Bacterium engineered with DNA in which thymine is replaced by synthetic building block

Source: Bacterium engineered with DNA in which thymine is replaced by synthetic building block

The project, coordinated by Rupert Mutzel (Institut für Biologie, Freie Universität Berlin) and Philippe Marlière (Heurisko USA Inc.), involved researchers of the French CEA (Commissariat à l’Energie Atomique et aux Energies Alternatives) and of the Katholieke Universiteit Leuven (Belgium). As described in the latest issue ofAngewandte Chemie International Edition, the experimental work was based on a unique technology developed by Marlière and Mutzel enabling the directed evolution of organisms under strictly controlled conditions. Large populations of microbial cells are cultured for prolonged periods in the presence of a toxic chemical — in this case, 5-chlorouracil — at sublethal levels, thereby selecting for genetic variants capable of tolerating higher concentrations of the toxic substance.

In response to the appearance of such variants in the cell population the concentration of the toxic chemical in the growth medium is increased, thus keeping the selection pressure constant. This automated procedure of long term evolution was applied to adapt genetically engineered Escherichia colibacteria unable to synthesize the natural nucleobase thymine to grow on increasing concentrations of 5-chlorouracil. After a culture period of about 1000 generations descendants of the original strain were obtained which used 5-chlorouracil as complete substitute for thymine. Subsequent genome analysis revealed numerous mutations in the DNA of the adapted bacteria. The contribution of these mutations to the adaptation of the cells towards the halogenated base will be the subject of follow-up studies.

Besides the obvious interest of this radical change in the chemistry of living systems for basic research the scientists consider the outcome of their work also to be of importance for “xenobiology,” a branch of synthetic biology. This young area of the life sciences aims at the generation of new organisms not found in nature harboring metabolic traits optimized for alternative modes of energy production or for the synthesis of high value chemicals. Like GMOs, such organisms are seen as a potential threat for natural ecosystems when released from their laboratory confinements, either through direct competition with wild type organisms or through diffusion of their “synthetic” DNA.

Scientists have recognized that physical containment cannot in every single case prevent engineered live forms from reaching natural habitats, in the same way as radioactive isotopes can leak into the surroundings of a nuclear power plant. However, synthetic organisms like those evolved by Marlière and Mutzel and their collaborators which depend on the availability of substances for their proliferation not found in nature or which incorporate non-natural building blocks in their genetic material could neither compete nor exchange genetic messages with wild type organisms, but would die in the absence of the xenobiotic.

Ants Are Experienced Fungus Farmers

Source: Ants Are Experienced Fungus Farmers

Entomologists Ted Schultz and Seán Brady at the Smithsonian’s National Museum of Natural History have been providing new insight into the agricultural abilities of ants and how these abilities have evolved throughout time. Using DNA sequencing, the scientists were able to construct an “evolutionary tree” of fungus-growing ants, which revealed a single pioneering ancestor that discovered agriculture approximately 50 million years ago.

In the past 25 million years, four different specialized agricultural systems have evolved, leading to the most recently evolved and best-known fungus-growing ant species–“leaf-cutter ants.” The ants do not eat the leaves; they grow their fungus gardens on them and then eat the fungus. By studying the agricultural evolution of leaf-cutter ants, as well as various other species, scientists may be able to develop improved human agricultural and medical methods.

“Agriculture is very rare in the animal world,” said Schultz. “We only know of four animal groups that have discovered agriculture: ants, termites, bark beetles and humans. By studying certain fungus-growing ants, which our study indicates are almost like ‘living fossils,’ we might be able to better understand steps involved in the evolution of ant agriculture.”

To complete their research, scientists spent more than 15 years assembling a comprehensive array of specimens, which included 91 ant species, 65 of which were fungus-growing ant species representing all different groups of fungus-growing ants. Researchers then used DNA sequencing, combined with a variety of state-of-the-art computer algorithms, to construct an evolutionary tree of fungus-growing ants. Dominican amber fungus-growing ant fossils were used to calibrate time intervals on the evolutionary tree.

From this evolutionary tree, scientists were able to determine that fungus-growing ants are all descended from a common ancestor that pioneered agriculture 50 million years ago during a period of global warming. The researchers also determined that in the past 25 million years, four different specialized agricultural systems emerged.

