Issue | April 2004 | April 2004 | The Scientist Magazine®

Features

Susan Warner | Apr 25, 2004 | 10+ min read

PictureQuestA plain tablet in a no-name blisterpack. It could save a life.Or maybe not.Since 1994, the Food and Drug Administration has approved year-to-year increases in the number of new candidate drugs for human testing in the United States, rising from 3,350 in 1996 to 3,900 in 2002.1 But the number of drugs that successfully negotiate the trial process and ultimately receive FDA approval is frustratingly low. Despite pharmaceutical companies' and the National Institutes of Health's research

From P Values to Bayesian Statistics, It's All in the Numbers

Steven Ross | Apr 25, 2004 | 4 min read

On first consideration, it seems a straightforward question: How effective and safe is drug A in treating condition B? But the design and analysis of the clinical trials that set out to answer this question are far from straightforward, involving an overwhelming number of variables.First, the subjects: Any group of human beings will show boundless variation in terms of both genetic makeup and non-genetic variation, such as age and lifestyle.Then the disease: Behind the convenient categorization,

Editorial

Pharma Should Publish Its Trial Results

I recently listened to a panel discussion on the future of biomedical science. The standout participant, an urbane and knowledgeable contributor, was the CEO of a major pharmaceutical company. He won the audience over with his optimistic vision for the future of drug development, his conviction of the necessity of collaboration between academia and industry, and his characterization of the high ethical standards that his company and the industry in general have met.My interest piqued by this and

Opinion

Are Pharmaceutical Company Mergers Rational?

Brad FitzpatrickAfter decades of relative stability, pharmaceutical industry mergers burgeoned about 15 years ago in three distinct waves. The first occurred in the late 1980s/early 1990s, the second happened a few years later, and the third at the beginning of this century. The first wave involved Bristol-Myers Squibb and Smith-Kline Beecham. The second saw: in 1994, American Home Products join with Ayerst and Wyeth, two subsidiaries that had been run independently; in 1995, Glaxo Wellcome, Pha

Letter

On Textbook Publishing

I was happy to see the flowchart for tracking a textbook up to its publication,1 but I think one important aspect of the publication process was missing from the chart. Your flowchart is missing the construction of an index to the material. Information is useless if it can't be located when it's needed. The writing of an index belongs in the chart just before the printing stage. Indexes are important to the reader, and because librarians and textbook purchasing groups use them when evaluating bo

Feared Science Rules

The idea that the "feared rules" addressed by Peg Brickley1 offer "scientists a comfort level" is certainly novel. The rules of the USA Patriot Act, and the sometime-Draconian enforcement measures that accompany them, focus attention on the easy targets, but may fail to attack the real problem. They look good politically, they suggest accomplishment to the uninformed, but may contribute minimally to national security.Ms. Brickley quotes NCID's Charles Schable as saying that current policies keep

Alone

The recent article "Assessing Amyloid β"1 discusses recent evidence for a physiological role for amyloid-β. Surprisingly, given such a role, the potential danger of removing this physiological protein is scant. However, this is exactly what the next generation "treatment" strategies are targeting. The termination of the initial clinical trial utilizing such a strategy due to side effects of brain inflammation may, however, be a direct consequence of removing physiologically useful amyl

Criticizing the Critics

Your article about British science1 misrepresented our Joint Code of Practice for Research. Far from wishing to "regulate" scientists or drown them in red tape, the Code of Practice is a significant and straightforward way in which we are striving to rebuild public confidence in science. We believe it is in everyone's interest that we ensure the highest quality standards in UK research.The criticisms in the article would perhaps be fair if, as the article suggests, our Code of Practice was a com

The Back and Forth on Open Access

After reading your article about open access1, the first thing that comes to mind is: What can I do to help this movement?I am a professor of Human Anatomy and Physiology and Exercise Physiology primarily involved in teaching. I often like to use examples of cutting-edge research in class. I come across many abstracts with relevant findings [but] I can't review the entire paper because my university doesn't have a subscription to that particular journal online. I find this appalling, especially

Snapshot

Aging Gracefully, Retiring Reluctantly

Of the 262 readers who participated in our survey, 63% have plans to retire at age 65 or later, and a hardy 10% want to stop working after 75, or not at all. Even among the 45 and younger set, 56% plan to retire at 65 or later. At the spectrum's other end, 20% of this age group expects to call it quits before reaching 60.How our readers think they will spend their retirement covers the gamut, from doing volunteer work to opening a microbrewery. Some are obviously dreaming: "Maybe my kids will su

