Scientists Identify Gene Essential for Nerve Regeneration. By Daniel Gorelick
Findings point to new mechanism for repairing damaged nerves
america.gov, January 27, 2009
Washington — Scientists have identified a gene required to repair severed nerve cells — a finding that could one day be used in the development of treatments for spinal cord injuries, according to a report published January 22 in the journal Science.
“We discovered a molecular target for a future drug that could vastly improve the ability of a neuron to regenerate after injury,” said Michael Bastiani, the University of Utah scientist who led the research team.
Each year, between 10 and 83 people out of every million people worldwide suffer a spinal cord injury, according to a 2006 study in the journal Spinal Cord. One-third of those injured become paralyzed in all four limbs. Complications from spinal cord injuries include urinary tract infections, depression, pneumonia and renal failure. The estimated lifetime costs are between $1 million and $3 million per injury, depending on the extent of the injury and the age at which it occurs, according to the Christopher Reeve Foundation, a nonprofit organization dedicated to curing spinal cord injuries.
The gene identified in the study, dlk-1, is unique because it is not required for normal growth in embryos, yet it is “absolutely required for regeneration” after injury, Bastiani said. “Most of us believed that virtually everything we found in regeneration also would be involved in development, so it is surprising.”
When the dlk-1 gene was mutated, neurons failed to regrow after injury. When scientists artificially activated dlk-1, regrowth was accelerated.
The study was performed using the nematode worm C. elegans, many of whose neurons are able to regenerate after injury. Many of the genes important for the function of the nervous system in worms, including dlk-1, are also present in humans.
SCREENING FOR REGENERATION
Although worms and humans seem worlds apart, the worm is an ideal tool to identify genes important for neuron regeneration, according to lead author Marc Hammarlund, assistant professor at Yale University School of Medicine.
The C. elegans worm is tiny and transparent, enabling scientists to watch its development unfold cell by cell from embryo to adult, a discovery that led to the Nobel Prize in medicine in 2002. The worm’s tiny size and completely sequenced genome make it amenable to genetic screens, a technique where researchers mutate thousands of genes to identify those few involved in a particular physiological function.
Hammarlund and colleagues used worms genetically engineered to contain a population of glowing green neurons, making them easy to distinguish under the microscope. (See “Four Americans Share in Nobel Science Prizes.”)
Researchers then mutated the beta-spectrin gene. Neurons in these mutants are damaged by the mechanical strain of normal movement. Unlike in mammals, worm neurons can regenerate, so as the worms move their neurons are cycling between damage and regrowth. Using a technique called RNA interference, Hammarlund interfered with the function of more than 5,000 genes individually and examined whether regeneration was impaired.
The dlk-1 gene stood out because when it was mutated, the neuron regeneration decreased dramatically, Hammarlund said. He then took normal worms and used a laser to severe nerve cells; when dlk-1 was over-activated, the severed neurons regrew faster than normal.
Hammarlund told America.gov that more than 60 genes were identified in the screen and could play a role in regeneration. The dlk-1 gene is, thus far, the best understood, but Lebanese postdoctoral fellow Rachid El Bejjani is now studying the other genes identified in the screen.
FUTURE GROWTH
The link between dlk-1 and nerve regeneration in worms prompts many questions as scientists look to translate their findings to humans.
The function of dlk-1 in normal, adult neurons is not known, Hammarlund said. He was surprised to discover that although dlk-1 is required for the regrowth of damaged neurons, it is not required for the initial growth of neurons in embryos.
In humans, damaged cells in the peripheral nervous system regrow far better than those in the central nervous system. It is not clear why, but it is possible that dlk-1 is preferentially active in the periphery, a question that scientists now will examine, according to Hammarlund. Also not known is whether dlk-1 can spur regrowth of neurons regardless of the damage — it may turn out that dlk-1 is more effective at repairing neurons damaged by trauma than those damaged by a stroke.
One caution is that dlk-1 needs to be activated at the time of injury — activation even two hours after neurons were cut with a laser failed to bring forth robust regrowth. Hammarlund acknowledges that this narrow window is a barrier to treating traumatic nerve damage in humans, but is confident that eventually “we’ll get there.”
“In the future, we would like to develop drugs that could activate this chain of molecular events in nerve cells and stimulate regeneration of diseased and injured nerve cells,” said Erik Jorgenson, a coauthor of the study and scientific director of the Brain Institute at the University of Utah. “At this point, we can’t do that. But this study gives us hope that in the future, we will have a rational approach for stimulating regeneration.”
Showing posts with label science. Show all posts
Showing posts with label science. Show all posts
Wednesday, January 28, 2009
Sunday, January 25, 2009
Medicine's Miracle Man
Medicine's Miracle Man. By John E. Calfee
Maurice Hilleman's remarkable period of industrial scientific research yielded the most cost-effective medicines ever made.
The American, Friday, January 23, 2009
The pharmaceutical industry has been under attack for longer than most people realize. In the 1950s and 1960s, when for the first time in history we had quite a few drugs that worked very well—including many antibiotics, the first miracle drugs—there was the full panoply of congressional hearings, outraged newspaper editorials, and dour experts who described an industry in which prices were too high, marketing too important, and innovation in decline amid a flood of “me-too” drugs barely distinguishable from the original innovative brands. But I doubt that the atmosphere then was as hostile as it has been in the past five years or so. A flood of books, including some by authors with academic credentials, have re-circulated many of the same arguments (albeit with more emphasis on safety). The more scholarly works include Merrill Goozner’s The $800 Million Pill: The Truth Behind the Cost of New Drugs; Jerome Kassirer’s On The Take: How Medicine’s Complicity with Big Business Can Endanger Your Health; and Jerry Avorn’s Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs. Others have a more muckrakian tone, beginning with the muchquoted The Truth About the Drug Companies by former New England Journal of Medicine editor Marcia Angell, and continuing on to many others including Ray Moynihan and Alan Cassels’s Selling Sickness: How the World’s Biggest Pharmaceutical Companies Are Turning Us All Into Patients; Howard Brody’s Hooked: Ethics, the Medical Professions, and the Pharmaceutical Industry; Alison Bass’s Side-effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial (about the drug Paxil); and Philip R. Lee’s Pills, Profits, and Politics.
What’s with R&D?
To my mind, the most serious of these indictments focus on industry research. No doubt, the stakes are high for the industry. If drugs are truly innovative life-modifiers or life-savers, the argument over prices and spending tends to be marginalized. But if there hasn’t been a lot of innovation and if the innovation we do get comes mainly from the taxpayer-supported National Institutes of Health and other nonprofit organizations, the politics of drugs becomes difficult for the industry to handle.
We need to look ahead, and when we do it’s hard not to get excited. The entire field of immunology has taken off along with so much else in this age of biotechnology.
I have had occasion to write about innovation and its sources in the pages of The American. As I explained in “The Golden Age of Medical Innovation” (March/April 2007), the critics have paid too much attention to the annual count of new drug approvals by the FDA and too little attention to two crucial developments. One is the increasing importance of research that occurs after a drug is approved. Newer drugs, especially so-called biotech drugs including monoclonal antibodies, involve complex biological processes that are themselves subject to ever more sophisticated research on everything from DNA to drug interactions. Basic research and clinical trials have been running side by side, often with drugs themselves serving as research tools to find out what happens when a particular receptor is suppressed (such as the epidermal growth factor receptor, or EGFR, to cite a target that is important for cancer and much more). Sometimes, scientists harvest a series of improved treatments using existing drugs without actually getting a new one approved. Rituxan, originally approved for certain types of non-Hodgkin’s lymphoma cancer, is now approved for other types of cancer along with multiple sclerosis, rheumatoid arthritis, and Crohn’s Disease, and is being researched to treat lupus, idiopathic thrombocytopenia purpura, and chronic lymphocytic leukemia.
The other phenomenon that has been largely lost in popular discussion of drug R&D and its discontents is the extraordinary role played by “follow-on” drugs (a much more accurate term than “me-too”). The story with statin cholesterol-reducing drugs, where a decade or more of research on follow-ons revolutionized the prevention and treatment of coronary heart disease, is a familiar one. Similar stories are playing out now, but much faster. Competition among rapidly developed drugs to attack a promising target (such as tumor necrosis factor inhibitors for rheumatoid arthritis) can bring about revolutions in treatments as doctors and patients dance through one drug after another while dealing with the unique mix of side effects and drug resistance that plague each individual patient.
The interested reader can get a flavor of this blend of basic science and practical drug development by reading the fascinating discussion by Jan Vermorken, et al., of evolving treatments for head-and-neck cancer in the September 11, 2008 issue of The New England Journal of Medicine. Much of this story involves Erbitux, the monoclonal antibody that put Martha Stewart in jail after a disappointing FDA decision put the owners of ImClone, the developer, into a panic. The many years of up-and-down research and results on that drug, costing hundreds of millions or even billions of dollars back when no revenues were in sight, is probably as good an example as any of the vagaries and payoffs from high-risk drug research informed by ongoing work in pure science.
Hilleman set out to develop vaccines for the chief life-threatening viral and bacterial infectious diseases of childhood. Amazingly, he came close to clearing the table.