Each of these systems has its own unique set of cultivated fungi. For example, approximately 20 million years ago one group of fungus-growing ants discovered “higher agriculture,” meaning they cultivated their fungi to produce specialized “fruits” that the ants would harvest and eat for food. Leaf-cutter ants, which belong to this group, originated recently–less than 10 million years ago. Finally, it also was discovered that there are certain fungus-growing ant species living in South America today that are “missing links” in evolution.

Nanotechnology used to harness power of fireflies

Source: Nanotechnology used to harness power of fireflies

It’s all about the size and structure of the custom, quantum nanorods, which are produced in the laboratory by Mathew Maye, assistant professor of chemistry in SU’s College of Arts and Sciences; and Rebeka Alam, a chemistry Ph.D. candidate. Maye is also a member of the Syracuse Biomaterials Institute. “Firefly light is one of nature’s best examples of bioluminescence,” Maye says. “The light is extremely bright and efficient. We’ve found a new way to harness biology for non-biological applications by manipulating the interface between the biological and non-biological components.”

Their work, “Designing Quantum Rods for Optimized Energy Transfer with Firefly Luciferase Enzymes,” was published online May 23 in Nano Letters and is forthcoming in print. Collaborating on the research were Professor Bruce Branchini and Danielle Fontaine, both from Connecticut College.

Fireflies produce light through a chemical reaction between luciferin and it’s counterpart, the enzyme luciferase. In Maye’s laboratory, the enzyme is attached to the nanorod’s surface; luciferin, which is added later, serves as the fuel. The energy that is released when the fuel and the enzyme interact is transferred to the nanorods, causing them to glow. The process is called Bioluminescence Resonance Energy Transfer (BRET).

“The trick to increasing the efficiency of the system is to decrease the distance between the enzyme and the surface of the rod and to optimize the rod’s architecture,” Maye says. “We designed a way to chemically attach, genetically manipulated luciferase enzymes directly to the surface of the nanorod.” Maye’s collaborators at Connecticut College provided the genetically manipulated luciferase enzyme.

The nanorods are composed of an outer shell of cadmium sulfide and an inner core of cadmium seleneide. Both are semiconductor metals. Manipulating the size of the core, and the length of the rod, alters the color of the light that is produced. The colors produced in the laboratory are not possible for fireflies. Maye’s nanorods glow green, orange, and red. Fireflies naturally emit a yellowish glow. The efficiency of the system is measured on a BRET scale. The researchers found their most efficient rods (BRET scale of 44) occurred for a special rod architecture (called rod-in-rod) that emitted light in the near-infrared light range. Infrared light has longer wavelengths than visible light and is invisible to the eye. Infrared illumination is important for such things as night vision goggles, telescopes, cameras, and medical imaging.

Maye’s and Alam’s firefly-conjugated nanorods currently exist only in their chemistry laboratory. Additional research is ongoing to develop methods of sustaining the chemical reaction — and energy transfer — for longer periods of time and to “scale-up” the system. Maye believes the system holds the most promise for future technologies that that will convert chemical energy directly to light; however, the idea of glowing nanorods substituting for LED lights is not the stuff of science fiction.

Researchers Achieve RNA Interference, in a Lighter Package

To achieve this type of gene shutdown, known as RNA interference, many researchers have tried — with some success — to deliver RNA with particles made from polymers or lipids. However, those materials can pose safety risks and are difficult to target, says Daniel Anderson, an associate professor of health sciences and technology and chemical engineering, and a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

The new particles, developed by researchers at MIT, Alnylam Pharmaceuticals and Harvard Medical School, appear to overcome those challenges, Anderson says. Because the particles are made of DNA and RNA, they are biodegradable and pose no threat to the body. They can also be tagged with molecules of folate (vitamin B9) to target the abundance of folate receptors found on some tumors, including those associated with ovarian cancer — one of the deadliest, hardest-to-treat cancers.

Anderson is senior author of a paper on the particles appearing in the June 3 issue of Nature Nanotechnology. Lead author of the paper is former MIT postdoc Hyukjin Lee, now an assistant professor at Ewha Womans University in Seoul, South Korea.

Genetic disruption

RNA interference (RNAi), a natural phenomenon that cells use to control their gene expression, has intrigued researchers since its discovery in 1998. Genetic information is normally carried from DNA in the nucleus to ribosomes, cellular structures where proteins are made. Short interfering RNA (siRNA) disrupts this process by binding to the messenger RNA molecules that carry DNA’s instructions, destroying them before they reach the ribosome.

siRNA-delivering nanoparticles made of lipids, which Anderson’s lab and Alnylam are also developing, have shown some success in turning off cancer genes in animal studies, and clinical trials are now underway in patients with liver cancer. Nanoparticles tend to accumulate in the liver, spleen and lungs, so liver cancer is a natural target — but it has been difficult to target such particles to tumors in other organs.

