Science Weekly: The world’s first artificial life form

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Alok Jha and an expert panel discuss the significance of Craig Venter’s creation of artificial life

Science Weekly Extra: Craig Venter announces a synthetic life form

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The full-length press conference at which Craig Venter announced the creation of a synthetic life form

From the mind of a genius……………limited only by.his imagination …..

impressively creative …Craig Ventor……….has done it again!

Starting from scratch: Scientists rebooted bacterial cells by transplanting a synthetic version of the Mycoplasma mycoides genome manufactured in the lab. The synthetic genome includes a marker gene that makes a blue compound, so the synthetic cells form blue colonies (top). The naturally occurring M. mycoides genome lacks that gene, so the wild-type cells form white colonies (bottom).      Credit: Science/AAAS

A genome built from scratch is a step toward synthesizing novel organisms

MIT Technology Review, May 21, 2010, by Jocelyn Rice  –   A genome built from scratch is a step toward synthesizing novel organisms.

In the culmination of a project spanning 15 years, scientists at the J. Craig Venter Institute have engineered the first cell controlled by a synthetic genome.

“This is the first time that the information of a genome sequence has been turned back into life,” says Chris Voigt, a synthetic biologist at the University of California, San Francisco, who was not involved in the project. “It’s really remarkable.”

Using a method developed in 2008, the researchers, led by genomics pioneer Craig Venter, synthesized the genome of a tiny bacterium called Mycoplasma mycoides, containing just over a million DNA base pairs. Next they transplanted the synthetic genome into a related bacterium, Mycoplasma capricolum, in a process they had previously perfected using nonsynthetic chromosomes.

Once the recipient cells incorporated the synthetic genome, they immediately began to carry out the instructions encoded within the genome. The cells manufactured only M. mycoides proteins, and within a few rounds of self-replication, all traces of the recipient species were gone. The results were published Thursday in the online edition of the journal Science.

To distinguish their synthetic genome from the naturally occurring version, the researchers encoded a series of watermarks into the sequence. They began by developing a code for writing the English alphabet, as well as punctuation and numbers, into the language of DNA–a decoding key is included in the sequence itself. Then they wrote in their names, a few quotations, and the address for a website people can visit if they successfully crack the code.

In terms of creating synthetic life, this project is a proof of principle: aside from the watermarks and a handful of gene deletions to reduce the species’ ability to cause disease, the synthetic genome essentially recreates a naturally occurring one. Venter hopes that in the future, the synthetic genomic technology can be used to design and develop entirely new organisms, with wide-ranging practical applications.

Venter and his colleagues are working with Novartis and the National Institutes of Health to synthesize cassettes–clusters of genes that could be inserted into a synthetic genome–for every known flu virus in an effort to streamline the vaccine manufacturing process. They envision a system where, if a new strain such as H1N1 emerged, developing a vaccine would be as straightforward as shuffling genes encoding the relevant viral fragments into a synthetic genome. This could then yield a cell that could be used to quickly manufacture the product.

The researchers are also collaborating with ExxonMobil to overhaul algal cells into living fuel factories that would efficiently convert carbon dioxide into hydrocarbons that could be processed in refineries. “There are no existing cells that we’ve been able to find that do that process efficiently enough to make it economically viable,” says Venter.

Other potential applications include designing synthetic microbes that could purify water or manufacture chemicals or food ingredients. “I predict within a decade, any cell that’s used in industrial processes will be made synthetically,” says Venter.

To this end, the researchers plan to eventually develop a kind of universal recipient cell that could “boot up” any donor genome. The transplant process has proven to be the most technically challenging aspect of building a synthetic cell, says Venter, and it would be ideal to avoid a new round of troubleshooting for each new system that is developed.

For now, says Voigt, the biggest hurdle in realizing the potential of synthetic genomics is the gap between our ability to synthesize DNA and our ability to design it. “That’s going to be the next generation of research,” he says. “The technology around building DNA is mature now, and it’s going to be the toolbox to design it that comes next.”

Beyond practical applications, Venter also hopes that synthetic cells will help elucidate the basics workings of life, perhaps allowing researchers to decipher exactly what every component of a bacterial cell does. Although the genomes of countless organisms have now been sequenced, says Venter, we still don’t fully understand how even the simplest life forms function. “We want to try to make one of these cells the best-understood cellular system in biology,” he says.

