The Future of the Mind (20 page)

Commenting on this work, Francesco Sepulveda of the University of Essex says, “This demonstrates how far we have come towards creating circuitry that could one day replace damaged brain areas and even enhance the power of the healthy brain.”

He also sees great potential for artificial brains in the future, adding, “
It will likely take us several decades to get there, but my bet is that specific, well-organized brain parts such as the hippocampus or the visual cortex will have synthetic correlates before the end of the century.”

Although progress in creating artificial replacements for the brain is moving remarkably fast given the complexity of the process, it is a race against time when one considers the greatest threat facing our public health system, the declining mental abilities of people with Alzheimer’s.

ALZHEIMER’S—DESTROYER OF MEMORY

Alzheimer’s disease, some people claim, might be the disease of the century.
There are 5.3 million Americans who currently have Alzheimer’s, and the number is expected to quadruple by 2050. Five percent of people from age sixty-five to seventy-four have Alzheimer’s, but more than 50 percent of those over eighty-five have it, even if they have no obvious risk factors. (Back in 1900, life expectancy in the United States was forty-nine, so Alzheimer’s was not a significant problem. But now, people over eighty are one of the fastest-growing demographic groups in the country.)

In the early stages of Alzheimer’s, the hippocampus, the part of the brain through which memories are processed, begins to deteriorate. Indeed, brain scans clearly show that the hippocampus shrinks in Alzheimer’s patients, but the wiring linking the prefrontal cortex to the hippocampus also thins, leaving the brain unable to properly process short-term memories. Long-term memories already stored throughout the cortices of the brain remain relatively intact, at least at first. This creates a situation where you may not remember what you just did a few minutes ago but can clearly recall events that took place decades ago.

Eventually, the disease progresses to the point where even basic long-term memories are destroyed. The person is unable to recognize their children or spouse and to remember who they are, and can even fall into a comalike vegetative state.

Sadly, the basic mechanisms for Alzheimer’s have only recently begun to be understood. One major breakthrough came in 2012, when it was revealed that Alzheimer’s begins with the formation of tau amyloid proteins, which in turn accelerates the formation of beta amyloid, a gummy, gluelike substance that clogs up the brain. (Before, it was not clear if Alzheimer’s was caused by these plaques or whether perhaps these plaques were by-products of a more fundamental disorder.)

What makes these amyloid plaques so difficult to target with drugs is that they are most likely made of “prions,” which are misshapen protein molecules. They are not bacteria or viruses, but nevertheless they can reproduce. When viewed atomically, a protein molecule resembles a jungle of ribbons of atoms tied together. This tangle of atoms must fold onto itself correctly for the protein to assume the proper shape and function. But prions are
misshapen proteins that have folded incorrectly. Worse, when they bump into healthy proteins, they cause them to fold incorrectly as well. Hence one prion can cause a cascade of misshapen proteins, creating a chain reaction that contaminates billions more.

At present, there is no known way to stop the inexorable progression of Alzheimer’s. Now that the basic mechanics behind Alzheimer’s are being unraveled, however, one promising method is to create antibodies or a vaccine that might specifically target these misshapen protein molecules. Another way might be to create an artificial hippocampus for these individuals so that their short-term memory can be restored.

Yet another approach is to see if we can directly increase the brain’s ability to create memories using genetics. Perhaps there are genes that can improve our memory. The future of memory research may lie in the “smart mouse.”

THE SMART MOUSE

In 1999, Dr. Joseph Tsien and colleagues at Princeton, MIT, and Washington University found that adding a single extra gene dramatically boosted a mouse’s memory and ability. These “smart mice” could navigate mazes faster, remember events better, and outperform other mice in a wide variety of tests. They were dubbed “Doogie mice,” after the precocious character on the TV show
Doogie Howser, M.D
.