In another recent article in The American, I addressed the thorny question of the role of publicly supported basic research in drug development (“The Indispensable Industry,” May/June 2008). To put it in the simplest terms, a close look reveals a striking pattern that seems to be little noticed by the critics of private drug development: no matter how far-flung the curiosity-driven NIH-supported research is, the only results that seem to get translated into useable drugs are the ones that are grabbed by drug firms and put through the difficult research necessary to produce appropriate quantities of promising substances to run through years of arduous clinical trials. Take away the private sector, and basic research nearly always languishes with little practical effect, as is unceasingly and tragically illustrated by the dearth of new drugs and vaccines for malaria and tuberculosis. Sometimes, the drug firms themselves do perform crucial basic research, as in the case of Genentech’s Avastin for cancer and Lucentis to prevent blindness. These were the fruits of the firm’s own top-tier basic research forces.
Just Two Words
But there is something else in drug development that hardly gets talked about: the sheer energy and determination that you find in the private sector. Combine that with substantial financial resources and you get what John Maynard Keynes called “animal spirits,” a singular motivating force in creative capitalism. When this force attacks big problems, the results can be both spectacular and unexpected, sometimes with fabulous benefits for mankind. It so happens that animal spirits are very much involved in one of the great blessings of modern medicine: an armamentarium of vaccines, mainly given to children, which have been saving lives by the millions at astonishingly low costs. “The most cost-effective treatments ever created by mankind” is a typical summary of the value of vaccines for mumps, measles, rubella (German measles), and half a dozen or so others, including those for diphtheria, whooping cough, hepatitis A, and hepatitis B.
Where, you might ask, did all those life-saving vaccines come from? Amazingly, for half or more of them, the answer can be summarized in two words: Hilleman and Merck. You’ve likely never heard of Maurice Hilleman even though he probably saved more lives than any other scientist in the 20th century. For most of his career, Hilleman was a biologist at Merck, where he developed one vaccine after another, stretching through four extraordinary decades of productive work. Along the way, he pioneered new ways to create, test, and manufacture vaccines, and played a crucial role in the creation of an entirely different class of drugs known as interferons.
We know a lot about Hilleman’s career thanks to a wonderful book published last year by Paul Offit: Vaccinated: One Man’s Quest to Defeat the World’s Deadliest Diseases. Offit was the perfect vehicle for getting this story the attention it deserves. A prominent academic immunologist at Children’s Hospital of Philadelphia and the University of Pennsylvania Medical School, Offit is also a vaccine developer. He is a co-inventor and co-developer of Rotateq, the first fully successful vaccine for rotavirus, a cause of deadly dehydration that kills thousands of children annually in poor nations.
Offit is attuned to public policy. He has been a member of the Advisory Committee on Immunization Practices, whose child vaccination recommendations are gospel for physicians and payers. His previous book, The Cutter Incident, was an insightful historical account of how litigation over an early miracle vaccine—for polio—helped shape (very much for the worse) the entire litigation environment of vaccines and pharmaceuticals. Offit’s academic journal articles and newspaper op-eds on the consequences of unscientific attacks on vaccine safety are required reading for anyone interested in this contentious topic.
Offit’s Vaccinated is informed by 11 interviews with the 85-year-old Hilleman in 2005, during the last months of his life before he succumbed to cancer. Judging by dozens of meaty quotes, Offit is a probing interviewer, capturing a great scientist’s personality and working style to a degree that cannot be matched without personal experience with the subject, and is seldom matched even then.
His basic strategy was simple: solve whatever problems had to be solved in order to reach the goal, which was usually a new vaccine.
Who was Maurice Hilleman and what did he do? Born to a German-American family in 1919 and raised on a Montana farm near his birthplace, Hilleman was a brilliant student on scholarship at Montana State University. After graduation he moved to the Midwest intellectual mecca at the University of Chicago, where in 1944 he finished a Ph.D. in microbiology based on groundbreaking research on the chlamydia bacterium (previously thought to be a virus). To the dismay of his new intellectual peers, Hilleman left academia to work for a pharmaceutical firm, E.R. Squibb, where he achieved advances in flu vaccine development and manufacturing. In 1948, he moved to the Walter Reed military hospital in Washington. His work there culminated in an extraordinary episode in 1957 when he correctly forecast the arrival of a new Asian Flu to which almost no one was immune. He led the development and manufacturing (by private firms) of a vaccine in time to save hundreds of thousands of lives and perhaps many more.
In 1957 Hilleman returned to the private sector, this time at Merck, where he was head of virus and cell biology in Merck’s relatively new vaccine enterprise. Hilleman apparently set out to develop vaccines for the chief life-threatening viral and bacterial infectious diseases of childhood. Amazingly, he came close to clearing the table. First was the mumps, with the approval in 1967 of the “Jeryl Lynn” vaccine based on a mumps virus taken from his daughter of that same name. A measles vaccine arrived the next year. In 1969, we got a vaccine for rubella. Hilleman soon concocted the immensely useful idea of combining these three vaccines into a single shot. Approved in 1971, this proved a blessing to untold millions of small children and their mothers. The 1981 vaccine for hepatitis B (not really a childhood disease, of course) was a scientific and technological tour de force essentially from start to finish. In 1995 came the hepatitis A vaccine. For chicken pox, pneumococcus, and Hib (haemophilus influenzae type b), Hilleman transformed relatively untested vaccines into the mass-produced tools with which we are now familiar. It is hard to imagine the cumulative benefits of this research. (Hilleman also developed a vaccine for a destructive form of chicken cancer, rescuing a substantial part of the poultry industry.) Hilleman’s work sometimes ranged beyond vaccines. Starting in the late 1950s, he figured out how to mass-produce a newly discovered virus-killing substance in chickens called interferon. He soon detailed interferon’s basic physical, chemical, and biological properties, discovering that it was produced in many animals, including humans, and that it could impede or kill many viruses, such as those involved in cancer. He correctly predicted that interferon could be used to treat chronic infections and cancer. Today, it is used against hepatitis B, hepatitis C, and several types of cancer.
Problem Solving for Fun and Profit
This is more than the history of medicine, science, and technology. It is also business history, a classic story of problem solving for fun and profit and humanity. How was Hilleman able to accomplish so much in basic research, drug development, and manufacturing technology, often working essentially from scratch because vaccine development was still in its infancy when he set to work? The answer lies in Hilleman’s decision to work at Merck instead of pursuing a top-tier academic career. He realized that to attack the most pressing illnesses susceptible to immune-based prevention, he would have to marshal massive forces even after solving the purely intellectual puzzles. Merck had supported that kind of work before in Max Tishler’s research on the vitamin B complex. Offit tells us relatively little about internal Merck affairs, but it is clear that Hilleman enjoyed an extraordinary degree of autonomy combined with generous funding increases for low-profit products (now there’s a combination we’d all like to have!).
The Nobel Prize committee was not willing to award a prize to an industry scientist. It is hard not to see this as a miscarriage of scientific justice.
Hilleman sometimes exercised an iron fist over such normally mundane matters as manufacturing, where any deviation from his recipe could result in undetectable dangers. Indeed, Hilleman was apparently a bit of a tyrant, demanding almost as much of his staff as of himself, facilitated by his mastery of the art of profanity. Nonetheless, he retained the respect and often the devotion of his hard-driven staff along with near-legendary status among his academic peers.
In 1984, when Hilleman reached Merck’s mandatory retirement age of 65, he refused to retire and Merck kept him on. One result was the hepatitis A virus vaccine that arrived in 1995, along with a steady stream of academic work of all sorts until shortly before his death in 2005. Hilleman never jettisoned the problem solving method of a successful Montana farmer. Like Orville and Wilbur Wright when they built the first successful heavier-than-air flying machine, Hilleman’s basic strategy was simple: solve whatever problems had to be solved in order to reach the goal, which was usually a new vaccine. The list of problems included daunting scientific puzzles, excruciating judgments about whether dangerous side effects had been defeated, and the vagaries of regulation (much easier before the FDA got into the action).
As the 80-plus-year-old Hilleman approached death, Offit and other academic scientists lobbied the Nobel committee to award Hilleman the Nobel Prize for Medicine, based partly on his vaccine work and partly on his contributions to the basic science of interferons. The committee made clear that it was not going to award the prize to an industry scientist. (Offit has assured me that the situation was even more hopeless than he describes in his book.) It is hard not to see this as a miscarriage of scientific justice. Perhaps Hilleman would have done better if his volcanic personality had not included a surprising element of self-effacement. None of the vaccines or the crucial agents or processes he created were named after himself. At one point, he even called the developer of a new rubella vaccine to say that he thought it should replace his own because it was better. Hilleman’s absence from the academic and public spotlight was quite extraordinary. In one of the most striking of the dozens of anecdotes told by Offit, Hilleman’s death was announced to a meeting of prominent public health officials, epidemiologists, and clinicians gathered to celebrate the 50th anniversary of the Salk polio vaccine. Not one of them recognized Hilleman’s name!
Next…
Thanks to Offit and his book, Hilleman’s light and the extraordinary research achieved by the Merck company will shine for many, many years. What about vaccine research itself? There have been formidable obstacles. One was the liability system, which in the 1980s nearly killed off the child vaccine market before Congress removed child vaccines from the liability system altogether. Another, more persistent problem has been low reimbursement rates, especially by government, for traditional child vaccines (including most of Hilleman’s crop). This can discourage new research and production, and cause shortages. The situation was sufficiently worrisome to trigger a 2003 report by the federally sponsored Institute of Medicine entitled “Financing Vaccines in the 21st Century: Assuring Access and Availability.” Reimbursement seems to have improved recently. Better yet, newer vaccines are sufficiently protected by patents so that prices are set through ordinary market forces rather than government fiat. Merck and its competitors, such as GlaxoSmithKline and Sanofi-Aventis plus smaller firms, have developed a series of important new vaccines—notable among them are the pneumococcal vaccine, a vaccine for the human papilloma virus (which causes cervical cancer), and two rotavirus vaccines (including the one co-invented by Offit). Traditional vaccine research is now flourishing but will probably never again be dominated by a single person’s laboratory like the one run by Hilleman in his prime.