Venter also points to what the cells–powered by genomes made in a lab from four bottles of chemicals, based on instructions stored on a computer–reveal about what life is. “This is as much a philosophical as a technological advance,” he says. “The notion that this is possible means bacterial cells are software-driven biological machines. If you change the software, you build a new machine. I’m still amazed by it.”

The development highlights the fact that we are moving out of the era where cells and DNA must be physically transferred from one location to another, says Voigt, to one in which biology is an information science. It would now be possible to sequence an organism’s genome in San Francisco, e-mail the sequence across the country, and bring that organism into being in a lab in Maryland. “Just the information alone is able to reconstruct that organism and convert it back into life,” says Voigt.

J. Craig Venter, Ph.D. 
Founder, Chairman & President
J. Craig Venter Institute 

Dr. Venter was honored in April as the 2010 Scientist of the Year.  Dr. Venter is regarded as one of the leading scientists of the 21st century for his numerous invaluable contributions to genomic research. He is Founder, Chairman, and President of the J. Craig Venter Institute (JCVI), a not-for-profit, research organization with approximately 400 scientists and staff dedicated to human, microbial, plant and environmental genomic research, the exploration of social and ethical issues in genomics, and to seeking alternative energy solutions through genomics.

Dr. Venter is also Founder and CEO of Synthetic Genomics Inc., a privately held company dedicated to commercializing genomic-driven solutions to address global energy and environmental challenges.

Dr. Venter began his formal education after a tour of duty as a Navy Corpsman in Vietnam from 1967 to 1968. After earning both a Bachelor’s degree in Biochemistry and a Ph.D. in Physiology and Pharmacology from the University of California at San Diego, he was appointed professor at the State University of New York at Buffalo and the Roswell Park Cancer Institute.  In 1984, he moved to the National Institutes of Health campus where he developed Expressed Sequence Tags or ESTs, a revolutionary new strategy for rapid gene discovery. In 1992 Dr. Venter founded The Institute for Genomic Research (TIGR), a not-for-profit research institute, where in 1995 he and his team decoded the genome of the first free-living organism, the bacterium Haemophilus influenzae, using his new whole genome shotgun technique. 

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed. This research culminated with the February 2001 publication of the human genome in the journal, Science.  He and his team at Celera also sequenced the fruit fly, mouse and rat genomes. 

Dr. Venter and his team at the Venter Institute continue to blaze new trails in genomics research having sequenced hundreds of genomes, and have published numerous important papers covering such areas as environmental genomics, synthetic genomics and the first complete diploid human genome in 2007.

Dr. Venter, one of the most frequently cited scientists, is the author of more than 200 research articles. He is also the recipient of numerous honorary degrees, public honors, and scientific awards, including the 2008 United States National Medal of Science, the 2002 Gairdner Foundation International Award and the 2001 Paul Ehrlich and Ludwig Darmstaedter Prize. Dr. Venter is a member of numerous prestigious scientific organizations including the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Society for Microbiology. 

FIRST SELF-REPLICATING SYNTHETIC BACTERIAL CELL

Overview

J. Craig Ventor Institute  –  Genomic science has greatly enhanced our understanding of the biological world. It is enabling researchers to “read” the genetic code of organisms from all branches of life by sequencing the four letters that make up DNA. Sequencing genomes has now become routine, giving rise to thousands of genomes in the public databases. In essence, scientists are digitizing biology by converting the A, C, T, and G’s of the chemical makeup of DNA into 1’s and 0’s in a computer. But can one reverse the process and start with 1’s and 0’s in a computer to define the characteristics of a living cell? We set out to answer this question.

In the field of chemistry, once the structure of a new chemical compound is determined by chemists, the next critical step is to attempt to synthesize the chemical. This would prove that the synthetic structure had the same function of the starting material. Until now, this has not been possible in the field of genomics. Structures have been determined by reading the genetic code, but they have never been able to be verified by independent synthesis.

In 2003, JCVI successfully synthesized a small virus that infects bacteria. By 2008, the JCVI team was able to synthesize a small bacterial genome; however they were unable to activate that genome in a cell at that time.

 

Colonies of the transformed Mycoplasma mycoides bacterium. Image Credit: J. Craig Venter Institute.

Now, this scientific team headed by Drs. Craig Venter, Hamilton Smith and Clyde Hutchison have achieved the final step in their quest to create the first synthetic bacterial cell. In a publication in Science magazine, Daniel Gibson, Ph.D. and a team of 23 additional researchers outline the steps to synthesize a 1.08 million base pair Mycoplasma mycoides genome, constructed from four bottles of chemicals that make up DNA. This synthetic genome has been “booted up” in a cell to create the first cell controlled completely by a synthetic genome.

