All complex societies require a division of labor. Human civilization has advanced to modern levels because people can specialize and become experts. Some produce food, while others design buildings, and still others care for the sick.
When it comes to division of labor, however, humans have got nothing on the social insects. These animals, such as honeybees, follow a rigid caste system. The system is incredibly efficient, and it has helped social insects become one of the greatest evolutionary success stories on the planet.
Social bees. Photo by Bente Smedal
We humans don’t want to have our lots in life decided in the cradle. However, studying how a bee grows up to be a queen can teach us a lot about how genes interact with the environment. ASU researchers studying bees are gaining insights into our own development, as well as seemingly unrelated areas as food choice and aging.
A female bee can become a worker or a queen. Queen bees are larger and live longer than workers. Queen bees are also fertile, while workers are essentially sterile. A queen lays eggs and keeps society together with potent pheromones that attract the workers. Workers tend the hive, care for the queen and larvae, and forage for food.
Male bees only come along when it’s time for the queen to mate.
“The queen will fly out after she’s about one week old, and she will meet with many drones in a congregation area. She will fly through the area and mate with the drones in flight. And the drones, they just die directly after they mate with the queen. That is really their sole purpose. While they are in the colony waiting for their flights, they basically sit around and get fed by the workers,” says Florian Wolschin, an assistant research professor in ASU’s School of Life Sciences, (SOLS), within the College of Liberal Arts and Sciences. Wolschin is also a senior scientist at the Norwegian University of Life Sciences.
The drones don’t fertilize the queen’s eggs right away. Instead, she holds onto their sperm and fertilizes her eggs as needed. To produce male bees, she lays unfertilized eggs.
Worker bees determine the fate of the female larvae. The amount and composition of the food the larvae receive determine whether they become workers or queens. Among workers, tasks are further divided into caring for the queen and larvae, and foraging for pollen or nectar. Some workers collect mostly pollen, while others prefer nectar.
Nurse bees take care of the brood. Photo by Bente Smedal
The bees’ genes
Bee social behavior is so structured that one might assume it’s hard-coded in their genes.
“There was an expectation that by sequencing honeybees one would find a key to social life. But there wasn’t much evidence in the genome for social genes or new gene products that had evolved to specifically contribute to controlling social life,” says Gro Amdam, an associate professor in SOLS and the Norwegian University of Life Sciences, and one of the scientists who first sequenced the honeybee genome.
“The incredible thing is that both of these types of female honeybees emerge from the same genome,” adds Wolschin. “So how does that happen?”
The fact that bees can develop so differently from the same genome makes them useful model animals for exploring our own development. Model organisms have contributed greatly to our understanding of biology. For instance, most of what we know about classical genetics comes from studies of fruit flies. And most of what we know about molecular genetics comes from looking at E. coli.
Social insects are excellent candidates for helping us advance a field called “epigenetics.” It is the study of how the function of genes can change without changing the sequence of the genetic code, or DNA.
For example, how does one stem cell “know” to develop into a liver cell, while another stem cell—carrying the exact same genes—becomes a neuron? Why do some people with a genetic predisposition for breast cancer get the disease, while others, who carry the same mutation, don’t?
Epigenetics combines genetics, biochemistry and the environment—nature and nurture put together. Environment is tough to study in humans, particularly when you are studying behavior. Furthermore, we cannot ethically tinker with peoples’ genes to see what will happen.
Enter the insects.
“The food choice behavior of bees was one of the first behaviors that was shown to have a genetic component. So bees have been used from early on as a model to study the genetics of complicated behavior, including social behavior,” says Amdam.
A woman’s role
Ancient bees were solitary creatures. Unlike the social bees we see today, these ancestors were do-it-yourselfers. Every female reproduced, foraged and nurtured larvae. Over time, social bees such as honeybees evolved and divided the workload.
The lack of distinctive “social genes” separating these two groups led Amdam and Robert Page, dean of SOLS, to present a new framework for social evolution. The scientists proposed that social life evolved through adoption of existing behavioral templates. In short, the ability to be social was in us from the start. Social creatures simply exaggerate it.