Hilleman was apparently a bit of a tyrant, demanding almost as much of his staff as of himself, facilitated by his mastery of the art of profanity.
But we need to look ahead, and when we do it’s hard not to get excited. The entire field of immunology—roughly speaking, the harnessing of the human immune system to fight disease—has taken off along with so much else in this age of biotechnology. We are discovering faster and more efficient ways to manufacture traditional vaccines (especially for the flu), better methods for identifying newly arrived infectious agents such as avian flu (the dreaded “bird flu” that could cause an epidemic on the scale of the one in 1918 that killed millions worldwide), and new techniques for developing vaccines once their targets have been identified.
And there is the extraordinary prospect of therapeutic vaccines, i.e., vaccines that harness the immune system to attack illnesses already present in the body rather than just preparing the body to reject infections that have not yet been encountered. None has been approved, but a brain cancer vaccine from the biotech firm Dendreon received a favorable rating from an FDA advisory committee and may yet gain approval from the FDA (despite its reluctance to approve highly innovative drugs in this era of attacks on it for paying too much attention to new benefits and too little attention to safety). Alzheimer’s Disease vaccines have achieved striking results against the beta-amyloid plaques typically found in the brains of Alzheimer’s patients. Other therapeutic vaccines are in various stages of testing.
It’s about time for the biotech revolution to hit the vaccine industry in a big way. It has already upended the treatment of rheumatoid arthritis and a few cancers, and is starting to do the same for multiple sclerosis and other conditions including rare diseases like psoriasis. Now let us see what happens in this once-quiet corner of the biopharmaceutical market. As Hilleman’s career demonstrates, when industrial science is harnessed to the profit motive, enormous advances in human welfare are possible.
John E. Calfee is a resident fellow at the American Enterprise Institute, which is about to publish a new book on recent developments in the vaccine market, U.S. Vaccine Markets: Overview, Case Studies, and Comparisons with Pharmaceuticals and Other Biologics, by economists Ernest Berndt, Rena N. Denoncourt, and Anjli C. Warner of MIT. It provides the best summary yet published of vaccine development in the past two decades, along with a preview of what is on the way.
Maurice Hilleman's remarkable period of industrial scientific research yielded the most cost-effective medicines ever made.
The American, Friday, January 23, 2009
The pharmaceutical industry has been under attack for longer than most people realize. In the 1950s and 1960s, when for the first time in history we had quite a few drugs that worked very well—including many antibiotics, the first miracle drugs—there was the full panoply of congressional hearings, outraged newspaper editorials, and dour experts who described an industry in which prices were too high, marketing too important, and innovation in decline amid a flood of “me-too” drugs barely distinguishable from the original innovative brands. But I doubt that the atmosphere then was as hostile as it has been in the past five years or so. A flood of books, including some by authors with academic credentials, have re-circulated many of the same arguments (albeit with more emphasis on safety). The more scholarly works include Merrill Goozner’s The $800 Million Pill: The Truth Behind the Cost of New Drugs; Jerome Kassirer’s On The Take: How Medicine’s Complicity with Big Business Can Endanger Your Health; and Jerry Avorn’s Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs. Others have a more muckrakian tone, beginning with the muchquoted The Truth About the Drug Companies by former New England Journal of Medicine editor Marcia Angell, and continuing on to many others including Ray Moynihan and Alan Cassels’s Selling Sickness: How the World’s Biggest Pharmaceutical Companies Are Turning Us All Into Patients; Howard Brody’s Hooked: Ethics, the Medical Professions, and the Pharmaceutical Industry; Alison Bass’s Side-effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial (about the drug Paxil); and Philip R. Lee’s Pills, Profits, and Politics.
What’s with R&D?
To my mind, the most serious of these indictments focus on industry research. No doubt, the stakes are high for the industry. If drugs are truly innovative life-modifiers or life-savers, the argument over prices and spending tends to be marginalized. But if there hasn’t been a lot of innovation and if the innovation we do get comes mainly from the taxpayer-supported National Institutes of Health and other nonprofit organizations, the politics of drugs becomes difficult for the industry to handle.
We need to look ahead, and when we do it’s hard not to get excited. The entire field of immunology has taken off along with so much else in this age of biotechnology.
I have had occasion to write about innovation and its sources in the pages of The American. As I explained in “The Golden Age of Medical Innovation” (March/April 2007), the critics have paid too much attention to the annual count of new drug approvals by the FDA and too little attention to two crucial developments. One is the increasing importance of research that occurs after a drug is approved. Newer drugs, especially so-called biotech drugs including monoclonal antibodies, involve complex biological processes that are themselves subject to ever more sophisticated research on everything from DNA to drug interactions. Basic research and clinical trials have been running side by side, often with drugs themselves serving as research tools to find out what happens when a particular receptor is suppressed (such as the epidermal growth factor receptor, or EGFR, to cite a target that is important for cancer and much more). Sometimes, scientists harvest a series of improved treatments using existing drugs without actually getting a new one approved. Rituxan, originally approved for certain types of non-Hodgkin’s lymphoma cancer, is now approved for other types of cancer along with multiple sclerosis, rheumatoid arthritis, and Crohn’s Disease, and is being researched to treat lupus, idiopathic thrombocytopenia purpura, and chronic lymphocytic leukemia.
The other phenomenon that has been largely lost in popular discussion of drug R&D and its discontents is the extraordinary role played by “follow-on” drugs (a much more accurate term than “me-too”). The story with statin cholesterol-reducing drugs, where a decade or more of research on follow-ons revolutionized the prevention and treatment of coronary heart disease, is a familiar one. Similar stories are playing out now, but much faster. Competition among rapidly developed drugs to attack a promising target (such as tumor necrosis factor inhibitors for rheumatoid arthritis) can bring about revolutions in treatments as doctors and patients dance through one drug after another while dealing with the unique mix of side effects and drug resistance that plague each individual patient.
The interested reader can get a flavor of this blend of basic science and practical drug development by reading the fascinating discussion by Jan Vermorken, et al., of evolving treatments for head-and-neck cancer in the September 11, 2008 issue of The New England Journal of Medicine. Much of this story involves Erbitux, the monoclonal antibody that put Martha Stewart in jail after a disappointing FDA decision put the owners of ImClone, the developer, into a panic. The many years of up-and-down research and results on that drug, costing hundreds of millions or even billions of dollars back when no revenues were in sight, is probably as good an example as any of the vagaries and payoffs from high-risk drug research informed by ongoing work in pure science.
Hilleman set out to develop vaccines for the chief life-threatening viral and bacterial infectious diseases of childhood. Amazingly, he came close to clearing the table.
In another recent article in The American, I addressed the thorny question of the role of publicly supported basic research in drug development (“The Indispensable Industry,” May/June 2008). To put it in the simplest terms, a close look reveals a striking pattern that seems to be little noticed by the critics of private drug development: no matter how far-flung the curiosity-driven NIH-supported research is, the only results that seem to get translated into useable drugs are the ones that are grabbed by drug firms and put through the difficult research necessary to produce appropriate quantities of promising substances to run through years of arduous clinical trials. Take away the private sector, and basic research nearly always languishes with little practical effect, as is unceasingly and tragically illustrated by the dearth of new drugs and vaccines for malaria and tuberculosis. Sometimes, the drug firms themselves do perform crucial basic research, as in the case of Genentech’s Avastin for cancer and Lucentis to prevent blindness. These were the fruits of the firm’s own top-tier basic research forces.
Just Two Words
But there is something else in drug development that hardly gets talked about: the sheer energy and determination that you find in the private sector. Combine that with substantial financial resources and you get what John Maynard Keynes called “animal spirits,” a singular motivating force in creative capitalism. When this force attacks big problems, the results can be both spectacular and unexpected, sometimes with fabulous benefits for mankind. It so happens that animal spirits are very much involved in one of the great blessings of modern medicine: an armamentarium of vaccines, mainly given to children, which have been saving lives by the millions at astonishingly low costs. “The most cost-effective treatments ever created by mankind” is a typical summary of the value of vaccines for mumps, measles, rubella (German measles), and half a dozen or so others, including those for diphtheria, whooping cough, hepatitis A, and hepatitis B.
Where, you might ask, did all those life-saving vaccines come from? Amazingly, for half or more of them, the answer can be summarized in two words: Hilleman and Merck. You’ve likely never heard of Maurice Hilleman even though he probably saved more lives than any other scientist in the 20th century. For most of his career, Hilleman was a biologist at Merck, where he developed one vaccine after another, stretching through four extraordinary decades of productive work. Along the way, he pioneered new ways to create, test, and manufacture vaccines, and played a crucial role in the creation of an entirely different class of drugs known as interferons.
We know a lot about Hilleman’s career thanks to a wonderful book published last year by Paul Offit: Vaccinated: One Man’s Quest to Defeat the World’s Deadliest Diseases. Offit was the perfect vehicle for getting this story the attention it deserves. A prominent academic immunologist at Children’s Hospital of Philadelphia and the University of Pennsylvania Medical School, Offit is also a vaccine developer. He is a co-inventor and co-developer of Rotateq, the first fully successful vaccine for rotavirus, a cause of deadly dehydration that kills thousands of children annually in poor nations.
