If you think slavery has been abolished, consider the case of the gypsy moth and the virus. For more than 100 years, people have noticed that some gypsy moth caterpillars climb to the top of trees before they die and decompose, or “melt.”

Melting releases more virus particles and is the normal fate of these caterpillars, but why did only some caterpillars perform this ascending death march?

Gypsy moths are voracious insects that have been spreading across the United States for a more than a century, so nobody is feeling too sorry for them, especially people who have seen them strip forests bare.

Still, it’s nice to read a good explanation for this peculiar “climb, croak, melt” behavior.

All the better to infect you with, my dear!

A study published today identifies a viral gene that blocks one stage of maturation in gypsy moth caterpillars, which normally hide during the day. But when Kelli Hoover, a professor of entomology at Penn State, and her colleagues infected bottled caterpillars with the virus of doom, the caterpillars showed the same climbing ‘n’ dying behavior that appears in the field.

In nature, those caterpillars would melt and then rain virus down to infect other gypsy moths.

The moth misbegotten

Gypsy moths were introduced to Massachusetts in the late 1800s by a bumbler who wanted to raise silk by crossbreeding them with silkworms — a different species, says Hoover. “It was crazy; this guy did not know anything about species, apparently.”

Still, the gypsy moths did bring fecundity and a ferocious appetite to the table — or forest. “They eat so many different kinds of trees and plants … in a bad outbreak, the insect frass dropping down sounds like rain, so you need a hat,” Hoover says.

We had to look it up to be sure, but frass is basically insect poop.

Gypsy moths are such effective defoliators that authorities try to control them with Bt, a bacterial spray that unfortunately kills beneficial insects, not just harmful ones.

Hoover’s study focused on a viral gene called egt, which inactivates a hormone that starts molting – a process that ends each stage, or “instar,” of the caterpillar’s development. “When they stop molting, they keep feeding, and that’s why we looked at egt,” Hoover says.

Photo: USDA APHIS Pest Survey Detection and Exclusion Laboratory

The battle against gypsy moths was joined before 1900, when an unknown chemical was sprayed against the invader.

ENLARGE

A dangerous meal

In every case, Hoover says, “if the gene was active, the moth died at the top of the bottle. If the gene was inactivated, it died at the bottom.”

It’s not clear, Hoover says, exactly why the gene changes behavior, but this is the first time it was traced to a single gene.

Because LdMNPV (the Lymantria dispar nucleopolyhedrovirus) infects only gypsy moths, and kill them at a young age, it might work as a biocontrol agent against a disastrous insect invasion. However, Hoover says, “the experiment’s goal was more basic – to understand how the virus enslaves its host.”

Certainly there is evolutionary logic behind changing your host’s behavior for your own benefit, assuming you are a pathogen or parasite, and “body-snatching” is well-known. For example, a fungus forces ants to climb, zombie-like, and die where they can easily spread fungal spores.

And it’s not just insects. The rabies virus, Hoover adds, “causes dogs, raccoons and bats to become more aggressive, to be out during the day, where they approach people and try to bite them,” which spreads the virus even though it endangers the animal.

And toxoplasmosis, a parasite, can make mice less fearful of cats, Hoover says, “so they are more likely to get eaten and infect the cat.”

There is even speculation that toxoplasmosis may cause men to behave with greater jealousy, Hoover says, “but the only thing that’s really been looked at is that mice with toxoplasmosis have a higher level of dopamine,” a feel-good neurotransmitter.

Is slavery therefore not all drudgery?

— David J. Tenenbaum

Using the tools of ultra-fast DNA sequencing, scientists have recently reported four ant genomes.

Before you doze off, take a moment to appreciate ants. These social insects are some of the most successful critters on the planet: Ants are invaders. Armies. Pests. Even farmers.

Ants live in colonies with dozens to millions of members, and whether judged by weight or impact, they can dominate ecosystems.

Explanations for the ants’ extraordinary success lie in their genomes – their entire catalog of genes. In the last month, scientists have published four ant genomes, adding to two published last year.

One of the new genomes covered the highly invasive Argentine ant, which has spread from its native South America to Europe, California and Japan. The ant “is a species of special concern because of its enormous ecological impact,” said Neil Tsutsui, associate professor at the Department of Environmental Science, Policy and Management at the University of California at Berkeley. “When the Argentine ants invade, they devastate the native insect communities while promoting the population growth of agricultural pests.”

ENLARGE

 

Photo: Thmazing

The Argentine ant is an ocean-crossing invader that harasses homeowners and native insects alike.