Dr. Tsien began by analyzing the gene NR2B, which acts like a switch controlling the brain’s ability to associate one event with another. (Scientists know this because when the gene is silenced or rendered inactive, mice lose this ability.) All learning depends on NR2B, because it controls the communication between memory cells of the hippocampus. First Dr. Tsien created a strain of mice that lacked NR2B, and they showed impaired memory and learning disabilities. Then he created a strain of mice that had more copies of NR2B than normal, and found that the new mice had superior mental capabilities. Placed in a shallow pan of water and forced to swim, normal mice would swim randomly about. They had forgotten from just a few days before that there was a hidden underwater platform. The smart mice, however, went straight to the hidden platform on the first try.

Since then, researchers have been able to confirm these results in other
labs and create even smarter strains of mice. In 2009, Dr. Tsien published a paper announcing yet another strain of smart mice, dubbed “Hobbie-J” (named after a character in Chinese cartoons). Hobbie-J was able to remember novel facts (such as the location of toys) three times longer than the genetically modified strain of mouse previously thought to be the smartest. “
This adds to the notion that NR2B is a universal switch for memory formation,” remarked Dr. Tsien. “It’s like taking Michael Jordon and making him a super Michael Jordan,” said graduate student Deheng Wang.

There are limits, however, even to this new mice strain. When these mice were given a choice to take a left or right turn to get a chocolate reward, Hobbie-J was able to remember the correct path for much longer than the normal mice, but after five minutes he, too, forgot. “
We can never turn it into a mathematician. They are rats, after all,” says Dr. Tsien.

It should also be pointed out that some of the strains of smart mice were exceptionally timid compared to normal mice. Some suspect that, if your memory becomes too great, you also remember all the failures and hurts as well, perhaps making you hesitant. So there is also a potential downside to remembering too much.

Next, scientists hope to generalize their results to dogs, since we share so many genes, and perhaps also to humans.

SMART FLIES AND DUMB MICE

The NR2B gene is not the only gene being studied by scientists for its impact on memory. In yet another groundbreaking series of experiments, scientists have been able to breed a strain of fruit flies with “photographic memory,” and also a strain of mice that are amnesiac. These experiments may eventually explain many mysteries of our long-term memory, such as why cramming for an exam is not the best way to study, and why we remember events if they are emotionally charged. Scientists have found that there are two important genes, the CREB activator (which stimulates the formation of new connections between neurons) and the CREB repressor (which suppresses the formation of new memories).

Dr. Jerry Yin and Timothy Tully of Cold Spring Harbor have been doing interesting experiments with fruit flies. Normally it takes ten trials for them to learn a certain task (e.g., detecting an odor, avoiding a shock). Fruit flies
with an extra CREB repressor gene could not form lasting memories at all, but the real surprise came when they tested fruit flies with an extra CREB activator gene. They learned the task in just one session. “
This implies these flies have a photographic memory,” says Dr. Tully. He said they are just like students “who could read a chapter of a book once, see it in their mind, and tell you that the answer is in paragraph three of page two seventy-four.”

This effect is not just restricted to fruit flies. Dr. Alcino Silva, also at Cold Spring Harbor, has been experimenting with mice. He found that mice with a defect in their CREB activator gene were virtually incapable of forming long-term memories. They were amnesiac mice. But even these forgetful mice could learn a bit if they had short lessons with rest in between. Scientists theorize that we have a fixed amount of CREB activator in the brain that can limit the amount we can learn in any specific time. If we try to cram before a test, it means that we quickly exhaust the amount of CREB activators, and hence we cannot learn any more—at least until we take a break to replenish the CREB activators.

“
We can now give you a biological reason why cramming doesn’t work,” says Dr. Tully. The best way to prepare for a final exam is to mentally review the material periodically during the day, until the material becomes part of your long-term memory.

This may also explain why emotionally charged memories are so vivid and can last for decades. The CREB repressor gene is like a filter, cleaning out useless information. But if a memory is associated with a strong emotion, it can either remove the CREB repressor gene or increase levels of the CREB activator gene.

