James Ntambi, second from right, with members of his laboratory

What is the best way to encourage science in Africa?

Some African scientists come to the United States to train and then return to their home countries to teach and perform research (read about two examples here).

James Ntambi took a different approach - after receiving his Ph.D. he remained in the United States and now leads a lab at the University of Wisconsin, where he trains African scientists and teaches Americans what life is like in Uganda.

Born and raised in Mukono, Uganda, Ntambi studied biochemistry at Makerere University in Kampala. In 1980 he received a Fulbright award to attend graduate school at the Johns Hopkins University School of Medicine in Baltimore - with every intention of returning to Africa. For his Ph.D. thesis he studied the biology of trypanosomes, parasites that cause sleeping sickness (endemic in parts of sub-Saharan Africa).

After receiving his Ph.D. Ntambi decided he needed more research experience. He remained at Hopkins for a research fellowship in the lab of Dan Lane, studying how fat cells develop. Though seemingly unrelated, the way in which fat cells and trypanosomes mature and develop is similar, and Ntambi hoped to learn more about trypanosomes by studying fat - intending to return to Africa to study trypanosomes. 

At the end of his fellowship in 1989, however, Ntambi got a job as an assistant professor at Georgetown Medical School. He decided that he could improve science in Africa by remaining in the U.S. but returning to Makerere to teach.

With funding from the NIH, Ntambi and a colleague from the City College of New York took 10-15 students from minority institutions (historically black colleges) to Makerere University every summer between 1990 and 1995. Ntambi paired the American students with their Ugandan counterparts and taught them all basic molecular biology techniques. The NIH funding also allowed Ntambi to set up a small laboratory at Makerere.

Now a full professor at the University of Wisconsin in Madison, Ntambi runs a similar program as part of a course called ‘international health and nutrition.’ Every fall, students in the course study public health issues that affect Africa - as part of their standard classroom work - and then spend three weeks in Uganda. Not just in Kampala, but also in rural Uganda, which comes as quite a shock to students from Wisconsin.

Ntambi stresses the value of teaching Americans about the difficulties people face in Africa. “After those three weeks, when they come back here, they are different people,” Ntambi told me. “They come back with a totally different perspective.”

Ntambi also hosts scientists from Uganda in his laboratory for three or four months at a time. These mini-sabbaticals allow Ugandan scientists to learn new techniques and develop networks with scientists in the U.S. In reality, most of the techniques they learn are conceptual - genetically engineering mice is standard practice at research institutions in the United States, but is not available in Uganda.

A visit to Ntambi’s laboratory is likely to encourage African scientists because of the exciting, cutting-edge work. Ntambi and his group recently showed that a protein in the skin regulates how the entire body stores fat. Mice genetically engineered to lack the SCD1 protein in the skin are lean, and do not become obese even when fed a diet high in fat. Surprisingly, the same is not true of mice genetically engineered to lack this protein in other parts of the body.  If you remove SCD1 from the liver or from fat tissue, the mice still became obese on a high-fat diet. It is the protein’s presence in the skin that regulates fat storage throughout the body.

We know the brain, the liver and the gut communicate with one another to monitor and control energy intake, storage and expenditure. Ntambi’s work suggests that the skin is part of this metabolic control apparatus as well. But while scientists have identified some of the hormones that the liver, brain and gut use to communicate with one another, it’s not known how the skin tells the body to store fat. Does the skin communicate with the liver or the brain or the gut, or directly with fat cells?

Ntambi is working to answer these questions. Meanwhile, he continues to lead students to Uganda, teaching African students that diet and exercise can prevent obesity and diabetes, stressing prevention over treatment. In Uganda, Ntambi explained, treatment is too expensive. Prevention is the only option.

Apply extract from a dead ant on live pupae (white), and worker ants carry the pupae to the refuse pile.

How does a worker ant recognize a dead ant? The answer has puzzled scientists for years, but new work by Dong-Hwan Choe and his colleagues may have provided an answer.

