Feeling stressed out? Anxious? Frustrated and angry? Looking for a way out?
Some significant advances in the neurosciences are revealing that stress is actually a complex relationship of internal and external factors, and that some relatively simple lifestyle changes can contribute to a sense of well being and improve health.
“A healthy lifestyle is the best way to reduce stress,” according to Bruce S. McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at the Rockefeller University in New York and co-author of the recently published The End of Stress As We Know It (Joseph Henry Press).
The notion that stress is the result of external pressures is incomplete, said McEwen, who summarized his book during a March 18 lecture at The New York Academy of Sciences (the Academy). Research now reveals how the body’s defense mechanisms are involved in keeping stress at bay, as well as how the body’s defense system breaks down from time to time.
When the body is working properly, a process known as “allostasis” helps individuals adapt to and survive the real or imagined threats that confront them in the course of everyday life. McEwen explained that the allostasis process is maintained by a complex network – including hormones, the autonomic nervous system, neurotransmitters in the brain, and chemicals in the immune system – in the body.
“When this network is working efficiently, its activity helps to mobilize energy reserves, promote efficient cardiovascular function, enhance memory of important events and enhance the immune defense towards pathogens,” McEwen said. Normally, the body is able to self-regulate the proper responses to external pressures, but occasionally it reaches a limit known as “allostatic overload.”
Bruce S. McEwen
External Stress Factors
Many external pressures can contribute to allostatic overload, according to McEwen, such as conflicts at work or home, fears about war and terrorism, overworking, lack of sleep, economic difficulties, lack of exercise, excessive drinking and bad eating habits. Genetic risk factors, such as a predisposition for cardiovascular disease or diabetes, can also contribute to allostatic overload.
“If the imbalances in the body’s regulatory network persist over long periods of time, the result can lead to disease,” McEwen said. “Hardening of the arteries, arthritis, diabetes, obesity, depressive illness and certain types of memory loss are among the disorders that are accelerated by allostatic overload,” he added. He cited research indicating that long-term stress also affects the amygdala and the hippocampus, the regions of the brain that regulate fear, emotions and memory.
According to McEwen, “genes, early development, and life experiences all contribute to determining how the brain responds to environmental stresses.” Research has revealed that external factors in society also can influence health and disease commonly related to stress.
“In industrialized societies, allostatic overload occurs with increasing frequency at lower levels of education and income,” McEwen noted. He pointed out that mortality rates and levels of diseases associated with allostatic load are much higher among people in lower socioeconomic status. “A combination of lifestyle, perceptions of inequality and stressful life experiences appear to play a role,” he said.
Best Antidote: Healthy Lifestyle
What can be done to reduce allostatic load and the stress associated with it? Changes in lifestyle are the best remedy, according to McEwen. “Maintaining social ties with friends and family is one of the most important factors in reducing stress,” he said. “In addition, restorative sleep, and regular, moderate exercise are all important,” he added. “Regular, moderate exercise not only increases muscle utilization of energy, but also enhances formation of new nerve cells in areas of the brain that support memory.”
McEwen said that, in addition to individual responses to counteract allostatic overload and reduce stress, the private sector and policy makers also can contribute to well-being. “Government policies that recognize the impact of inequality, promote comprehensive health care and reduce smoking, and provide housing and community services are also very important,” he said.
Stress reduction is not only critical for individuals, he added, but for the health and welfare of the wider society as well. “By 2020, depression will be the second-leading cause of disease in this country,” he concluded.
One of the dichotomies between basic and clinical research into childhood mental illness has been the nomenclature of classification. Psychiatrists have historically used “categories” to classify neurological disorders; psychologists have turned to “dimensions.”
Thus, the Roots of Mental Illness in Children and Adolescents conference organizers set out to find a keynote speaker who could bridge this sometimes “cavernous gap,” said Doreen S. Koretz, chief of the Developmental Psychopathology and Prevention Research Branch, Division of Mental Disorders, Behavioral Research and AIDS, at the National Institute of Mental Health, Bethesda. The conference was supported by The New York Academy of Sciences (the Academy).
They turned to Sir Michael Rutter, MD, F.R.S., professor of Developmental Psychopathology at the Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, in London, and a leading expert in child psychiatric research.
By his own admission, Sir Michael took a rather “British approach” and, one by one, challenged “meta-theoretical claims” behind the two approaches. “The battle, as it has sometimes been, between dimensional and categorical approaches is rather futile,” he admitted. Ultimately, both are necessary.
Among the claims he challenged to reach that conclusion were:
Sir Michael Rutter, MD, F.R.S.
Dimensional analyses have greater statistical power. But, says Sir Michael, odds ratios can sometimes be preferable. A recent study using Canadian data, for example, found no difference between maternal care and group day care on physical aggression in children ages two and three — except when the children came from families at high psychosocial risk. “Where there was high family risk, the rates of aggression were substantially higher among those receiving family home care,” he said.
Another assumes that the most important environmental influences are outside the family and only extreme environments have any effects of functional importance. “Both are demonstrably false,” said Sir Michael. A French study has shown that children removed from their parents because of abuse or neglect and then adopted between the ages of four and six-and-a-half have a rise in IQ at adolescence, the degree of which is systematically related to the socio-educational level of the adoptive homes. “These are differences within the relatively narrow range of adoptive homes,” he explained.
A further wrong assumption is that causal inferences can be partitioned into those that are genetically or environmentally mediated, with their summation amounting to 100 percent of effects. One example of the shortcoming of this claim is the role that people themselves play in selecting and shaping their environment. A longitudinal study of girls at age 10 with anti-social behavior found that, in the absence of marital support, there is a high degree of persistence 18 years later. “But, given marital support, there is a huge improvement in social functioning,” said Sir Michael.
“There’s an American saying, which says something like, ‘It ain’t ignorance that does the harm, it’s knowing too many things that ain’t true,’” Sir Michael said. “I’m a great believer in that.”
Scientists and clinicians are pursuing the root causes of mental health struggles specific to young people to develop effective behavioral interventions.
Early childhood experiences appear to shape brain function in ways that confer either vulnerability or resilience to mental illness in children and adolescents. As scientists unravel the genetics and physiological mechanisms behind these changes in animals, clinicians are eager to translate their findings into new behavioral interventions. A recent Academy conference, to be the subject of a future Annals volume, explored how they can come together to do this.
Neonatal rats are programmed to form bonds with their mothers. During the first nine days of life, they develop a preference for their mother’s odor regardless of the quality of care that they receive, according to research done by Regina M. Sullivan, PhD, professor of Zoology at the University of Oklahoma.