Offit is attuned to public policy. He has been a member of the Advisory Committee on Immunization Practices, whose child vaccination recommendations are gospel for physicians and payers. His previous book, The Cutter Incident, was an insightful historical account of how litigation over an early miracle vaccine—for polio—helped shape (very much for the worse) the entire litigation environment of vaccines and pharmaceuticals. Offit’s academic journal articles and newspaper op-eds on the consequences of unscientific attacks on vaccine safety are required reading for anyone interested in this contentious topic.
Offit’s Vaccinated is informed by 11 interviews with the 85-year-old Hilleman in 2005, during the last months of his life before he succumbed to cancer. Judging by dozens of meaty quotes, Offit is a probing interviewer, capturing a great scientist’s personality and working style to a degree that cannot be matched without personal experience with the subject, and is seldom matched even then.
His basic strategy was simple: solve whatever problems had to be solved in order to reach the goal, which was usually a new vaccine.
Who was Maurice Hilleman and what did he do? Born to a German-American family in 1919 and raised on a Montana farm near his birthplace, Hilleman was a brilliant student on scholarship at Montana State University. After graduation he moved to the Midwest intellectual mecca at the University of Chicago, where in 1944 he finished a Ph.D. in microbiology based on groundbreaking research on the chlamydia bacterium (previously thought to be a virus). To the dismay of his new intellectual peers, Hilleman left academia to work for a pharmaceutical firm, E.R. Squibb, where he achieved advances in flu vaccine development and manufacturing. In 1948, he moved to the Walter Reed military hospital in Washington. His work there culminated in an extraordinary episode in 1957 when he correctly forecast the arrival of a new Asian Flu to which almost no one was immune. He led the development and manufacturing (by private firms) of a vaccine in time to save hundreds of thousands of lives and perhaps many more.
In 1957 Hilleman returned to the private sector, this time at Merck, where he was head of virus and cell biology in Merck’s relatively new vaccine enterprise. Hilleman apparently set out to develop vaccines for the chief life-threatening viral and bacterial infectious diseases of childhood. Amazingly, he came close to clearing the table. First was the mumps, with the approval in 1967 of the “Jeryl Lynn” vaccine based on a mumps virus taken from his daughter of that same name. A measles vaccine arrived the next year. In 1969, we got a vaccine for rubella. Hilleman soon concocted the immensely useful idea of combining these three vaccines into a single shot. Approved in 1971, this proved a blessing to untold millions of small children and their mothers. The 1981 vaccine for hepatitis B (not really a childhood disease, of course) was a scientific and technological tour de force essentially from start to finish. In 1995 came the hepatitis A vaccine. For chicken pox, pneumococcus, and Hib (haemophilus influenzae type b), Hilleman transformed relatively untested vaccines into the mass-produced tools with which we are now familiar. It is hard to imagine the cumulative benefits of this research. (Hilleman also developed a vaccine for a destructive form of chicken cancer, rescuing a substantial part of the poultry industry.) Hilleman’s work sometimes ranged beyond vaccines. Starting in the late 1950s, he figured out how to mass-produce a newly discovered virus-killing substance in chickens called interferon. He soon detailed interferon’s basic physical, chemical, and biological properties, discovering that it was produced in many animals, including humans, and that it could impede or kill many viruses, such as those involved in cancer. He correctly predicted that interferon could be used to treat chronic infections and cancer. Today, it is used against hepatitis B, hepatitis C, and several types of cancer.
Problem Solving for Fun and Profit
This is more than the history of medicine, science, and technology. It is also business history, a classic story of problem solving for fun and profit and humanity. How was Hilleman able to accomplish so much in basic research, drug development, and manufacturing technology, often working essentially from scratch because vaccine development was still in its infancy when he set to work? The answer lies in Hilleman’s decision to work at Merck instead of pursuing a top-tier academic career. He realized that to attack the most pressing illnesses susceptible to immune-based prevention, he would have to marshal massive forces even after solving the purely intellectual puzzles. Merck had supported that kind of work before in Max Tishler’s research on the vitamin B complex. Offit tells us relatively little about internal Merck affairs, but it is clear that Hilleman enjoyed an extraordinary degree of autonomy combined with generous funding increases for low-profit products (now there’s a combination we’d all like to have!).
The Nobel Prize committee was not willing to award a prize to an industry scientist. It is hard not to see this as a miscarriage of scientific justice.
Hilleman sometimes exercised an iron fist over such normally mundane matters as manufacturing, where any deviation from his recipe could result in undetectable dangers. Indeed, Hilleman was apparently a bit of a tyrant, demanding almost as much of his staff as of himself, facilitated by his mastery of the art of profanity. Nonetheless, he retained the respect and often the devotion of his hard-driven staff along with near-legendary status among his academic peers.
In 1984, when Hilleman reached Merck’s mandatory retirement age of 65, he refused to retire and Merck kept him on. One result was the hepatitis A virus vaccine that arrived in 1995, along with a steady stream of academic work of all sorts until shortly before his death in 2005. Hilleman never jettisoned the problem solving method of a successful Montana farmer. Like Orville and Wilbur Wright when they built the first successful heavier-than-air flying machine, Hilleman’s basic strategy was simple: solve whatever problems had to be solved in order to reach the goal, which was usually a new vaccine. The list of problems included daunting scientific puzzles, excruciating judgments about whether dangerous side effects had been defeated, and the vagaries of regulation (much easier before the FDA got into the action).
As the 80-plus-year-old Hilleman approached death, Offit and other academic scientists lobbied the Nobel committee to award Hilleman the Nobel Prize for Medicine, based partly on his vaccine work and partly on his contributions to the basic science of interferons. The committee made clear that it was not going to award the prize to an industry scientist. (Offit has assured me that the situation was even more hopeless than he describes in his book.) It is hard not to see this as a miscarriage of scientific justice. Perhaps Hilleman would have done better if his volcanic personality had not included a surprising element of self-effacement. None of the vaccines or the crucial agents or processes he created were named after himself. At one point, he even called the developer of a new rubella vaccine to say that he thought it should replace his own because it was better. Hilleman’s absence from the academic and public spotlight was quite extraordinary. In one of the most striking of the dozens of anecdotes told by Offit, Hilleman’s death was announced to a meeting of prominent public health officials, epidemiologists, and clinicians gathered to celebrate the 50th anniversary of the Salk polio vaccine. Not one of them recognized Hilleman’s name!
Next…
Thanks to Offit and his book, Hilleman’s light and the extraordinary research achieved by the Merck company will shine for many, many years. What about vaccine research itself? There have been formidable obstacles. One was the liability system, which in the 1980s nearly killed off the child vaccine market before Congress removed child vaccines from the liability system altogether. Another, more persistent problem has been low reimbursement rates, especially by government, for traditional child vaccines (including most of Hilleman’s crop). This can discourage new research and production, and cause shortages. The situation was sufficiently worrisome to trigger a 2003 report by the federally sponsored Institute of Medicine entitled “Financing Vaccines in the 21st Century: Assuring Access and Availability.” Reimbursement seems to have improved recently. Better yet, newer vaccines are sufficiently protected by patents so that prices are set through ordinary market forces rather than government fiat. Merck and its competitors, such as GlaxoSmithKline and Sanofi-Aventis plus smaller firms, have developed a series of important new vaccines—notable among them are the pneumococcal vaccine, a vaccine for the human papilloma virus (which causes cervical cancer), and two rotavirus vaccines (including the one co-invented by Offit). Traditional vaccine research is now flourishing but will probably never again be dominated by a single person’s laboratory like the one run by Hilleman in his prime.
Hilleman was apparently a bit of a tyrant, demanding almost as much of his staff as of himself, facilitated by his mastery of the art of profanity.
But we need to look ahead, and when we do it’s hard not to get excited. The entire field of immunology—roughly speaking, the harnessing of the human immune system to fight disease—has taken off along with so much else in this age of biotechnology. We are discovering faster and more efficient ways to manufacture traditional vaccines (especially for the flu), better methods for identifying newly arrived infectious agents such as avian flu (the dreaded “bird flu” that could cause an epidemic on the scale of the one in 1918 that killed millions worldwide), and new techniques for developing vaccines once their targets have been identified.
And there is the extraordinary prospect of therapeutic vaccines, i.e., vaccines that harness the immune system to attack illnesses already present in the body rather than just preparing the body to reject infections that have not yet been encountered. None has been approved, but a brain cancer vaccine from the biotech firm Dendreon received a favorable rating from an FDA advisory committee and may yet gain approval from the FDA (despite its reluctance to approve highly innovative drugs in this era of attacks on it for paying too much attention to new benefits and too little attention to safety). Alzheimer’s Disease vaccines have achieved striking results against the beta-amyloid plaques typically found in the brains of Alzheimer’s patients. Other therapeutic vaccines are in various stages of testing.
It’s about time for the biotech revolution to hit the vaccine industry in a big way. It has already upended the treatment of rheumatoid arthritis and a few cancers, and is starting to do the same for multiple sclerosis and other conditions including rare diseases like psoriasis. Now let us see what happens in this once-quiet corner of the biopharmaceutical market. As Hilleman’s career demonstrates, when industrial science is harnessed to the profit motive, enormous advances in human welfare are possible.
