Tim Tully is a professor of genetics at Cold Spring Harbor Labs on Long Island, New York. A native of Washington, IL, Tully attended the University of Illinois, where he obtained a B.Sc. in both Biology and Psychology and a Ph.D. in Genetics.

Tully investigates the genetic basis of memory. His research seeks to identify the genes involved in neural development as well as neural function. The goal of his work is to develop effective treatments for memory loss, both behavioral and pharmacological. His experiments on "photographic memory" in fruit flies was the first demonstration of genetically enhanced memory in history.

He lives in New York with his wife Nance and their two sons, Benjamin and Schuyler. Tully also he has five siblings and 26 first-cousins, from whom, he notes, he gained an intuitive understanding of Mendelian inheritance.

Tully's response:
No "real" therapy (drug or behavioral) yet exists. Emerging literature, primarily from cognitive psychologists however, suggests that "brain exercise" may work to maintain optimal functioning of working (one type of short-term) memory.

More generally, recent research suggests one MOST IMPORTANT thing you can do to maintain cognitive vitality as you age - exercise (!) Physical exercise works to promote cognitive health in two ways. First, cardiovascular fitness (low cholesterol and less artherosclerosis) minimizes the chances of "mini-strokes." Modern brain imaging studies have revealed a high incidence of these clinically undiagnosed events. Presumably, they cause small but cumulative damage to the brain, which eventually results in memory loss. Second, physical exercise actually produces increases in a brain chemical called, BDNF. BDNF promotes neuronal survival and may protect against the damaging effects (cell death) of stress. Combined, these positive effects of physical exercise are 40 times more important for cognitive health than any other known factor.

10.23.01 Meg asks:
A simple one, really...I thought your experimental design was interesting! Just wondered if you varied the odors that the flies were exposed to so that you made sure the response wasn't related to the particular odors you chose. Thanks!

Tully's response:
Indeed we do. In a typical experiment, we actually train two separate groups of flies. For the first group, odor A is paired with footshock and odor B is not. We reverse this relation for the second group; odor B is paired with shock and odor A is not. The results from these two group then are averaged to produce ONE "learning index." Arithematic and control experiments have shown that this method eliminates any small bias that the flies may show to one odor versus another - and the only way to obtain a learning index greater than zero is if the flies learn to avoid the shock-paired odor.

10.25.01 Gretchen A. asks:
We watched your discussion with Alan Alda with great interest, as our son, diagnosed with Asperger's disorder, tests in the 2d percentile for short term memory, and in the 98th percentile for long term memory. Might your research into the CREB gene eventually serve to even out this imbalance? There are also issues with being unable to read social cues, which may also be due to his short term memory deficits. We are interested in whether your studies might be applicable to the early years as well as the later.

Tully's response:
Unfortunately, we simply don't know whether our emergent drugs that enhance the CREB pathway will help those diagnosed with Asperger's disorder (and others). Further research may establish one possibility, however, based on the following speculation: Perhaps the primary function for the brain is to be plastic - to perceive and process new experiences and then to change its function in response to this "knowledge." Brain plasticity is an ongoing process, likely to persist in all regions of the brain. Relatively mild genetic predispositions, exerting their effects early in development, then might yield apparently large defects in brain function - which nevertheless might be altered toward normal function by intense brain exercises focused on the particular cognitive dysfunction(s). In this manner, it might be possible to reshape some "heritable" cognitive disabilities. To this end, Scientific Learning Corp. is developing training protocols for several aspects of cognitive dysfunction.

11/01/01 Rosanne K. asks:
Dr. Tully,
What an interesting segment. I am very much interested in your work because my husband has a brain injury which greatly affects his short term memory. Could this gene help him someday with his memory? I'm just curious and would love to follow your accomplishments- how can a layman follow your work? Thank you for your time and the work you are doing.