“When you think of metastatic cancer, you don’t want to just stop in the liver,” Anderson says. “You also want to get to more diverse sites.”

Another obstacle to fulfilling the promise of RNAi has been finding ways to deliver the short strands of RNA without harming healthy tissues in the body. To avoid those possible side effects, Anderson and his colleagues decided to try delivering RNA in a simple package made of DNA. Using nucleic acid origami — which allows researchers to construct 3-D shapes from short segments of DNA — they fused six strands of DNA to create a tetrahedron (a six-edged, four-faced pyramid). A single RNA strand was then affixed to each edge of the tetrahedron.

“What’s particularly exciting about nucleic acid origami is the fact that you can make molecularly identical particles and define the location of every single atom,” Anderson says.

To target the particles to tumor cells, the researchers attached three folate molecules to each tetrahedron. Short protein fragments could also be used to target the particles to a variety of tumors.

Using nucleic acid origami, the researchers have much more control over the composition of the particles, making it easier to create identical particles that all seek the right target. This is not usually the case with lipid nanoparticles, says Vinod Labhasetwar, a professor of biomedical engineering at the Lerner Research Institute at the Cleveland Clinic. “With lipid particles, you’re not sure what fraction of the particles are really getting to the target tissue,” says Labhasetwar, who was not involved in this study.

Circulate and accumulate

In studies of mice implanted with human tumors, the researchers found that once injected, the nucleic acid nanoparticles circulated in the bloodstream with a half-life of 24 minutes — long enough to reach their targets. The DNA tetrahedron appears to protect the RNA from rapid absorption by the kidneys and excretion, which usually happens with RNA administered on its own, Anderson says.

“If you take a short interfering RNA and inject it into the bloodstream, it is typically gone in six minutes. If you make a bigger nanoparticle using origami methods, it increases its ability to avoid excretion through the kidneys, thereby increasing its time circulating in the blood” he says.

The researchers also showed that the nucleic acid nanoparticles accumulated at the tumor sites. The RNA delivered by the particles was designed to target a gene for luciferase, which had been added to the tumor cells to make them glow. They found that in treated mice, luciferase activity dropped by more than half.

The team is now designing nanoparticles to target genes that promote tumor growth, and is also working on shutting off genes involved in other genetic diseases.

The research was funded by the National Institutes of Health, the Center for Cancer Nanotechnology Excellence, Alnylam Pharmaceuticals and the National Research Foundation of Korea.

Source: Massachusetts Institute of Technology (2012, June 4). Researchers achieve RNA interference, in a lighter package. ScienceDaily. Retrieved June 10, 2012, from http://www.sciencedaily.com­/releases/2012/06/120604125601.htm

Berkeley scientists turn harmless virus into piezoelectric generator

Scientists at the Lawrence Berkeley National Laboratory (Berkeley Lab) have created a harmless, genetically-modified virus that’s piezoelectric — in other words, it generates electricity when pressure is applied. This virus might eventually find its way into piezoelectric generators in the sole of your shoe, which would generate electricity (for your smartphone) while you walk.

The concept of piezoelectric energy harvesting is hardly new, but according to Berkeley Lab the materials used to make piezoelectric devices are toxic, and are thus no good for internal use or for consumer-facing applications (such as the aforementioned shoe-sole power generator). The The M13 bacteriophage (literally “bacteria devourer”) virus, however, is: piezoelectric, harmless to humans, easy to genetically modify, and readily aligns itself into an orderly film — and, being a virus, it readily replicates itself millions of times, so you don’t need to worry about running out of juice at an inopportune moment.

To turn the M13 phage into into a power source, the scientists genetically engineered the virus to create a higher voltage, stacked 20 layers of the virus on top of a gold substrate, attached some wires, and voila: a piezoelectric generator that produces no less than six nanoamperes at 400 millivolts. This might not sound like a lot (OK 6 nA isn’t a lot), but in the video below you can see that it’s enough to power a simple LCD display — or, alternatively, a low-power sensor.