John E. Calfee is a resident fellow at the American Enterprise Institute, which is about to publish a new book on recent developments in the vaccine market, U.S. Vaccine Markets: Overview, Case Studies, and Comparisons with Pharmaceuticals and Other Biologics, by economists Ernest Berndt, Rena N. Denoncourt, and Anjli C. Warner of MIT. It provides the best summary yet published of vaccine development in the past two decades, along with a preview of what is on the way.
Saturday, January 24, 2009
New Partnership to Ensure South Asia's Food Security
New Partnership to Ensure South Asia's Food Security in the Face of Climate Change
Press release, USAID, January 23, 2009
The U.S. Agency for International Development is working with the Bill and Melinda Gates Foundation to support the Cereals Systems Initiative for South Asia (CSISA), a program that will help more than six million small farmers in South Asia achieve significant cereal yield increases over the next ten years.
The initiative will work through public and private sector partners in local hubs in South Asia to accelerate the development and uptake of new crop varieties and to make cereal systems more sustainable. By producing at least five million tons more grain annually as a result of CSISA, farmers will add economic value of more than $1.5 billion per year and will achieve substantial savings in production costs. It will reduce hunger and malnutrition and increase the incomes of small-holder farm families in South Asia.
The rising costs of energy and fertilizer and diminishing water availability are major constraints for farmers in South Asia. CSISA will develop and disseminate integrated cereal production packages - including new high-yielding, stress tolerant cereal varieties, better information technology and improved resource management practices. These interventions will help farmers grow more food in the face of climate change impacts while using less energy, water and fertilizer.
The initiative will be led by the International Rice Research Institute and three other Consultative Group for International Agriculture Research (CGIAR) Centers, CIMMYT, IFPRI and ILRI, along with partners in India, Pakistan, Bangladesh and Nepal. The combined funding for the first three years includes $15 million from USAID and almost $19.59 million from the Gates Foundation for CSISA and related projects.
Press release, USAID, January 23, 2009
The U.S. Agency for International Development is working with the Bill and Melinda Gates Foundation to support the Cereals Systems Initiative for South Asia (CSISA), a program that will help more than six million small farmers in South Asia achieve significant cereal yield increases over the next ten years.
The initiative will work through public and private sector partners in local hubs in South Asia to accelerate the development and uptake of new crop varieties and to make cereal systems more sustainable. By producing at least five million tons more grain annually as a result of CSISA, farmers will add economic value of more than $1.5 billion per year and will achieve substantial savings in production costs. It will reduce hunger and malnutrition and increase the incomes of small-holder farm families in South Asia.
The rising costs of energy and fertilizer and diminishing water availability are major constraints for farmers in South Asia. CSISA will develop and disseminate integrated cereal production packages - including new high-yielding, stress tolerant cereal varieties, better information technology and improved resource management practices. These interventions will help farmers grow more food in the face of climate change impacts while using less energy, water and fertilizer.
The initiative will be led by the International Rice Research Institute and three other Consultative Group for International Agriculture Research (CGIAR) Centers, CIMMYT, IFPRI and ILRI, along with partners in India, Pakistan, Bangladesh and Nepal. The combined funding for the first three years includes $15 million from USAID and almost $19.59 million from the Gates Foundation for CSISA and related projects.
Monday, January 19, 2009
Post mortem with President Bush's point man on science, John Marburger
After the Storm, by Adam Bly & TJ Kelleher
An exclusive and revealing post mortem with President Bush's point man on science, John Marburger.
Seed Magazine, January 13, 2009 08:33 AM
Excerpts:
Seed: So let's start big. What is the state of science in America?
[...]
JM: All right. America continues to lead the world in its investments in science, in virtually every field. Although we have about 5 percent of the world's population, we employ about 20 percent of the world's scientists and engineers. No large country other than Japan devotes as much of its GDP to research and development as the US. On the federal level, about half is in the Department of Defense. The other half is the nondefense research. Nondefense research is always a constant fraction of the nondefense discretionary budget, so as the discretionary budget grows or shrinks, the budget for nondefense science grows or shrinks along with it. That pattern has held for four decades, and I expect that to continue.
There are some imbalances in funding. When the Cold War ended, support for physical science, engineering, math, and computer science really flattened out. But with that leveling off, the support for biomedical research was growing steadily, as it had been during the Cold War. In recent years the NIH budget doubled; 60 percent of that money was provided by this administration. The president embraced it as he had a number of things, including nanotechnology and information technology initiatives, that actually had their seeds in the previous administration.
Seed: Could we take the budgetary dimension out of the equation for a moment?
JM: That's very hard to do. The health of science depends on having money for people and facilities and infrastructure that science needs to fly. It's a major aspect, probably the primary aspect of science health.
Seed: But would you acknowledge that another aspect of the state of science is a culture of science? Could you compare the culture of science in America eight years ago to today?
JM: Virtually unchanged, as far as I'm concerned. Science has its own culture. And it's a relatively nonpolitical, almost apolitical, culture. We've seen some increased visibility of the science community during the Bush administration. I think that was part of a political strategy of the Democratic Party, which was somewhat successful, to undermine the credibility of the Bush administration by fixing on these issues. His position on stem cells was attacked as a scientific position, when in fact it's an ethical position. He was attacked for his position on the Kyoto protocol, despite its serious flaws, and the fact that the Senate had already refused to ratify it. But the way it was handled gave an opportunity to the detractors of the president to use those issues to portray the administration as negative toward science.
Seed: So there's no merit to those criticisms?
JM: That image is an urban legend. He made federal money available for embryonic stem cell research for the first time. Furthermore, his State of the Union addresses as well as other speeches often emphasized technology and how important it was. When he unveiled his American Competitiveness Initiative, he stated clearly that it was important to double the budgets for the agencies that did the most critical basic research in physical science.
Seed: Is America still competitive with the rest of the world in science and technology?
JM: The concerns are not about the present. The concern is all about the future. And certainly, the longest term issue in competitiveness is the preparation of a technical workforce. The weakness is manifest in the first place by the rate at which young people choose to go into technical careers of any sort. The No Child Left Behind Act, like other initiatives in science and education that the president has launched, sought to address that lack of preparation. The main criticisms tend to be that it has not been enough.
The quality of science education is very poor because we don't have qualified teachers in the classrooms. Important components of No Child Left Behind and also the American Competitiveness Initiative were designed to address that. The quality of teaching in science and mathematics needs to be enhanced in the US, absolutely.
Seed: Okay. Let's compare that with the state of science in the world.
JM: About a third of the world's R&D is performed in North America, nearly all of it in the US. About a third in Europe and about a third in Asia. Asia is dominated by Japan and now China. North America is dominated by the US. In Europe it is more balanced. Europe is trying to forge coherence in its very fragmented system of education and research, and doing a pretty good job of it. Then there is this huge north/south split. There is emerging research in South Africa, Brazil, Indonesia, Southeast Asia, but it is tiny, and the infrastructure is growing slowly. The percentage of GDP devoted to research in those countries is very small.
Those are areas that we should be concerned about, because investments in science and technology are important stabilizing features for the economies, and they are important nucleations for development programs. You don't have to have people working on particle physics or cosmology in Africa, but you need people who understand them to act as role models and attract young people into technical studies.
Seed: Did America's strategy on science as a soft power change at all over the past eight years?
JM: Many countries pursue science as soft power, but America is unique among nations in this respect. After World War II, the US alone had the remaining economic capacity to develop the opportunities presented by science. Consequently, the world sent its aspiring scientists to us. Because of that, we haven't had to have a focused office of international science diplomacy. It is happening, and it is happening probably more powerfully than for any other country. Whenever I travel to other countries, I see colleagues and students of mine and other faculty. Now some of those students are getting a little old, and I'd like to see more and younger ones.
Seed: How does the US get more?
JM: It should be easier to get into the US as a student. And it should be easier to stay here and become a citizen if you want to, after you get an advanced degree. The president has some very interesting ideas about immigration, which are way out in front of his own party. I wish Democrats had supported them more strongly.
In any case, we've got soft diplomacy. We only have to avoid stepping on our own toes to let it work. By that I mean to be cautious about the post 9/11 provisions that we've made for homeland security. We really need to be careful about our openness to the world.
Seed: Has the US missed an opportunity to enhance American soft power by building something like the Large Hadron Collider?
JM: I don't think so. The US is actually — in a way, unfortunately — dominating the science community at CERN. And the CERN people are a little bit uncomfortable about that. And anyway, that's only one instrument. There are these lovely pictures of protein structures and glowing fish, for which two Americans just got the Nobel Prize. And you've got Hubble and the Mars rovers.
We have ongoing imaginative technological sagas that are capturing the world's attention. The world doesn't always connect them with the US, but the US is the primary player, even on questions like climate science. This is American science.
The biggest threat to that science is the inexorable growth of the mandatory budget for Social Security, Medicare, and other programs. The growth of the mandatory budget is squeezing everything. It is squeezing science, infrastructure, renewal. If not for that, we wouldn't have all these priority decisions to make. We could double NIH and NSF and NASA and everything else in reasonable amount of time. But the fact is that our discretionary budget is not increasing at the same rate as our economy or the needs and aspirations of our society. We have got to do something about it.
Seed: Our magazine has advanced the idea that we must consider science not simply as a thing that we fund, but as a lens through which we should look at the world. Does the structure of science advice to government correlate with the place of science in the world?
