Scientists Create Smarter Mice by Adding Gene
By adding a single gene to fertilized eggs, Princeton University researchers have been able to create smarter mice, a feat that could lead to the development of more intelligent animals and that hints at the feasibility of producing so-called designer babies with enhanced intelligence.
The accomplishment demonstrates for the first time that a complex trait like intelligence can be genetically manipulated in mammals. It also reveals a common biochemical mechanism at the root of all learning, a discovery that could eventually be translated into new drugs and treatments for the prevention of memory loss in the elderly, they said.
The added gene enabled the otherwise ordinary mice to learn new tasks more quickly and to remember them longer, a team from Princeton, MIT and Washington University in St. Louis reports in today’s Nature.
It also made the brains of older mice perform more like those of juveniles, which generally are better at grasping large amounts of new information.
This “is interesting and fundamental work,” said neuroscientist Ira Black of Rutgers University. “It’s very exciting and holds the hope of not only making animals smarter, but also, ultimately, of having a gene therapy for use in areas such as dementia.”
Still, experts cautioned that it will be many years before it can be put to any practical use in humans.
“To jump from this very elegant molecular work in a mouse model to humans is a very, very big jump,” said psychiatrist Robert Malenka of the Stanford University School of Medicine. “Nevertheless, it is a jump we can make and will make eventually.”
But geneticist Stuart Newman of New York Medical College, a board member of the Council for Responsible Genetics, argued that “mouse intelligence is not that comparable to human intelligence. Only in the most crude sense would you infer that [such changes are feasible in humans] from this experiment.”
The attention surrounds a gene called NR2B, which biologists believe is a key switch that controls the brain’s ability to associate one event with another--the core feature of learning. Neurobiologist Joe Z. Tsien and his colleagues at Princeton previously had produced genetically engineered mice lacking the NR2B gene and found that they had impaired learning and memory. Adding new or improved function, however, is a harder task and a more rigorous test of the gene’s function.
Using a long, thin needle, Tsien inserted extra copies of the NR2B gene into the nuclei of fertilized mouse eggs, which were then allowed to grow into adult animals. Tsien named the new strain of mice Doogie after the intellectually precocious hero of the television series “Doogie Howser, M.D.,” and studied their intelligence in a variety of ways.
Learning and Memory Tests
One such experiment tested the mice’s ability to remember an object. Tsien put the mice into a space with two Lego-like objects and let them explore the objects for five minutes. Several days later, one object was changed and the mice returned to the space. Normal mice, which didn’t remember their previous experience, spent equal time on both objects. But the Doogie mice concentrated on the new object, indicating they remembered the old one.
By repeating the experiment at various intervals, the team found that the Doogie mice remembered objects four to five times longer than their normal counterparts.
Several other tests of learning and memory showed similar results. “They’re learning things much better and remembering longer,” Tsien said. “They are smarter.”
Furthermore, neuroscientist Guosong Liu of MIT used newly developed techniques to show that the brain cells of the mice had increased numbers of a receptor called NMDA, which is the product of the NR2B gene. The team was thus able to associate the increased intelligence with a specific biological activity.
Tsien not only gave the mice extra copies of the gene, but he modified the gene so that it produced more NMDA protein as the animals aged, counteracting the decline in activity of the naturally occurring gene. He then found that the adult brains retained physical features that usually characterize juvenile animals. In particular, they had an unusually high level of “plasticity,” the ability to form long-term connections between neurons.
NMDA, which is present in all mammals, including humans, is like a double lock on a door. It needs two keys--two signals--before it opens. For this reason, it is an effective tool for creating memory, a process that fundamentally consists of associating two events.
A brain cell might receive one signal that a paw, or finger, has touched an electrical grid. The second signal would be that it caused pain, and the receptor would form a strong bond between two cells. In this way, an animal or human would learn not to touch the grid again.
That theoretical process is called long-term potentiation, and some researchers have argued that it is not necessary for learning. But Tsien’s work, said neuroscientist Charles Stevens of the Salk Institute in La Jolla, “is one of the best pieces of evidence so far” that long-term potentiation plays a key role, because activating the NMDA receptor clearly leads to such potentiation.
Potential Ethical Dilemmas
The insertion of the gene may one day give scientists the ability to increase human intelligence, Tsien said. But the desirability of making such alterations had been a subject of great contention. Some researchers have suggested that such modification may be desirable to block the transmission of genetic defects, but critics fear that such efforts may lead to unsuspected side effects.
Perhaps nowhere are those fears greater than in schemes that propose using genetic engineering to alter babies’ innate characteristics--to make them stronger, better looking or more intelligent.
Although today’s report suggests that such modifications may be possible, most everyone agrees that the risks are still too great. “Would you want your child to have this gene?” Newman asked.
Ethicist Art Caplan of the University of Pennsylvania Medical Center added, “All of this is extremely hypothetical, but we need to start talking about it now, or in 10 years some doctor will hang out his shingle and start advertising enhanced babies.”
Although proponents and critics have focused on the potential applications in humans, “what might be more unnerving is using it to change animals,” Caplan said.
Caplan argues that early uses of the technology might be to create, for example, more intelligent guide dogs, monkeys that are smart enough to be household helpers, or dolphins that could retrieve enemy weapons.
“That’s disturbing because our relationships with animals are driven by how smart we think they are, whether they are a pet or in a lab, zoo or rodeo,” Caplan said. “This is going to change our ability to identify and empathize with animal thoughts and emotions. It could set off a lot of debate.”
