It’s tough to make predictions, especially about the future.—Attributed to Yogi Berra
When I ﬁrst went into neurology more than 40 years ago, my colleagues asked, “What do you want to go into that ﬁeld for? All you can do is describe things.” They might have added (at least silently), “and watch your patients progress through the stages of various brain diseases.”
Their comments, unfortunately, were all too true. Until relatively recently, neuroscience was mostly descriptive. We could characterize disease processes in the brain. Sometimes we could predict how they would end. Rarely, though, could we inﬂuence those outcomes.
By 2000, we were into the phase of discovering mechanisms to determine what was going wrong. What literally was occurring in the brain and central nervous system to cause the symptoms we observed? Was there a stage during which we could intervene?
Between now and 2025, however, the theme will be manipulation: acting to prevent disease or alter its progression and promote a patient’s recovery. How is this likely to occur, and in what areas? Where does progress look most promising? What are the holdouts likely to be, the citadels that, at least today, seem impregnable?
BACK TO BASICS
Start by considering our changing ideas about the basic properties of neurons. Approximately 110 years ago, the great Spanish anatomist Santiago Ramón y Cajal put forth a basic idea, the “neuronal doctrine,” to the effect that the neuron or nerve cell is the essential unit of brain function. The neuron’s functions are the anatomic, physiologic, chemical, and genetic bases of how the brain works. In recent times, we have added to that list the concept of the neuron as the basic unit of information processing, as well.
Implied in Cajal’s doctrine was the principle of neuronal stability. Once cells of the brain and central nervous system are formed during development and take their proper places, they do not divide further. The connections among them are also stable. In other words, the brain is “hard-wired.” Recently, scholars have argued that Cajal was not dogmatic on this point, that he merely drew it as an implication of what was then known and observed. That may be true, but the concept of the hard-wired human brain and central nervous system have nonetheless been neuroscience orthodoxy for a century.
To generations of medical students I have preached, “You are born with all the nerve cells you will ever have. After that, they can only die.” Someone once said that half of everything taught to medical students is wrong; the problem is knowing which half. Well, I have contributed to the wrong half with that statement about nerve cells. It is becoming clear that even in the adult brain, new nerve cells do indeed form, particularly in a part of the brain involved in memory, the hippocampus.
A continuing supply of these new nerve cells may possibly even be required for normal memory functions. In experimental animals, when the replacement of old nerve cells with new ones is blocked, memory processes appear to be compromised.
How might this replacement of nerve cells take place? Pasco Rakic, a brain researcher at Yale University, has hypothesized that it might be like the mouth of a shark, whose old teeth drop out and new teeth migrate forward to take their place. (As someone with a pathologic fear of sharks, I must confess to ﬁnding that mental image of how my brain might be working rather disconcerting.)
The implication that the nerve cells of the brain can replace themselves normally, or as a mechanism of repair, or possibly both, opens new vistas of research. What controls this replenishment? Might we be able to intervene to modify this process? Evidence suggests more neuronal replacement in younger brains than in older. If that is so, why? These are some of the questions that will be approached between now and 2025.
USING CELLS IN TREATMENTS
The concept that our brains can replace cells brings us to the related question of transplanting tissue or cells into the human brain.
If, in 1975, you had proposed to the National Institutes of Health that you wanted to perform transplantation in the brain, not only would your research grant have been rejected but the reviewers would probably have recommended that you be locked up. In 2001, however, transplantation of brain tissue is a fait accompli.
The ﬁrst transplantation of human tissue to modify a disease moved the patient’s own adrenal tissue into the brain in the hope of treating Parkinson’s disease. When adrenal transplants did not prove very successful, other sources were sought for the neurotransmitter missing in Parkinson’s disease, dopamine. Recent research has focused on a part of the brain rich in this chemical messenger: the substantia nigra of the human fetal brain. There were some anecdotal reports of therapeutic beneﬁt from such transplants, but more than 10 years passed before controlled study of efﬁcacy was completed and reported. This study compared, over one year, people with Parkinson’s disease who had received transplanted fetal tissue with other people who had undergone sham surgery, with no tissue transplantation.