JM: Yes, it does. This is an area of vast ignorance because the majority of people motivated to understand science policy and the structure of science advice are government employees. Those are the people who are motivated to understand this stuff. What they know — what the science community at large does not — is that the structure of science advice reflects the full panoply of government activities in a very sophisticated way. Most of what we do here is to coordinate this vast machinery of science in government so that it produces a coherent science program.
When I want to know what to tell the president, I go to NOAA, I go to NASA, I go to NSF, I go to the Department of Energy and bring the right guys in. If I want to learn about climate change, I go to Jim Hansen. Jim Hansen has his own personal point of view. He will tell you that it's his own personal point of view that there's a tipping point, that we can't go over a certain atmospheric concentration of carbon dioxide. That's fine. As long as he makes it clear that that's his opinion, it's fine with me. He's a controversial person because he's one of the few scientists who's willing to state his opinion. It makes me a little nervous because of his authority as a scientist. Whenever science is recruited in the service of opinion, it makes me very nervous. Everybody wants to use the credibility of science to bolster their opinions. And I don't like that. I try to avoid getting into that trap in this office.
Seed: Did you see President Bush ever change his mind based on the scientific evidence that you presented him?
JM: As far as I can tell, the president, as a matter of principle, doesn't think it's wise to defy nature. By the time I've arranged a presentation about something for the president, all science questions have been resolved. And he expects it. He would probably fire me if I permitted a science question to leak into his briefings. I'm there to make sure that his advisors and his agencies have consulted with the science community, and that all the science issues have been taken care of before anything gets to him.
Seed: Was there a dimension, an approach, or a philosophy held by the president's other advisors that most commonly confronted your advice?
JM: I only give advice about science. I don't give advice about politics or foreign affairs or economics or legal affairs. I stay out of those things. All of the issues that the president needs to decide are in those domains. They are not in my domain. The president doesn't need to make decisions about science. Science does not tell you how to implement policies, except in rare cases. And the real tough part of governing is implementing.
I mean, the tough issues, about climate, for example, are not about whether the Earth is warming or whether it is caused by humans; the real question is how do you go about addressing the problem at a scale that is significant enough to make a difference.
Seed: Except if it takes an extra day or year or term to accept those scientific conclusions as foundational to economic or political strategy, doesn't that seem to be in violation of the principles of science?
JM: The president has had a very practical approach to a response to climate change. In 2001, before I came to Washington, the president established the Federal Climate Science Program to punch up our knowledge and focus on the remaining uncertainties in the science, and he started an initiative in climate technology, which was the seed for lots of subsequent energy initiatives, including the most recent advanced energy initiative. The president reentered ITER, the international nuclear fusion program. He has encouraged the use of nuclear power. Those were decisions that were made by the president.
The president has not said that we have to wait until the certainties are resolved before we do something about climate change. He has actually said just the opposite. It is not easy for me to understand how the public discourse can get so off track as to hold that the president says, "Oh, let's do more research, so we don't have to take any action."
Seed: Why do you think the public holds the belief that it does?
JM: That's actually a science question. I've read a wonderful book called Predictably Irrational, by Daniel Ariely, that addresses this. This is something marketing people, political consultants, and politicians know about, almost instinctively: informational cascades. Scientists, I think, are particularly vulnerable to the informational cascade phenomenon. They know who the good scientists are, and when a good scientist says something, the others tend to say, "Gee, I know he is smart or she is smart, so what he's saying must be right." So it doesn't take too much to tilt a community like this toward a mythology or a mistaken impression. In the absence of some strong rebuttal, I think it is likely to take root in the media environment that we have today.
Seed: Have you ever been troubled by the degree to which science informed the decision about a nonscientific subject?
JM: My job is to make sure that the president understands the issues. I think he has understood every science issue that I have ever talked with him about. Actually, I think he's understood well, much better than people would imagine.
[...]
Seed: What challenges will President-elect Obama face? What advice would you give him and his science advisor?
JM: President-elect Obama, godspeed to him, will face similar difficulties. He ran such a perfect campaign, I hesitate to give him any advice. But, I would say, have respect for the science and for the structures that generations of his predecessors have labored to put in place to make science work for America.
An exclusive and revealing post mortem with President Bush's point man on science, John Marburger.
Seed Magazine, January 13, 2009 08:33 AM
Excerpts:
Seed: So let's start big. What is the state of science in America?
[...]
JM: All right. America continues to lead the world in its investments in science, in virtually every field. Although we have about 5 percent of the world's population, we employ about 20 percent of the world's scientists and engineers. No large country other than Japan devotes as much of its GDP to research and development as the US. On the federal level, about half is in the Department of Defense. The other half is the nondefense research. Nondefense research is always a constant fraction of the nondefense discretionary budget, so as the discretionary budget grows or shrinks, the budget for nondefense science grows or shrinks along with it. That pattern has held for four decades, and I expect that to continue.
There are some imbalances in funding. When the Cold War ended, support for physical science, engineering, math, and computer science really flattened out. But with that leveling off, the support for biomedical research was growing steadily, as it had been during the Cold War. In recent years the NIH budget doubled; 60 percent of that money was provided by this administration. The president embraced it as he had a number of things, including nanotechnology and information technology initiatives, that actually had their seeds in the previous administration.
Seed: Could we take the budgetary dimension out of the equation for a moment?
JM: That's very hard to do. The health of science depends on having money for people and facilities and infrastructure that science needs to fly. It's a major aspect, probably the primary aspect of science health.
Seed: But would you acknowledge that another aspect of the state of science is a culture of science? Could you compare the culture of science in America eight years ago to today?
JM: Virtually unchanged, as far as I'm concerned. Science has its own culture. And it's a relatively nonpolitical, almost apolitical, culture. We've seen some increased visibility of the science community during the Bush administration. I think that was part of a political strategy of the Democratic Party, which was somewhat successful, to undermine the credibility of the Bush administration by fixing on these issues. His position on stem cells was attacked as a scientific position, when in fact it's an ethical position. He was attacked for his position on the Kyoto protocol, despite its serious flaws, and the fact that the Senate had already refused to ratify it. But the way it was handled gave an opportunity to the detractors of the president to use those issues to portray the administration as negative toward science.
Seed: So there's no merit to those criticisms?
JM: That image is an urban legend. He made federal money available for embryonic stem cell research for the first time. Furthermore, his State of the Union addresses as well as other speeches often emphasized technology and how important it was. When he unveiled his American Competitiveness Initiative, he stated clearly that it was important to double the budgets for the agencies that did the most critical basic research in physical science.
Seed: Is America still competitive with the rest of the world in science and technology?
JM: The concerns are not about the present. The concern is all about the future. And certainly, the longest term issue in competitiveness is the preparation of a technical workforce. The weakness is manifest in the first place by the rate at which young people choose to go into technical careers of any sort. The No Child Left Behind Act, like other initiatives in science and education that the president has launched, sought to address that lack of preparation. The main criticisms tend to be that it has not been enough.
The quality of science education is very poor because we don't have qualified teachers in the classrooms. Important components of No Child Left Behind and also the American Competitiveness Initiative were designed to address that. The quality of teaching in science and mathematics needs to be enhanced in the US, absolutely.
Seed: Okay. Let's compare that with the state of science in the world.
JM: About a third of the world's R&D is performed in North America, nearly all of it in the US. About a third in Europe and about a third in Asia. Asia is dominated by Japan and now China. North America is dominated by the US. In Europe it is more balanced. Europe is trying to forge coherence in its very fragmented system of education and research, and doing a pretty good job of it. Then there is this huge north/south split. There is emerging research in South Africa, Brazil, Indonesia, Southeast Asia, but it is tiny, and the infrastructure is growing slowly. The percentage of GDP devoted to research in those countries is very small.
Those are areas that we should be concerned about, because investments in science and technology are important stabilizing features for the economies, and they are important nucleations for development programs. You don't have to have people working on particle physics or cosmology in Africa, but you need people who understand them to act as role models and attract young people into technical studies.
Seed: Did America's strategy on science as a soft power change at all over the past eight years?
JM: Many countries pursue science as soft power, but America is unique among nations in this respect. After World War II, the US alone had the remaining economic capacity to develop the opportunities presented by science. Consequently, the world sent its aspiring scientists to us. Because of that, we haven't had to have a focused office of international science diplomacy. It is happening, and it is happening probably more powerfully than for any other country. Whenever I travel to other countries, I see colleagues and students of mine and other faculty. Now some of those students are getting a little old, and I'd like to see more and younger ones.
Seed: How does the US get more?
JM: It should be easier to get into the US as a student. And it should be easier to stay here and become a citizen if you want to, after you get an advanced degree. The president has some very interesting ideas about immigration, which are way out in front of his own party. I wish Democrats had supported them more strongly.
In any case, we've got soft diplomacy. We only have to avoid stepping on our own toes to let it work. By that I mean to be cautious about the post 9/11 provisions that we've made for homeland security. We really need to be careful about our openness to the world.
Seed: Has the US missed an opportunity to enhance American soft power by building something like the Large Hadron Collider?
JM: I don't think so. The US is actually — in a way, unfortunately — dominating the science community at CERN. And the CERN people are a little bit uncomfortable about that. And anyway, that's only one instrument. There are these lovely pictures of protein structures and glowing fish, for which two Americans just got the Nobel Prize. And you've got Hubble and the Mars rovers.