Like all social insects, Argentine ants communicate via chemical signals, and in 2009 Tsutsui ignited an ant war among friendly ants by doping them with chemicals that trigger aggressive behavior. Similar endeavors could be aided by the new genome map, which detected 367 genes for odor and 116 for taste.

Although the human genome project has yet to deliver its promised cargo of health benefits, Tsutsui said the new genome for the pesky ant “will provide a huge resource for people interested in finding effective, targeted ways of controlling the Argentine ant” by manipulating genes to interfere with mating, sparking inter-colony wars, developing repellants or luring ants into traps.

Ants practice agro-forestry

Another new ant genome covers the industrious leaf-cutter ant, which lives in giant colonies and farms fungus for a living. (Seen the ant-cam?)

Leaf-cutters nibble tree leaves into pieces, then haul them, porter style, to underground “gardens” where the leaves are devoured by a fungus.

This is not ornamental gardening. The fungus is the only thing these ants eat.

After million of years, the ants and fungi have evolved together, developing a serious case of co-dependency. “The ants need the fungus, and if they lose it, they die,” says Garret Suen, an assistant professor of bacteriology at the University of Wisconsin-Madison.

Suen, a key author of a recent genome of the leaf-cutter, adds that the reverse may also be true, since fungus has never been found outside ant gardens, and “it has co-evolved in tight association with the ants.”

ENLARGE

 

Photo: Hans Hillewaert

Give us this day our daily leaf: Leaf-cutter ant delivers leaf fragments to the garden.

This is some crazy co-evolution! The subterranean garden of one ant colony can reach a volume of 600 cubic meters. To feed the fungus, leaf-cutters ants can harvest as much as 17 percent of the leaves in a forest –- making this tiny critter the biggest herbivore in many new-world tropical forests. (Leaf-cutters don’t live in Asia, Africa or Europe.)

Other insects, like termites, house symbiotic microbes that “eat” biomass for them, but with the leaf-cutters, the symbiotic microbes live externally.

The new genome emphasizes the fundamental nature of the symbiosis, says Suen, because it showed that the ants lack a gene for synthesizing the amino acid arginine. Amino acids are building blocks of proteins, and all ants require arginine, but the pathway to make arginine in the leaf-cutter is broken, Suen says. “Presumably it used to be complete, and it’s complete in all other ants and many other social insects, except for our ant.”

When Suen and his colleagues finish analyzing the genetic sequence of the fungus, he suspects it may well show an enhanced ability to make arginine.

Photo: Wolfgang Hoffmann, University of Wisconsin-Madison.

Giant colonies of leaf-cutter ants are major but indirect plant-eaters in New-World tropical forests, where they harvest up to 17 percent of all leaves. The leaves support the huge underground fungus gardens that feed the ants.

 

Photo: Adrian Smith

The red harvester ant, native to the Southwest United States, has many detoxification genes, perhaps a response to past environmental changes. Red harvester ants have at least 344 genes related to smell, more than any other known insect.

Losing a gene

Evolution selects for genes that are needed for survival and reproduction, but since it’s wasteful to make things that have no purpose, genes that are no longer needed tend to break down or disappear over time.

Because leaf-cutter ants descended from ants that grew fungus with less sophistication, in much smaller gardens, the gene may have disappeared even before the leaf-cutters evolved between 8 and 12 million years ago, says Cameron Currie, associate professor of bacteriology at UW-Madison and study co-author. “They could have lost the genes 30 million years ago. Other symbiotic systems that are dependent on each other for nutrition have evidenced a similar loss of genes.”

The leaf-cutter also has a deficit in genes for making trypsin, an enzyme that breaks down proteins in food to make amino acids. “They are feeding on the fungus and it provides them with free amino acids, so it does not need these enzymes,” Suen says.

Another gene that evolution has shortchanged – but not totally eliminated – makes the protein hexamerin, which stores amino acids until they are needed during development. ”We think the developing brood has a constant source of amino acids from the fungus,” Suen says, “so it does not have to store them.”

Photo: Jürgen Liebig

Royalty reigns! When a jumping-ant queen dies, the workers battle to replace her. These new queens outlive their worker siblings. A recent jumping-ant genome showed that these replacement queens make many proteins linked to longevity.

Family obligations

Beyond confirming predictions of evolutionary theory, these genetic deletions could explain the long-lasting mutualism between ant and fungus, says Currie. If the ants would die without their fungus crop, they have a survivalist interest in blocking the entry of other fungi.