Tully's response:
As per explanations above and below, development of drugs that target the CREB pathway may someday lead to beneficial therapies for your husband. Some of the brain circuitry that has not been damaged by the injury might be trained to take on some of the function(s) lost in injured region. As with stroke rehabilitation, however, such training-based therapy requires a lot of intensive practice and often does not result in a complete recovery of brain function. We hope, at least, that CREB-enhancing drugs will reduce the amount of practice required to reach the therapeutic maximum.

As for your second question, you can follow scientific progress by watching television programs like Scientific American Frontiers and by keeping an eye out in the popular press, such a newspapers and science magazines. Though our work is slow and often esoteric, I consider it important to try to communicate the essence of what we do to others. My mother always used to say, "Just tell me about your work in a way that I can understand." I've taken that loving advice as a challenge.

10/31/01 Lance M. asks:
You said something about taking certain medicines in the future which will cause memories to be stored as long-term. Could this extra long-term information cause the brain to overload? Thank you very much.

Tully's response:
Perhaps, if the drug is strong and is taken for a long period of time (see above). That's why it may be best to use such drugs acutely -- in combination with deliberate and specific brain exercises.

11/02/01: Marilyn P. asks:
Do you have a theory on what the gene therapy is doing inside the brain? Is there any change in the amount of any specific neurotransmitter being produced in the brain? In the human brain, would you expect changes to be happening in the hippocampus?

Tully's response:
So far, we only have a crude theory of what is going on. There's reasonable evidence for changes in synaptic structure during long-term memory formation, but little evidence yet exists to implicate specific molecules. These are the experiments that several of us now are working on. Genetic experiments in rats clearly have shown that CREB functions in the hippocampus during long-term memory formation. It follows, then, that drugs which enhance the CREB pathway also will enhance hippocampal-dependent long-term memory formation, if they reach that part of the brain.

11/02/01: Rob Reiner asks:
Dr. Tully,
1) Is there anything that is currently available for humans that will help long-term memory?
2) If not, what types of treatments do you foresee being available for humans (i.e. pharmacological, genetic therapy, etc.)? What time frame do you foresee them being available to humans?
3) Do you have any suggestions for how I could improve my long-term memory today? 4) As a layman interested in memory research, I sometimes find it difficult to find new relevant information on the subject matter. Besides Scientic American, can you suggest any publications?

Thanks for your time (and your research breakthroughs!)

P.S. I look forward to hearing about your next breakthrough!

Tully's response:
1. The bona fide cognitive enhancers currently available are those marketed for the treatment of Alzhiemer's diseases. These all are cholinesterase inhibitors, which act to elevate levels of the neurotransmitter, acetylcholine. Higher levels of acetylcholine increase "attentional" processes, including working memory. Better working memory, then, helps indirectly to improve long-term memory.

2. In the near future, I anticipate the development of traditional pharmaceutical treatments for long-term memory loss. A few lead compounds currently are being identified. Given the (wise) FDA approval process, the first of these may be ready for use sometime in the next ten years. I do not foresee viable gene therapies for long-term memory loss in the near future. The techniques necessary to deliver such genetic constructs to specific regions of the brain simply do not yet exist.

3. Brain exercise!! If you don't use it, you'll lose it. From studies of the prevalence of Alzhiemer's disease emerged the puzzling statistic that people with a higher level of academic achievement appear somewhat less suseptable. Researchers believe that this may occur because (i) those with more schooling have learned how to exercise their mind and (ii) a lifestyle of more exercise has produced a "reserve capacity" in these people against which neurodegeneration must act longer before memory loss becomes apparent (and see answer to #1 above).

4. That's difficult. Of late, I've been impressed by the amount of reasonable, intelligible information that can be found on the Web.

10/25/01: Lori asks:
Do you have any suggestions for repairing neurological damage that affects memory? We're assuming that my daughter's memory problems stem from a bout of RSV, during which her brain was oxygen deprived.

A second question: What can we do to improve our own memories? Will there be gene therapy available for humans soon? My own memory has been blipping in and out. Doctors assume that it is due to constant stress. I've heard that cortisol exposure affects memory. Thank you for a fascinating glimpse of your work.

