Second Thoughts on Fluoride

Second Thoughts on Fluoride

New research indicates that a cavity-fighting treatment could be risky if overused

 
TOO MUCH OF A GOOD THING: Fluoride is in many foods, beverages and dental products. The ubiquity of the cavity-fighting chemical can result in overconsumption, particularly among young children.

• Researchers are intensifying their scrutiny of fluoride, which is added to most public water systems in the U.S. Some recent studies suggest that overconsumption of fluoride can raise the risks of disorders affecting teeth, bones, the brain and the thyroid gland.
• A 2006 report by a committee of the National Research Council recommended that the federal government lower its current limit for fluoride in drinking water because of health risks to both children and adults.

Long before the passionate debates over cigarettes, DDT, asbestos or the ozone hole, most Americans had heard of only one environmental health controversy: fluoridation. Starting in the 1950s, hundreds of communities across the U.S. became embroiled in heated battles over whether fluorides—ionic compounds containing the element fluorine—should be added to their water systems. On one side was a broad coalition of scientists from government and industry who argued that adding fluoride to drinking water would protect teeth against decay; on the other side were activists who contended that the risks of fluoridation were inadequately studied and that the practice amounted to compulsory medication and thus was a violation of civil liberties.

The advocates of fluoride eventually carried the day, in part by ridiculing opponents such as the right-wing John Birch Society, which called fluoridation a communist plot to poison America. Today almost 60 percent of the U.S. population drinks fluoridated water, including residents of 46 of the nation’s 50 largest cities. Outside the U.S., fluoridation has spread to Canada, the U.K., Australia, New Zealand and a few other countries. Critics of the practice have generally been dismissed as gadflies or zealots by mainstream researchers and public health agencies in those countries as well as the U.S. (In other nations, however, water fluoridation is rare and controversial.) The U.S. Centers for Disease Control and Prevention even lists water fluoridation as one of the 10 greatest health achievements of the 20th century, alongside vaccines and family planning.

Tumor Time Bombs Set Off by Stem Cells

Tumor Time Bombs Set Off by Stem Cells

Deadly call and response recruits stem cells to nourish ticking tumors

 
SLEEPERS: A new study reveals that blood vessel-forming stem cells from bone marrow (green) trigger the expansion of breast cancer cells (blue) that have budded off from the primary tumor.

Researchers say they have identified a switch that makes dormant breast cancer cells that have traveled to the lungs swell to lethal proportions—completing the dreaded process of metastasis or cancer spread. A team from Cold Spring Harbor Laboratory in Long Island, N.Y., reports that it staved off full-blown metastasis in mice by preventing mini-tumors in the lungs from recruiting stem cells called endothelial progenitors, which assemble into blood vessels to nourish the malignancy.

Researchers do not know if the same thing would work for other types of cancer or cancer cells lodged in other body organs. Still, they hope to discover drugs that could put the brakes on at least some metastases by short-circuiting the ability of endothelial progenitors to respond to chemical cues sent out by tumors.

As tumors grow and develop, they shed micro-metastases, clusters of a few cells that take up residence in far-flung organs such as the brain, liver and bone. Without new vessels to bring them fresh nutrient-rich blood, however, they may lay dormant for years before suddenly sprouting into macro-metastases large enough to damage organs and cause death.

"They're sleeping and suddenly they wake up, and that's very dangerous," says Cold Spring cancer biologist Vivek Mittal. Metastatic cancer is rarely curable.

To explain the so-called angiogenic switch, or sudden growth of new blood vessels, some have pointed to endothelial progenitors, which live in bone marrow but are found in more than half of all solid tumor types, says hematology oncologist Shahin Rafii of Weill Cornell Medical College in New York City. Their significance wasn't clear, though, given that they only account for 12 to 15 percent of a tumor's blood vessels.