We have ongoing imaginative technological sagas that are capturing the world's attention. The world doesn't always connect them with the US, but the US is the primary player, even on questions like climate science. This is American science.
The biggest threat to that science is the inexorable growth of the mandatory budget for Social Security, Medicare, and other programs. The growth of the mandatory budget is squeezing everything. It is squeezing science, infrastructure, renewal. If not for that, we wouldn't have all these priority decisions to make. We could double NIH and NSF and NASA and everything else in reasonable amount of time. But the fact is that our discretionary budget is not increasing at the same rate as our economy or the needs and aspirations of our society. We have got to do something about it.
Seed: Our magazine has advanced the idea that we must consider science not simply as a thing that we fund, but as a lens through which we should look at the world. Does the structure of science advice to government correlate with the place of science in the world?
JM: Yes, it does. This is an area of vast ignorance because the majority of people motivated to understand science policy and the structure of science advice are government employees. Those are the people who are motivated to understand this stuff. What they know — what the science community at large does not — is that the structure of science advice reflects the full panoply of government activities in a very sophisticated way. Most of what we do here is to coordinate this vast machinery of science in government so that it produces a coherent science program.
When I want to know what to tell the president, I go to NOAA, I go to NASA, I go to NSF, I go to the Department of Energy and bring the right guys in. If I want to learn about climate change, I go to Jim Hansen. Jim Hansen has his own personal point of view. He will tell you that it's his own personal point of view that there's a tipping point, that we can't go over a certain atmospheric concentration of carbon dioxide. That's fine. As long as he makes it clear that that's his opinion, it's fine with me. He's a controversial person because he's one of the few scientists who's willing to state his opinion. It makes me a little nervous because of his authority as a scientist. Whenever science is recruited in the service of opinion, it makes me very nervous. Everybody wants to use the credibility of science to bolster their opinions. And I don't like that. I try to avoid getting into that trap in this office.
Seed: Did you see President Bush ever change his mind based on the scientific evidence that you presented him?
JM: As far as I can tell, the president, as a matter of principle, doesn't think it's wise to defy nature. By the time I've arranged a presentation about something for the president, all science questions have been resolved. And he expects it. He would probably fire me if I permitted a science question to leak into his briefings. I'm there to make sure that his advisors and his agencies have consulted with the science community, and that all the science issues have been taken care of before anything gets to him.
Seed: Was there a dimension, an approach, or a philosophy held by the president's other advisors that most commonly confronted your advice?
JM: I only give advice about science. I don't give advice about politics or foreign affairs or economics or legal affairs. I stay out of those things. All of the issues that the president needs to decide are in those domains. They are not in my domain. The president doesn't need to make decisions about science. Science does not tell you how to implement policies, except in rare cases. And the real tough part of governing is implementing.
I mean, the tough issues, about climate, for example, are not about whether the Earth is warming or whether it is caused by humans; the real question is how do you go about addressing the problem at a scale that is significant enough to make a difference.
Seed: Except if it takes an extra day or year or term to accept those scientific conclusions as foundational to economic or political strategy, doesn't that seem to be in violation of the principles of science?
JM: The president has had a very practical approach to a response to climate change. In 2001, before I came to Washington, the president established the Federal Climate Science Program to punch up our knowledge and focus on the remaining uncertainties in the science, and he started an initiative in climate technology, which was the seed for lots of subsequent energy initiatives, including the most recent advanced energy initiative. The president reentered ITER, the international nuclear fusion program. He has encouraged the use of nuclear power. Those were decisions that were made by the president.
The president has not said that we have to wait until the certainties are resolved before we do something about climate change. He has actually said just the opposite. It is not easy for me to understand how the public discourse can get so off track as to hold that the president says, "Oh, let's do more research, so we don't have to take any action."
Seed: Why do you think the public holds the belief that it does?
JM: That's actually a science question. I've read a wonderful book called Predictably Irrational, by Daniel Ariely, that addresses this. This is something marketing people, political consultants, and politicians know about, almost instinctively: informational cascades. Scientists, I think, are particularly vulnerable to the informational cascade phenomenon. They know who the good scientists are, and when a good scientist says something, the others tend to say, "Gee, I know he is smart or she is smart, so what he's saying must be right." So it doesn't take too much to tilt a community like this toward a mythology or a mistaken impression. In the absence of some strong rebuttal, I think it is likely to take root in the media environment that we have today.
Seed: Have you ever been troubled by the degree to which science informed the decision about a nonscientific subject?
JM: My job is to make sure that the president understands the issues. I think he has understood every science issue that I have ever talked with him about. Actually, I think he's understood well, much better than people would imagine.
[...]
Seed: What challenges will President-elect Obama face? What advice would you give him and his science advisor?
JM: President-elect Obama, godspeed to him, will face similar difficulties. He ran such a perfect campaign, I hesitate to give him any advice. But, I would say, have respect for the science and for the structures that generations of his predecessors have labored to put in place to make science work for America.
Tuesday, January 6, 2009
Christiane Nüsslein-Volhard On Biotech Opponents
Biotech Opponents Are Playing with Human Lives, by Till Behrend
Nobel laureate Christiane Nüsslein-Volhard discusses the environmentalists' war against genetically modified food.
Pajamas Media, January 3, 2009
There is a specter haunting Europe: the specter of genetically modified foods. Although regularly consumed in the U.S. and around the world, in Europe GM foods are the target of veritable scare campaigns by environmental pressure groups and in the media. As a consequence, even GM crops that have been formally approved by the European Commission are the subject of increasing restrictions in Germany, France, and other European countries. GM crops — including such as have been planted merely for experimental purposes — are regularly destroyed by anti-GM militants in acts of would-be “civil disobedience.” Till Behrend of [1] the German weekly Focus spoke with the geneticist and Nobel Prize laureate Christiane Nüsslein-Volhard about the sources of biotech-phobia.
John Rosenthal (Translator)
***
FOCUS: Professor Nüsslein-Volhard, farmers all around the world are cultivating genetically modified crops on an ever larger scale. But many Germans appear to be afraid of the new technology. Are they right to be?
Nüsslein-Volhard: Well, we Germans are always afraid of new things. But what are these people actually afraid about? They’re afraid that they will assimilate alien genes while eating genetically modified foods. But that’s nonsense. The genes are digested, broken down, and eliminated from the body just like in the case of traditional foods. This has been proven beyond any shadow of a doubt. The human genome is sequential and you can examine whether there are any cow genes or plant genes in there. Have no fear: there aren’t any.
FOCUS: What distinguishes, then, classically bred crops from genetically modified crops?
Nüsslein-Volhard: People seem to be unaware that practically all the grains and vegetables that we eat nowadays have been highly genetically modified as compared to their natural forms. There’s hardly any crop as artificial as a potato. In the wild, potatoes are tiny and highly poisonous. It took thousands of generations to turn the potato into a decent sort of food. In contrast to the classical development of new plant strains, “green” biotechnology has the advantage that with its help one can proceed much faster and in a much more targeted fashion.
FOCUS: It’s true that for plant breeders that might be a fine thing. But lots of people want to do what’s right for nature and for themselves, and consequently they insist on “organic” products.
Nüsslein-Volhard: Given our level of material well-being and the fertility of our soil, we can afford to do that. But actually that’s a snobby, elitist attitude. Organic farming cannot feed large cities. And it certainly cannot feed the world’s population. It’s not possible, since the yields of organic farming are too small and the area one has to plant is way too much. It really makes more sense to use the particularly rich fields that we have intensively and in a sustainable manner by planting high-yield crops. The environment benefits, too, since then we can return other fields to their natural state.
FOCUS: Nonetheless, organic farming is thought to stand for a more respectful treatment of the environment.
Nüsslein-Volhard: Wrongly. Or do you imagine perhaps that organic farming can do without the spraying of pesticides? On organic farms, too, one sprays pesticides constantly and all over the place! In this respect, genetic engineering really has more intelligent solutions to offer. For example, with the help of genetic engineering we can make corn or cotton that is resistant to insect damage. If we incorporate a particular gene, they become poisonous for harmful insects, but not for humans or for mice. Then you can do without the insecticide. I find this rather smart. There are also strains being developed that grow with less water or that grow on salt-affected soils. It’s both sophisticated and ecologically beneficial!
FOCUS: If green biotechnology is so beneficial, why hasn’t it gained ground here in Germany?
Nüsslein-Volhard: We have groups like Greenpeace to thank for that: groups that put ideology above everything else — regardless of all the positive results that have been had [with GM crops] in the meanwhile in many countries. As a consequence, green biotechnology is practically a social taboo here.
FOCUS: What are the implications for scientific research?
Nüsslein-Volhard: For theoretical research, there are no consequences. But as soon as it’s a matter of practical applications, things become difficult for the scientists. In Germany, there are practically no positions to be found anymore that would permit them to translate their ideas and research into practice. We do have a biotechnology law, which to some extent makes possible the field experiments that are necessary to gain authorization [for GM crops]. But if the fields are constantly being destroyed and nothing is done about it, then it’s just not possible. Not far from here, at the University of Hohenheim, a whole course had to be canceled because anti-GM militants tore up all the experimental fields. The consequence is that Germany exports exceptionally well-trained scientists to other countries. They don’t see any future for themselves here.
FOCUS: Using the techniques of genetic engineering, German scientists have developed the so-called golden rice. The rice is enriched with vitamin A and it has the potential to spare millions of people in the world’s poorest countries from losing their eyesight. Greenpeace is opposed to the golden rice, because they don’t want people in the Third World to serve as guinea pigs. Do you share this concern?