She has shown that this learning, which enables nipple attachment and other activities necessary for survival, occurs in an experimental model whether the pups receive a “reward” of milk, a stroke or a shock after being exposed to an odor. And, given that about 12 of every 1,000 children are abused or neglected, she expects the same attachment pattern to be true in humans. “My working hypothesis is that the human child’s brain is wired to form an attachment whether the parent is being kind or not,” she said.
Sullivan’s data, though based on a rat model, could have other implications for research into the mental health of human children. There are physiological parallels between learning in human and rat infants. Thus the neural circuitry responsible for this attachment process, which involves the locus coeruleus in neonatal rats, might be shared.
Surprisingly Little Translational Research
While much of today’s medical knowledge is based on animal studies, there has been surprisingly little translational research in this area.
The March 2003 conference – Roots of Mental Illness in Children and Adolescents – at which Sullivan presented her findings was a first step toward filling this gap. The conference was organized by The New York Academy of Sciences (the Academy). It brought students of developmental neurobiology, developmental psychobiology and developmental psychopathology to New York City for two-and-a-half days of focused presentations and discussions.
According to Israel I. Lederhendler, PhD, director of the Behavioral and Systems Neuroscience Research Program at the National Institute of Mental Health and one of the conference organizers, the goal was “a little bit experimental and lots of fun.” Judging from the dialogue that resulted, it appears to have succeeded. The conference “strengthened the sense that there are important linkages that need to be explored and that the science is at the point where translational research is likely to lead to important breakthroughs,” said Megan R. Gunnar, PhD, Distinguished McKnight University Professor at the Institute of Child Development, University of Minnesota.
Attachment Disorders
Secure attachment between infants and their caregivers is known to be a protective factor and insecure attachment a risk factor for subsequent psychopathology. Charles H. Zeanah, Jr., MD, professor of Psychiatry and Pediatrics at Tulane University Health Sciences Center, has been studying one form of insecure attachment, called disorganized attachment, at an orphanage in Bucharest. “There’s a point at which attachment itself is reflective of a psychopathology, reactive attachment disorder, that’s defined in early childhood,” he said.
Zeanah has found the two patterns of this disorder, characterized either by emotional withdrawal or indiscriminate social extroversion, to be “readily identifiable” in these institutionalized children. Interestingly, however, a pilot project that aimed to reduce the number of caregivers for children in one unit of the institution dramatically reduced their signs of emotionally withdrawn reactive attachment disorder. “Secure attachment relationships appear to be protective in the context of high-risk environments,” he concluded.
Maternal separation in rats, where mothers are taken away from their offspring for three hours a day early in the first neonatal week, has been found to be associated with a transient decrease in hippocampal neurogenesis, reductions in hippocampal dendritic branching and a reduction in synaptic density. “This one fairly modest manipulation during the early part of these rats’ lives has profound long-term effects,” said Paul M. Plotsky, PhD, GlaxoSmithKline Professor of Psychiatry and Behavioral Sciences at Emory University School of Medicine. “There are a whole host of changes in the neurochemistry, behavioral profiles and morphology of these animals.”
Genetic Vulnerability
Nonetheless, only 33 to 45 percent of the animals in Plotsky’s study exhibit these effects in response to early maternal separation experiences. This suggests that some rats are genetically vulnerable to maternal separation and others are not. Studies done by Thomas R. Insel, director of the NIMH, in prairie voles underscore the importance of social experience in forming attachments.
Adult prairie voles form life-long partnerships, but only after mating triggers a release of dopamine in the nucleus accumbens. A D2 receptor agonist, which has no affect on mating behavior, eliminates partner preference in these animals. “The key then is that social attachment requires that social stimuli become linked to this major information stream in the forebrain,” said Insel.
Social behavior and physiology also appear to be linked in humans. Eye contact, for example, tenses middle ear muscles that enable the human voice to be distinguished from background noise. “If we extract from some of the animal and human work, we start realizing that some social behaviors are not learned behaviors but appear to be emergent properties of specific physiological states,” explained Stephen W. Porges, PhD, professor of Psychiatry at the University of Illinois at Chicago.
False Perceptions
Adult rhesus monkeys whose entire amygdala has been lesioned lose innate fear, such as that of snakes, but are able to function in social environments. However, when these monkeys are lesioned early in development, they show increased fear in social settings. There are very few people with amygdala lesions, but these findings are consistent with the behavior of one such female patient, “S.M.,” in her 30s. Though this woman appears to engage in normal social interactions, she is unable to detect fear in faces.
This interplay between fear and social motivation was further investigated in a recent study at the University of California, Davis. David G. Amaral, PhD, a professor of Psychiatry, found that amygdala-lesioned animals failed to demonstrate preference for their mothers over another female in a novel environment. Though this might appear to suggest failed maternal attachment, these monkeys didn’t seek out the comfort of their mothers, as they were unable to detect the novel environment as dangerous. “The amygdala may play some role in issues of impairment, such as in society anxiety,” Amaral concluded.
Bradley S. Peterson, MD, Suzanne Crosby Murphy Associate Professor in Pediatric Neuropsychiatry at Columbia University, is studying premature infants as a means to understand how disturbances in normal brain development might contribute to mental illnesses in children. A functional magnetic resonance imaging study of language processing found that they, unlike their full-term counterparts, tend to use phonological circuitry to process semantic material in their environment. “Preterm children may tend to hear semantic material, meaningful sounds and speech utterances, as meaningless junk,” he said.
Responding to Social Cues
Physically abused children studied by Seth D. Pollak, PhD, assistant professor in the Departments of Psychology and Psychiatry at the University of Wisconsin at Madison, also failed to respond appropriately to social cues in their environment. In this instance, however, the children were extremely sensitive to facial expressions of anger. They identified this emotion early in its formation and also detected it with little perceptual information from scrambled facial images.
“Their categories for anger are more inclusive,” explained Pollak. “A face that has maybe 30 percent anger in it but 70 percent sadness or fear is being interpreted as being an angry face. This really changes how children are interpreting social information that they’re receiving from the world.”
Though this heightened perception of anger might be beneficial in their home environments, it will likely cause them to misread cues in other social settings. “If we want to understand human development, especially with the goal of understanding the development of psychopathology, we need to bring together not only an understanding of the neuroscience of what is in children’s heads, but an understanding of what (environment) children’s heads are in,” Pollak concluded.
Doctors and researchers studying the molecular and clinical aspects of Alzheimer’s disease are learning more about the mechanisms of this devastating condition.
While proteins involved in the generations of Alzheimer’s disease (AD) continue to perplex researchers, progress is being made in the presymptomatic and early identification of patients.