Choe was born and raised in Seoul, South Korea. After receiving his undergraduate degree there he came to the University of California in Riverside to study entomology: insects, specifically Argentine ants.

“There is better opportunity in the U.S. for studying entomology,” Choe told me. In South Korea, as in much of the world, universities don’t have entomology departments. Instead entomologists are scattered throughout biology and biomedical research departments.

The United States is an exception, perhaps due to its large agricultural industry, for whom pest removal is a lucrative problem worthy of research funding. In urban entomology, the study of insects associated with people and cities, big money comes from pest control research. The United States, for example, contains many termite-susceptible buildings, so research aimed at improving our understanding of termite biology and behavior is relatively well funded here.

It’s ironic that entomologists enjoy studying insects, but funding for research comes from companies that want to kill insects. Choe was funded by a scholarship from the Western Exterminator Company.

His sponsors can be proud, as Choe, working in the laboratory of Michael Rust, found that live ants secrete two chemicals, dolichodial and iridomyrmecin, which rapidly degrade upon an ant’s death. The absence of these chemicals appears to unmask a signal that marks a dead ant, which, once identified, is removed from the colony. (This process is known as necrophoresis.)

When Choe treated baby ants, called pupae, with extracts from dead ants, worker ants carried pupae to the refuse pile. (See photo.) Pupae were then treated with dolichodial and iridomyrmecin and placed in a foraging area near the nest. Workers initially ignored the treated pupae and took longer to bring them back to the nest, suggesting that dolichodial and iridomyrmecin are chemicals that adults use to signify life.

Due to technical limitations, Choe did not put dolichodial and iridomyrmecin on a dead adult worker and seeing if this delays its removal to the refuse pile. (Adult ants are soft and easily damaged, unlike the more solidly constructed pupae. The experimental manipulations damage the adults and cause the release of bodily secretions that could confound the results.)

Choe hopes to remain in the United States for a postdoctoral research fellowship, and then become faculty at a U.S. university. Otherwise, he’ll return to South Korea.

His family in South Korea understands that professional opportunities are good in the United States, although they want him back. With direct flights it’s only a 12-hour trip between Los Angeles and Seoul. Choe and his family have visited one another one or two times a year.

For Choe, the distance is “not a huge deal.” Proving how ants recognize their dead – that’s a different story.

Source: “Chemical signals associated with life inhibit necrophoresis in Argentine ants” by Dong-Hwan Choe, Jocelyn G. Millar and Michael K. Rust, published online in PNAS on May 4, 2009 (doi: 10.1073/pnas.0901270106).

In a triumph of nutritional enhancement, scientists in Spain and Germany have genetically engineered South African elite white corn to produce high levels of three vitamins in its kernels. The modified corn appears orange due to beta carotene, a vitamin that gives carrots their orange color. 

Cereal grains like rice, wheat and corn lack essential vitamins and minerals. Fruits and vegetables supplement nutrients lacking in grains, but in poor areas of the world with reduced access to fruits and vegetables, a monotonous grain diet poses a health problem. About 40 to 50 percent of the world’s population suffers from a disease caused by vitamin or mineral deficiency, according to the Food and Agriculture Organization of the United Nations.

One solution is to generate corn that contains vitamins normally found in fruit. Scientists have genetically engineered plants to contain higher levels of a single nutrient - beta carotene fortified rice or lycopene rich tomatoes - but this ignores deficiencies in other nutrients, such as ascorbate (vitamin C) and folate (vitamin B9).

Shaista Naqvi, Changfu Zhu and Paul Christou and their colleagues have raised the bar by adding five genes and gene fragments from two different bacteria, barley, wheat, rice and a different variety of corn to white corn, essentially introducing new assembly lines for 3 vitamins, beta carotene, ascorbate and folate, normally absent from white corn. The added genes provide the machinery allowing the corn to produce these nutrients.