Ultimately, the most exciting aspect about piezoelectricity is that it can be generated from almost any “wasted” movement — this could be as obvious as swinging your legs and feet, but piezoelectric generators could also harvest power from dance floors, the office stairs, or the vibrations from heavy machinery.

It’s also worth bearing in mind that a self-assembling piezoelectric generator is rather desirable — especially in today’s world, where mass production of genetically modified viruses is a lot easier than rearranging individual atoms with a scanning tunneling microscope. Byung Yang Lee, one of the scientists behind the discovery, says, “We’re now working on ways to improve on this proof-of-principle demonstration… piezoelectric materials based on viruses could offer a simple route to novel microelectronics in the future.”

View the research paper here: http://www.nature.com/nnano/journal/v7/n6/full/nnano.2012.69.html

Parasitic Plants Steal Genes from Their Hosts

Vertical gene transfer is that between parents and their offspring, while horizontal gene transfer is the movement of genes between two different organisms. Bacteria use horizontal gene transfer to exchange resistance to antibiotics. Recent studies have shown that plants can also use horizontal gene transfer, especially parasitic plants and their hosts due to their intimate physical connections.

Rafflesia cantleyi is an obligate holoparasite (dependent on its host, and only that host, for sustenance), which grows on Tetrastigma rafflesiae, a member of the grape family. Researchers from Singapore, Malaysia and USA collaborated to systematically investigate the possibility of horizontal gene transfer between these two plants. By looking at the transcriptome (the transcribed products of switched on genes) they found 49 genes transcribed by the parasite, accounting for 2% of their total transcriptome, which originally belonged to the host. Three quarters of these transcripts appear to have replaced the parasites own version.

Most of these genes had been integrated into the parasite’s nucleus, allowing the researchers to perform genomic analysis. Over time DNA randomly mutates and investigation of genetic drift between the genes for these transcripts, between the parasite and host, showed that some time has passed since the genes were acquired and that they were acquired gradually.

Prof Charles Davis, from the Harvard University Herbaria, who co-led this project with Prof Joshua Rest from Stony Brook University, explained, “The elevated rate of horizontal gene transfer between T. rafflesiae and its parasite R. cantleyi raises the possibility that there is a ‘fitness’ benefit to the parasite. For example they may improve the parasites ability to extract nutrients from the host, or help it evade the host’s defences, as has been seen for a bacterial pathogen of citrus trees.”

Prof Davis continued, “Furthermore it appears that about one third of the parasites own genes have evolved to be more like those of T. rafflesia. Finding out how T. rafflesia manages its genomic deception will provide us with real insights into the slow war between plant parasites and their hosts.”

New research yields insights into Parkinson’s disease

Researchers at the University of Toronto Scarborough (UTSC) used an innovative technique to examine chemical interactions that are implicated in Parkinson’s Disease.

The work details how a protein called alpha-synuclein interacting with the brain chemical dopamine can lead to protein misfolding and neuronal death.

Parkinson’s Disease is a neurodegenerative disease which results in loss of motor control and cognitive function. Although the cause isn’t known precisely, the disease involves the death of brain cells that produce dopamine, a chemical important in neuronal signaling. The disease also involves a protein called alpha-synuclein which aggregates in the neurons of people with the disease.

Kagan Kerman, a chemist in the Department of Physical and Environmental Sciences, and Ian R. Brown, a neuroscientist who founded UTSC’s Centre for the Neurobiology of Stress in the Department of Biological Sciences, looked at the way dopamine interacts with alpha-synuclein to form aggregates that may be toxic to neurons.

“This is very fundamental,” says Kagan Kerman. “It gives us a new point of view of the misfolding proteins and how they are affected by dopamine.”

These sorts of interactions are often studied using microscopy. But the UTSC researchers decided to use an electroanalytic technique called voltammetry. By studying tiny changes in electric current as dopamine and alpha-synuclein interacted they were able to determine details about the early phases of the interaction.

Using the technique, they were able to detail how changes in pH levels and ionic strength of the solution affected the interaction. They found that at higher pH levels and higher ionic strengths, dopamine interacted much more strongly with alpha-synuclein, forming aggregates more quickly.

The results could have implications for understanding and treating the disease. Normally dopamine is contained in structures called vesicles, in which pH levels are low and dopamine is unlikely to interact with alpha-synuclein. 

Outside of the vesicles dopamine encounters higher pH levels and, according to the new research, is much more likely to interact to create aggregates.