But the use of genetic testing, brain imaging and other available technologies to identify people who are likely to develop Alzheimer’s will remain problematic until disease modifying therapies become available, according to Norman Relkin, MD, PhD, associate professor of Clinical Neurology and Neuroscience at New York-Presbyterian Hospital, Weill Medical College of Cornell University.
“This information is viewed as toxic information that is potentially very, very harmful,” Relkin told participants at the Fourth New York Alzheimer’s Research Symposium held last Nov. 20. “It’s one thing to tell someone they’re at risk, it’s quite another thing for there to be nothing that they can do about it.”
The lifetime risk of AD is estimated to be 10 to 15 percent among the general population, meaning that one-in-10 women who live to 80 and one-in-seven men who live to 76 will develop the disease. This risk doubles to 20 to 30 percent for first-degree relatives – mother, father, sister, brother, daughter or son – of people with AD.
Convened by The New York Academy of Sciences (the Academy), the afternoon symposium brought together three experts on the evolving molecular and clinical aspects of Alzheimer’s disease. Its co-sponsors included The Institute for the Study of Aging, The New York City Chapter of the Alzheimer’s Association and The New York City Metro Area Chapter of the Society for Neuroscience.
The Calsenilin Story Evolves
One of the main pathological hallmarks of AD is the presence of amyloid plaques in patient brains. These plaques are composed of amyloid beta-peptide (Aβ), which is derived from gamma-secretase cleavage of the beta-amyloid precursor protein (APP).
Several years ago Joseph Buxbaum, PhD, associate professor of Psychiatry and head of the Laboratory of Molecular Neuropsychiatry at Mount Sinai School of Medicine, identified a novel protein that interacts with presenilin, a protein required for γ−secretase cleavage of APP that many scientists believe should be inhibited to prevent or treat Alzheimer’s. Named calsenilin, for calcium and presenilin binding protein, it was subsequently identified by other researchers as a transcription factor regulating dynorphin expression (DREAM) and a potassium channel interacting protein (KChIP3).
Buxbaum developed a calsenilin knockout mouse to determine the true physiological function of this protein. This work is important because it helps to identify the side effects of potential Alzheimer’s drugs, in this case drugs targeting presenilin that might affect calsenilin function as well. But calsenilin “has resisted, very effectively, easy analysis,” he said.
His initial results, which found Aβ formation and K+ currents decreased and long-term potentiation in the dentate gyrus of the hippocampus increased, suggested a role for calsenilin in regulating presenilin and voltage-gated potassium channel (Kv4) function. Further, the animals were found to be more sensitive to shock and, therefore, it seemed unlikely that calsenilin was involved in modulating pain sensitivity through the antagonism of dynorphin expression.
Calsenilin as a Dynorphin Suppressor
But data published by another lab showing that calsenilin knockouts were less sensitive to pain led Buxbaum to reevaluate the knockout using the tail-flick flick latency test. This test measures the time taken for a mouse to flick its tail away from a heat source, and has long been thought to be analogous with shock sensitivity.
The tail-flick results confirmed that the knockout mice were less sensitive to pain, and thus a role for calsenilin as a dynorphin suppressor could not be ruled out. These results also are likely to get much attention from those working in pain research. “The take-home message is that shock sensitivity is actually not reflective at all of tail-flick sensitivity,” he said.
Though the exact role of calsenilin in Alzheimer’s disease remains unclear, Buxbaum’s current hypothesis is that calsenilin affects Aβ formation by modulating calcium levels in the cell. There is a relationship between calcium abnormalities and Alzheimer’s, and it’s known that increases in cellular calcium result in the production of more and more Aβ.
Selective Degeneration
A pathological feature of AD, in addition to amyloid plaque and neurofibrillary tangle formation, is selective neurodegeneration. “In patients with Alzheimer’s disease, not all neurons are dying at the same time,” said Tae-Wan Kim, PhD, assistant professor at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. “There is remarkable specific and selective degeneration and this underlies a lot of cognitive deficits.”
Focusing on the basal forebrain cholinergic neurons, a prime site of neuronal death in AD patients that also correlates with their cognitive deficits, Kim used proteomics to identify novel substrates that are cleaved by γ-secretase. He did this by comparing the protein profile of normal cells to those lacking functional γ-secretase.
“We wanted to find substrates expressed predominantly in these neurons that are affected in AD,” Kim explained. Notch, a developmentally regulated protein important for cell plate determination and neurogenesis, and ErbB4, a receptor tyrosine kinase, have previously been identified as γ-secretase substrates. Like APP, these substrates are cleaved in the transmembrane region and their cleavage is dependent on functional presenilins, early-onset familial AD genes.
Kim’s recent analysis found that the p75 neurotrophin receptor (p75-NTR), a protein that has been implicated in Alzheimer’s and other diseases due to its regulation of cell survival and death, is a γ-secretase substrate. He did this by demonstrating that p75-NTR undergoes ectodomain shedding, a step that is required for γ-secretase cleavage, and that the p75-NTR cleavage is blocked in cells treated with a γ-secretase inhibitor. Further, the p75-NTR cleavage site was found to be in the transmembrane region and similar to that of Aβ40, one of the APP peptide fragments.
Risk and Risk Perception
In future work, Kim plans to investigate whether shedding and cleavage by γ-secretase can regulate neuronal cell death and survival. “If that is the case then we might have a molecular basis for selective neurodegeneration of basal forebrain cholinergic neurons in AD,” he said. He also would like to use microarray analysis to identify downstream target genes.
Eighteen months before announcing he had been diagnosed with Alzheimer’s disease, former President Ronald Reagan gave a speech of about 90 minutes in length without a single error.
“He spoke perfectly,” said Relkin, who assessed a videotape of the 1992 speech for signs or symptoms of incipient AD. “When one considers that we’re trying to come to a point in which we can diagnose AD in its presymptomatic stages, or at least predict with reasonable accuracy who is going to develop the disease, performances like that are daunting.”
Relkin also sees it as a lesson that predictive testing should involve more than clinical interviews and observational methods.
The field has moved from diagnosing Alzheimer’s by exclusion to direct diagnosis. In addition, clinicians have begun subcategorizing patients with mild cognitive impairment (MCI) who are believed to have an increased likelihood of developing AD or other forms of dementia in the near future.
Managing Risk Perception
One of these subgroups, AD-like MCI, includes patients whose symptoms are found to have an “AD-like flavor.” It’s estimated that from 5 to 40 percent of them go on to develop AD each year.