It’s like taking the Porsche automobile plant in Stuttgart, Germany, which produces the sleek and small 911 sports car, and modifying it so that it also produces the large and boxy Cayenne sport utility vehicle. The Cayenne is so different from the 911 that it is produced in a separate factory in Leipzig - which should give you an idea of how amazing it is to be able to add the machinery to produce three new vitamins in corn.

White corn is the predominant food corn in sub-Saharan Africa. A typical 100 or 200 gram portion of the new, vitamin-rich corn would provide the recommended daily intake of beta carotene (the source of vitamin A), an “adequate” level of folate (undefined by the authors) and 20 percent of the recommended levels of ascorbate.

Scientists hope that their work leads to the development of cereals “loaded with vitamins, minerals, essential amino acids and long-chain polyunsaturated fatty acids, providing a nutritionally complete meal without the need for artificial supplementation.”

Cost-benefit analysis and other policy studies must be examined before introducing such crops locally. But it’s clear, according to the authors, that the results from genetic engineering are better than conventional breeding. The best fortification strategies will likely involve genetic engineering and conventional breeding.

Source: “Transgenic multivitamin corn through biofortification of endosperm with three vitamins representing three distinct metabolic pathways” by Shaista Naqvi, Changfu Zhu, Gemma Farre, Koreen Ramessar, Ludovic Bassie, Jürgen Breitenbach, Dario Perez Conesa, Gaspar Ros, Gerhard Sandmann, Teresa Capell and Paul Christou, published online April 27 in PNAS (doi: 10.1073/pnas.0901412106).

Fossil fuels account for 95 percent of world energy usage.  Consumption of coal, petroleum, and natural gas has increased significantly over the last several decades, as have carbon dioxide emissions, the primary reason for global climate change.

The implications of climate change have stimulated significant efforts to discover and commercialize renewable sources of energy that have zero or reduced net carbon dioxide emissions.  Finding replacements for gasoline has received significant attention in the United States, where the transportation sector consumes the most energy.  Biofuels, liquid fuels derived from renewable plants, have been viewed as prime candidates to replace gasoline.

Commercialized Biofuels

The two predominant biofuels on the U.S market today are corn ethanol and soybean biodiesel.  Corn ethanol has drawbacks that might hurt its long-term chances in the biofuels market.  It is not as energy-rich as gasoline – a gallon of ethanol contains less energy than a gallon of gasoline. Ethanol can’t be distributed using existing infrastructure because it has different chemical properties than gasoline. Unless significant modifications are made to current automobiles, ethanol can only be used in low percentage blends with gasoline.

The other major biofuel, biodiesel, is derived from lipids (fat) in plant seeds.  Biodiesel’s biggest barrier to widespread use is the availability of raw material.  A recent study showed that if all the plant (and even animal lipids) in the United States were dedicated to produce biofuels, the amount of biofuel produced would be less than five percent of the total volume of liquid fuels consumed each year.

The raw material for both corn ethanol and soybean biodiesel is food crops, so increasing production could create challenging impacts on global food markets.    

Advanced Biofuels: cellulosic ethanol and algal biodiesel

Cellulosic ethanol is a well-publicized new biofuel that can be produced from non-food crops (cellulose is a carbohydrate found in all plants). Cellulosic ethanol produces 300 percent more energy than is used in its production, a significantly better energy yield than corn ethanol or soybean biodiesel, but it shares the inherent energy and distribution disadvantages of corn ethanol.

One of the most immediate challenges with commercialization of cellulosic ethanol is that cellulose and a related carbohydrate, hemicellulose, are difficult, and hence expensive, to break down into the simple sugars required for ethanol production. Thus, improving the efficiency of the initial cellulose processing steps is key to making this and other biofuels economically feasible.

There is interest in using microscopic algae to produce biodiesel. While providing the benefits in energy density and engine compatibility of biodiesel, it may not suffer from the same supply issues because simple sugars (and potentially cellulose) can be used as a starting material. Algae are also better stores of oils than plant seeds.