 

The assembly of a synthetic M. mycoides genome in yeast.

Figure from Gibson, D. G., J. I. Glass, et al. 2010. Creation of a bacterial cell controlled by a chemically synthesized genome. Science, Published online May 20 2010.

View high resolution PDF.

http://www.jcvi.org/cms/fileadmin/site/research/projects/first-self-replicating-bact-cell/handouts/image5-lettersize.pdf

The work to create the first synthetic bacterial cell was not easy, and took this team approximately 15 years to complete. Along the way they had to develop new tools and techniques to construct large segments of genetic code, and learn how to transplant genomes to convert one species to another. The 1.08 million base pair synthetic M. mycoides genome is the largest chemically defined structure ever synthesized in the laboratory.

While this first construct—dubbed M. mycoides JCVI-syn1.0, is a proof of concept, the tools and technologies developed to create this cell hold great promise for application in so many critical areas. Throughout the course of this work, the team contemplated, discussed, and engaged in outside review of the ethical and societal implications of their work.

 

Negatively stained transmission electron micrographs of dividing M. mycoides JCVI-syn1. Freshly fixed cells were stained using 1% uranyl acetate on pure carbon substrate visualized using JEOL 1200EX transmission electron microscope at 80 keV. Electron micrographs were provided by Tom Deerinck and Mark Ellisman of the National Center for Microscopy and Imaging Research at the University of California at San Diego.

View High Resolution JPEG.

The ability to routinely write the software of life will usher in a new era in science, and with it, new products and applications such as advanced biofuels, clean water technology, and new vaccines and medicines. The field is already having an impact in some of these areas and will continue to do so as long as this powerful new area of science is used wisely. Continued and intensive review and dialogue with all areas of society, from Congress to bioethicists to laypeople, is necessary for this field to prosper.

Funding

Synthetic Genomics, Inc.

Synthetic genomes: Shown here is a circular piece of DNA synthesized from scratch–the first bacterial genome to be created this way.      Credit: J. Craig Venter Institute

 

Scientists say the results represent a new stage in synthetic biology

MIT Technology Review, by Emily Singer  –  In a technical tour de force, scientists at the J. Craig Venter Institute, in Rockville, MD, have synthesized the genome of the bacterium Mycoplasma genitalium entirely from scratch. The feat is a stepping stone in creating precisely engineered microbial machines capable of generating biofuels and performing other useful functions.

“It really is groundbreaking that you can synthetically build a genome for a bacterium,” says Chris Voigt, a synthetic biologist at the University of California, San Francisco, who was not involved in the project. “It’s bigger by orders of magnitude than what’s been done before.”

Biologists creating genetically engineered organisms now routinely order pieces of DNA that are 10,000 to 20,000 base pairs long–big enough to incorporate the genes for a single metabolic pathway. That allows researchers to engineer microbes that can perform specific tasks, but the ability to synthesize entire genomes could grant a whole new level of control over biological design. (See “Tumor-KillingBacteria.”)

In the new study, scientists ordered 101 DNA fragments, encompassing the entire Mycoplasma genome, from commercial DNA synthesis companies. These fragments were designed so that each overlapped its neighboring sequence by a small amount; these overlapping stretches stick together, thanks to the chemical properties of DNA. Researchers then bound the fragments piece by piece, eventually generating the full 582,970 base pair Mycoplasma sequence. The findings were published Thursday in the online edition of Science.

“We consider this a second and significant step in a three-step process of our attempt to create the first synthetic organism,” says Craig Venter, president of the Venter Institute. Venter and his colleagues ultimately want to create a minimal genome–one with the least number of genes needed to sustain life. Pinpointing the minimal genome will both shed light on key cellular processes and provide a base for designing sophisticated synthetic organisms. “We ultimately want to design cells that could function in a robust fashion to make unique biofuels,” says Venter.

The researchers’ next step will be to show that the synthetic genome functions as it should. “We have the whole genome assembled in a tube, but we need to transplant it into the cell of a different species to show that it can reboot the cell,” says Hamilton Smith, a Nobel laureate who oversaw the project at the Venter Institute. Last year, Smith’s group transplanted the genome of one species of Mycoplasma into another, demonstrating that this type of transplant is possible. (See “Transplanting a Genome.”)