Nüsslein-Volhard: But that’s total nonsense. The behavior of Greenpeace in this matter is profoundly inhuman! Without a second thought, they are playing with human lives. I’ll give you another example. A few years ago, the Americans sent aid shipments of corn to African countries that were suffering from famine. The corn was genetically modified. In America, everyone eats it (including the German tourist), but the starving Africans were not permitted to eat the corn, because Greenpeace and other groups warned that it was genetically modified. These are unbelievable absurdities. I find it extremely depressing.
FOCUS: Critics of green biotechnologies complain that small farmers in the Third World become dependent on the big agro-industrial firms, which have their newly developed crop strains patented.
Nüsslein-Volhard: Okay, I find this criticism bizarre. As if it is somehow immoral to sell corn kernels as seed. Nobody is giving cars away, after all! The seed for all high-performance crop strains, including those that have not been genetically engineered, is specially produced nowadays, in order to guarantee the maximum yield. It’s just that hardly anyone knows that. The image of the farmer who retains a part of his harvest and replants the kernels the following spring is very romantic, of course. But in the case of corn, for example, such behavior would be totally irrational, since he would then only be able to collect half of the potential yields. But farmers have to try to get as much out of their land as possible. When they don’t manage to do so in an economically efficient fashion, then they need subsidies. Of course, we could pay them such subsidies, in order for them to continue sowing seed that they have themselves harvested. But I don’t find this particularly shrewd.
FOCUS: You’re reputed to be a passionate cook and you’ve even published a cookbook. As a cook, what would you like to see done with biotechnology?
Nüsslein-Volhard: Sometimes I regret the fact that you can’t find certain old-fashioned sorts of fruit in the stores anymore, simply because they spoil too quickly. There are particularly tasty sorts of strawberries or sour cherries, for example, that don’t keep well. You can tell that many types of fruits and vegetables are cultivated for their robustness and the quantity of the yield, but not for their flavor. If it would be possible by using genetic engineering to make the tastier sort of strawberries keep longer, personally I’d have nothing against it. You can’t have everything. But by using genetic engineering you can perhaps have more.
Christiane Nüsslein-Volhard is the director of the Max Planck Institute for Developmental Biology in Tübingen. In 1995, she was awarded the Nobel Prize for Medicine. The above interview first appeared on the German news site [2] Focus-Online. The German version is available [3] here. The English translation is by John Rosenthal.
[References at the original link at the beginning]
Nobel laureate Christiane Nüsslein-Volhard discusses the environmentalists' war against genetically modified food.
Pajamas Media, January 3, 2009
There is a specter haunting Europe: the specter of genetically modified foods. Although regularly consumed in the U.S. and around the world, in Europe GM foods are the target of veritable scare campaigns by environmental pressure groups and in the media. As a consequence, even GM crops that have been formally approved by the European Commission are the subject of increasing restrictions in Germany, France, and other European countries. GM crops — including such as have been planted merely for experimental purposes — are regularly destroyed by anti-GM militants in acts of would-be “civil disobedience.” Till Behrend of [1] the German weekly Focus spoke with the geneticist and Nobel Prize laureate Christiane Nüsslein-Volhard about the sources of biotech-phobia.
John Rosenthal (Translator)
***
FOCUS: Professor Nüsslein-Volhard, farmers all around the world are cultivating genetically modified crops on an ever larger scale. But many Germans appear to be afraid of the new technology. Are they right to be?
Nüsslein-Volhard: Well, we Germans are always afraid of new things. But what are these people actually afraid about? They’re afraid that they will assimilate alien genes while eating genetically modified foods. But that’s nonsense. The genes are digested, broken down, and eliminated from the body just like in the case of traditional foods. This has been proven beyond any shadow of a doubt. The human genome is sequential and you can examine whether there are any cow genes or plant genes in there. Have no fear: there aren’t any.
FOCUS: What distinguishes, then, classically bred crops from genetically modified crops?
Nüsslein-Volhard: People seem to be unaware that practically all the grains and vegetables that we eat nowadays have been highly genetically modified as compared to their natural forms. There’s hardly any crop as artificial as a potato. In the wild, potatoes are tiny and highly poisonous. It took thousands of generations to turn the potato into a decent sort of food. In contrast to the classical development of new plant strains, “green” biotechnology has the advantage that with its help one can proceed much faster and in a much more targeted fashion.
FOCUS: It’s true that for plant breeders that might be a fine thing. But lots of people want to do what’s right for nature and for themselves, and consequently they insist on “organic” products.
Nüsslein-Volhard: Given our level of material well-being and the fertility of our soil, we can afford to do that. But actually that’s a snobby, elitist attitude. Organic farming cannot feed large cities. And it certainly cannot feed the world’s population. It’s not possible, since the yields of organic farming are too small and the area one has to plant is way too much. It really makes more sense to use the particularly rich fields that we have intensively and in a sustainable manner by planting high-yield crops. The environment benefits, too, since then we can return other fields to their natural state.
FOCUS: Nonetheless, organic farming is thought to stand for a more respectful treatment of the environment.
Nüsslein-Volhard: Wrongly. Or do you imagine perhaps that organic farming can do without the spraying of pesticides? On organic farms, too, one sprays pesticides constantly and all over the place! In this respect, genetic engineering really has more intelligent solutions to offer. For example, with the help of genetic engineering we can make corn or cotton that is resistant to insect damage. If we incorporate a particular gene, they become poisonous for harmful insects, but not for humans or for mice. Then you can do without the insecticide. I find this rather smart. There are also strains being developed that grow with less water or that grow on salt-affected soils. It’s both sophisticated and ecologically beneficial!
FOCUS: If green biotechnology is so beneficial, why hasn’t it gained ground here in Germany?
Nüsslein-Volhard: We have groups like Greenpeace to thank for that: groups that put ideology above everything else — regardless of all the positive results that have been had [with GM crops] in the meanwhile in many countries. As a consequence, green biotechnology is practically a social taboo here.
FOCUS: What are the implications for scientific research?
Nüsslein-Volhard: For theoretical research, there are no consequences. But as soon as it’s a matter of practical applications, things become difficult for the scientists. In Germany, there are practically no positions to be found anymore that would permit them to translate their ideas and research into practice. We do have a biotechnology law, which to some extent makes possible the field experiments that are necessary to gain authorization [for GM crops]. But if the fields are constantly being destroyed and nothing is done about it, then it’s just not possible. Not far from here, at the University of Hohenheim, a whole course had to be canceled because anti-GM militants tore up all the experimental fields. The consequence is that Germany exports exceptionally well-trained scientists to other countries. They don’t see any future for themselves here.
FOCUS: Using the techniques of genetic engineering, German scientists have developed the so-called golden rice. The rice is enriched with vitamin A and it has the potential to spare millions of people in the world’s poorest countries from losing their eyesight. Greenpeace is opposed to the golden rice, because they don’t want people in the Third World to serve as guinea pigs. Do you share this concern?
Nüsslein-Volhard: But that’s total nonsense. The behavior of Greenpeace in this matter is profoundly inhuman! Without a second thought, they are playing with human lives. I’ll give you another example. A few years ago, the Americans sent aid shipments of corn to African countries that were suffering from famine. The corn was genetically modified. In America, everyone eats it (including the German tourist), but the starving Africans were not permitted to eat the corn, because Greenpeace and other groups warned that it was genetically modified. These are unbelievable absurdities. I find it extremely depressing.
FOCUS: Critics of green biotechnologies complain that small farmers in the Third World become dependent on the big agro-industrial firms, which have their newly developed crop strains patented.
Nüsslein-Volhard: Okay, I find this criticism bizarre. As if it is somehow immoral to sell corn kernels as seed. Nobody is giving cars away, after all! The seed for all high-performance crop strains, including those that have not been genetically engineered, is specially produced nowadays, in order to guarantee the maximum yield. It’s just that hardly anyone knows that. The image of the farmer who retains a part of his harvest and replants the kernels the following spring is very romantic, of course. But in the case of corn, for example, such behavior would be totally irrational, since he would then only be able to collect half of the potential yields. But farmers have to try to get as much out of their land as possible. When they don’t manage to do so in an economically efficient fashion, then they need subsidies. Of course, we could pay them such subsidies, in order for them to continue sowing seed that they have themselves harvested. But I don’t find this particularly shrewd.
FOCUS: You’re reputed to be a passionate cook and you’ve even published a cookbook. As a cook, what would you like to see done with biotechnology?
Nüsslein-Volhard: Sometimes I regret the fact that you can’t find certain old-fashioned sorts of fruit in the stores anymore, simply because they spoil too quickly. There are particularly tasty sorts of strawberries or sour cherries, for example, that don’t keep well. You can tell that many types of fruits and vegetables are cultivated for their robustness and the quantity of the yield, but not for their flavor. If it would be possible by using genetic engineering to make the tastier sort of strawberries keep longer, personally I’d have nothing against it. You can’t have everything. But by using genetic engineering you can perhaps have more.
Christiane Nüsslein-Volhard is the director of the Max Planck Institute for Developmental Biology in Tübingen. In 1995, she was awarded the Nobel Prize for Medicine. The above interview first appeared on the German news site [2] Focus-Online. The German version is available [3] here. The English translation is by John Rosenthal.
[References at the original link at the beginning]
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