The results are a glass half full but also half-empty. The transplanted tissue did survive and did produce dopamine; and some younger patients (but not older ones) did beneﬁt. But in the second year after transplantation, unfortunately, the transplants took too well in some recipients, resulting in symptoms of dopamine overdose, including excessive uncoordinated movements, so-called dyskinesias. These results underline how much we still do not know about the requirements for successful transplantation: how much tissue to use, how to prepare it, where to place it, what other factors may inﬂuence the process, and how to control the results better. Future transplantation will most likely be of not already differentiated tissues but of speciﬁc cell types derived from stem cells.
There has been an explosion of interest in stem cells, both scientiﬁcally and politically. Along with this has come much confusion about what stem cells are and what they can potentially do. Stem cells are primitive cells that have the potential to keep dividing and to differentiate into the cells of any organ in the body, including brain, muscle, or liver cells. Initially they were derived from very early embryos. In humans, the source was early results of in vitro fertilization, residing in a laboratory dish, not a mother’s body. These are called “embryonic stem cells.”
Now it is recognized that many differentiated adult tissues, such as brain or skin, also contain primitive cells that can divide and differentiate. It is not yet known whether these adult-derived stem cells have the same potentials as embryonic stem cells, but this is a crucial area of research. The hope is that stem cells can be used as cellular replacements in brain diseases such as Alzheimer’s or Parkinson’s disease, or that they might aid recovery following stroke or spinal cord injury.
Stem cells also have been proposed for treatment of nonbrain diseases—for example, as a source of new heart muscle after a heart attack or of cells to produce insulin in diabetics. These may be easier goals than reproducing the complex functions of nerve cells in the brain. The ﬁrst use in the brain may not even be to replace nerve cells. Stem cells may ﬁrst be used to produce cells with only one, highly speciﬁc function—for example, oligodendrocytes that make myelin, the insulating material around nerve ﬁbers that is missing in people with multiple sclerosis.
Without doubt, we will see new attempts to use stem cells to modify brain diseases. Many questions raised about transplanted tissue also apply to stem cells, which may also have beneficial without actually becoming mature, functioning nerve cells. Might they be a means of delivering genes or proteins to the brain? Or a source of supportive, growth-promoting trophic factors that the brain seems to need to maintain normal functioning or to recover from injury?
The use of stem cells is going to be explored, regardless of the recent decision of the Bush administration limiting research. Even if scientists in the United States are constrained, in other countries they are not. If stem cells prove to be beneﬁcial for treating diseases we cannot now alter, they will be used.
THE PLASTIC BRAIN
Back in 1975, scientists had a simpliﬁed view of how the brain was wired for internal communication. We thought the wiring, once established, did not change. We now know that the brain can be rewired, with new connections, strengthening and weakening of contacts, and other changes in response to activity and needs.
That is one reason that every single brain, including the brains of identical twins (who share all the same genes) is different. What we do modiﬁes our brains. For example, for violinists, the area of the brain that directs the movements of the ﬁngers of the left hand is larger than the area that directs movements of the right hand in holding the bow. Alternatively, if you were to lose a ﬁnger your brain would devote larger areas to the remaining ﬁngers. As you listen to music, or read, you form new connections or reinforce existing ones. As you recover from injury, new functional connections are established. This is the remarkable plasticity of the brain.
We know little about how these adaptive processes actually work. I suspect that this will be one of the major areas of brain research in coming years, and in this research lies our hope of promoting recovery from strokes and other brain injuries. There is as yet no successful repair and recovery from an injury that completely severs the spinal cord, but experimental cell replacements are testing methods of stimulating the growth of new connections.
Similarly, our knowledge of the chemicals that nerve cells use to communicate, the brain’s neurotransmitters, was much simpler 25 years ago. Since then, we have gone from identifying simple molecules such as acetylcholine, dopamine, and serotonin, to understanding amino acids like glutamate, peptides like the endorphins, and gases like nitric oxide or even carbon monoxide.