To clarify their role, the Cold Spring group allowed breast tumors implanted in mice to form  micro-metastases in the lungs. The team then introduced short RNA molecules that deactivate a gene called Id1, which promotes angiogenesis and is active in endothelial progenitors.

Treated mice formed fewer tumors and showed less angiogenesis, and half survived to day 40, whereas all untreated mice died within 30 days, the group reports in Science. The treated mice also showed a 96 percent reduction in the flow of endothelial progenitors from bone marrow to lung.

"It's very novel," says Rafii, who was not involved in the study. "You shut off 12 percent of cells, and 50 percent of the mice survive much longer."

He says that the mechanism is unlikely to work in all tumor types or metastases, but that it is definitely worth exploring its potential ability to turn some fatal cancers into chronic diseases. "At least in mouse systems it works, so it has to be tested in humans eventually."

Of Ants, Elephants and Acacias: A Tale of Ironic Interdependence

Of Ants, Elephants and Acacias: A Tale of Ironic Interdependence

Without large grazing herbivores to eat them, acacia trees suffer because of a shift in the ant populations they house

 
ANTS AND ACACIA: These ants actually harm acacia in the absence of large herbivores by allowing infestations by other harmful insects, such as the parasitic scale bugs also pictured here.

 
BROWSE ME PLEASE: Without constant browsing by large herbivores, like the giraffes pictured here, the whistling thorn acacia also pictured suffers.

Acacia trees are the iconic shrub of the East African savanna. Their thorny thickets house a host of creatures and provide sustenance to the local charismatic megafauna, from elephants to zebras. In light of this continual foraging, the plants have struck a mutually beneficial bargain with several species of ants. The insect armies swarm intrusive browsers in exchange for housing and food. But according to new research in Science, it appears that without such browsing—a state of affairs the acacia might be thought to long for—the trees suffer.

Zoologist Todd Palmer and his colleagues examined the interdependence of one such acacia species—the whistling thorn tree, Acacia drepanolobium—the ants it hosts and the herbivores that eat it. He compared six such trees in Kenya that have been surrounded by an electrified fence since 1995 (by entomologist Truman Young of the University of California, Davis) with six trees open to local giraffes, elephants and other acacia-eaters.

In the absence of herbivores, the whistling acacia stopped producing little ant houses in hollow thorns—known as domatia—and excreting the sweet nectar that its bodyguard ants eat. But instead of spurring more growth, the acacias found themselves more than twice as likely to be providing a home to another type of ant—Crematogaster sjostedti—which do not defend the trees and rely on invasions of the bark-boring cerambycid beetle larvae to build the holes in which they dwell. "The cavity-nesting antagonistic ants actually promote the activities of the stem-boring beetle," says biologist Robert Pringle of Stanford University.

This, in turn, stunts the trees' growth and causes them to die twice as often than when they are being regularly eaten by giraffes, elephants and other large African herbivores. "The trees are actually making a shortsighted decision by defaulting on their end of the mutualism bargain," Pringle says. "If they sustained production of ant rewards in the absence of large mammals, they would reduce their probability of being taken over by this somewhat nasty antagonistic ant."

This counterintuitive result may apply only to the whistling thorn acacia, one of the only species of that genus in Africa that relies on ants as bodyguards rather than thorns and / or chemical defenses. After all, in the wake of disappearing large mammals across Africa, these other types of acacia have proliferated, says ecologist Jacob Goheen of the University of British Columbia.

But it does provide an example of how the disappearance or extinction of elephants, giraffes, zebras and other large herbivores in a region can have unexpected and unintended consequences—much like the boom in leaf-eating beetles and the lizards that prey on them shown in earlier work—whereas the decline of such mammals continues nearly continent-wide through the loss of habitat and overhunting.

"Large herbivores are tremendously important players in these systems," Pringle says. "Not just because of the direct effects they have upon plants, but also because of the myriad effects they exert on smaller, less conspicuous components of biodiversity." For want of an elephant, a protective ant species diminished and left the whistling thorn acacia in dire straits.

