget has been reduced by 30% for the next 3 years. Visits to cancer care and research facilities allow participants to see the intricacies of discovery and treatment firsthand. Participants encounter positive results too, such as, “The drug you developed is ready to come to market and is expected to bring in large profits to the university during its patent lifetime. The new science building on campus will be named in your honor.” In the patient scenario, some of the challenges participants learn about are lack of insurance coverage for clinical-trial patient-care costs, the importance of proper insurance authorization for specific treatments, and the intensive recovery that occurs with an allogeneic marrow transplant for acute myeloid leukemia. In some cases, policymakers get a chance to talk with patients participating in clinical trials who are living proof of research's value, Carlson notes. She is confident that cancer centers across the country will find the program beneficial. “By partnering with our elected officials, we can take cancer care to the next level,” she says. The Ohio legislative cancer education program, Project Cancer Education, is set to roll out nationwide. The program gives elected officials a chance to walk in the shoes of researchers and patients. Legislators and their staffs experience firsthand the challenges faced by cancer centers. Cancer centers will receive toolkits from AACI to help tailor their own programs.

Judy Lewent, Joe Fuller, David Scharfstein, Rick Passov · 9 authors

In light of the challenges facing the pharmaceutical industry, a distinguished group of pharma executives and strategic and financial advisers discusses the following corporate decisions: Strategy : What business model is most likely to maximize long‐term shareholder value? For example, is diversification by big pharma into areas like consumer healthcare and generics a reliable way to create sustainable value? Capital allocation : What are the best methods for evaluating investments in pharma R&D, and for deciding which programs should be terminated and which assets divested? If conventional DCF isn't much help in a world where R&D outcomes are so uncertain, what about proposed models like real options? Corporate governance and incentive systems : Should big pharma continue to outsource ever more of its R&D functions to biotech and venture capital? Or can it overcome the problems associated with size by creating more decentralized business units and trying to replicate the accountability and incentives of smaller biotech firms? Capital structure and payout policy : Are the large cash and equity positions and minimal payouts of big pharma, typically justified as cushioning the uncertainties associated with pharma R&D, likely to be the value‐maximizing capital structure in the future? With many biotechs struggling and venture capital scarce, where are the new sources of capital for the industry? And can future deals be structured in ways that help bring about higher returns for big pharma as well as the R&D providers? Disclosure : What should management tell investors to help ensure that their companies' policies and promising investments are reflected in their stock prices?