As we learned more about these neuro-transmitters, we hoped that we would be able to develop drugs that would modify their actions; and, indeed, we have developed pharmacological treatments for schizophrenia, depression, epilepsy, and Parkinson’s disease. As we learn more, however, we realize that the action of most of the agents we are using is much less speciﬁc than we thought. Nor do we understand very well how or why they work. We are still searching for magic bullets that will affect a speciﬁc transmitter or a speciﬁc receptor for a transmitter. The result would be drugs that are more effective, work in a larger percentage of cases, and have fewer side effects.
Until now, our models of how cells interact in the brain have been at the level of one nerve cell modifying the behavior of only a few others. We know that cannot be the case. There are one hundred billion or more nerve cells in our brains, and a single nerve cell communicates with as many as ten thousand others. Do the math; you get big numbers of connections. The future may be in understanding how large populations of nerve cells inﬂuence one another and so give rise to processes such as attention, alertness, and concentration— the world of the mind familiar to all of us through introspection.
If we use the analogy of a thermostat, we can ask: How is the thermostat of functioning set higher or lower for a population of nerve cells? Set for more attention or less? More anxiety or less? Our brains reset our level of mental functioning every night during sleep, of course—but how? As I will discuss, newer forms of imaging will make it possible to ascertain which of the brain’s circuits are being activated and which are being shut off when we intervene in various ways. Using this information, we will develop new drugs to modify these processes. There will be new agents for sleep, for promoting concentration, and for improving memory.
A WINDOW ON THE BRAIN AT WORK
If you ask what has been the greatest change in how we practice neurology or neurosurgery, the answer is the incredible advances in our ability to image brain structure and functioning. Twenty-five years ago, we were able to look at structural changes in detail by computerized tomography (CT scanning). Shortly thereafter, magnetic resonance imaging (MRI) gave us a new generation of structural analysis that transformed the way we diagnose brain tumors and multiple sclerosis, and the way we learn how the brain has been damaged by a stroke. We could look and see.
What followed was a great ﬂowering of imaging technology. The intactness of blood vessels can be determined (by MRI angiography), new damage from a stroke can immediately be seen (by diffusion-weighted imaging or DWI), and changes in brain constituents can be measured (by magnetic resonance spectroscopy or MRS).
These are all methods of imaging the brain’s structure, however, and what interests us as much or more than structure is functioning. Now, thanks to the same imaging revolution, our ability to localize brain functions by positron emission tomography (PET) or functional MRI (fMRI) is nothing short of spectacular. We can now determine what part of your brain you are using while you are listening to music, writing a letter, or thinking about what you want to say. The neurologist of 1975 could only speculate (and many did) about how the brain might carry out these actions. Few professionals predicted that in less than two decades they would be able to check their guesses by observing the brain in living color.
There is more to come. Right now, our methods of observing the functioning of the brain depend upon images of changing blood constituents, which are related to changes in the activity of the brain’s nerve cells. There is a lag of one or two seconds between this nerve cell activity and changes in the blood. Thus, current functional imaging methods are not in real time with brain activity; they are too slow by a factor of 100 or more. The big advance will be to develop functional imaging techniques that show us—as it is happening—how various areas of the brain interact. That is, we will see not only the location of brain activity but also its speed. Do not ask me what the basis of this new imaging will be. A combination of electrical recording and changes in some other brain properties perhaps? Whatever the method, this souped-up imaging will enable us to investigate how brain circuits work, how one part of the brain modiﬁes the functions of other parts, and how these circuits adapt to new situations or damage to existing circuits.
We will also be able to use imaging to study the cells of the brain. I spoke of transplanting cells into the brain. How will we know where these transplants are, what they are doing, and how their properties may be changing? Transplanted cells and their changes can be tracked by molecules on their surfaces. Speciﬁc markers can be attached to these molecules as tags that can be spotted by imaging, like radio collars on wolves moved to a new terrain. Other cells, scavenger cells that are part of our immune system, can be tracked into and out of the brain as they respond to injury or to therapies.