Great New Tool, or Great Risk?

Great New Tool, or Great Risk?

Wikis, blogs and other collaborative web technologies could usher in a new era of science. Or not.

The explosively growing World Wide Web has rapidly transformed retailing, publishing, personal communication and much more. Innovations such as e-commerce, blogging, downloading and open-source software have forced old-line institutions to adopt whole new ways of thinking, working and doing business.

Science could be next. A small but growing number of researchers--and not just the younger ones--have begun to carry out their work via the wide-open blogs, wikis and social networks of Web 2.0. And although their efforts are still too scattered to be called a movement--yet--their experiences to date suggest that this kind of Web-based "Science 2.0" is not only more collegial than the traditional variety, but considerably more productive.

"Science happens not just because of people doing experiments, but because they're discussing those experiments," explains Christopher Surridge, editor of the Web-based journal, Public Library of Science On-Line Edition (PLoS ONE). Critiquing, suggesting, sharing ideas and data--communication is the heart of science, the most powerful tool ever invented for correcting mistakes, building on colleagues' work and creating new knowledge. And not just communication in peer-reviewed papers; as important as those papers are, says Surridge, who publishes a lot of them, "they're effectively just snapshots of what the authors have done and thought at this moment in time. They are not collaborative beyond that, except for rudimentary mechanisms such as citations and letters to the editor."

The technologies of Web 2.0 open up a much richer dialog, says Bill Hooker, a postdoctoral cancer researcher at the Shriners Hospital for Children in Portland, Ore., and the author of a three-part survey of open-science efforts in the group blog, 3 Quarks Daily. "To me, opening up my lab notebook means giving people a window into what I'm doing every day. That's an immense leap forward in clarity. In a paper, I can see what you've done. But I don't know how many things you tried that didn’t work. It's those little details that become clear with open notebook, but are obscured by every other communication mechanism we have. It makes science more efficient." That jump in efficiency, in turn, could have huge payoffs for society, in everything from faster drug development to greater national competitiveness.

Of course, many scientists remain highly skeptical of such openness--especially in the hyper-competitive biomedical fields, where patents, promotion and tenure can hinge on being the first to publish a new discovery. From that perspective, Science 2.0 seems dangerous: using blogs and social networks for your serious work feels like an open invitation to have your online lab notebooks vandalized--or worse, have your best ideas stolen and published by a rival.

To Science 2.0 advocates, however, that atmosphere of suspicion and mistrust is an ally. "When you do your work online, out in the open,” Hooker says, “you quickly find that you're not competing with other scientists anymore, but cooperating with them."

Rousing Success
In principle, says PLoS ONE's Surridge, scientists should find the transition to Web 2.0 perfectly natural. After all, since the time of Galileo and Newton, scientists have built up their knowledge about the world by "crowd-sourcing" the contributions of many researchers and then refining that knowledge through open debate. "Web 2.0 fits so perfectly with the way science works, it's not whether the transition will happen but how fast," he says.

The OpenWetWare project at MIT is an early success. Launched in the spring of 2005 by graduate students working for MIT biological engineers Drew Endy and Thomas Knight, who collaborate on synthetic biology, the project was originally seen as just a better way to keep the two labs' Web sites up to date. OpenWetWare is a wiki--a collaborative Web site that can be edited by anyone who has access to it; it even uses the same software that underlies the online encyclopedia Wikipedia. Students happily started posting pages introducing themselves and their research, without having to wait for a Webmaster to do it for them.

But then, users discovered that the wiki was also a convenient place to post what they were learning about lab techniques: manipulating and analyzing DNA, getting cell cultures to grow. “A lot of the 'how-to' gets passed around as lore in biology labs, and never makes it into the protocol manuals," says Jason Kelly, a graduate student of Endy's who now sits on the OpenWetWare steering committee. "But we didn't have that." Most of the students came from a background in engineering; theirs was a young lab with almost no mentors. So whenever a student or postdoc managed to stumble through a new protocol, he or she would write it all down on a wiki page before the lessons were forgotten. Others would then add whatever new tricks they had learned. This was not altruism, notes steering-committee member Reshma Shetty. "The information was actually useful to me." But by helping herself, she adds, "that information also became available around the world."