In the future, we can expect more breakthroughs in understanding the genetic basis of memory. Not just one but a sophisticated combination of genes is probably required to shape the enormous capabilities of the brain. These genes, in turn, have counterparts in the human genome, so it is a distinct possibility that we can also enhance our memory and mental skills genetically.

However, don’t think that you will be able to get a brain boost anytime soon. Many hurdles still remain. First, it is not clear if these results apply to humans. Often therapies that show great promise in mice do not translate well to our species. Second, even if these results can be applied to humans, we do not know what their impact will be. For example, these genes may
help improve our memory but not affect our general intelligence. Third, gene therapy (i.e., fixing broken genes) is more difficult than previously thought. Only a small handful of genetic diseases can be cured with this method. Even though scientists use harmless viruses to infect cells with the “good” gene, the body still sends antibodies to attack the intruder, often rendering the therapy useless. It’s possible that the insertion of a gene to enhance memory would face a similar fate. (In addition, the field of gene therapy suffered a major setback a few years ago when a patient died at the University of Pennsylvania during a gene therapy procedure. The work of modifying human genes therefore faces many ethical and even legal questions.)

Human trials, then, will progress much more slowly than animal trials. However, one can foresee the day when this procedure might be perfected and become a reality. Altering our genes in this way would require no more than a simple shot in the arm. A harmless virus would then enter our blood, which would then infect normal cells by injecting its genes. Once the “smart gene” is successfully incorporated into our cells, the gene becomes active and releases proteins that would increase our memory and cognitive skills by affecting the hippocampus and memory formation.

If the insertion of genes becomes too difficult, another possibility is to insert the proper proteins directly into the body, bypassing the use of gene therapy. Instead of getting a shot, we would swallow a pill.

A SMART PILL

Ultimately, one goal of this research is to create a “smart pill” that could boost concentration, improve memory, and maybe increase our intelligence. Pharmaceutical companies have experimented with several drugs, such as MEM 1003 and MEM 1414, that do seem to enhance mental function.

Scientists have found that in animal studies, long-term memories are made possible by the interaction of enzymes and genes. Learning takes place when certain neural pathways are reinforced as specific genes are activated, such as the CREB gene, which in turn emits a corresponding protein.
Basically, the more CREB proteins circulating in the brain, the faster long-term memories are formed. This has been verified in studies on sea mollusks, fruit flies, and mice. The key property of MEM 1414 is that it accelerates the production of the CREB proteins. In lab tests, aged animals given MEM 1414
were able to form long-term memories significantly faster than a control group.

Scientists are also beginning to isolate the precise biochemistry required in the formation of long-term memories, at both the genetic and the molecular level. Once the process of memory formation is completely understood, therapies will be devised to accelerate and strengthen this key process. Not only the aged and Alzheimer’s patients but eventually the average person may well benefit from this “brain boost.”

CAN MEMORIES BE ERASED?

Alzheimer’s may destroy memories indiscriminately, but what about selectively erasing them? Amnesia is one of Hollywood’s favorite plot devices. In
The Bourne Identity
, Jason Bourne (played by Matt Damon), a skilled CIA agent, is found floating in the water, left for dead. When he is revived, he has severe memory loss. He is being relentlessly chased by assassins who want to kill him, but he does not know who he is, what happened, or why they want him dead. The only clue to his memory is his uncanny ability to instinctively engage in combat like a secret agent.

It is well documented that amnesia can occur accidentally through trauma, such as a blow on the head. But can memories be selectively erased? In the film
Eternal Sunshine of the Spotless Mind
, starring Jim Carrey, two people meet accidentally on a train and are immediately attracted to each other. However, they are shocked to find that they were actually lovers years ago but have no memory of it. They learn that they paid a company to wipe memories of each other after a particularly bad fight. Apparently, fate has given them a second chance at love.

Selective amnesia was taken to an entirely new level in
Men in Black
, in which Will Smith plays an agent from a shadowy, secret organization that uses the “neuralizer” to selectively erase inconvenient memories of UFOs and alien encounters. There is even a dial to determine how far back the memories should be erased.