“I think it’s really easy to relate to that through an analogy of dogs,” says Amdam. There is great variety among dog breeds, from the tiny Chihuahua to the massive great Dane. We have bred dogs for behaviors in addition to looks. “We have retrievers, we have pointers, we have dogs that fight, we have dogs that run.”
All of these behaviors are present in wolves, the ancestors of domestic dogs. In dogs, however, certain behaviors are emphasized. For example, a retriever over-emphasizes fetching, while a greyhound over-emphasizes speed.
Solitary bees are like wolves. They do a variety of tasks equally well. Honeybees are more like dogs. Each bee does one task extremely well, to the detriment of other skills. But how does this happen?
A forager bee collects food. Photo by Christofer Bang
Solitary bees go through phases, and those phases are related to the state of their ovaries. For instance, a solitary bee will collect and hoard pollen when her ovary is large and she is getting ready to lay eggs, because the larvae will need pollen to eat. Among social bees, the workers still have ovaries, even though they don’t reproduce.
“The view before we started launching our idea was that these ovaries were a problem,” says Amdam. “Evolution for advanced social harmony would say worker ovaries should go away, because they are a potential source of conflict. As long as workers have ovaries they could lay eggs and become selfish competitors for their own reproduction.”
But what the researchers discovered is that ovaries play a role in the bees’ division of labor.
“What we found was a correlation between the size of the ovary and the food-hoarding preferences of the bees. So the larger the ovary was, the more likely it was that the workers would be doing this pollen collecting behavior,” says Amdam.
“And so we said that is too much of an association to be coincidental. We suggested that the female reproductive cycle had been adopted by social evolution. So instead of getting rid of the ovary, it was actually a resource for social life. The colony could, by creating variation in ovary size, create variation in the propensity of different bees to collect different kinds of food.”
The hive benefits from having specialists, and so bees have used the link between the ovary and behavior to create variation in what workers do. This helps explain why the genome doesn’t change much from solitary to social bees, says Amdam. The same genes are involved in solitary and social behaviors.
But what genes are they? Amdam and her colleagues went looking for a smoking gun. Their search led them to a gene called the Insulin Receptor Substrate (IRS), which communicates the insulin response.
The IRS connection
Insulin is a hormone that regulates movement of sugar from the bloodstream into cells where it can be used for fuel or stored as fat. IRS in the brain also affects appetite. It is involved in the feedback loop that lets you know you are full and should stop eating.
“But the pathway had never been linked to choice of food. So a natural thing to do would be to test if in bees, signaling from this gene in the brain could change food choice,” says Amdam.
Unfortunately, researchers have not yet developed a good method to manipulate genes within bees’ brains. So Amdam and her colleagues from ASU and the Norwegian University of Life Sciences inhibited IRS in bees’ fat cells instead. They found that the bees lost some of their craving for sugar. They began collecting more pollen and less nectar. The finding demonstrates that IRS affects what food bees prefer in addition to how much.
A bee collects pollen and carries it in sacs on her back legs. Photo by Osman Kaftanoglu
“Of course this doesn’t prove that it’s like this in people,” Amdam says. “But no one bothered to look before, for how that gene could affect the choices between foods when expressed in fat.”
Wolschin, Amdam and postdoctoral researcher Navdeep Mutti have added another link to the food-reproduction-development link. They found that IRS is a key factor in determining whether a bee grows up to be a worker or a queen.
Worker bees influence a larva’s destiny through its diet. In nature, larvae that receive a queen’s diet grow up to be queens, and larvae that receive a worker diet grow up to be workers. But diet, it turns out, is only part of the equation.
The researchers inhibited IRS in larval bees. This time they weren’t looking at food choice. Instead, they wanted to know whether the insulin pathway affects caste development.
After suppressing IRS in the larvae, the researchers fed them a queen’s diet. But the bees did not turn out to be queens. They developed into workers instead.
Scientists have also linked IRS to fertility in flies. This makes sense when you consider that reproduction is tied to food intake. Among humans, female athletes become infertile when their body fat drops below a certain level.
“When female bodybuilders reduce their body fat to almost nothing, there’s feedback in the system that tries to balance out the investment in fertility versus survival. If you’re that thin your body believes that you’re starving. Your body doesn’t see that the store you’re going to is full of food and there’s money in your pocket,” says Amdam. “The take-home message from these connections is that reproduction is fundamentally linked to metabolic biology.”