Indeed, Kelly points out, "Most of our new users came to us because they'd been searching Google for information on a protocol, found it posted on our site, and said 'Hey!' As more and more labs got on, it became pretty apparent that there were lots of other interesting things they could do."

Classes, for example. Instead of making do with a static Web page posted by a professor, users began to create dynamically evolving class sites where they could post lab results, ask questions, discuss the answers and even write collaborative essays. "And all stayed on the site, where it made the class better for next year," says Shetty, who has created an OpenWetWare template for creating such class sites.

Laboratory management benefited too. "I didn't even know what a wiki was," recalls Maureen Hoatlin of the Oregon Health & Science University in Portland, where she runs a lab studying the genetic disorder Fanconi anemia. But she did know that the frenetic pace of research in her field was making it harder to keep up with what her own team members were doing, much less Fanconi researchers elsewhere. "I was looking for a tool that would help me organize all that information," Hoatlin says. "I wanted it to be Web-based, because I travel a lot and needed to access it from wherever I was. And I wanted something my collaborators and group members could add to dynamically, so that whatever I saw on that Web page would be the most recently updated version."

OpenWetWare, which Hoatlin saw in the spring of 2006, fit the bill perfectly. "The transparency turned out to be very powerful," she says. "I came to love the interaction, the fact that people in other labs could comment on what we do and vice versa. When I see how fast that is, and its power to move science forward--there is nothing like it."

Numerous others now work through OpenWetWare to coordinate research. SyntheticBiology.org, one of the site's most active interest groups, currently comprises six laboratories in three states, and includes postings about jobs, meetings, discussions of ethics, and much more.

In short, OpenWetWare has quickly grown into a social network catering to a wide cross-section of biologists and biological engineers. It currently encompasses laboratories on five continents, dozens of courses and interest groups, and hundreds of protocol discussions--more than 6100 Web pages edited by 3,000 registered users. A May 2007 grant from the National Science Foundation launched the OpenWetWare team on a five-year effort to transform OpenWetWare to a self-sustaining community independent of its current base at MIT. The grant will also support development of many new practical tools, such as ways to interface biological databases with the wiki, as well as creation of a generic version of OpenWetWare that can be used by other research communities such as neuroscience, as well as by individual investigators.

Skepticism Persists
For all the participants' enthusiasm, however, this wide-open approach to science still faces intense skepticism. Even Hoatlin found the openness unnerving at first. "Now I'm converted to open wikis for everything possible," she says. "But when I originally joined I wanted to keep everything private"--not least to keep her lab pages from getting trashed by some random hacker. She did not relax until she began to understand the system's built-in safeguards.

First and foremost, says MIT's Kelly, "you can't hide behind anonymity." By default, OpenWetWare pages are visible to anyone (although researchers have the option to make pages private.) But unlike the oft-defaced Wikipedia, the system will let users make changes only after they have registered and established that they belong to a legitimate research organization. "We've never yet had a case of vandalism," Kelly says. Even if they did, the wiki automatically maintains a copy of every version of every page posted: "You could always just roll back the damage with a click of your mouse."

Unfortunately, this kind of technical safeguard does little to address a second concern: Getting scooped and losing the credit. "That's the first argument people bring to the table," says Drexel University chemist Jean-Claude Bradley, who created his independent laboratory wiki, UsefulChem, in December 2005. Even if incidents are rare in reality, Bradley says, everyone has heard a story, which is enough to keep most scientists from even discussing their unpublished work too freely, much less posting it on the Internet.