While the synthesis of a genome might be impressive from a scientific perspective, it is not yet a practical way to engineer microbes to make biofuels. Instead, several companies, including Synthetic Genomics, a biotech company founded by Venter to engineer microbes for energy, are using more traditional metabolic engineering techniques to generate fuel-producing bacteria. (See “Building Better Biofuels.”) “What we’re doing with synthetic chromosomes will be the design process for the future,” says Venter.

Others in the field are excited about that prospect. “Being able to synthesize genomes opens up a new world,” says Voigt. “You can build things on the scale of the genome.” For example, he says, scientists are now engineering bacteria to perform different steps in the conversion of biomass into ethanol–one strain to break down the biomass, another to make ethanol. But ideally, scientists could put those processes together to create one organism that could eat biomass and spit out fuel. (See “The Price of Biofuels.”) “That would require genome-scale design,” Voigt says.

He likens the current project, which required multiple steps to glue the fragments together, to the last computers designed before automated manufacturing and microfabrication techniques were introduced. Similar advances are needed for more ambitious genome-synthesis projects. “We still need to develop ‘one step’ genome construction methods in order to reduce the costs and turn time of genome construction,” says Drew Endy, a synthetic biologist at MIT.

Researchers have captured the bacterium Shewanella’s behavior on film

ScienceNews.org, Laura Sanders  –  New videos have caught bacteria in the act of a completely new behavior. A study appearing in the Dec. 14 Proceedings of the National Academy of Sciences finds that Shewanella cells briefly touch an electron-accepting surface, lift off and swim furiously, and then return to the metal surface.

The researchers call this flighty new behavior electrokinesis, and think it may be a way for bacteria to dump built-up electrons before taking off in search of food, much like a whale surfacing for a breath before diving. Understanding this frenetic movement may help scientists design better microbial fuel cells, which harness these electron-shuttling bacteria to produce energy.

“As far as we know, it is a new behavior,” says study coauthor and microbiologist Ken Nealson of the University of Southern California in Los Angeles. “It’s a new way of thinking about what bacteria do. The really great thing is that it’s probably opened up 10 times more questions and created 10 times more hypotheses than we had when we started.”

Until now, Shewanella bacteria were thought to lead relatively simple lives, sometimes moving around and at other times sticking to a surface and depositing electrons on it. But the new study finds that the lifestyle of Shewanella is complicated.

In the new study, researchers led by Howard Harris also of the University of Southern California videotaped Shewanella cells as they came into contact with materials that could store electrons, such as manganese oxide and electrodes. From the movies, it became apparent that Shewanella cells were having what study coauthor Orianna Bretschger of the J. Craig Venter Institute in San Diego calls “touch-and-go” interactions with the surface. The cells “touch the surface, then quickly swim away, only to return again later for another fleeting interaction,” she says. What’s more, when researchers varied the electrode’s potential to accept more electrons from the bugs, the cells swam away even faster, the researchers found.

To show that the behavior was new, and not a form of chemotaxis, in which bacteria sense different amounts of chemicals in their surroundings, the researchers tested Shewanella mutants that lacked the genes necessary for chemotaxis. These mutants performed electrokinesis just as well as the normal cells, indicating that the new behavior is not like chemical sensing, Nealson says. The bacteria don’t need to sense and approach the electron-accepting surface before interacting with it.

Although the researchers don’t yet know why the bacteria engage in this behavior, one idea is that it helps the microbes balance the needs to breathe and to eat. Shewanella cells get energy by shuffling electrons to a surface that can accept them. In this case, the place where the bugs respire, or exchange electrons, may be different from where they find food. Bretschger likens the situation to an abalone diver who takes a breath of air and then dives deep down for the delicacy.

Since Shewanella cells respire on the surface of an electron acceptor such as metal, depositing all their electrons onto a metal is like taking a deep breath. With their electron storage tank empty, the cells are ready to swim away looking for food. As the cells’ electron sinks become full again, the cells return to the metal and dump their load.

The team “captured a very interesting behavior of Shewanella on film,” comments Jeffrey Gralnick of the University of Minnesota in St. Paul. Because researchers knew that Shewanella needed to offload electrons in order to get the energy to swim, the increased swimming after they bump into an electron acceptor “makes perfect sense,” he says.

Understanding this behavior may help scientists develop new microbial fuel cells, Nealson says. Such devices could generate small amounts of electricity while purifying water at a treatment plant. Swimming behavior is not ideal for such a system, so figuring out how to change the bugs’ behavior would be helpful. “This is exactly what you would like the bugs in the fuel cell not to do.”