IRS is not the only protein known to affect caste development in bees. In the past, Amdam has shown that suppressing another protein, called TOR, can also produce workers from larvae that eat like a queen.
“In mice and fruit flies we know that both IRS and TOR are interconnected and they cross-talk. Their actions depend on amino acids and sugars. Those components are crucial parts of the diets of the bees and of humans, too. It appears that the same mechanisms that influence growth, survival and lifespan in mice and fruit flies may also be of great importance in bees and humans,” says Wolschin.
Other molecules, including DNA methyltransferase and juvenile hormone, have also been shown to play a role in caste development.
“Those are all very important and fundamental mechanisms,” says Wolschin. “One single part cannot alone be responsible. It has to be the interplay between different mechanisms that finally results in the divergence of queens and workers.”
Unlocking the secrets of youth
Why should we care about teasing out the many components involved in bee development? For one thing, bees may be able to help us understand the aging process in humans.
For centuries, people have used bee products like honey and royal jelly to make cosmetics and supplements claiming to prolong youth. But the ASU scientists are not interested in pills and facial creams. They are looking at the bees’ genetic underpinnings to unlock the mysteries of aging.
Think about it. All bees develop from the same genome. All female larvae have the potential to become either workers or queens. But the bees that do become queens will live 10 or even 20 times as long as the bees that become workers.
Bees have another remarkable quality related to aging. “In most organisms, aging cannot be reversed. In bees, some signs of aging can be reversed by manipulating the colony,” says Wolschin.
When worker bees are young, they stay in the nest, tending the brood and caring for the queen. When they reach about two to three weeks of age, they leave the nest and begin foraging for pollen, nectar and water.
“What you can do experimentally is take away all the young bees from the colony, but leave the queen and brood in there. The foragers come back from their flights and there’s no one to take care of the brood,” says Wolschin.
Some of the foragers will rise to the occasion, returning to their youthful tasks of tending to the queen and cleaning the nest. Studies in Amdam’s laboratory show that they revert to a younger state biologically, as well. For instance, certain proteins that decline in older bees return to their youthful levels.
As if that isn’t odd enough, the bees’ get “younger” performance-wise, as well. As bees age they lose some of their learning ability. Scientists can test this in the lab by pairing a specific scent with a reward—sugar. Bees respond to sugar by extending their tongues. So researchers can measure a bee’s ability to learn by finding out how many times she must be exposed to a scent/reward pair before she will extend her tongue in response to the scent alone.
A bee extends her tongue during a learning trial. Photo by Bente Smedal
Nicholas Baker, a research technician in SOLS, showed that while older foragers tend to lose some of their learning ability, they begin performing better on learning tests when they are forced back into their younger roles.
“So there are signs on the behavioral, the physiological, and on the molecular level that show us that parts of the bees’ overall biology can be reverted. That’s pretty unique. You don’t have other model organisms in aging research that can do that,” says Wolschin.
The scientists hope that learning how bees develop can help us understand our own development and aging. Perhaps someday we can use what we know of bees to retain cognitive abilities with age or to improve recovery after illnesses and injuries.
“We don’t work with people or furry little animals that are probably closer to people than insects are,” cautions Amdam. Yet, she says, insect research like her food choice study can inspire other scientists to explore areas they may not have considered before.
“People who have been totally focused on the brain with regard to this gene can look at this paper and say, ‘wait a minute, that’s like—bees. And they changed their food-related behavior when things happened to this gene in fat. What says it can’t be like that in mammals?’ And then perhaps a mice researcher studies it.”
She continues: “We unravel, we bring to the surface, a new insight. And then a researcher that works with organisms close to people, or with people in a clinical setting, can pick up on that and try it. That’s one of the most important contributions of model organism science—the inspiration.”
Bee research at ASU has been funded by the National Science Foundation, the PEW Charitable Trust, the Norwegian Research Council, the Wissenschaftskolleg zu Berlin, the Alexander-von-Humboldt Foundation, the National Institute of Aging and the Binational Science Foundation.