There have been increasing efforts to genetically engineer well-known organisms, such as the bacteria E. coli, to produce novel biofuels efficiently. Researchers have hijacked E. coli’s biosynthetic pathway for the amino acid valine to produce isobutanol, a more energy dense, less volatile alcohol than ethanol. Our own research has focused on the production of energy-dense fuels using the fatty acid biosynthetic pathway in E. coli.

Mariusz Nowacki began studying plant biology in Poland and wound up studying single-celled microorganisms in the United States. Along the way he encountered prions in Paris and solved the mystery of how an animal destroys 95 percent of its DNA and unscrambles and rearranges the remaining pieces to form a working genome. Scientific research takes you in unexpected directions intellectually and geographically.

Mariusz grew up in Warsaw, Poland, attended Warsaw University (Uniwersytet Warszawski) and began graduate studies examining viruses that infect plants. Thanks to a new student exchange program, he spent three months working in Eric Meyer’s laboratory at the Ecole Normale Supérieure in Paris.

Meyer’s lab studies ciliates, not plants, so in order to spend time in Paris Mariusz switched projects. Now he was looking for prion proteins in ciliates, single-celled organisms found in, among other places, cows’ digestive systems. Prions can cause mad-cow disease; Mariusz and Meyer thought that cows were exposed to prions through ciliates. The project was so exciting that Mariusz applied for and received a fellowship from the French government, allowing him to continue his studies as a PhD student in Meyer’s lab.

In one species of paramecium (a type of ciliate), Mariusz found two proteins that looked like prions – each contained an area similar to part of the prion protein that causes mad-cow disease. But the other areas of these proteins were completely new, function unknown. Mariusz and his colleagues discovered that these proteins are required for rearranging the paramecium genome – unscrambling it after reproduction, so that genes function correctly.

Each ciliate has two genomes: one that is silent, except during sexual reproduction, and one that speaks often, instructing the organism to produce proteins so that it can eat, move and reproduce. The silent genome serves as a reservoir, an unaltered reference manual passed down from one generation to the next. During reproduction, the silent genome briefly speaks: it makes hundreds of copies of itself. Two of these copies become the silent genome of the daughter paramecium. The remaining copies are extensively rearranged, chopped up into hundreds of fragments and reordered to form the active genome, the one that speaks often.

Looking for prions in paramecium, Mariusz had stumbled upon a protein required for rearranging the genome, a discovery which showed that an external factor, not the DNA of the silent genome itself, was sparking these rearrangements.

By this time Mariusz was hooked on ciliates, so he joined Laura Landweber’s lab at Princeton University in New Jersey for a postdoctoral fellowship (there are only a handful of labs around the world that study ciliate genetics, and Landweber’s is one of the best).

Mariusz now turned to the ciliate Oxytricha trifallax. Like paramecium, Oxytricha’s ‘active’ genome requires extensive rearrangements before it can work properly, but in a cool twist 95 percent of the DNA is destroyed during the rearrangement. Apparently, it’s junk.

In 2008 Mariusz and his colleagues figured out that RNA orchestrates the rearrangement of the DNA (the two prion-like proteins Mariusz found earlier bind RNA and help this process along).

But how is the DNA cut, and how does Oxytricha know which pieces are junk? Much of the Oxytricha’s silent genome is composed of jumping genes, pieces of DNA that, like viruses, can cut themselves out of the genome and past themselves back into a different location. (Jumping genes are called transposons because they transpose themselves from one part of the genome to another.) Mariusz and colleagues showed that during reproduction, transposons instruct Oxytricha to produce proteins that cut the transposons out of the active genome (the silent genome stays intact). When Mariusz prevented these proteins from being produced, daughter cells had abnormally rearranged DNA.

Normally, transposons, like viruses, do not benefit the host. We humans have the remnants of thousands of transposons scattered throughout our genomes. Presumably, when a new transposon hopped into our genome, our cells did everything possible to mutate the transposon so that it would be inactivated, unable to jump and further damage our DNA.