Right now, I might give a patient a pill for epilepsy, or to treat a brain tumor, or to relieve depression, but I do not have a very good idea where that medication goes in the brain, what nerve cells it inﬂuences, or what it is actually doing to the brain. The newer forms of imaging will enable me to track that compound and monitor its effects. I will be able to tell whether one person is responding differently from another. Bluntly stated, I will have a much better idea of what the heck I am doing.
In 1975, we still depended on one of the oldest methods of evaluating brain function, electroencephalography (EEG). That technique is still valuable for detecting the abnormal brain activity in epileptic seizures or the absence of brain activity as part of the criteria for “brain death.” Now we have gone beyond this, to using electrical stimulation actually to change brain activity. To be sure, stimulation of the brain has been used for some decades, when the brain is open for surgery, to identify where different functions are located. The new twist is implanting electrodes at speciﬁc sites in the brain to alter the activity of its circuits. The best example is deep brain stimulation to intervene in Parkinson’s disease. In this instance, an electrode is placed in a very speciﬁc part of the brain and an electric current is applied, which interrupts the ﬂow of information to and from that part of the brain. For a person with a tremor, the results can be spectacular. When the current is on, the tremor disappears. When the current is turned off, the tremor returns.
We have learned from colleagues in cardiology, who use electrical stimulation to dictate the rhythm of the heart—the so-called cardiac pacemaker—to use electrical stimulation to change timing in the brain. We will be able to detect when the brain’s own signals are not quite right, to trigger a pace-setting response from the implanted stimulation, and to block the continued spread of the abnormal activity. One can see how this might be a new approach to epilepsy. As the abnormal electrical ﬁring from the nerve cells begins with the onset of a seizure, it will be detected; the stimulator will discharge electric current to counter it, driving the nerve cells back toward a normal ﬁring pattern. The same might apply to other disorders that occur at episodic intervals, like the mood swings of depression. Maybe even “normal” signals could be modiﬁed in this fashion—for example, the signals that tell you to eat too much or give you a craving for a recreational drug.
GENETICS: MORE THAN WE KNOW HOW TO USE
In the ﬁeld of genetics, we have gone from a relatively few basic concepts to a gusher of data from the Human Genome Project, information that scientists will be building on for decades. Twenty-ﬁve years ago, we still followed the ideas of the 19th-century monk Gregor Mendel, who experimented with growing different-colored pea plants and demonstrated that some traits were inherited in a dominant fashion and some in a recessive fashion. In those terms, genetics was simple: You either had a trait or you did not. Our genetics tools were equally simple: We obtained a history of diseases in the generations of a family. Sometimes we could identify what biochemical abnormality was involved, or even use the absence of a biochemical factor, an enzyme, to detect a disease. Preventing genetically determined disease took the form of prenatal testing, followed by therapeutic abortion of affected fetuses, or counseling a parent-to-be with a family history of inherited disorders about possible consequences for his or her own offspring.
In the intervening 25 years, we have realized that genetic mechanisms are much more complex. Some genes modify other genes; some diseases are inﬂuenced by multiple gene interactions. As we learn more about genetics, it becomes clear that different genetic mechanisms can result in what we now consider a single disease, like Alzheimer’s or Parkinson’s. When we get all this sorted out, we may well come to the conclusion that Alzheimer’s is not one disease, but multiple diseases that share a similar pathophysiology, such as the accumulation of a toxic fragment that damages nerve cells.
Genes may not only be involved in the mechanism of a disease; they may also increase one’s risk of getting a disease. Each of us has patterns of genes that heighten our risk for some diseases and protect us from others. We do not know how these risk-factor genes work. In most instances, they are not the whole story, anyway; there must be interactions between genetic inﬂuences and environmental factors. Some people smoke and do not get lung cancer, or eat high-fat diets and do not get heart disease. Why?
How will we use this new information? Certainly we will use it to ascertain who is at risk for alcoholism, various forms of cancer, and Alzheimer’s disease. Preventive measures can then be pinpointed for these susceptible populations. We will also understand the genetic inﬂuences that govern responses to therapies and be able to gauge the chances of a particular intervention’s success.