However, the Web provides better protection that the traditional journal system, Bradley maintains. Every change on a wiki gets a time-stamp, he notes, “so if someone actually did try to scoop you, it would be very easy to prove your priority--and to embarrass them. I think that's really what is going to drive open science: the fear factor. If you wait for the journals, your work won't appear for another six to nine months. But with open science, your claim to priority is out there right away."

Under Bradley's radically transparent "open notebook" approach, as he calls it, everything goes online: experimental protocols, successful outcomes, failed attempts, even discussions of papers being prepared for publication. "A simple wiki makes an almost perfect lab notebook," he declares. The time-stamps on every entry not only establish priority, but allow anyone to track the contributions of every person, even in a large collaboration.

Bradley concedes that there are sometimes legitimate reasons for researchers to think twice about being so open. If work involves patients or other human subjects, for example, privacy is obviously a concern. And if you think your work might lead to a patent, it is still not clear that the patent office will accept a wiki posting as proof of your priority. Until that is sorted out, he says, "the typical legal advice is: do not disclose your ideas before you file."

Still, Bradley says the more open scientists are, the better. When he started UsefulChem, for example, his lab was investigating the synthesis of drugs to fight diseases such as malaria. But because search engines could index what his team was doing without needing a bunch of passwords, "we suddenly found people discovering us on Google and wanting to work together. The National Cancer Institute contacted me wanting to test our compounds as anti-tumor agents. Rajarshi Guha at Indiana University offered to help us do calculations about docking--figuring out which molecules will be reactive. And there were others. So now we're not just one lab doing research, but a network of labs collaborating."

Blogophobia
Although wikis are gaining, scientists have been strikingly slow to embrace one of the most popular Web 2.0 applications: Web logging, or blogging.

"It's so antithetical to the way scientists are trained," Duke University geneticist Huntington F. Willard said at the April 2007 North Carolina Science Blogging Conference, one of the first national gatherings devoted to this topic. The whole point of blogging is spontaneity--getting your ideas out there quickly, even at the risk of being wrong or incomplete. "But to a scientist, that's a tough jump to make," says Willard, head of Duke's Institute for Genome Sciences & Policy. "When we publish things, by and large, we've gone through a very long process of drafting a paper and getting it peer reviewed. Every word is carefully chosen, because it's going to stay there for all time. No one wants to read, 'Contrary to the result of Willard and his colleagues…’."

Still, Willard favors blogging. As a frequent author of newspaper op-ed pieces, he feels that scientists should make their voices heard in every responsible way possible. Blogging is slowly beginning to catch on; because most blogs allow outsiders to comment on the individual posts, they have proved to be a good medium for brainstorming and discussions of all kinds. Bradley's UsefulChem blog is an example. Paul Bracher's Chembark is another. "Chembark has morphed into the water cooler of chemistry," says Bracher, who is pursuing his Ph.D. in that field at Harvard University. "The conversations are: What should the research agencies be funding? What is the proper way to manage a lab? What types of behavior do you admire in a boss? But instead of having five people around a single water cooler you have hundreds of people around the world."

Of course, for many members of Bracher's primary audience--young scientists still struggling to get tenure--those discussions can look like a minefield. A fair number of the participants use pseudonyms, out of fear that a comment might offend some professor's sensibilities, hurting a student’s chances of getting a job later. Other potential participants never get involved because they feel that time spent with the online community is time not spent on cranking out that next publication. "The peer-reviewed paper is the cornerstone of jobs and promotion," says PLoS ONE's Surridge. "Scientists don't blog because they get no credit."

The credit-assignment problem is one of the biggest barriers to the widespread adoption of blogging or any other aspect of Science 2.0, agrees Timo Hannay, head of Web publishing at the Nature Publishing Group in London. (That group's parent company, Macmillan, also owns Scientific American.) Once again, however, the technology itself may help. "Nobody believes that a scientist's only contribution is from the papers he or she publishes," Hannay says. "People understand that a good scientist also gives talks at conferences, shares ideas, takes a leadership role in the community. It's just that publications were always the one thing you could measure. Now, however, as more of this informal communication goes on line, that will get easier to measure too."