If you missed reading about this important research going on two years ago.

take a look now………………..

Bright bug: Chrisantha Fernando of the U.K.’s National Institute for Medical Research, in London, says that bacteria such as this E. coli can be trained through associative learning.
Credit: Rocky Mountain Laboratories, NIAID, NIH

Teaching Bacteria to Behave

Single-celled organisms could be “trained” to deliver drugs.

MIT Technology Review, by Michael Day  –  A century after Pavlov’s dog first salivated at the sound of a bell, researchers are saying that single-celled organisms such as bacteria can be “trained” to react in a similar way. Rather than use complex networks of nerve cells, or neurons, bacteria can “learn” to associate one stimulus with another by employing molecular circuits, according to a multidisciplinary team from Germany, Holland, and the United Kingdom.

This raises the possibility that bioengineers could teach old bacteria new tricks by having them act as sentinels for the human body, ready to spot and respond to signs of danger, the team says in the October issue of Journal of the Royal Society Interface (DOI: 10.1098/rsif.2008.0344). The basis for the claim is that single-celled organisms are able to associate stimuli that are applied simultaneously, according to the theoretical model produced by Chrisantha Fernando at the U.K.’s National Institute for Medical Research, in London, and his collaborators.
As with Pavlov’s dog and all other examples of associative learning, the bacteria in the model learn to build stronger associations between the two stimuli the more they occur together. The Canadian neuropsychologist Donald Hebb established an underlying explanation back in 1945. Now called Hebbian learning, it’s often expressed as a situation in which “neurons that fire together wire together.” In the hungry dog’s case, nerve cells triggered by the smell of food started to make physical links with the nerve cells simultaneously triggered by the sound of a bell. According to Hebb’s theory, the more often the two stimuli are applied at the same time, the greater the link or “synaptic weight” between them.

Bacteria, of course, don’t have synapses or nerve cells. Nonetheless, there are indications that single-celled organisms can learn. In the 1970s, Todd Hennessey claimed that paramecia, the single-celled pond dweller, could be conditioned in the lab. He electrocuted them and associated this with a buzzer. Following the simultaneous exposure to the buzzer and to electric currents, he claimed that the paramecia swam away from the buzzer when they had not done so before. The finding was never properly reproduced, but it raised the intriguing possibility that some sort of associated learning was possible for single-cell life forms.

Now Fernando’s team has proposed a model for how bacteria might be trained. He has designed a cellular circuit that consists of several genes and their promoters, which produce proteins (transcription factors) that act to switch each other on and off like a digital electric circuit. The researchers’ theoretical circuit consists of three fictional genes. Two of these genes, A and B, produce proteins pA and pB, which react with other transcription factors, iA and iB, to switch on the third gene, C.

The gene products pA and pB would persist in the cell and therefore act as a memory that lasts for a long time once they have been produced. Their concentrations are the equivalents of the synaptic weights in the Pavlovian-dog model. Only in conjunction with these molecules can iA and iB (the analogs of the smell and the bell) have their effects. By the researchers pairing the iA and iB, the bacteria is able to respond to iB, whereas before it only responded to iA. This means that the bacterium has been “trained” to respond to iB, says Fernando.

Eva Jablonka, a theoretical biologist at Tel-Aviv University and a leading researcher in the field, agrees. “This is conceptually a bit difficult,” she says, “but if you look at the definition of learning–because of something happening, you have some kind of physical traces, and this changes the threshold of the response in the future–then this is what you have here.” She adds, “I think that it is a good and potentially very useful paper, and I think they do demonstrate associative learning.”

The model is based on the assumption that such a chemical-genetic circuit could be created and planted into a bacterium such as E. coli. “It seems to me quite possible at the theoretical level, and I don’t see great obvious hurdles for the construction of the suggested vectors,” says Jablonka, who published a paper on conditioning in single-celled organisms this month.

Significantly, Fernando estimates that the changes induced in the bacteria could easily persist for the 30-minute life cycle of an E. coli bacterium. This would make the changes, or “learning,” heritable. This is an especially important point when it comes to medical applications for trained bacterium. “After all, diseases or drug doses are going to last longer than 30 minutes,” notes Jablonka.

The trick would be to train bacteria to recognize chemical processes in the body that are associated with danger. This might be an adverse and dangerous reaction to a drug, or to the presence of tumor cells, indicating that a medicine in the system needs to be activated in certain tissues.