Translating this subcategorization into general practice without more specific diagnostic criteria, however, will be problematic. This is where technologies such as genetic testing, proteomic analysis and structural/functional neuroimaging can be used to improve differential diagnosis and presymptomatic detection of AD.
As more information becomes available, managing patients’ risk perception will become important. The general population is more influenced by their perceptions of risk than by numbers representing the probability they will develop a disease, said Relkin. “Perceptions are altered by life experiences, like caring for patients in the family with the disease, and have a greater impact on how one views one’s risk of AD.”
Results he presented from an ongoing study, called REVEAL (Risk Evaluation and Education for Alzheimer’s Disease), confirm this. People in the survey tended to remember their genotype, that is whether or not they carry the APOE 4 allele associated with an increased risk of AD, more than their numeric lifetime risk estimates.
Sending medical specimens off to labs can mean lengthy waits for results needed to make or confirm diagnoses. But help is on the way in the form of a developing nanotechnology called Doctor-on-a-Chip (DoaC).
In broad terms, DoaC technology will allow a sample of bodily fluid to be processed to test for a disease’s DNA marker. Research teams at universities in the United Kingdom and the United States are working on such devices. DoaCs will allow clinicians to perform many more medical diagnostic tests in their offices and in the field, and promise delivery of results in as little as 5 to 10 minutes.
At Brunel University in London, Professor Wamadeva Balachandran (Bala) heads a six-member research team working on a DoaC. In the United States, a team of 70 researchers led by Professor Chad A. Mirkin, of Northwestern University, is working on a similar program.
Bala believes the system of taking a patient sample and sending it to a lab – where it may takes days for the results to be determined and communicated back to the doctor – can be dangerous. “In certain cases it could be a life-and-death situation,” he said. “The idea here (with DoaC devices) is that doctors can get the results while still talking with their patient.”
In the DoaC concept, the doctor places a drop of the patient’s blood on the front end of a polymer chip and waits 5 to 10 minutes for the chip to do its tests and display the results. The device will initially be the size of a credit card, Bala said, and eventually the size of a microprocessor chip.
Faster Diagnostic Tests
Prof. Wamadeva Balachandran (Bala)
Going into more detail, Mirkin explained, “A sample (blood, saliva or urine) is processed through microfluidics (micro- or nano-scale devices for manipulating fluids). Then the marker DNA (for the diseases of interest) is delivered to the reader portion of the chip. If marker DNA binds to this portion of the chip…nanoparticle probes are used to develop the chip (also through microfluidics).” The readout device will measure the conductivity of the particles between microelectrodes.
Bala said the idea behind his device involves the Electric Field Manipulation of DNA (characterizing DNA using electrical fields to move them and then to look at their properties). His original thinking, three or four years ago, was that if you could identify various characteristics you could confirm a particular virus in terms of its properties.
“But, of course, during this period the genome sequencing has moved on so fast,” Bala explained. “Various medical colleagues were all saying that if there were a system, which could be easily utilized to detect viruses by GPs (general practitioners) in their offices, that would speed up the process of diagnosis and save a lot of lives.” So he decided to work on it. Bala’s idea now is to use this technique to move DNA into a chamber to look for a particular type of DNA linked to a virus. Once confirmed as the suspect DNA type, “it comes out of that chamber and we again use electrical techniques to categorize the DNA: electrical impedance, for example.”
Results in 5-10 Minutes
Prof. Chad A. Mirkin
The technology involved in the tests is nothing new. “The challenge is to bring the technique down to the microscale, to put it on a single chip,” Bala said, “and we’re doing that now.”
Processing the sample involves attaching probes to the DNA. The type of virus that’s suspected determines the type of probe that is used. The sample then goes through a polymerase chain reaction (PCR) and then through the chamber with the medium for dielectrophoretic measurement. It then passes through various dielectrophoretic chambers. “In 5-10 minutes the doctor will be able to look at his computer screen and know whether you have hepatitis A or hepatitis B, for example, or whether you don’t have any virus,” he said.
Early models of Bala’s chip will check for various kinds of viral infections sequentially, one virus type after another being tried until a match is found. Eventually, he expects DoaCs to have the ability to run through a whole series of tests for various viruses.
“The (DoaC) potential,” concludes Mirkin, “is enormous.”
More than 2000 infants around the world are infected with HIV every day. In sub-Saharan Africa alone up to 46 percent of pregnant women carry the virus, and some 25 to 35 percent of their children will be born infected.
Arthur J. Ammann, MD, is succeeding in improving those statistics. As President of Global Strategies for HIV Prevention, Ammann oversees the Save a Life program, which provides HIV testing and medication to prevent HIV transmission from pregnant women to their infants in Africa, Asia and South America.
At the heart of the program is the antiretroviral drug nevirapine. Giving a single tablet of nevirapine to a woman during labor and delivery together with a single dose of nevirapine syrup to her newborn reduces HIV transmission by 50 percent. Moreover, in many countries the cost of treatment is as little as 85 cents for both mother and child. The program has helped some 50,000 women and infants in more than 72 hospitals in 18 nations. Save a Life also provides antibiotics to prevent opportunistic infections in HIV-infected women.
Obtaining and Administering Nevirapine
Global Strategies makes it easier for start-up programs in developing countries to obtain and administer nevirapine for this use. “They just tell us what they do and how much they need,” explains Ammann. “This is especially helpful for small programs that have the infrastructure to test women and give the drugs, but which may be waiting for additional funding from larger organizations.”
Ammann’s commitment to helping women and children with HIV began some two decades ago. As a professor of Pediatric Immunology at the University of California, San Francisco (where he is still on the faculty), Ammann and his colleagues diagnosed the first child with HIV in this country. The epidemic grew, and in 1987 AZT was introduced as the first anti-HIV drug.
In 1994, a landmark study showed that giving AZT to pregnant women could prevent transmission of the virus to newborns. Thanks to AZT, the number of new pediatric AIDS cases in the United States and Europe plummeted from 2,000 per year to less than 200. “However, that remarkable success story was paralleled by a lack of success in developing countries,” notes Ammann, “where 1,800 children are born with HIV every day.”
HIV Treatment
So, in 1997 Ammann founded Global Strategies. Through a series of international conferences held every two years, and with the assistance of organizations such as the Elizabeth Glaser Pediatric AIDS Foundation, Global Strategies has called on nations to immediately implement countrywide programs to prevent HIV infection of infants, identify HIV-infected women, and provide treatment for children and mothers with HIV. One major step in that direction is the production and distribution of more than 30,000 copies of an educational CDROM.