The analysis was done using chemicals deposited onto screen-printed electrodes only 12.5 mm by 4 mm. The electrodes were manufactured at Osaka University, where Kerman completed his PhD work. Because they are so small, the electrodes allowed analysis to be done on tiny samples.

The technique is a potentially quicker and cheaper way to study protein misfolding, and could be automated to screen drugs that might treat the disease, says Brown.

The research was published in Chemical Neuroscience, published by the American Chemical Society.

New drug strategy attacks resistant leukemia and lymphoma

Scientists build a synthetic peptide that overcomes cancer cells’ survival defenses
  

BOSTON–Scientists at the Dana-Farber/Children’s Hospital Cancer Center have developed an anti-cancer peptide that overcomes the stubborn resistance to chemotherapy and radiation often encountered in certain blood cancers when the disease recurs following initial treatment.

The strategy could pave the way for much needed new therapies to treat relapsed and refractory blood cancers, which are difficult to cure because their cells deploy strong protein “deflector shields” to neutralize the cell death signals that chemotherapy agents used against them initially, say the researchers.

The prototype compound, called a “stapled BIM BH3 peptide,” is designed to disable the cancer’s defenses by hitting a family of protein targets that regulate cell death.

In proof-of-concept studies in mice with transplanted, drug-resistant leukemia tumors, the compound alone suppressed cancer growth, and when paired with other drugs, showed synergistic anti-cancer activity, say researchers led by Loren Walensky, MD, PhD, of Dana-Farber/Children’s Hospital Cancer Center.

Their paper has been posted online by the Journal of Clinical Investigation and will appear in the journal’s June issue. Walensky is the senior author and James LaBelle, MD, PhD, is the first author.

A cell’s “fate” – when and whether it lives or dies – depends on a tug-of-war between pro-death and anti-death forces within the cell that serve as a check-and-balance system to maintain orderly growth. The system is regulated by the BCL-2 family of proteins, which contains both pro-death and pro-survival members.

When cells are no longer needed or are damaged beyond repair, the body activates pro-death BCL-2 proteins to shut down mitochondria – the power plants of the cell– resulting in an orchestrated cellular destruction known as apoptosis, or programmed cell death.

Many cell-killing cancer treatments work by triggering these “executioner proteins” to cause tumor cells to commit suicide in this fashion. But cancer cells can escape their death sentence – and even become immortal – by hyperactivating the survival arm of the family; these proteins intercept the executioner proteins and block their lethal mission.

“When cancers recur, they activate not just one type of survival protein, but many,” explains Walensky, whose laboratory has extensively studied the cell-death system and makes compounds to manipulate it for research and therapeutic purposes.

“It’s as if relapsed cancers ‘learned’ from their initial exposure to chemotherapy such that when they come back, they put up a variety of formidable barriers to apoptosis,” he adds. “To reactivate cell death in refractory hematologic cancers, we need new pharmacologic strategies that broadly target these obstacles and substantially lower the apoptotic threshold.”

When cancers specifically rely on one or two survival proteins, treating them with selective BCL-2 inhibitors can be very effective at eliminating the cancer cells’ survival advantage. But relapsed cancers often evade such agents by deploying a battery of alternate survival proteins, so what’s needed, Walensky says, are “next-generation” compounds that can block a wider range of survival proteins without jeopardizing normal tissues.

In the current research, the scientists built a chemically-reinforced peptide containing the death-activating BH3 domain of an especially potent killer protein, BIM, which is able to tightly bind with and neutralize all of the BCL-2 family survival proteins. This ‘stapled’ peptide, which incorporates the natural structure and properties of BIM BH3, not only disables the survival proteins, but also directly activates pro-death BCL-2 family proteins in cancer cells, making them self-destruct. Importantly, non-cancerous cells and tissues were relatively unaffected by the treatment.

“The diversity of BCL-2 family survival proteins blunts the anti-tumor activity of essentially all cancer treatments to some degree,” Walensky points out. “By using Nature’s solution to broad targeting of the BCL-2 pathway with a stapled BIM BH3 peptide, our goal is to eliminate cancer’s protective force field and enable the arsenal of cancer treatments to do their job.”