Research on genetically engineering remote-controlled bacteria to release drugs is already under way. In 2005, for example, a team from the National Institutes of Health proposed genetically engineering naturally occurring bacteria to release antiviral treatments for HIV. The realization that such bacteria might be trained to do this work more effectively could bring a whole new dimension to the field.

Inhaled pollutants may inflame more than the lungs

Tiny inhaled motes can travel beyond the lungs; new research suggests these particles may ravage the brain

 

ScienceNews.org, May 22, 2010, by Janet Raloff  –  Destination brainTiny inhaled motes can travel beyond the lungs; new research suggests these particles may ravage the brain. Stephanie Maze/Getty Images

When Lilian Calderón-Garcidueñas recruited children for a study probing the effects of air pollution, Ana was just 7. The trim girl with an above-average IQ of 113 “was bright, very beautiful and clinically healthy,” the physician and toxicologist recalls.

But now Ana (not her real name) is 11. And after putting her and 54 other children from a middle-class area of Mexico City through a new battery of medical and cognitive tests, Calderón-Garcidueñas found that something has been ravaging the youngsters’ lungs, hearts — and, especially troubling, their minds.

Brain scans and screening for chemical biomarkers in the blood pointed to inflammation affecting all parts of the brain, says Calderón-Garcidueñas, of the National Institute of Pediatrics in Mexico City and the University of Montana in Missoula. On MRI scans, white spots showed up in the prefrontal cortex. In the elderly, she says, such brain lesions tend to denote reduced blood flow and often show up in people who are developing dementias, including Alzheimer’s disease.

In autopsies of seemingly healthy Mexico City children who had died in auto accidents or other traumatic events, Calderón-Garcidueñas uncovered brain deposits of amyloid-beta and alpha-synuclein, proteins that serve as hallmarks of Alzheimer’s and Parkinson’s diseases. Several years earlier, she had found similar abnormalities in homeless Mexico City dogs and exaggerated versions of the abnormalities in local 20- to 50-year-olds. 

She has published studies linking the insidious changes to the metro region’s air quality. The area’s 20-plus million inhabitants make it one of the world’s largest megacities, a roughly 7,000-square-kilometer region choking with smog and particles containing carbon, metals and more (SN: 9/8/07, p. 152). Most are nanoparticles — too small to see but just the right size to migrate into tissues throughout the body. Further clouding the air are solvents and other reactive gases — as well as toxins contributed by livestock feces.

Scientists have known that air pollution can impair airways and blood vessels. The emerging surprise is what it might do to the brain. Increasingly, studies have been highlighting inflammation-provoking nanopollutants as a potential source of nerve cell damage.

Calderón-Garcidueñas has been correlating Mexico City’s stew of air pollutants with a suite of symptoms in people of all ages. In March in Salt Lake City at the annual meeting of the Society of Toxicology, Calderón-Garcidueñas unveiled some of her latest data. At age 11, Ana shows persistent, growing brain lesions, the toxicologist reported. As do the other Mexico City children surveyed. They also exhibit cognitive impairments in memory, problem solving and judgment and deficiencies in their sense of smell compared with age-matched children from a cleaner city 120 kilometers away.

Metals in the air Particles collected from the air above Mexico City (two shown) contain metals including manganese, iron, zinc, tin, lead and mercury (labeled). New research suggests that the particles can end up in the brain.Kouji Adachi and Peter R. Buseck/Environmental Sci. Technol. 2010

Other toxicologists at the meeting presented data, largely from animal studies, tracking the movement of billionth-of-a-meter–scale particles into the brain, where they triggered inflammation and abnormalities characteristic of Alzheimer’s or Parkinson’s.

Until recently, most air pollution toxicology has focused on impacts to the lungs and heart, observes James Antonini of the National Institute for Occupational Safety and Health’s lab in Morgantown, W. Va. The challenge now, he says, is to identify which pollutants are harming the nervous systems of Ana and others who live in areas with particularly dirty air.

Fuzzy thinking

Mexico City is not the only source of real-world pollution that has been linked to mental impairments.

Ulrich Ranft and colleagues at the Environmental Health Research Institute at Heinrich Heine University in Düsseldorf, Germany, studied 400 or so highly functioning local women in their mid- to late 70s. Elderly women who lived within 50 meters of very busy streets exhibited poorer memory skills than did women of the same age whose homes were well removed from highly trafficked roadways, the team reported in the November 2009 Environmental Research.

The study turned up no similar link between cognitive scores and average levels of particles in the women’s communities. That makes sense, Ranft says, because the levels of ultrafine motes emitted by traffic can be quite high along streets, “but drop off very fast, falling to almost background levels when you get just 100 meters away from the road.”