5-Prime

Science and the Golden Years

1. What does it mean to age?More than just annual birthday parties, wrinkles, and gray hairs, aging has two main components: primary aging, which is the natural process of senescence; and secondary aging, due to age-related diseases such as cancer, Alzheimer's, Parkinson's, osteoporosis, osteoarthritis, and macular degeneration.2. What's responsible for aging in humans?Outside of gender (see next question) only 25% of lifespan variability is due to genetics; the rest depends on behavior and the

Frontlines

Reading Eukaryotic Barcodes

If cereal can be barcoded, so can Daphnia or a butterfly, or a hummingbird, or any eukaryotes. A worldwide consortium of research organizations, led by the Smithsonian's National Museum of Natural History (NMNH), has begun a 2 1/2-year project with $669,000 in seed money from the Sloan Foundation, which they hope will lead to a relatively simple, fast, and cheap way of identifying eukaryotic organisms in the field.The point of the Barcode of Life Initiative, to be based at NMNH, is to sequence o

The Physics of Footwear

Erica P. JohnsonTo bring scientific concepts into the mainstream, sometimes explaining popular culture helps. Inspired by TV's Sex and the City and its heroine, Carrie, who often wobbles around in designer shoes, Paul Stevenson at the UK-based Institute of Physics developed a formula to determine the maximum "safe" height for such footwear. Stevenson, of the University of Surrey, wanted to see just how high Carrie could go. "As you get up in a high heel," Stevenson says, "your base of support is

Foundations

The Day the Earth Stood Still

Courtesy of Harry Ransom Center, U of Texas at AustinThere are many milestones on the road to modern science, but few equal the summer afternoon in 1826 when French inventor Joseph Nicephore Niepce (1765–1833) captured the first permanent image. Niepce, a tinkerer and amateur scientist, set out to automate the lithography process in 1812. Experiments with various acids and other substances failed. Still tinkering 15 years later, he set up a pewter plate layered with photosensitive bitumen

First Person

J. Craig Venter

Do you believe that biological production of hydrogen will exist someday?File PhotoMolecular biologist J. Craig Venter is a scientist whose status transcends his own circle. Within the last year, Venter has been interviewed or mentioned in dozens of newspaper stories. His bold, singular scientific adventures generate comment and criticism, and his direct, conversational approach sounds more plebian than patrician. He's not a man who readily bows to barriers, a quality the press finds irresistibl

Research

Scouring Sequences for the Fountain of Youth

"EVERY man desires to live long; but no man would be old," wrote Jonathan Swift. In the quest to live life long and well, people have consumed everything from turtle soup to owl meat to gladiator's blood. Russian French microbiologist Ilya Mechnikov thought a human could live for 150 years on a steady diet of milk cultured with bacteria (he died at 71). While the Internet offers a wide variety of products for fountain-of-youth seekers, some researchers have turned their attention to the genes (s

Enter the Matrix

WHAT A TANGLED WEB:Courtesy of Philip B. MessersmithFibroblasts are cellular workhorses of extracellular matrix production, spinning out the majority of collagens, the most abundant proteins in the animal kingdom.Appreciation in biology can come slowly. Researchers once deemed as junk the parts of genes not represented in proteins; likewise, neuroglia were thought to be mere bystanders to neurons. So it is with the extracellular matrix (ECM), the "scaffolding" and "glue" that fill the spaces amo

More Than Skin Deep

© 2003 Massachusetts Medical SocietyPsoriatic skin and an immune synapse (Inset). (From T.S. Kupper, N Eng J Med, 349:1987–90, 2003.)The red, cracked, and bleeding scales of psoriasis appear on the scalps, knees, elbows, and trunks of 2% of the global population. Psoriasis is more than the annoying skin condition portrayed in the 1960s-era advertisements bemoaning "the heartbreak of psoriasis." Understanding the immunological underpinnings of the disease has spawned new treatments and

o's Imprint

SELECTIVE PRESSURE:Courtesy of Richard DaviesInvertebrate seed predators, like this Alcidodes ramezii from Thailand, may exert selective pressure influencing El Niño-associated dipterocarp bumper crops.Human activities often disrupt the delicate balance between predators and prey, but an unusual example has come to light among the equatorial rainforests of Indonesia. Dipterocarp, the economically important canopy trees that account for 70% of the region's biomass, are vanishing. Indeed, pro