Although such a symbiosis looks like a great deal for both parties, cheaters can sabotage symbioses. “Evolution predicts that there should be instability, or cheating, in these cooperative relationships,” Currie says. “If I am giving a benefit to you at a cost to me, you can just take your benefit and not provide anything in return, which means you would be more successful compared to someone who cooperates and pays the cost.”

If you take your ailing auto to the car-fix, you could save money – once — by writing a rubber check. But repeated interaction is conducive to cooperation, Currie says. “If you write a bad check, next time you will not get your car fixed, and this applies to mutualism as well.”

In the ant-fungus relationship, Currie says, “The partners just can’t go and find new partners; they are locked together.”

In other words, the deletion of the ant’s arginine gene could explain why the co-dependency has lasted upwards of 8 million years.

Leave the leaves alone!

As ants don’t do a lot of reading and talking, chemical communication will likely be a focus for further genomic analysis. Plants dislike being eaten by any herbivore, so they produce toxic compounds to deter would-be browsers. Although the ant-fed fungus can eat more than 10 percent of the species of tree in the forest, some leaves are toxic to the fungus.

How do the ants know which type of leaves will kill it’s sole food, and how do they “talk about it”? It’s clear that the ants keep an eye on their crops, Suen says. When, as an experiment, scientists treated leaves with fungicide, the ants quit collecting that species, Suen says. “The ants remember and won’t touch those trees for two weeks because they are killing the fungus. How they do this, we have no idea, but now we can do an experiment to see what genes are being turned on or off” under those circumstances, and therefore must be involved in recognizing the death, and warning the colony about it. “We are pretty sure there is some communication between the fungus and the ant,” Suen says.

Social structure

More broadly, information about the genes of a highly successful organism with millions of cooperating individuals ought to be intriguing to another highly successful, but sometimes less cooperative, organism that has more brains, fewer legs, and equally large cities.

Leaf-cutter ants live a complicated life, and the identical set of genes allows them to become queens, soldiers, or several types of worker. “They do this with a brain that is incredibly small, but it’s collective, hard-wired behavior,” Currie says. “It’s amazing; there are 5 to 10 million ants with many different tasks that are done by different workers of different sizes,” and it all starts from the same genes.

The genome has yet to reveal a “farmer gene,” Currie says. He expects that candidate farmer genes will emerge when the leaf-cutter’s genome is compared to close relatives that do not farm. These may explain the leaf-cutter’s curious capacity for growing its food with the help of fungi, “But we are a long way from that.”

Can a gene that causes dwarfism also confer major health benefits? Perhaps, according to a new study showing that a group of extremely short people in Ecuador get no diabetes, even though they are unusually obese.

The 22-year study of people living in villages on the slopes of the Andes mountains also found just one case of cancer in the 99 patients it tracked, many fewer than among non-dwarf relatives.

The absence of two of the worst diseases of aging was strong evidence that the mutation that causes what’s called “Laron syndrome” has an upside, says Valter Longo, a gerontologist at the University of Southern California, and the senior author on the new study. “If you talk to anybody in the field, there is no way you can have a population with increased obesity and no diabetes. What was particularly strange was having zero deaths from cancer with 22 years of direct monitoring.”

Unfortunately, the subjects did not outlive the comparison group of relatives, due to large numbers of accidents and other alcohol-related problems.

The Laron’s patients are descendants of “Conversos,” Jews who were forcibly converted to Catholicism in Spain after 1492, and who emigrated to Latin America to escape continued persecution. Laron’s syndrome is also found in Israel and several other Middle-eastern countries.

The root of Laron’s syndrome, AKA growth hormone receptor deficiency, is a genetic mutation that disables the growth-hormone receptor, says Arlan Rosenbloom, a professor emeritus of pediatric endocrinology at the University of Florida who has long studied the Ecuadorian group but was not involved with the current report. “Growth hormone binds to its receptor on cell surfaces to stimulate production of insulin like growth factor-I (IGF-I) which is the real ‘growth hormone,’” Rosenbloom says. “Failure of the growth-hormone receptor cuts growth after birth by 50 percent. The Ecuadorians with this condition, 99 living individuals, comprise upwards of one-third of all individuals in the world with growth-hormone receptor deficiency.”

Image: Mikael Häggström

Growth hormone, secreted by the pituitary gland, travels to the liver, where it stimulates the formation of insulin-like growth factor 1, which stimulates bone growth.