Ultimately we will be able to modify genes, introducing new genes or changing existing ones to make compounds our brains need. One potential use of stem cells is as carriers to introduce new genes where they are needed to make speciﬁc products: new proteins, new enzymes, new growth-promoting trophic factors.
A UNIFIED SCIENCE OF THE BRAIN
By 2025, I think neurology and psychiatry will have become a single clinical neuroscience. The causes of the big psychiatric disturbances, schizophrenia and major depression, may involve behavior, but at root they are disturbances of brain function. Now that was a statement I could not have risked 25 years ago. (The Neurology and Psychiatry professional societies both would have drummed me out!)
What we learn from one episodic disorder, such as epilepsy, has application to other episodic disorders, such as depression or schizophrenia—or, for that matter, perhaps to alcoholism or, according to some intriguing recent thinking, suicide attempts. We already treat these disorders with similar medications, and will do so even more in the future.
Neurosurgeons have contributed mightily to the treatment of trauma and vascular diseases as well as stroke, epilepsy, and brain tumors. I already mentioned deep brain stimulation for Parkinson’s disease. Surgeons will have a still greater role in the future: not by removing tissue but by adding it, replacing cells in the course of treating neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The same will be true in the treatment of stroke, spinal cord injury, and brain cancer.
Psychologists, psychiatrists, and others in cognitive ﬁelds now have a basis in brain sciences for their observations of behavior. Twenty-ﬁve years ago, correlations between behavior and brain mechanisms were based on the study of brain lesions. This was classical neurology, the approach of Paul Broca and Carl Wernicke in the 19th century. A person exhibited a speciﬁc pattern of behavior, such as difﬁculty in expressing language (in the case of Broca’s work), and that pattern was correlated with a lesion in a particular part of the brain. But there were problems with this approach. You had to wait for the affected person to die before the brain could be studied to locate the lesion. A less obvious problem was that a lesion somewhere in a complex circuit might interrupt a function, but that does not necessarily mean that the lesioned area had been producing the function. Consider this analogy. Say you are in New York City watching the Olympics take place in Australia. The signal to your television set originates in Australia, is sent via satellite to a receiving station in New York, and then by cable to your TV. If something happens to the power in New York, you lose your signal; but you do not infer from that that the Olympics have been interrupted. Too often, however, that is the kind of assumption that was made about the lesioned brain.
Today, correlations between behavior and brain function can be made by imaging methods such as PET and fMRI. The brain basis of both normal and abnormal aspects of behavior can be analyzed, but these imaging techniques, as amazing as they are, are in their infancy. As faster techniques, more concurrent with the processing of information by the brain, are devised, ever better correlations should be possible.
Fairness prompts me to add that imaging studies, too, have their pitfalls. Often studies are made of a complex human function such as homicidal aggression or craving for a drug. Certainly we may see where the brain lights up during simulations of these behaviors, but are we equally speciﬁc about what the underlying mental activity really is? We are basically seeing blood ﬂow to a part of the brain that is becoming more active; exactly what brain behavior are we pinpointing that is supposed to correlate with these complex behavioral tendencies? We must be very careful not to put one unknown on top of another and call the result the truth.
Despite the limitations, these are wonderful technologies that will keep getting better. The day will come when we will be able to ascertain how the brain functions differently when one is in a bout of depression, and how that changes in response to therapies. We may even get to the broader questions: the brain basis for both positive, creative behaviors and negative, antisocial behaviors.
TREATING BRAIN DISORDERS
We in neurology will be participating in this new era of active intervention. In 1975, we did have therapies for diseases such as epilepsy, Parkinson’s, and myasthenia gravis. In the last few years, treatments have been added for some “biggies”: Alzheimer’s disease, acute stroke, multiple sclerosis, depression, and schizophrenia. Are these new therapies the ultimate answers—breakthroughs that strike at a disease’s root cause? Probably not. They are, nonetheless, important steps in that they are improving people’s lives.