Young children’s minds may be especially sensitive to tiny airborne particles spewed by traffic, according to Shakira Franco Suglia of the Harvard School of Public Health in Boston and her colleagues. In studies of roughly 200 Boston 10-year-olds, the researchers found that those living in areas with the highest average airborne concentrations of soot, a pollutant primarily associated with traffic, had lower IQs and lower scores on memory tests. 

From nostril to brainHuman: BSIP/Photo Researchers, Inc.; Rodent: T. Dube

The team divided the kids by exposure levels into four groups. The average IQ drop between one group and the next averaged about three points — comparable to that seen in kids whose mothers had smoked during pregnancy, Franco Suglia’s group reported in 2008 in the American Journal of Epidemiology.

Taking note of non-scents

A few studies, including the recent one by Ranft’s group, have also observed a somewhat impaired sense of smell among people living in polluted regions.

At the toxicology meeting, Calderón-Garcidueñas reported that kids and young adults in Mexico City have a somewhat worse sense of smell than those living in cleaner cities. Roberto Lucchini of the University of Brescia in Italy reported much the same for adolescents living in communities around now-closed iron-alloy manufacturing plants. Both groups’ data also turned up signs the youngsters have been experiencing at least subtle nerve damage.

The findings, the researchers say, are especially worrisome since a number of studies have shown that a sense of scents wanes in people developing Alzheimer’s and Parkinson’s.

Though metal pollution hasn’t been confirmed as a cause of these diseases, Lucchini was able to link pollution in Brescia to reduced smelling abilities and to motor impairments.

Until 2001, alloy plants in northern areas of the province spewed a number of metals into the air. Manganese remains a substantial pollutant in the air, soil and house dust in this part of Italy. Work by Lucchini’s team uncovered unusually high rates of symptoms including tremors, slowed movement and rigidity among adults living near the now-defunct plants. The local prevalence of these and other Parkinson’s-like symptoms is about 400 per 100,000 inhabitants. That’s two and a half times the usual rate in Italy.

Unnerving signsDiffuse amyloid plaques (brown blotches), like those seen in Alzheimer’s patients (top), have shown up in adults (middle) and children (bottom) from Mexico City. L. Calderon-Garciduenas

Lucchini’s team, which had already planned to examine 300 middle schoolers for neural effects of local pollution, included a smell assay in the tests. To measure exposures, the researchers collected blood and urine from the 11- to 13-year-olds. A third of the kids also carried a backpack fitted with an air-sampling device and a GPS to pair up readings and precise locations. Some children lived near the former alloy plants, others at Garda Lake, a relatively clean comparison region in the province.

At the toxicology meeting, Lucchini reported that among kids living near the alloy plants, “Odor identification was clearly impaired compared to children living in the [Garda Lake] region.” The smell-threshold reduction was “preclinical,” he explains, meaning the children wouldn’t notice the change but it could be picked up with testing.

His team also linked exposures to manganese-rich dust particles with motor impairments — such as a reduction in the speed at which children could clench their hands or sequentially touch the fingers of each hand to the thumb. Though it’s too early to speculate about whether the symptoms will evolve into something resembling Parkinson’s disease, Lucchini says, these are the first data to link such motor impairments to inhaled manganese.

Nosing out the problem

While these data are just coming in, a growing body of evidence suggests that nerves in the nose can provide a highway along which some inflammatory pollutants, such as metals, motor directly from the outside world to the brain.

How efficient the conduit is varies by pollutant particle, according to new experiments by Wolfgang Kreyling of the Helmholtz Center and the German Research Center for Environmental Health in Munich. In rats, 20-nano-meter–diameter agglomerations of at least 100 radioactively labeled iridium particles entered the brain whether inhaled through the nose or pumped directly into the lungs.

By comparing what has been deposited after one-hour exposures via the two routes, Kreyling’s team showed that for such small particles, two-thirds of what ends up in the rat brain comes directly from the nose, the rest via a more circuitous route that starts in the lungs, moves into the bloodstream and then goes to the brain.

Well under 1 percent of inhaled particles made it to the brain via either route, Kreyling reported at the toxicology meeting. However, he added, once those insoluble particles arrive in the brain, “we do not see much clearance.” So continuous exposure over time could leave substantial amounts of inflammatory particles in the brain, he speculates.