Tully's response:
"Brain exercise," as discussed herein, might work for your daughter - and is analogous to the usual rehabilitative therapies after stroke. Unfortunately, however, such therapy cannot repair all of the damage from injury and, consequently, does not often yield a full recovery of function. In any case, don't give up! The brain is far more plastic than we previously were inclined to believe.

To your second question: brain exercise, physical exercise, etc. (see above) all improve memory. Gene therapy: hope not; traditional drug therapy is more reasonable and more likely to become available in the next decade. Stress: Yes, stress has a negative effect on memory. Some studies, in fact, have shown that stress promotes neuronal death in the hippocampus - that part of your brain involved with conscious (declarative) memory. Here again, however, physical exercise can help to reduce and manage stress. That's why I put a treadmill in front of my television!!

10/30/01: Mike asks:
Why does the mind forget? Wouldn't it best serve an organism to remember every experience and lesson it is exposed to? Does the fading of memory have some purpose for the brain? Thanks!

Tully's response:
No one knows for sure - but we certainly can speculate. In spite of the fact that the human brain contains perhaps as many as 70 trillion synaptic connections, this still represents a finite number. Given enough time (and now we live almost twice as long as evolution normally has allowed) and experience (we live in an information age), we nevertheless might "fill the hard drive." Hence, the CREB switch might have evolved to function as an "information filter" for most circuits in the brain. Exposure to one experience on a single day may not be sufficient to activate the switch and induce long-term memory formation, thereby preserving some synaptic connections for more important (recurrent) events.

Psychological studies of people born with truly exceptional idetic memories seem to support this notion. Such people show extraordinary memory capabilities. The famous Sherenshevski, for instance, once was asked to memorize a complex mathematical formula, in which the psychologist deliberately had place an error. After a day of practice, Sherenshevski was able to recall the formula perfectly (with the error in it) more than 15 years later!. In spite of this memory capacity, Sherenshevski could not remember two separate conversations with the same person. Consequently, his social skills were seriously impaired, and he could not hold a steady job. These observations suggest that having too much long-term memory may not be a good thing. But, another important interpretation current exists. Perhaps, Sherenshevski's disabilities were developmental and not directly due to his enhanced memory. Only further research will distinguish these alternatives.

11/01/01: Dale K asks:
You mentioned that fruit flies had an optimum time period between "lessons" that worked best for long term memory. (I believe it was 15 min.). As a musician who would like to memorize as efficiently as possible, I am interested in what the optimum period would be for humans. Has this been worked out?

Tully's response:
No. "It" has not been worked out. More to the point, there may be different optima for different types of tasks (sensory modalities). This notion of a rest interval for spaced training applies to the cellular process of long-term memory formation - and the underlying changes in synaptic structure. Some evidence from higher vertebrates also suggests a circuit-level process of memory formation. With declarative tasks, for instance, (protein synthesis-dependent) memory is dependent on hippocampal function for the first two-to-four weeks. Afterwards, however, declarative memory is intact even if the hippocampus is surgically removed! These and related studies suggest that one circuit-level function of the hippocampus is to "transfer" LTM to other cortical regions of the brain. A different line of experimentation has revealed another circuit-level phenomenon. Work on rats and even on humans has shown that preventing the subject from entering deep-wave sleep will eliminate any increase in long-term memory produced by spaced training. Research on rats implanted with multiple electrodes in the hippocampus suggests why this might be: Shortly after learning a new experience, researchers detect an organized pattern of neuronly activity in the hippocampus. This same firing pattern then reappears during deep-wave sleep!

My interpretation of these observations is that higher vertebrates have evolved a "play back circuit," which is used to provide implicit spaced training to drive the cellular process of long-term memory formation. Lower organisms that don't possess this circuitry, must receive explicit, spaced repetitions of an experience to drive the same cellular process.