The genetic angle

The new comparison of genetic differences between Laron patients and their non-dwarf relatives emerged from what Rosenbloom calls “spectacular epidemiological observations” by first author Jaime Guevara-Aguirre, an Ecuadorian endocrinologist who treats the Laron’s patients.

Working with Rafael de Cabo, a collaborator at the National Institute on Aging, Priya Balasubramanian from Longo’s research group exposed human epithelial cells, where most human cancers originate, to blood serum from control and Laron subjects. Serum is the cell-free portion of blood. “We wanted to know how this would affect the expression of dozens of genes,” says Longo, who studies cellular changes in aging.

The springboard of modern aging research is caloric restriction, because a diet with roughly 65 percent of normal calories is the only life-extension technique that works in a vast range of organisms. Although a similar group of protective genes activate under caloric restriction in yeast, fruitflies and mice, “We did not expect that a lot of the genes we study in yeast would come out as the most affected” in patients with a broken growth-hormone receptor, Longo says. “Serum from the Laron patients caused changes that we and others have shown to be highly protective in simple systems [like yeast]. We hoped for this but never really expected that many of the same genes would be coming up.”

At the molecular level, a key mechanism of aging is “oxidative stress,” damage to proteins and DNA caused by reactive molecules and fragments containing oxygen. When the researchers exposed human cells to the oxidant hydrogen peroxide, far fewer DNA breaks appeared in cells bathed in serum from the Laron patients, suggesting that they were protected against cancer.

The study found a second critical difference: When the DNA was damaged, cells in Laron serum were much more likely to commit suicide through apoptosis. Because apoptosis is a major obstacle to cancer, this suggested that cells in a Laron patient that had started on the path toward cancer would be more likely to kill themselves before going rogue.

Combined, the two phenomenon seem to explain why during the 22-year study only one of the Laron’s patients being tracked had a cancer, which was successfully treated. About 17 percent of their normal-height relatives had cancer during the same period.

Growing more confident

The study illuminates the role of insulin-like growth factor-1 (IGF-1), a growth hormone that, while required during development, may cause problems later on. “Large population studies show that people with the highest levels of IGF-I are at increased risk for certain types of cancer,” says Rosenbloom.

Longo notes that the effects of IGF-1 may depend on whether it is formed in an individual organ or distributed in blood. “Our hypothesis is that we do not need a ton of circulating IGF-1,” Longo says. Laron patients have between 0 and 10 percent of the normal level of IGF-1, “but they are fine, several made it into their 80s.”

The Ecuadorian study was more evidence that IGF-1 formation requires a functioning growth-hormone system. A drug that blocks the growth-hormone receptor has been approved for treating acromegaly, or gigantism, which is caused by excessive production of growth hormone.

You don’t have to be a hypochondriac to wonder if such a drug could prevent cancer and diabetes in adults, but the new study shows correlation, not proof, and Longo advocates a more modest first step in clinical trials. Return to caloric restriction for a moment: Studies in mice show that fasting reduces IGF-1 and protects healthy cells — but not tumor cells — from damage during chemotherapy, and some cancer patients have begun fasting to reduce collateral damage during chemo. “I think that soon enough, we will start with a clinical trial of this growth-hormone receptor antagonist to protect cancer patients against chemotherapy toxicity,” Longo says.

The new study is further proof, that, up and down the line from yeast to mice to people, similar “conserved” biochemical mechanisms influence aging, cancer and diabetes, Longo says. “The conservation hypothesis is something I am very convinced of, but I did not expect what we saw. Maybe we would see major reductions in cancer and insulin resistance [a marker of diabetes], but to see not one case of diabetes, not one cancer death, and to see the genetic matches with the simple systems that we study, that was as good as we could hope for.”

The evolution of a cancer

Genetically, cancer is a mess. Tumor cells don’t do the work of a healthy cell, but they are awfully good at making sloppy copies of themselves. Removed from the normal restraints and error-checking that keep healthy cells honest, cancer cells can change over time as they evolve to fight the immune system and cancer drugs.

 

Chart: NIH

The new study in Nature tracks the evolution of a breast cancer, a diagnosis that becomes more common with age.

Until now, getting a picture of these genetic changes has been an insurmountable task. Just “reading” the normal DNA in one person cost billions and took about a decade. But now, techniques for hyperspeed DNA sequencing are starting to produce libraries of genetic data, raising the hope of unraveling the varying genetics of cancer.