But Mariusz’s studies suggest that actively jumping transposons benefit Oxytricha, to the point where they are now an indispensable part of Oxytricha’s genome.

With such a body of work, Mariusz is clearly ready to lead his own laboratory. He applied for positions at universities throughout the United States, but received no offers. Several places, including a department at Harvard, cancelled their faculty searches due to the economic crises. Mariusz fared better in Europe, where he has an offer from a university in Paris and is interviewing at several other institutions.

Mariusz has mixed feelings. Assistant professors in the United States have more freedom to study what they want. In Europe, junior professors (American style assistant professors are rare) are part of a senior professor’s lab, so they must ultimately bow to his or her scientific wishes. But with freedom comes the responsibility to secure funding. Junior professors in Europe can rely to some extent on senior professors to bring in the research money, while assistant professors in the United States rely almost entirely on themselves. Returning to Poland is not an option for Mariusz, as he told me there is “not enough [money] to do serious research.”

So, barring a last minute offer from a U.S. university, Mariusz will likely jump to Europe to pursue his next scientific adventure.

Incidentally, we still don’t know whether the two prion-like proteins discovered in paramecium are actually prions.

Source: “A Functional Role for Transposases in a Large Eukaryotic Genome” by Mariusz Nowacki, Brian P. Higgins, Genevieve M. Maquilan, Estienne C. Swart, Thomas G. Doak and Laura F. Landweber, published in Science online on April 16 (DOI: 10.1126/science.1170023).

Of the more than 3 billion bases, or individual units, of DNA in the human genome, less than 2 percent contain instructions for producing proteins. The genome regions that specify protein production are the genes (in science jargon genes are said to code for proteins); the rest of the DNA, the noncoding portions, have been dismissively referred to as junk.

Junk – obviously not a very scientific term – implies that because the DNA doesn’t code for proteins, it isn’t functional. (For a similar debate, see Norman Pace on purging “prokaryote” from science textbooks.)

In recent years, researchers proved that junk plays an important role in switching genes on and off. Identifying a gene is one thing, but knowing when it’s instructing a particular cell to produce proteins or when it’s remaining silent is crucial to understand how organisms develop and function.

Axel Visel wants to know how the genome decides which genes get turned on when. Raised and educated in Hannover, Germany, Visel also spent two years studying in the United States. After receiving his doctorate at Germany’s Max Planck Institute, Visel returned to the United States for a fellowship with Eddy Rubin and Len Pennacchio at the Lawrence Berkeley National Laboratory in California. Rubin and Pennacchio spearheaded the development of many tools to analyze genome sequences.

The portions of DNA that switch genes on are called promoters and enhancers. For a gene to be switched on, specialized proteins must bind to promoters and enhancers and coordinate with each other to transcribe RNA from the gene. That RNA is then translated into a protein. Promoters and enhancers don’t code for genes themselves; their only function is to regulate when and where genes are turned on – they are regulatory sequence.

Identifying regulatory sequence has been challenging. Promoters tend to be located adjacent to the genes they control, but enhancers are scattered throughout the genome, sometimes 1 million bases of DNA away from the gene they regulate.

Visel, Matthew Blow and their colleagues found a way to identify when enhancers are regulating genes. A protein called p300, produced throughout the body, is thought to bind to many enhancers. It’s also required for embryonic development, a crucial time when activated genes are literally building the body.

Visel dissected forebrain, midbrain and limb tissue from more than 150 mouse embryos and treated them with a chemical to strengthen the attachment between proteins and DNA. Normally the proteins bound to enhancers can be easily unbound, but the chemical linking prevents this. The DNA is then cut up into millions of pieces (DNA bound to protein is protected). Using antibodies, Visel and his colleagues purified only those pieces of DNA bound to p300 and then sequenced that DNA and identified it as a possible enhancer. This technique, called chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq), is not new, but using p300 as the bait was a clever twist.