Hot Paper

Melanopsin Lights the Way

THE EYES HAVE IT-SO DOES THE BRAIN:Courtesy Samer HattarAt top left, an X-gal stained retina from a mouse heterozygous for a LacZ knockin at the melanopsin locus reveals axons coursing toward the optic disc. At top right, a melanopsin antibody labels cell bodies, dendrites and initial axon segments of roughly 1% of ganglion cells in the rat retina. At bottom left, a coronal section from the brain of a heterozygous animal shows bilateral innervation of the suprachiasmatic nucleus (SCN). At bottom

Vision

SIR2

WITHSTANDING FEAST AND FAMINE:Courtesy of Leonard P. GuarenteYeast form dormant spores during times of starvation in order to survive for future times of plenty. The cycle between diploid a/α cells and haploid spores is regulated by SIR2 and the related gene HST1.Since the dawn of consciousness, humans have been in a unique position to contemplate their own mortality. While this exercise has been a boon to philosophical musings, it has not led to any real scientific progress in understandin

Briefs

The Immunity Job

Courtesy of Jessica BonameLike the impossibly well-funded thieves from a good heist film, viruses pull immune-escape strategies from a deep bag of tricks. Murine γ-herpesvirus-68 (MHV-68) fine-tunes its attack on MHC class I molecules by degrading components of the complex that loads them with peptides.1"There's the primary targeting of the class I heavy chain," says Jessica Boname, in Philip Stevenson's lab at the University of Cambridge, who showed previously that MHV-68's MK3 protein dir

Particulate Matters

Courtesy of Almut MeckeRemoving the positive charge on nanoparticles can improve their chemotherapeutic efficiency, say investigators at the University of Michigan, Ann Arbor. Research presented in March at the annual meeting of the American Physical Society in Montreal showed that without the positive charge, the drug-carrying nanoparticles are less likely to be taken up by normal cells and more likely to be taken up by cancer cells.1 "That way we can direct them to tumor cells and decrease the

HDAC Confidential

Courtesy of David S. GoodsellHistone deacetylases (HDACs), closely associated with gene silencing, may have a broader role in the cell than previously thought. Research suggests that HDACs have been misclassified simply because histones were the first substrates identified for these enzymes.Holly Goodson and colleagues, University of Notre Dame, dug through genome databases and characterized the prokaryotic distribution of HDAC homologs, providing evidence that these proteins predate eukaryote e

Patent Watch

Shining the Light on Nanofabrication

With its name, it's probably no surprise that San Diego-based Nanogen http://www.nanogen.com has quickly amassed a portfolio of patents covering nanoassembly. "We were very lucky because we have incredibly early priority on this," says Nanogen cofounder Michael Heller, of a trio of now-patented nanofabrication methods.In January, Patent Watch highlighted patent 6,652,808 for a method that allows for the self-assembly of DNA particles on preformed motherboard substrates.1 Like this and the other

Tech Watch

Scientists Unveil Mouse Chromosome Substitution Panel

Tracking down the genes behind non-Mendelian traits can be complicated given the sheer numbers of genes involved. Now Eric Lander of the Whitehead Institute for Biomedical Research, Cambridge, Mass., Joseph Nadeau of Case Western Reserve University, Cleveland, Ohio, and colleagues have created a resource that could make the job easier.1The researchers bred a series of 22 C57BL/6J mouse strains, each containing a single chromosome or mitochondrial DNA from an A/J donor. This chromosomal substitut

Software Watch

To siRNA with Love

Just as the use of RNA interference has mushroomed throughout the world over the last six years, the number of bioinformatics tools to screen for siRNA has blossomed, too. More than a half-dozen proprietary and open-source programs are available, many sponsored by siRNA and reagent vendors.So Jonathan Rux, a bioinformatician at the Wistar Institute at the University of Pennsylvania, was surprised to find that all these resources lacked a critical tool: They didn't account for gene specificity. S

Technology

Rendering Images in 3-D

INSIDE THE MIND OF A FLY:Courtesy of Rachel JoynesDorsoventral view of a thin section through the larval central nervous system of the fruit fly, stained in red for serotonin, and in green for dopaminergic and sertonergic neurons. The cell bodies are at the lower ventral part of the photos, and above the cell bodies is an extensive array of synaptic varicosities.To the uninitiated, three-dimensional microscopy makes the pretty pictures of fluorescently labeled cells that grace the covers of scie

Improving the Lives of Laboratory Animals

DigitalVisionPhysically and behaviorally, few creatures have been measured, tested, and probed as much as the laboratory mouse. Yet what do scientists know about making mice happy or free of pain? Often, the answer is not nearly enough. This is a knowledge vacuum with ethical and experimental ramifications.Pain management and environmental enrichment are hot topics in laboratory animal science. They are also conundrums defying easy fixes. Researchers may want to mitigate pain and suffering in th