Change the 20-nanometer iridium to same-sized soot particles and the uptake rate falls by 75 percent. Expose animals to 20-nanometer particles made from titanium dioxide or to 80-nanometer particles of iridium, and the rate of brain uptake drops by about 90 percent.

But no one’s sure how well such studies model what happens in people, points out David Dorman of North Carolina State University in Raleigh. Long-snouted rodents depend far more than humans do on the sense of smell and have evolved a much bigger and more efficient system linking the outside environment to the brain. For instance, Dorman notes that half of the nasal cavity of a rat is lined with olfactory-system cells. In humans, this receptive area is much smaller, he says — “only about 3 to 5 percent.”

His team has shown that even for particles that begin moving up the olfactory highway, some stop partway. One type that does seem to go the distance: manganese. When Dorman’s group exposed rats to manganese, the same metal that taints the dust Lucchini has been studying in Italy, nearly all of the pollutant particles entering the nasal tissue migrated at least as far as the olfactory bulb, a structure in the brain.

Regardless of what percentage of particles make it all the way, such data suggest that inhaled airborne motes can enter the brain, where they would be expected to foster inflammation, a primary underlying trigger of tissue damage and neurodegenerative disease.

Moreover, Calderón-Garcidueñas has linked the pollutants with a breakdown in the lining of the nose, which could facilitate particles’ access to olfactory highways serving the brain.

A burning issue

Although the source and chemistry of air pollutants affecting the brain differ, all seem to share the same toxic modus operandi: inflammation. Some pollutants turn on genes that release inflammatory chemicals, others call out immune cells that quash invaders and clean up trash using inflammatory mechanisms. Still more induce biologically destructive electron-stripping chemical reactions that won’t quiet down without a copious release of antioxidants.

Krishnan Sriram, a neurotoxicologist with NIOSH, reported at the toxicology meeting that following 10-day and 28-week exposures to manganese welding-fume particles, rodents developed brain changes resembling many of those in Parkinson’s patients — nerve-cell inflammation, tissue damage from oxidation and loss of nerve cells from a region of the brain that makes dopamine.

In addition, his team looked at some of the family of Park genes; mutations in these genes are associated with an elevated risk of developing Parkinson’s disease. In rodents exposed to manganese, the researchers saw a reduction in the genes’ production of proteins that normally help rid the body of misshapen nerves and that quash the oxidation responsible for excessive inflammation.

Bellina Veronesi of the U.S. Environmental Protection Agency and Lung-Chi Chen of the New York University School of Medicine laboratory in Tuxedo reported data at the toxicology meeting from mice exposed to dense concentrations of pollutants collected from outdoor air. Animals without functioning apolipoprotein genes, which normally help control the production and activity of certain fats in the bloodstream, experienced runaway brain inflammation and nerve damage. This finding suggests that properly working apolipoproteins may be essential for coping with tiny inhaled particles.

People born with a particular apolipoprotein gene variant — known as APOE-4 — face a greatly elevated risk of developing late-onset Alzheimer’s disease and more general cognitive declines. In North America, Calderón-Garcidueñas says, roughly one-fifth of people carry this variant. And in Mexico City, she has found that children and young adults with the variant exhibit the most inflammation, the greatest cognitive declines and the most rapid deposition of amyloid-beta.

But Calderón-Garcidueñas has yet to prove that deposition in the brain of air particles primarily explains the brain inflammation she’s measured, says Dorman. One has to wonder, he says, whether the “widespread nasal damage” that she depicted was a major contributor to inflammatory brain damage or independent of it.

Calderón-Garcidueñas is aware of the issue. She notes that work by others has shown that inflammation-provoking cells or chemicals have the potential to migrate from distant sites into the brain, triggering fallout damage there.

But whatever the source of inflammation in the brain, Calderón-Garcidueñas would like to see people who may face an elevated risk for pollution-triggered neural damage identified and counseled about lifestyle changes that could reduce that risk. For instance, people with the APOE-4 gene variant might give up cigarettes, take low-dose anti-inflammatory drugs or find jobs that won’t expose them to inflammatory agents, such as the endotoxin in chicken manure.

These people might also look to change their diet, eating foods rich in inflammation-limiting antioxidants, like brightly colored fruits and vegetables, or dark chocolate. She recently began feeding commercially available chocolate rich in polyphenols, a class of natural antioxidants, to treat inflammation ravaging the hearts and minds of mice.

The data are still preliminary, cautions Calderón-Garcidueñas. But from all appearances, she chuckles, the chocolate “works wonders!”