While Save a Life is clearly rescuing the futures of thousands of infants, Ammann notes that challenges remain. Programs to continue drug treatment of HIV-infected women, as well as their sexual partners, require further development. A new drug that could be used when HIV eventually develops resistance to nevirapine remains to be found. And educational opportunities and support for children orphaned by AIDS need to be expanded.
In the meantime, counseling is becoming more available to women without HIV, so they remain uninfected. “We’re working at the end of the process, the point where HIV infection has already occurred,” says Ammann. “Where we want to go is the beginning, to keep the infection from happening in the first place. Then all those other problems would go away.”
Nearly two centuries after James Parkinson first defined “shaking palsy” in 1817, million of people throughout the world struggle daily with the disabling effects of Parkinson’s Disease. Neither a cause nor a cure has yet been found for this enigmatic and deadly disease.
Published November 1, 2002
By Vida Foubister
First Parkinson’s disease patient. Photograph taken March 24, 1965. John H. Lawrence Collection-5521. Photograph by Doug Bradley via National Archives Catalog.
Speaking as chair of the opening session at a recent three-day seminar on Parkinson’s Disease, sponsored by The New York Academy of Sciences (the Academy), Stanley Fahn, MD, director of the Center for Parkinson’s Disease and Other Movement Disorders at Columbia University, wasted no time in summing up the dilemma.
Many decades ago, he told the large gathering of scientists and clinicians – whose registry resembled a global “who’s who” in PD research – “two basic science findings in clinical, pathological and animal models led to the dopamine hypothesis of Parkinson’s disease. And we’ve been there ever since.”
Dopamine, produced by the dopaminergic neurons in the substantia nigra region of the brain, was found to reverse bradykinesia in animals. Bradykinesia, which includes difficulty initiating movement, slowness in movement and paucity or incompleteness of movement, is considered the most prominent and disabling symptom of PD. The second finding was that PD patient brains were markedly depleted in dopamine and the amount of depletion correlated with the disease’s severity.
Since the 1960s, the early features of the disease have been treated with levodopa (L-dopa) and similar drugs that function by replacing the lost dopamine. “Before my drug takes effect, I am unable to move well enough to really get out of bed,” explains Joan I. Samuelson, president of the Parkinson’s Action Network. “Then, an hour later, I can get up, get dressed and walk into the room and function. That’s miraculous.”
Treating Symptoms, Not PD
The fact that this drug exists, and that PD was the first neurological disease to be treated with pharmacological drugs, isn’t trivialized. However, there is a growing sense that the field is ripe to move beyond this early discovery and symptomatic treatment.
L-dopa and other related drugs often cause significant side effects, most notably dyskinesias – or involuntary movements – that limit their usefulness. And even though many patients initially respond well to therapeutics, they lose their effectiveness as the disease progresses. Most importantly, these drugs only function to treat the symptoms of Parkinson’s and do nothing to slow the disease process.
Patients, clinicians and scientists spent three days in September, essentially sequestered at a wooded retreat near Princeton, N.J., discussing where the field should go. As the organizers hoped, the setting of this conference, Parkinson’s Disease: The Life Cycle of the Dopamine Neuron, brought people together across many disciplines and stimulated discussions that continued from early morning sessions into impromptu evening debates.
The high level of interaction at the conference stimulated both new ideas for research and treatment, as well as connections between the existing body of scientific and clinical knowledge. Yet it also highlighted the dichotomy that exists in the field. Despite all that is known about Parkinson’s, its cause remains essentially unknown and untreatable.
That dichotomy was reflected by the participants. Some pushed for more basic research, including investigation into the non-motor aspects of the disease that are often overlooked due to the focus on the role of dopamine neurons. However, others urged the scientists to move their many promising new findings out of the lab and into the clinic.
Important Leads
Robert E. Burke, M.D., of Columbia University was a conference speaker and member of the organizing committee.
John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research at the University of Pennsylvania School of Medicine, is among those who believe there are a “number of phenomenally important leads that have potential implications for therapies.” He pointed to new findings about some of the proteins that have been implicated in PD, namely alpha-synuclein and parkin. “Knowing the culprits, the molecular criminals, is the first step towards taking them out of the action or doing something to improve what’s broken,” Trojanowski said.
Lewy bodies, a pathological marker of Parkinson’s disease in the substantia nigra, contain a fibrillar form of alpha-synuclein. Though it’s long been known that patients with the familial form of the disease can have a mutation in the gene coding for this protein, new data presented at the conference suggests that alpha-synuclein abnormalities in patients with sporadic Parkinson’s might be due to mitochondrial dysfunction. (Sporadic Parkinson’s is more common than the familial form of the disease.)
“We know from a genetic standpoint that alpha-synuclein does what it does because you have a mutation, but why in everybody else does synuclein go bad?” asked Ted M. Dawson, MD, PhD, director of the Morris K. Udall Parkinson’s Disease Research Center of Excellence at the Johns Hopkins University School of Medicine. “Well, it might be because oxidative stress is hammering it.”
Some New Clues
Peter T. Lansbury Jr., PhD, an associate professor of neurology at Harvard Medical School, presented some new clues about what in the alpha-synuclein fibrillization process causes disease. His research suggests that an intermediate, called a protofibril, is toxic to dopamine neurons and he has also found that the formation of this protofibril can be inhibited by beta-synuclein.
“Beta-synuclein has a nice therapeutic profile: It stops oligomerization all together,” Lansbury said. “We are proceeding with this idea as a therapeutic strategy. Specifically, we’re interested in developing small molecules that would induce increased expression of endogenous beta-synuclein.”
Mutations in parkin, another so-called molecular criminal, are the most common cause of familial PD. It’s been found to function as a unbiquitin E3 ligase that labels proteins for degradation and disposal. That means when parkin isn’t functioning, proteins such as synphilin-1 and Pael receptor build up in the cell. “The current theory is that the accumulation of these substrates causes Parkinson’s disease,” Dawson said. “So enhancing the function of parkin, identifying the substrates and then figuring out ways to get them degraded” are possible therapeutic approaches.
The Cellular Level
Moving from proteins to the cellular level, another session at the conference focused on the mitochondria and the circumstances under which it produces toxic oxygen-free radicals that lead to apoptosis or cell death.
“There’s more and more reason to believe that in Parkinson’s disease, either because of environmental toxins like pesticides or because of genetic defects, the mitochondria produce an abnormally high level of these reactive oxygen species,” said Gary Fiskum, PhD, professor and research director in the department of anesthesiology at the University of Maryland School of Medicine.