To confirm these regions of DNA actually regulate gene expression, Visel and his colleagues identified analogous regions from human DNA, and genetically engineered mice such that the human DNA enhancer sequence was in a position to regulate a gene that produces a nontoxic protein that turns the cell blue. If the enhancer DNA regulated gene expression in the mouse embryo’s limb, but not in the brain, then the human version of the enhancer would turn only the mouse’s limbs blue.

In most cases, that’s what happened. (See photo.) This method is especially good because it’s large-scale, enabling scientists to study thousands of enhancers throughout the genome from any tissue during any time in an animal’s life. Visel and colleagues identified thousands of enhancers active in the brain and limbs of mouse embryos and verified more than 80 using genetically engineered mice. (For more on using transgenic mice to report gene expression, see Gianpaolo Rando’s blog.)

Visel is happy in the United States. Lawrence Berkeley National Laboratory provided help with his visa, but he is still stuck doing government paperwork. “It can all be done, but I wish one would have to spend less time on it.” Visel says “it would be nice” to return to Germany and be near friends and family, but the “stimulating scientific environment” at Berkeley enables him to pursue interesting projects.

As my graduate adviser used to say, if you put junk in, you get junk out. Clearly junk DNA is anything but.

Source: “ChIP-seq predicts tissue-specific activity of enhancers” by Axel Visel, Matthew J. Blow, Zirong Li, Tao Zhang, Jennifer A. Akiyama, Amy Holt, Ingrid Plajzer-Frick, Malak Shoukry, Crystal Wright, Feng Chen, Veena Afzal, Bing Ren, Edward M. Rubin and Len A. Pennacchio, published in the February 12 issue of Nature (doi:10.1038/nature07730, Visel and Blow contributed equally to this work).

Maxi D’Angelo grew up in Neuquén, Argentina. During his graduate studies in molecular biology at the University of Buenos Aires, he and Marcela Raices, a graduate student in the lab next door, fell in love. They married and came to the San Diego area for postdoctoral fellowships, in different labs, because the United States has the most resources, “by far,” for research, he said.

Leaving Argentina for a postdoctoral fellowship is “necessary training,” Maxi told me. It broadens connections and allows scientists to attend more international scientific meetings, because many are held in the United States and because U.S. labs have the resources to send fellows to meetings around the world. Also, moving to the United States is a good way to improve English, a refrain I’ve heard before from non-American scientists.

Maxi’s research centers on the cell’s nucleus, where DNA is stored and copied, where RNA is transcribed and then exported outside the nucleus to specify protein production. The nucleus is surrounded by two membranes that act as a barrier, separating it from the rest of the cell’s interior. Many molecules need to be transported into or out of the nucleus, so the nuclear membranes have pores, tunnels that regulate access to the nucleus. The only nuclear membrane pore that spans both membranes, linking the interior of the nucleus directly to the rest of the cell, is the creatively named nuclear pore complex, composed of many copies of 30 different proteins.

At the core of this large complex is a scaffold that surrounds the actual channel. When cells divide, the entire nuclear core complex disassembles and reassembles in the daughter cells. But when the cell is not dividing, only the proteins in the outer part of the complex, not the scaffold, are replaced – part of routine maintenance. So how is the structural integrity of the nuclear pore scaffold maintained in cells, like neurons in the adult brain, that no longer divide?

It isn’t. As Maxi discovered while working in Martin Hetzer’s lab, the proteins that make up the scaffold are not produced or replaced in nondividing cells. To make matters worse, as cells age their scaffolds degrade, and this compromises the nucleus, allowing proteins that are normally blocked to enter the nucleus. Maxi performed these experiments in the roundworm C. elegans, thanks to his wife, who uses the worm in her research. He got similar results using cells from rat brains, proving again that the core machinery in cells is similar throughout the animal kingdom.