Department of Biotechnology Announces A Pathbreaking Research:an International Consortium Sequences Tomato Genome

The Secretary, Department of Biotechnology Shri M K Bhan today announced a major leap forward in the field of Biotechnology Research. Mr. Bhan informed the media persons in New Delhi that the Tomato Genome Consortium (TGC), a group of over 300 scientists from fourteen countries, has sequenced the genomes of the domesticated tomato and its wild ancestor, Solanum pimpinellifolium. This achievement is expected to lower costs and speed up efforts to improve the worldwide tomato production, making it better equipped to combat the pests, pathogens, drought and diseases that now plague growers. The work may also speed up improvements in other crops. This important result is published in this week’s issue of Nature as cover story.

Main contributor Director of National Institute of Plant Genome Research Prof. Akhilesh Kumar Tyagi said that India contributed sequence of euchromatic region with emphasis on chromosome 5 of tomato and provided support to generate 5-fold sequence coverage of the entire tomato genome by Next Generation Sequence (NGS) technology. Indian Team also participated in performing annotation of all predicted proteins using international databases as a part of the International Tomato Annotation Group (ITAG). Simultaneously, Indian researchers have taken up analysis of specific genes/gene families related to ripening, nutrition, disease resistance and abiotic stress tolerance based on transcriptome data and comparative genomics. The genomic resources generated are expected to greatly accelerate improvement of tomato by functional genomics and molecular breeding. The University of Delhi South Campus (Principal Investigator- J.P. Khurana), National Research Centre on Plant Biotechnology, Indian Agricultural Research Institute (Principal Investigator- N.K. Singh), and National Institute of Plant Genome Research (Principal Investigator- D. Chattopadhyay), New Delhi, under the auspices of the Indian Initiative on Tomato Genome Sequencing (IITGS; Coordinator- A.K. Tyagi) participated in the international Tomato Genome Consortium (TGC). The Indian initiative was funded by the Department of Biotechnology, Government of India, and supported by the Indian Council for Agricultural Research.

Mr. Tyagi mentioned that the sequences provide a detailed overview at the functional portions of the tomato genome and its closest relative, revealing the order, orientation, types and relative positions of their 35,000 genes. The sequences will help researchers decipher the relationships between tomato genes and traits and broaden their understanding of genetic and environmental factors that interact to determine a field crop’s health and viability. Tomato is a member of the Solanaceae or nightshade family, and the new sequences are expected to provide reference points helpful for identifying important genes in tomato’s relatives. The group includes potato, pepper, eggplant and petunia and is the world’s most important vegetable plant family in terms of both economic value and production volume. Solanaceae members serve as sources of food, spices, medicines and ornamentals.

Elaborating further the Director of NIPGR Mr. Tyagi mentioned that the sequences also offer insight into how the tomato has diversified and adapted to new environments. They show that the tomato genome expanded abruptly about 60 million years ago, at a time close to one of the large mass extinctions. Subsequently, most of this genetic redundancy was lost. Some of the genes evolved during that event survive till today and control some of the most appealing traits of tomato.

Mr. Bhan said that the previous efforts have led to the sequencing of a number of other crop plants, including rice, corn, sorghum, poplar, potato, soybean, grape and Arabidopsis thaliana, a plant widely studied as a model organism. The availability of tomato genome sequence will not only serve as a reference for other Solanaceous species but also help in comparative genomics among diverse taxa.

TGC was established as a result of a scientific conference organized in 2003 in Washington, DC. Consortium members include scientists from Argentina, Belgium, China, France, Germany, India, Israel, Italy, Japan, Korea, Spain, the Netherlands, the United Kingdom and the United States.

The genome sequence and related resources can be accessed at the Solgenomics website
(http://solgenomics.net) and at http://mips.helmholtz-muenchen.de/plant/tomato/index.jsp

Scientists decipher how T cells hunt down infection

T cells ‘hunt’ parasites like animal predators seek prey, study shows

By pairing an intimate knowledge of immune-system function with a deep understanding of statistical physics, a cross-disciplinary team at the University of Pennsylvania has arrived at a surprising finding: T cells use a movement strategy to track down parasites that is similar to strategies that predators such as monkeys, sharks and blue-fin tuna use to hunt their prey.

With this new insight into immune-cell movement patterns, scientists will be able to create more accurate models of immune-system function, which may, in turn, inform novel approaches to combat diseases from cancer to HIV/AIDS to arthritis.

The research involved a unique collaboration between the laboratories of senior authors Christopher Hunter, professor and chair of the Pathobiology Department in Penn’s School of Veterinary Medicine, and Andrea Liu, the Hepburn Professor of Physics in the Department of Physics and Astronomy. Penn Vet postdoctoral researcher Tajie Harris and physics graduate student Edward Banigan also played leading roles in the research.