One way to elucidate this pathogenic mechanism is by using genomics and proteomics to identify genes that are expressed in response to environmental toxins and mitochondrial oxidative stress. “The idea is that you may come up with things you have no preconceived notion would be associated with the disease process and that, conceivably, might give you a new insight into the disease,” explained M. Flint Beal, MD, neurologist-in-chief at The New York Presbyterian Hospital.
Beal’s research has focused on two known antioxidants – coenzyme Q10 and creatine – that act either to inhibit the production of mitochondrial free radicals or to detoxify them once they’re produced. “We have good animal data that [coenzyme Q10 and creatine] prevent damage to dopaminergic neurons,” he said. “What we’re going to do now is see if we can administer those in combination with some anti-inflammatory drugs and get even better protection.”
New Approaches
Courtesy of Dr. Stanley Fahn.
Much excitement has been generated in the field by the promise of two approaches to replace the dopamine neurons that are lost in patients with Parkinson’s disease. One involves manipulating endogenous precursor cells in the adult brain to become dopamine neurons. The other approach focuses on transplanting embryonic stem cells, which have been coaxed to become dopamine neurons, into the adult brain.
“There’s evidence that even a mature and degenerating brain will accept new cells, including neurons, that will grow to reconnect damaged parts,” said Ole Isacson, Dr. Med. Sci., M.B., director of The Morris K. Udall Parkinson’s Disease Research Center of Excellence at Harvard University Medical School.
The implications of these therapies for patients, though not novel, can be dramatic. Such was the film clip presented by Isacson that showed a patient with advanced Parkinson’s disease walk down a hallway before and after receiving a transplantation of fetal dopamine cells. The first walk down the hall seemed to take forever, as the patient struggled with every step. Then, after the transplant, the patient appeared to stride down the hall and back.
Though this demonstrates the potential of this strategy, Ronald McKay, PhD, senior investigator at the National Institute of Neurological Disorders and Stroke, doesn’t believe it represents a possible therapy for patients. “It’s just too difficult,” he said. Among the problems he cited is the challenge of obtaining a sufficient number of fetal cells for the procedure.
The Promise of Embryonic Stem Cells
Instead, McKay emphasized the promise of embryonic stem cells that have been engineered to become dopamine neurons – both for cell therapy and for further study of the disease. Those studies include determining what signals and factors are required to make an immature cell become a dopamine neuron. “The title of this meeting is the life cycle of the dopamine neuron. We’re essentially dissecting the life cycle of the neuron,” he said. “There’s many signals at different stages that influence the properties of the cells.”
Manipulating precursor cells in the brain to become dopamine neurons might have some advantages due to their existing regional differentiation. “Rather than one tube of all-purpose cells, one potentially can recruit precursors that would give rise to the right kind of replacement neurons,” commented Jeffrey D. Macklis, MD, D.HST, associate professor of Neurology and Neuroscience at Harvard Medical School.
Overall, the basic scientific understanding of Parkinson’s disease appeared to reach a new level at the conference, generating hope that the focus of the next such meeting will be on clinical therapies. “This kind of session tells you how complicated [the disease] is, but any day now there could be a revolutionary big idea,” Samuelson said. “If it’s in the treatment end of things, it could revolutionize the lives of a million people pretty quickly, and that’s a big deal.”
Louis Pasteur once noted: “Chance favors the prepared mind.” Denham Harman’s mind was unusually prepared to develop a notion that took well over a decade to attract any serious attention, but is now a driving force in biomedical research: the free-radical theory of aging, a phrase Harman coined in 1960.
Now professor emeritus at the University of Nebraska Medical Center and still spry at 86, Harman recently edited Annals of the New York Academy of Sciences volume 959, Increasing Life Span: Conventional Measures and Slowing the Innate Aging Process. The volume also includes a recent paper by Harman on Alzheimer’s Disease: Role of Aging in Pathogenesis.
Free radicals are molecules or atoms that feature an unpaired electron. Because electrons prefer to travel in pairs, free radicals can set off chain reactions – their loner electrons cut in on the dance of another molecule’s two electrons in an attempt to grab one. This move satisfies the original unpaired electron, but merely creates a new free radical bent on pairing up.
Thus, like bulls in the china shop of living cells, free radicals, especially the hydroxyl radical, damage delicate cell membranes and muck up proteins whose functions depend on their structure. And the cellular damage wrought by free radicals is the mechanism, according to Harman, of the natural process we take for granted as aging.
A Circuitous Route
Harman took a circuitous, but in retrospect necessary, route to this conclusion. He was born in 1916 in San Francisco, but did live briefly as a boy in New York City, where his father worked for a jewelry company located just blocks from the site of The New York Academy of Sciences (the Academy) on 63rd Street near Fifth Avenue. The family returned to the Bay area in 1932, and Harman graduated from Berkeley High School two years later. Jobs were scarce, but Harman’s father happened to meet the director of the Shell Development Company, the chemical research division of the Shell Oil Company, at a local tennis club. Harman began working for Shell as a lab assistant.
The position sparked a true interest in chemistry. Harman went on to receive his undergraduate degree and, in 1943, his doctoral degree from the University of California, Berkeley, in chemistry. He continued with Shell the entire time, at first working with lubricating oils. But he was fortunately transferred – to the reaction kinetics department, where much of the work concerned free-radical reactions. During seven years there, Harman was instrumental in gaining 35 patents for Shell, including work on the active ingredient of something designed to shorten, not extend, life: the famous “Shell No-Pest Strip.”
Time to Think
In December 1945, Harman’s wife Helen put a bee in his bonnet. “She showed me a magazine article she thought might be of interest. It was a well-written piece by William Lawrence of the New York Times about aging research in Russia,” he recalls. Harman knew a lot of chemistry, but not much biochemistry or physiology. And the idea of aging as a biochemical process so fascinated him that in 1949 he decided to attend medical school. Berkeley turned him down because of his advanced age – he was 33 – but Stanford accepted him.
After his internship, Harman became a research associate at the Donner Laboratory back at Berkeley. “Donner was great,” he remembers, “because I didn’t really have to do anything, other than a hematology clinic on Wednesday mornings. I could just think.” And what he thought about was aging. “One thing you learn in biology,” he notes, “is that Mother Nature has a tendency to use the same processes over and over. My impression was that since everything ages, there was probably a single, basic cause.”
Pondering the issue at first left him frustrated. “I thought perhaps there wasn’t even enough knowledge available at the time to solve the problem,” he says. “And then in November of 1954 I was sitting at my desk when all of a sudden the thought came to me: free radicals. In a flash, I knew it could explain things.”
He quickly discussed the idea with medical colleagues – most thought it was interesting but too simple to explain such a complex phenomenon. “I got encouragement from only two people, both of whom were organic chemists, not medical doctors,” he recalls.