Nature is now reporting the most thorough study of evolution in a single patient’s breast cancer. “This week, for the first time, we have looked in detail at the evolution of a cancer genome over time,” says Samuel Aparicio, a professor at the BC [British Columbia] Cancer Research Center and the paper’s senior author. The study compared the cancer’s genes before and after it had spread, nine years later.

One disease, or many?

The ability to look in detail at cancer genes raises the prospect of eventually understanding the cause of the many diseases we call cancer. Cancer is a curious beast, and its genetics can get more bizarre with time. In the Aparicio study, the tumor cells nine years after diagnosis showed 32 significant mutations, only five of which were common in the original tumor.

Understanding these early and late mutations could shed light on the origin and spread of cancer.

 

From original graphic by DOE

Understanding the genetics of cancer could help in prevention and in treatment.

High-speed sequencing could eventually help doctors select treatments based on the genetics of the cells in the tumor, and Aparicio says his team has already begun tracking patient’s genes. “We will be able to build up our idea of what mutations might be conferring resistance or sensitivity to drugs. Eventually, we can ask, ‘did this or that genome respond better to this drug?’”

Making treatment decisions could be complicated, however, as even the original tumor showed genetic weirdness that is not found in healthy tissue. This genetic diversity is important, Aparicio says. “When one considers developing a therapeutic strategy, we tend to regard the cancer genome as a single entity. Cancer biologists have known this for decades, but we just have not had the means to see it.”

Moral of the story: Weapons against a “single” cancer are actually confronting multiple foes, which have — or may evolve — multiple genetic tricks for evading cancer-killing medicines and the immune system.

 

From graphic by NIH

Sequencing DNA relies upon matching pairs of components that have specific preferences for partners. If you know the sequence on one strand, you can predict the sequence of the other.

Consequential sequencing system

Scientists have wanted to understand the changing genetics of cancer for decades, but this study was only possible due to phenomenal advances in sequencing speed that are meanwhile causing the cost to drop, some say, faster than the price of computers.

Ultra-speed “synthesis DNA sequencing” relies on DNA’s ladder-shaped, double-stranded structure. The molecule is built of pairs of components called “bases” that are picky about partners: The base nicknamed “A” will only link to “T”. Likewise, “G” is specific to “C.”

Any time you see a C, you know it’s got to be linked to a G. So knowing the sequence on one strand tells you the sequence on its complementary strand.

Technicians start synthesis sequencing by splitting the DNA ladder lengthwise and anchoring millions of short strands to a sample plate. The sequencing machine then introduces new bases and watches as they complete the anchored strands. Because each base will only link to its complementary pair member, the process of attachment shows the structure of the DNA fragments that were originally attached to the plate.

Synthesis sequencing is just catching on, and the current study looked at one tumor, from one patient. To understand which mutations are most dangerous, “one really has to … look at multiple cancers,” Aparicio says.

However, one mutation that already seems portentous is HAUS3, which causes defects in proteins that organize the chromosomes as they undergo the delicate process of uncoiling, duplicating, and recoiling during cell division, Aparicio says. “We know from other studies that if we deplete those proteins, cell division becomes error-prone, which leads to instability in the genome, so conceivably mutations in those genes might have been involved in the early stages of cancer.”

 

Graphic: National Cancer Institute

The secondary cancer, called a metastasis, is more likely to cause death than the primary tumor.

A first look

As an early look into the tangled genomics of cancer, the study is a good first step, says Michael Gould, an oncologist at the University of Wisconsin-Madison School of Medicine and Public Health. “In this data from one patient, the original tumor had a lot fewer meaningful mutations than previous reports on breast cancer cell lines. If this holds up for other solid tumors, and I believe it will, there will not be a huge catalog of mutations in any individual [primary] tumor, and that’s good.”

However, Gould adds that compared to a previous study of the blood cancer leukemia, the British Columbia study also found more genetic change over time. “In leukemia, the primary and metastatic tumors had the same spectrum of mutations, and people concluded there was not necessarily genetic evolution going on, that maybe when the cancer first comes up, you either have a metastatic mutation or you don’t. In this [breast cancer] study, and maybe it’s generalizable to other solid tumors, there is some evolution going on between the primary and metastatic tumor.”

As Aparicio says, the treatment goal of this type of genomic analysis is already beginning, as researchers try to correlate different genetics with treatment outcomes. But learning about gene damage in the primary tumor may also identify the original cause of the cancer. Whether that cause resides in the environment or the patient, such insights should become the basis for better cancer prevention.

David J. Tenenbaum