The study, which will be published in the journal Nature, was conducted in mice infected with the parasite Toxoplasma gondii. This single-celled pathogen is a common cause of infection in humans and animals; as much as a third of the world’s population has a dormant form of this infection present in the brain. However, in immunocompromised individuals, such as those with HIV/AIDS or undergoing organ transplantation, this infection can have serious consequences, including brain inflammation and even death.

Earlier work had shown that T cells — a key immune-cell type — are central in preventing disease caused by T. gondii. In the new study, the Penn researchers used the infected mice as a natural model system to learn how the movement of T cells in the brain affects the body’s ability to control this infection.

Among immunologists, it’s widely believed that the movement of immune cells is governed in part by signaling proteins called chemokines. The Penn-led team demonstrated that a specific chemokine, CXCL10, and its receptor were abundantly produced in the brains of T. gondii-infected mice. When CXCL10 was blocked, mice had fewer T cells, a greater parasite burden and actively reproducing parasites.

Next the researchers sought to pinpoint the exact movement patterns of individual T cells in living tissue from T. gondii-infected mice. This was possible with multi-photon imaging, a technique that relies on a refined yet powerful microscope that can display living tissues in three dimensions in real time. Using this approach, the team found that CXCL10 appeared to play a role in the speed at which T cells are able to search for and control infection.To the extent that immunologists had considered T-cell movement patterns at all, many assumed that they moved in a highly directed fashion to find infected cells. But when the researchers analyzed the movement of T cells, they found their data did not match what would be expected: the T cells showed no directed motion.

That’s where the statistical physics expertise of Liu and Banigan came in.

“We looked at a much more complete way to quantify these tracks and found that the standard model didn’t fit at all,” Liu said. “After some work we managed to find a model that did fit the tracks beautifully.”

“The model that finally led us down the right path,” Banigan said, “had a strong signature of something really interesting,” a model known as a Lévy walk.

This “walk,” or a mathematically characterized path, tends to have many short “steps” and occasional long “runs.” The model was not fully consistent with the data, however.

“Rather, I had to look at variations on the Lévy walk model,” Banigan said, because the researchers also observed that the T cells paused between steps and runs. Like the movements of the cells, the pauses were usually short but occasionally long.

Hunter likened the model to a strategy a person might employ to find misplaced keys in the house.

“When you lose your keys, how do you go about looking for them? You look in one place for a while, then move to another place and look there,” he said.

“What that leads to is a much more efficient way of finding things,” Liu said.

And, indeed, when the team modeled the generalized Lévy strategy against other strategies, they confirmed that the Lévy walk was a more efficient technique to find rare targets. That makes sense for T cells, which have to locate sparsely distributed parasites in a sea of mostly normal tissue.

Interestingly, T cells are not alone in employing a Lévy-type strategy to find their targets. Several animal predators move in a similar way — with many short-distance movements interspersed with occasional longer-distance moves — to find their prey. The strategy seems particularly common among marine predators, including tuna, sharks, zooplankton, sea turtles and penguins, though terrestrial species like spider monkeys and honeybees may use the same approach to locate rare resources.

This parallel with animal predators also makes sense because parasites, like prey species, have evolved to evade detection.

“Many pathogens know how to hide, so T cells are not able to move directly to their target,” Hunter said. “The T cell actually needs to go into an area and then see if there’s anything there.”

The model is also relevant to cancer and other immune-mediated diseases, Hunter noted.

“Instead of looking for a parasite, these T cells could be looking for a cancer cell,” he said. By knowing what controls T cell movement, “you might be able to devise strategies to make the T cells more efficient at finding those cells.”

On the physics side, while the Lévy-walk model is not new, the fact that T cells pause in between their steps or runs is something that hadn’t been recognized before when mapping the paths in other contexts.

“From a physics point of view, to have runs and pauses is a new model,” Liu said. “Biological phenomena can illustrate what we wouldn’t have thought about otherwise.”

The Penn collaborators are working to plot the tracks of other cell types and credit their unique partnership for their discovery.

“We’ve said all along that this study could only happen because [our physics colleagues] had such a great expertise and we had our own separate expertise,” Tajie Harris said. “They took a chance working with us, and it turned out to be something really rewarding.”