Tools and Technology

Electroporation and the Single Cell

ELECTROPORATION ACTION:Courtesy of James Rae, The Mayo Clinic, Rochester, Minn.At left, two α-Tn4 cells in the process of completing cell division. Each contains the protein products encoded by ECFP-vimentin and dsRed1-mito plasmids electroporated into one of the cells on consecutive days. At right, an example of successful serial single-cell electroporation on three consecutive days. The plasmids used: dsRed1-mito on day one, EYFP-Golgi on day two, and ECFP-vimentin on day three.To date, e

Caliper Upgrades Microfluidics Platform

Courtesy of Caliper Life SciencesMaking its latest foray into the microfluidics ring, Hopkinton, Mass.-based Caliper Life Sciences http://www.caliperls.com has introduced the new LabChip 3000 Drug Discovery System, a second-generation tool that builds on the foundation laid by its predecessor, the Caliper 250.Intended for high-throughput drug-detection studies, including a range of assay applications such as kinases, proteases, and phosphatases, the LabChip 3000 is both smaller and easier to use

A DNA Vending Machine

Courtesy of GenVaultEvery year, the Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey preserves 3,000 DNA samples, each bathed in liquid nitrogen in ever-expanding banks of freezers."The samples are a national resource for research and a database of baseline information for studying new diseases or epidemics," explains Geraldine McQuillan, senior infectious disease epidemiologist at the CDC's National Center for Health Statistics, which runs the survey

Tip Trove

Imagining Science

Courtesy of Neurosciences InstituteScience is imagination in the service of the verifiable truth. Its satisfactions come from the realization of imagination in well-designed experiments. That realization is like the satisfactory scratching of a mental itch. If you lose the itch or you feel that the mere working out of details will not scratch the itch you have, it is time to consider changing fields.- Gerald Edelman, 1972 Nobelist and director of the Neurosciences Institute in San Diego

Data Points

Full Speed Ahead

Moved to LearnFrancesco FiondellaThe number of foreign students enrolled in EU colleges and universities in 1999In OverdriveAverage annual real growth of seed and start-up venture capital investment, 1995 to 2001

Profession

French Government Concedes to Researchers

Courtesy of Agnès Anne/LEM P7During a day of mourning marking a three-month protest by French researchers, a brass band played a requiem as a living effigy of Louis Pasteur emerged from a Paris Metro station to mourn the "death" of French science reportedly brought about by government budget cuts and belt-tightening. This ghost of Pasteur declared himself revolted by the fate of the nation's young researchers: "They will discover the drugs and vaccines of tomorrow, but they are thrown away

Managing Academic Lab Recruitment

A good marketing plan is essential if you want a shot at hiring top research talent, says Maurice P. Boland, acting vice president for research at the University College Dublin. One of the most important parts of the plan starts with internal university work: building infrastructure, and lobbying nationally for funding. "It comes down to how well the applicant perceives the program they are going into, and ... the infrastructure, and how well the applicant sees the leadership from the top," Bola

Postdoc Talk

Universities Segregate Stem Cell Research

The Bush Administration ban on federal funding for research involving human embryonic stem cell lines created after Aug. 6, 2001 has presented scientists with practical problems, as well as moral and ethical dilemmas. According to the policy, no federal dollars can feed work on new lines of human embryonic stem cells. Such research could hold hope for patients with Alzheimer and Parkinson diseases, diabetes, spinal cord injuries, and other afflictions.Now that private and state funds are arrivin

Getting Over Academic Science

Since the 11th grade, I wanted to be a research scientist. In college, I was always looking for opportunities to get involved in research, and by the time I finished my bachelor's degree I was headed to what I thought was intellectual heaven: graduate school! There, my colleagues and I learned that higher education is a grind; many either quit or failed to cut the mustard. Nevertheless, throughout graduate school, my professors encouraged me to prepare for a postdoctoral fellowship and the ultim

Closing Bell

Rituals and Deities in the Lab

As a young postdoc, I accidentally stumbled upon the secret to getting my protein preps to work; unfortunately, my solution is unpublishable. It's an unnamed, hand-sized, stuffed purple dragon with a fuzzy mane and shiny wings. I got it at a museum gift shop on a particularly bad protein-prep day. Something, I have no clue what, told me to buy it. When I returned to the lab, magic started happening. I had thought all my protein had precipitated, but it was back in solution. My column, which I ha