The Ubiquitous Enzyme Superoxide Dismutase
Helen and Denham Harman
Harman spent the next decade on virtually a lone research effort that produced circumstantial evidence for his idea. The limits of the instrumentation of that time made it difficult to even show that free radical species existed in living cells. Electron spin resonance studies found free radicals in yeast in 1954, but it was not until 1965 that free radicals were detected in human blood serum.
Then in 1967 biochemists discovered the ubiquitous enzyme superoxide dismutase, whose job it is to protect cells by sopping up free radicals formed during aerobic respiration in cells. The presence of a defense implies that free radicals are indeed a clear and very present danger to cells.
Ensuing research has implicated free radicals in cancer, heart disease, Alzheimer’s disease and other conditions. And observations of the animal kingdom are especially suggestive of the general aging theory. Harman points out that rats and pigeons, for example, have about the same body weights and metabolic rates. But pigeons produce far less hydrogen peroxide (formed from the superoxide radical) during cellular processes than do rats – and the birds live some 15 times longer than the rodents.
Judging by the sales of antioxidant supplements that scavenge free radicals, the American public has clearly subscribed to Harman’s ideas. Many physicians and scientists also have signed on to his view of aging, with the free-radical theory underlying much of current aging research.
“I think we’re now getting to a point where we may be able to actually intervene in the aging process,” Harman says. If his prediction proves true, our extra years will be owed to his many well-spent ones.
Nanotechnology has potential to revolutionize our daily lives and one aspect that makes this technology so promising and effective is its bottom-up approach.
Nanotechnology has gained widespread recognition with the promise of revolutionizing our future through advances in areas ranging from computing, information storage and communications to biotechnology and medicine. How might one field of study produce such dramatic changes?
At the most obvious level nanotechnology is focused on the science and technology of miniaturization, which is widely recognized as the driving force for the advances made in the microelectronics industry over the past 30 years. However I believe that miniaturization is just one small component of what makes and will make nanoscale science and technology a revolutionary field. Rather, it is the paradigm shift from top-down manufacturing, which has dominated most areas of technology, to a bottom-up approach.
The bottom-up paradigm can be defined simply as one in which functional devices and systems are assembled from well-defined nanoscale building blocks, much like the way nature uses proteins and other macromolecules to construct complex biological systems. The bottom-up approach has the potential to go far beyond the limits of top-down technology by defining key nanometer-scale metrics through synthesis and subsequent assembly – not by lithography.
Producing Structures with Enhanced and New Functions
Of equal importance, bottom-up assembly offers the potential to produce structures with enhanced and/or completely new function. Unlike conventional top-down fabrication, bottom-up assembly makes it possible to combine materials with distinct chemical composition, structure, size and morphology virtually at will. To implement and exploit the potential power of the bottom-up approach requires that three key areas, which are the focus of our ongoing program at Harvard University, be addressed.
First and foremost, the bottom-up approach requires nanoscale building blocks with precisely controlled and tunable chemical composition, structure, morphology and size, since these characteristics determine their corresponding physical (e.g. electronic) properties. From the standpoint of miniaturization, much emphasis has been placed on the use of molecules as building blocks. However, challenges in establishing reliable electrical contact to molecules has limited the development of realistic schemes for scalable interconnection and integration without having key feature sizes being defined by the conventional lithography used to make interconnects.
My own group’s work has been focused on the nanoscale wires and, in particular, semiconductor nanowires as building blocks. This focus was initially motivated by recognition that the one-dimensional nanostructures represent the smallest morphology structure for efficient routing of information – either in the form of electrical or optical signals. Subsequently, we have shown that nanowires can also exhibit a variety of critical device function, and thus can be exploited as both the wiring and device elements in functional nano-systems.
Control Over Nanowire Properties
Currently, semiconductor nanowires can be rationally synthesized in single crystal form with all key parameters – including chemical composition, diameter and length, and doping/electronic properties – controlled. The control that we have over these nanowire properties has correspondingly enabled a wide range of devices and integration strategies to be pursued. For example, semiconductor nanowires have been assembled into nanoscale field-effect transistors, light-emitting diodes, bipolar junction transistors and complementary inverters – components that potentially can be used to assemble a wide range of powerful nano-systems.
Tightly coupled to the development of our nanowire building blocks have been studies of their fundamental properties. Such measurements are critical for defining their limits as existing or completely new types of device elements. We have developed a new strategy for nanoscale transistors, for example, in which one nanowire serves as the conducting channel and the other crossed nanowire as the gate electrode. Significantly, the three critical device metrics are naturally defined at the nanometer scale in assembled crossed nanowire transistors:
(1) a nanoscale channel width determined by the diameter of the active nanowire;
(2) a nanoscale channel length defined by the crossed gate nanowire diameter; and
(3) a nanoscale gate dielectric thickness determined by the nanowire surface oxide.
These distinct nanoscale metrics lead to greatly improved device characteristics such as high gain, high speed and low power dissipation. Moreover, this new approach has enabled highly integrated nanocircuits to be defined by assembly.
Hierarchical Assembly Methods
Second and central to the bottom-up concept has been the development of hierarchical assembly methods that can organize building blocks into integrated structures. Obtaining highly integrated NWs circuits requires techniques to align and assemble them into regular arrays with controlled orientation and spatial location. We have shown that fluidics, in which solutions of nanowires directed in channels over a substrate surface, is a powerful and scalable approach for assembly on multiple-length scales.
In this method, sequential “layers” of different nanowires can be deposited in parallel, crossed and more complex architectures to build up functional systems. In addition, the readily accessible crossed nanowire matrix represents an ideal configuration since the critical device dimension is defined by the nanoscale cross point, and the crossed configuration is a naturally scalable architecture that can enable massive system integration.
Third, combining the advances in nanowire building block synthesis, understanding of fundamental device properties and development of well-defined assembly strategies has allowed us to move well beyond the limit of single devices and begin to tackle the challenging and exciting world of integrated nano-systems. Significantly, high-yield assembly of crossed nanowire structures containing multiple active cross points has led to the bottom-up organization of OR, AND, and NOR logic gates, where the key integration did not depend on lithography. Moreover, we have shown that these nano-logic gates can be interconnected to form circuits and, thereby, carry out primitive computation.
Tremendous Excitement in the Field
Prof. Lieber
These and related advances have created tremendous excitement in the nanotechnology field. But I believe it is the truly unique characteristics of the bottom-up paradigm, such as enabling completely different function through rational substitution of nanowire building blocks in a common assembly scheme, which ultimately could have the biggest impact in the future. The use of modified nanowire surfaces in a crossed nanowire architecture, for example, has recently led to the creation of nanoscale nonvolatile random access memory, where each cross point functions as an independently addressable memory element with a potential for integration at the 1012/cm2 level.