Maxi said he would love to return to Argentina as an assistant professor and lead a lab (this discovery makes him a competitive candidate at top universities around the world), but the lack of resources and physical space in which to work are barriers. In Argentina there are good scientists doing good work, but the low budget makes it “difficult to do the latest science,” work. For now, Maxi plans to apply for faculty positions at universities in the United States and Europe.

When Maxi and Marcela came to the United States in 2003, Maxi began working in Larry Gerace’s laboratory at the Scripps Research Institute. It wasn’t a good fit, so a year later he moved across town to work with Hetzer at the Salk Institute, and once again found himself next door to Marcela. “We’re destined to be next to each other in the lab.”

Like two proteins in the nuclear pore complex scaffold.

Source: “Age-Dependent Deterioration of Nuclear Pore Complexes Causes a Loss of Nuclear Integrity in Postmitotic Cells” by Maximiliano A. D’Angelo, Marcela Raices, Siler H. Panowski, and Martin W. Hetzer, published in the January 23 issue of Cell.

After my trip to Chicago, I came down with a cold. There is no cure, and the treatments attack the symptoms – runny nose, sinus congestion, airway obstruction – not the underlying cause. Antibiotics are useless because the cold is caused by a virus.

Scientists have collected and stored 99 different strains of rhinovirus as part of a cold virus reference library. Many other strains may also exist.

Now scientists have sequenced the genome of those 99 cold viruses along with 10 others from patients with influenza-like symptoms in an effort to understand how the viruses mutate as they spread from one person to another, why some cold strains exacerbate asthma and why exposure to colds during infancy may cause asthma later in life.

Genomes are the genetic codes that define the particular characteristics of every organism. They are composed of DNA, which is made up of pairs of nucleotide bases: adenine, cytosine, guanine, or thymine. When we sequence DNA, we map the order of these bases to determine the unique genetic code of that organism. Each cold virus genome is about 7000 base pairs, so researchers were able to achieve about 6x coverage per genome (meaning the sequence quality is pretty good). They then aligned all of the sequences and compared them with one another, hoping to identify genetic similarities and differences.

Such comparisons identified a new species of cold virus. Scientists also found that people can be infected with multiple different strains of cold virus and that these viruses might undergo DNA exchange (recombination), producing unique strains with “different biological properties,” according to the authors.

DNA sequencing technology is advanced enough that instead of classifying viruses based on which proteins are present on its surface (serologic testing), future studies should sequence the entire genome of cold viruses.

I wonder which cold viruses are incubating inside me?

Source: “Sequencing and Analyses of All Known Human Rhinovirus Genomes Reveals Structure and Evolution” by Ann C. Palmenberg, David Spiro, Ryan Kuzmickas, Shiliang Wang, Appolinaire Djikeng, Jennifer A. Rathe, Claire M. Fraser-Liggett, Stephen B. Liggett, published on-line in Science on February 12, 2009.

Animals, plants and microorganisms produce a wide variety of chemicals, ranging from analgesics, such as opiates produced by opium plants, to cancer treatments, such as taxol produced by Pacific yew trees. Some types of wormwood make artemisinin, a treatment for malaria. Extracting chemicals from nature is often costly and damaging to the environment. Artemisinin, which is in short supply, is expensive and time consuming to synthesize in the laboratory.

One solution to this production problem comes from the burgeoning field of synthetic biology.  As I learned this morning at the AAAS annual meeting in Chicago, researchers are using genetic tricks to turn microorganisms, such as bacteria and yeast, into factories that produce artemisinin, which can then be easily purified.

It takes many chemical reactions for wormwood cells to make artmesinin. To boost production, scientists need to be able to purify chemicals from fast growing, fast producing microorganisms such as cultured yeast and bacteria. So University of California Berkeley professor Jay Keasling and his colleagues genetically engineered yeast to produce the proteins required for the myriad metabolic pathways required to manufacture artemisinin. (Keasling also heads the Joint BioEnergy Institute.)