Alzheimer’s disease is a good example of the trends. In 1975, Alzheimer’s was barely recognized as a speciﬁc disease. It was viewed as a rare cause of dementia and loss of memory and other cognitive functions primarily in younger people. We had only the ﬁrst inkling that a much larger group of older people, whose cognitive problems were being attributed to “senility” or “hardening of the arteries,” had the same symptoms and pathology we saw in the younger patients.
We have since gotten a remarkable education about Alzheimer’s disease, most of it in the last few years. We have a good idea of the basic mechanism: A fragment of a protein, “amyloid,” which is normally present in the brain, accumulates and is toxic to nerve cells.
With this knowledge, our current approaches to treatment try to prevent the accumulation of amyloid or to accelerate its removal. How will we use the new information about Alzheimer’s?
First, take prevention. There are families, rather rare, with a genetically determined form of Alzheimer’s disease. Far more common are older people who have the genes that increase their risk of Alzheimer’s. As we learn more about what determines these risks, we will be able to identify who is or is not a target. In this at-risk population, medications, lifestyle changes, and even genetic modiﬁcations may help to prevent or delay the onset of the disease. We may soon have drugs to prevent accumulation of amyloid, or vaccines or other approaches to promote its removal by the brain.
What about recovery for those who are already afﬂicted? That will be harder. Until very recently, we thought that once a nerve cell had died, it could not be replaced. Now we are not so sure. Perhaps new nerve cells can be enticed to form. Or perhaps they can be introduced in the form of stem cells from elsewhere.
THE WORLD OF 2025
Scientists of the worldwide Dana Alliance for Brain Initiatives recently articulated a vision of the future. Its opening statement reads as follows: “Imagine a world...”
- In which Alzheimer’s, Parkinson’s, Lou Gehrig’s (ALS) diseases, and retinitis pigmentosa and other causes of blindness are commonly detected in their early stages, and are swiftly treated by medications that stop deterioration before signiﬁcant damage occurs.
- In which spinal cord injury doesn’t mean a lifetime of paralysis because the nervous system can be programmed to re-wire neural circuits and re-establish muscle movement.
- In which drug addiction and alcoholism no longer hold people’s lives hostage because easily available treatments can interrupt the changes in neural pathways that cause withdrawal from, and drive the craving for, addictive substances.
- In which the genetic pathways and environmental triggers that predispose people to mental illness are understood, so that accurate diagnostic tests and targeted therapies—including medications, counseling, and preventive interventions— are widely available and fully employed.
- In which new knowledge about brain development is used to enhance the beneﬁts of the crucial early learning years and combat diseases associated with aging.
- In which people’s daily lives are not compromised by attacks of depression or anxiety because better medications are being developed to treat these conditions.
Is this vision utopian? If you interpret it as a ﬁrm prediction, it is, but if you interpret it as an optimistic projection of today’s trends, it is not. We are at an exciting time in the march of neuroscience. Research in just the past decade has taken us further than we had imagined. For the ﬁrst time, we can understand some basic mechanisms at work in the brain. We can begin to harness the healing potential of that knowledge.
We have begun to devise strategies, technologies, and treatments to combat a range of neurological diseases and disorders. By setting therapeutic goals, and applying what we know, we will ﬁnd effective treatments and, in some instances, cures.
We should be alert to the danger that progress can create complacency. As we enjoy the payoff of new knowledge of the brain, we should seize every occasion to remind ourselves how we got here. The work of thousands of basic and clinical scientists in disciplines from molecular structure and drug design, to brain imaging and genomics, to cognitive science, to clinical investigation has wrested from nature the knowledge we need to dream—and more than dream—about treating or preventing brain diseases and disorders. For all we have learned in neuroscience, we have learned, too, how much we do not know.
I ask myself how many of the advances of the last 25 years I would have predicted. Not many. Some came from logical, sequential explorations of how the brain works. Others were great leaps that kicked over strongly held beliefs. Others came about through luck, albeit the luck of very patient and alert investigators. The same combination will shape the next 25 years of brain research.