In a completely different area, we have shown that nanowires can serve as nearly universal electrically based detectors of chemical and biological species with the potential to impact research in biology, medical diagnostics and chem/bio-warfare detection. Lastly, and to further highlight this potential, we have shown that nanoscale light-emitting diode arrays with colors spanning the ultraviolet to near-infrared region of the electromagnetic spectrum can be directly assembled from emissive electron-doped binary and ternary semiconductor nanowires crossed with non-emissive hole-doped silicon nanowires. These nanoscale light-emitting diodes can excite emissive molecules for sensing or might be used as single photon sources in quantum communications.
The bottom line – focusing on the diverse science at the nanoscale will provide the basis for enabling truly unique technologies in the future.
Charles M. Lieber moved to Harvard University in 1991 as a professor of Chemistry and now holds a joint appointment in the Department of Chemistry and Chemical Biology, where he holds the Mark Hyman Chair of Chemistry, and the Division of Engineering and Applied Sciences. He is the principal inventor on more than 15 patents and recently founded a nanotechnology company, NanoSys, Inc.
Researchers are making significant advances in nanotechnology which someday may help to revolutionize medical science for everything from testing new drugs to cellular repair.
When it comes to understanding biology, Professor Carl A. Batt believes that size matters – especially at the Cornell University-based Nanobiotechnology Center that he codirects. Founded in January 2000 by virtue of its designation as a Science and Technology Center, and supported by the National Science Foundation, the center seeks to fuse advances in microchip technology with the study of living systems.
Batt, who is also professor of Food Science at Cornell, recently presented a gathering – entitled Nanotechnology: How Many Angels Can Dance on the Head of a Pin? – with a tiny glimpse into his expanding nano biotech world. The event was organized by The New York Academy of Sciences (the Academy). “A human hair is 100,000-nm wide, the average circuit on a Pentium chip is 180 nm, and a DNA molecule is 2 nm, or two billionths of a meter,” Batt told the audience.
“We’re not yet at the point where we can efficiently and intelligently manipulate single molecules,” he continued, “but that’s the goal. With advances in nanotechnology, we can build wires that are just a few atoms wide.
“Eventually, practical circuits will be made up of series of individual atoms strung together like beads and serving as switches and information storage devices.”
Speed and Resolution
There is a powerful rationale behind Batt’s claim that size is important to the understanding of biology. Nanoscale devices can acquire more information from a small sample with greater speed and at better resolution than their larger counterparts. Further, molecular interactions such as those that induce disease, sustain life and stimulate healing all occur on the nanometer scale, making them resistant to study via conventional biomedical techniques.
“Only devices built to interface on the nanometer scale can hope to probe the mysteries of biology at this level of detail,” Batt said. “Given the present state of the technology, there’s no limit to what we can build. The necessary fabrication skills are all there.”
Scientists like Batt and his colleagues at Cornell and the center’s other academic partners are proceeding into areas previously relegated to science fiction. While their work has a long way to go before there will be virus-sized devices capable of fighting disease and effecting repairs at the cellular level, progress is substantial. Tiny biodegradable sensors, already in development, will analyze pollution levels and measure environmental chemicals at multiple sample points over large distances. Soon, we’ll be able to peer directly into the world of nano-phenomena and understand as never before how proteins fold, how hormones interact with their receptors, and how differences between single nucleotides account for distinctions between individuals and species.
The trick – and the greatest challenge posed by an emerging field that is melding the physical and life sciences in unprecedented ways – is to adapt the “dry,” silicon-based technology of the integrated circuit to the “wet” environment of the living cell.
Bridging the Organic-Inorganic Divide
Nanobiotechnology’s first order of business is to go beyond inorganic materials and construct devices that are biocompatible. Batt names proteins, nucleic acids and other polymers as the appropriate building blocks of the new devices, which will rely on chemistries that bridge the organic and inorganic worlds.
In silicon-based fabrication, some materials that are common in biological systems – sodium, for example – are contaminants. That’s why nano-biotech fabrication must take place in unique facilities designed to accommodate a level of chemical complexity not encountered in the traditional integrated-circuit industry.
But for industry outsiders, the traditional technology is already complex enough. Anna Waldron, the Nanobiotechnology Center’s Director of Education, routinely conducts classes and workshops for schoolchildren, undergraduates and graduates to initiate them into the world of nanotechnology, encourage them to pursue careers in science, and foster science and technology literacy.
In a hands-on presentation originally designed for elementary-school children, Waldron gives the audience a taste – both literally and figuratively – of photolithography, a patterning technique that is the workhorse of the semiconductor industry. Instead of creating a network of wells and channels out of silicon, however, Waldron works her magic on a graham cracker, a chocolate bar and a marshmallow, manufacturing a mouthwatering “nanosmore” chip in a matter of minutes.
Graham crackers are substituted for silicon substrate, while chocolate provides the necessary primer for the surface. Marshmallows act as the photoresist, an organic polymer that, when exposed to light, radiation, or, in this case, a heat gun, can be patterned in the desired manner. Finally, a Teflon “mask” is placed on top of the marshmallow layer and a blast from the heat gun transfers the mask’s design to the marshmallow’s surface – a result that appeared to leave a lasting impression on the Academy audience as well.
What’s Next?
According to Batt, it won’t be too long before the impact of the nanobiotech revolution will be felt in the fields of diagnostics and biomedical research. “Progress in these areas will translate the vast information reservoir of genomics into vital insights that illuminate the relationship between structure and function,” he said.
Prof. Batt
Also down the road, ATP-fueled molecular motors may drive a whole series of ultrasmall, robotic medical devices. A “lab-on-a-chip” will test new drugs, and a “smart pharmacist” will roam the body to detect abnormal chemical signals, calculate drug dosage and dispense medication to molecular targets.
Thus far, however, there are no manmade devices that can correct genetic mutations by cutting and pasting DNA at the 2-nanometer scale. One of the greatest obstacles to their development, Batt said, doesn’t lie in building the devices, but in powering them. Once the right energy sources are identified and channeled, we’ll have a technology that speaks the language of genomics and proteomics, and decodes that language into narratives we can understand.
Microbiologist Carl A. Batt is professor of Food Science at Cornell University and co-director of the Nanobiotechnology Center, an NSF-supported Science and Technology Center. He also runs a laboratory that works in partnership with the Ludwig Institute for Cancer Research.