The problem is that yeast do not normally produce artemisinin, so adding these “unnatural” metabolic pathways often damaged the cell. According to Keasling, troubleshooting such genetically modified microorganisms is the biggest bottleneck — his laboratory spent years trying to boost production efficiency.

A big problem was low yield. The proteins produced intermediates in the artemisinin pathway, but these intermediate chemicals would often accumulate and harm the cell. Keasling likens this to a leaky pipe. If you have several pieces of pipe, but no way of connecting them, whatever is flowing between them will leak. Researchers need a way to connect the pipes — the proteins — to minimize the leaks, but there are no standard “protein connectors.” The solution was a scaffold, a physical method to link the proteins to keep them in close proximity to each other. That way, when the first protein produced an intermediate, that intermediate would be picked up by the second protein, waiting nearby, and converted into the second intermediate, and so forth, until artemisinin was produced.

When Keasling and his team placed three key enzymes on a scaffold, they boosted their artemsinin yield to over 25 g/ml, the level needed to make synthetic production economically viable.

Keasling has now partnered with the French pharmaceutical company Sanofi-Aventis to scale up and optimize production for use in treating malaria. The microbially produced artemisinin will be on the shelves in a year or two, sold at a reduced price in Africa, according to Keasling.

Yichao Wu lived through a middle-school nightmare: In Ma’anshan, China, she survived a mathematics class taught by her mother.

“Math was not my best subject,” Wu admitted. Despite this experience, she went on to receive medical and doctoral degrees from Nanjing University, and in 2004 came to the United States to work in the lab of Mary Loeken at the Joslin Diabetes Center, part of Harvard Medical School in Boston.

A year later, Wu switched labs and joined Judy Lieberman’s virology group (also at Harvard), where Wu excelled.

Lieberman and others had designed small interfering RNAs (siRNA) to turn off specific genes in the herpes virus and had showed that intravaginal siRNA administration could prevent herpes transmission in mice, but the protection was short-lived. To get the cells in the genital tract to take up the siRNA, scientists attached it to lipids, fat molecules that access the cell by slipping into the surrounding membranes, themselves composed of lipids. This lipid-siRNA complex had to be applied just before intercourse, otherwise it failed to protect mice from infection.

Wu figured out the lipids attached to the siRNA actually enhanced infection, explaining why protection lasted only a day. She went on to show that when the siRNA was attached to cholesterol, instead of lipids, the treatment protected mice from infection for one week. If the results hold up during testing, a cholesterol-based siRNA could one day be used to prevent herpes infection in humans and possibly could be extended to prevent transmission of other viruses, such as HIV.

Wu says getting a job in Lieberman’s lab directly from China would have been nearly impossible because without a face-to-face interview, a lab like Lieberman’s wouldn’t consider her application. Loeken offered Wu a job after a phone interview, a “brave decision,” Wu said appreciatively.

Her biggest challenge living in the United States was the language. “I was the top English student in school [in China], I come here and it’s like I’m deaf.” But after two years, she gained confidence and became fluent.

Wu soon will begin a clinical research position at the Dana Farber Cancer Institute and plans to apply to U.S. residency programs. Her ultimate goal is to see patients and do research, something difficult to do in China. According to Wu, some Chinese hospitals have posts for physician-scientists, but the practice is not as widespread there as in the United States.

Of course, Wu’s family wants her to return, and her husband, a Chinese national working as a banker in Boston, feels similar pressures. But both have chosen to stay in the United States.

“Living abroad is sometimes lonely, it’s better to have family support,” Wu said. She advises her peers to be mentally strong and focus on their work in order to maximize the “amazing” resources available. In her case, moving to the United States “opened my mind to a whole new world.”

Have you been faced with a similar choice in your science career? Share your story in the comment box below.

Source: “Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene” by Yichao Wu, Francisco Navarro, Ashish Lai, Emre Basar, Rajendra K. Pandey, Muthiah Manoharan, Yang Feng, Sandra J. Lee, Judy Lieberman, Deborah Palliser. Cell Host & Microbe, January 22, 2009.