Thomas R. Webb

The current dogma of cancer research is that the accumulation of gene mutations in a single cell is responsible for the development and progression of human cancers. “Almost everybody believes that cancer requires certain gene mutations,” noted Christoph Lengauer, Ph.D., associate professor of oncology at Johns Hopkins University, Baltimore. “Several genes have to be affected in order to generate cancer, and genetic instability [caused by gene mutations] allows for the accumulation of [these] mistakes.” But this theory is open to debate. Robert Weinberg, Ph.D., professor of cancer research at the Massachusetts Institute of Technology, Cambridge, agrees with Lengauer and believes that tumor cells arise from disruptions in critical signaling pathways as a result of mutations in various oncogenes and tumor suppressor genes. However, Peter Duesberg, Ph.D., professor of molecular and cellular biology at the University of California at Berkeley, believes that aneuploidy, an abnormal number or complement of chromosomes, is the critical mutation responsible for all solid human cancers, independent of specific gene mutations. Both theories have plenty of research—and unanswered questions—behind them. As codiscoverer of viral oncogenes in the 1970s, Duesberg spent 10 years testing the hypothesis that cellular oncogenes cause cancer, but was unsuccessful. “I had my own interests at stake,” said Duesberg. “I realized that the fundamental difference that set apart human oncogenes from viral oncogenes was that viral oncogenes have very strong promoters and express [the gene product] 1000-fold higher. We cannot find such a dominant human oncogene.” Because of this, he criticizes the widespread use of viral promoters in already aneuploid cells, such as NIH3T3, to prove that an oncogene causes cancer. Duesberg began to explore alternative cancer theories. “All of a sudden you see a forest when you were looking for trees,” said Duesberg on aneuploidy, predicted to be the cause of cancer almost a century ago. “Aneuploidy is a very solid correlation.” It is present in nearly all nonviral, solid cancers, and it explains the growing list of nonmutagenic carcinogens and why human oncogenes cannot turn human cells into cancer cells. In addition, “aneuploidy changes thousands of cellular pathways,” he noted, explaining the unique properties of cancer cells. He said he believes that aneuploidy is the only somatic mutation that explains all of the characteristics of a cancer cell. William Brinkley, Ph.D., vice president and dean of Baylor College of Medicine, Houston, is also examining the relationship between aneuploidy and cancer. “My view is that aneuploidy is an essential mutation for transformation to malignancy. Aneuploidy is brought about by defects in the mitotic apparatus that result in cell progeny with chromosomal imbalance. Therefore, a defective mitosis leading to aneuploidy is a decisive event in the initiation of genomic instability, a complex process that results largely in cell death but also favors selective clonal outgrowth of tumor cells.” However, Brinkley believes that aneuploidy “must be preceded by additional mutations or altered gene expression that results in defective mitosis.” He is examining the role of a specific mitosis gene that he believes is involved in this process. Duesberg believes that carcinogens generate defects in the mitotic apparatus by directly targeting the spindle apparatus or fragmenting the chromosomes. In addition to causing cancer, Duesberg predicts that aneuploidy, by reassortment of the chromosomes, is responsible for tumor recurrence and multidrug resistance observed in cancer patients. “Most people believe that aneuploidy is important for cancer development,” said Lengauer, who supports Duesberg’s work. “But [Duesberg] goes a little too far in his belief that cancer can occur independent of gene mutations.” Lengauer agrees that carcinogens may be able to induce aneuploidy in the absence of gene mutations, but he does not believe that this by itself can cause cancer. Weinberg believes that aneuploidy is only a consequence of the cancer process, and may not even be a requirement. “Over the last 25 years, no one had ever succeeded in taking a normal human cell and transforming it into a tumor cell through the introduction of mutant genes,” said Weinberg. However, Weinberg and colleagues did just that. In Nature last year, they described the first genetically defined human tumor cells, by adding three mutant genes to two normal human cell lines, embryonic kidney and fibroblasts. In this study, four cellular pathways were important. An oncoprotein of SV40 virus (large T antigen) simultaneously knocked out two tumor suppressor proteins, p53 and Rb. “And both of them must be inactivated, we believe, in order to create a human tumor cell. At the same time, hTERT [telomerase] must be upregulated [to enable cells to grow indefinitely], and finally the mitogenic growth-promoting pathway indicated by ras must also be upregulated.” The resulting cells were anaplastic, highly angiogenic, minimally invasive, and nonmetastatic. “They set the stage for the long process of trying to relate the genes that are damaged in a human genome with the complex behavioral phenotype of the cancer cell,” noted Weinberg. “Of course, there’s much that lies ahead because the genes that we’ve introduced are hardly representative of those that are found mutated in spontaneously arising human tumors.” In response to Weinberg’s publication, Duesberg analyzed the cells and published his observations in Proceedings of the National Academy of Sciences, arguing that what was important about the tumor cells was their aneuploidy, not the introduced genes. “And in fact,” noted Weinberg, “he argued that this was a troubled hypothesis [gene mutation], and these genes were really an epiphenomenon of the whole process of cancer formation, rather than being at the center of the process.” Weinberg recently had the cells re-examined at the National Cancer Institute, and mentioned that one of the cell lines was found to be diploid, in complete contradiction to Duesberg’s observation. Weinberg believes this is proof that “aneuploidy is not an essential prerequisite to the creation of a transformed human malignant cell.” “If present at the scene of a crime, you are a suspect. If not present, you are excused,” noted Duesberg, an analogy to the observation that “not one gene [mutation] has been identified that is consistently found in a highly specific cancer.” Weinberg and others believe that many of the identified oncogenes/tumor suppressor genes lie in the same critical pathways that need to be disrupted for cancer development. Lengauer pointed out that 88% of nonhereditary colon cancers have a mutation in the APC gene, and a nonoverlapping 10% have a mutated β-catenin gene. Both of these genes lie in the same cellular pathway. But can gene mutations and aneuploidy really work independently to cause cancer? Can they work together? “Currently, I believe both may be involved in some cancers,” said Baylor College of Medicine’s Brinkley. “Carcinogens that are mutagens may target oncogenes that ultimately destabilize mitosis, setting conditions for errors that lead to aneuploidy. In the case of nongenotoxic carcinogens such as asbestos, aneuploidy appears to be sufficient to cause cancer. The fact that non-mutagenic agents can cause cancer, and the fact that it has been impossible to isolate cellular genes from cancer cells that transform normal human cells, leads me to seriously question whether gene mutation alone (without aneuploidy) can cause cancer.” Dr. Robert Weinberg Dr. Peter Duesberg The photos above show the 46 chromosomes (plus x and y) from a normal diploid cell (left) and the chromosomes from a cancer cell that exhibits aneuploidy—it has 85 chromosomes.