Collaboration the Payoff
The acceptance of any such measure would require a big change in the culture of academic science. But for Science 2.0 advocates, the real significance of Web technologies is their potential to move researchers away from an obsessive focus on priority and publication, toward the kind of openness and community that were supposed to be the hallmark of science in the first place. "I don't see the disappearance of the formal research paper anytime soon," Surridge says. "But I do see the growth of lots more collaborative activity building up to publication." And afterwards as well: PLoS ONE not only allows users to annotate and comment on the papers it publishes online, but to rate the papers' quality on a scale of 1 to 5.

Meanwhile, Hannay has been taking the Nature group into the Web 2.0 world aggressively. "Our real mission isn't to publish journals, but to facilitate scientific communication," he says. "We've recognized that the Web can completely change the way that communication happens." Among the efforts are Nature Network, a social network designed for scientists; Connotea, a social bookmarking site patterned on the popular site del.icio.us, but optimized for the management of research references; and even an experiment in open peer review, with pre-publication manuscripts made available for public comment.

Indeed, says Bora Zivkovic, a circadian rhythm expert who writes at Blog Around the Clock, and who is the Online Community Manager for PLoS ONE, the various experiments in Science 2.0 are now proliferating so rapidly that it is almost impossible to keep track of them. "It's a Darwinian process," he says. "About 99 percent of these ideas are going to die. But some will emerge and spread."

"I wouldn't like to predict where all this is going to go," Hooker adds. "But I'd be happy to bet that we're going to like it when we get there."

For Remote-Control Cells, Just Add Magnets

For Remote-Control Cells, Just Add Magnets

Magnetic particles turn cell signals on and off 

 
MAGNET THERAPY: A new technique for activating cells' internal communication networks uses a magnet to bring together protein receptors on the cell surface that are linked to iron oxide beads.
Courtesy Donald Ingber

A new study suggests that to meld living cells with the digital world, think of them as you would a refrigerator door—a handy place to stick magnets.

Researchers report in Nature Nanotechnology that they triggered immune system cells to begin a biochemical process that produces histamine (the chemical responsible for allergic responses) by dusting them with iron particles and applying a magnetic field.

They say the technique could lead to lighter weight, lower power biosensors for detecting pathogens, or novel ways of delivering drugs to specific parts of the body—if not the healing powers sometimes attributed to magnetism. "The idea was, could you actually have an interface with living cells that would be analogous to a machine interface or a computer interface," says cell biologist Donald Ingber of Harvard Medical School and Children's Hospital Boston.

Cells are studded with a variety of receptor proteins that activate when certain molecules latch onto them, triggering a cascade of biochemical events inside the cells that result in actions such as the secretion of hormones or destruction of pathogens.

In order to send such a signal, receptors often must also knock into one another. Ingber and his colleagues sought to magnetically induce this jostling by coating particles of iron oxide with dinitrophenyl (DNP) molecules that attach to the receptors on histamine-producing mast cells.

The 30-nanometer-wide iron oxide beads (about the size of a virus) were superparamagnetic, or capable of repeatedly becoming magnetic in the presence of a true magnet. When magnetized, the beads would attract one another, forcing the receptors to huddle and activate.

The researchers report that when they switched on an electromagnet near the coated cells, there was a spike in the calcium levels inside them, which is the first step in the histamine secretion process. The spike ended when they switched off the magnet. The results demonstrate "unprecedented control" over individual cell receptors using an electromagnetic field, University of Pennsylvania bioengineer Christopher Chen wrote in an editorial accompanying the study.

Ingber envisions one day using a similar trick to create pacemaker-like systems for regulating insulin levels in the blood or to deliver antidotes to soldiers exposed to chemical or biological weapons. But first, he notes, researchers will have to see if they can apply the process to other cells and get the desired effects.