* * * *
Indira and Tuekakas stood by the window in his office, admiring the view.
"You didn't mention bringing the Active SETI system on line,” Indira reminded him. “You had a good point about the possibility of avoiding a second strike with the right message."
"You're absolutely right,” Tuekakas admitted. “I'll need to bring it up soon. Let them digest the new situation a while."
"Don't wait too long. If the ... Achirdians? Vogons? If the aliens have another weapon ready, they may not wait long to launch after they see Sol did not nova. You know, some of the amateurs are already sending their own messages to the Achirdians."
"Nothing too sweet and charming, I assume.” Tuekakas raised an eyebrow. “Or detectable?"
"Not very, on all counts,” Indira replied. “So far, nobody is sending anything conforming to the Achirdian translation construct. And I doubt any of the signals are more than a three on the San Marino scale. But I wouldn't count on things staying that way for long."
Tuekakas nodded slowly, gazing into the distance. “That could work to our advantage ... incentive for an official message. What would we tell them? We could thank them for giving us the last secrets of the interstellar ramjet, with the promise we would use it against them if, but only if, we detected another launch against us."
"To say that, you need Gates's delegation to agree."
"Absolutely.” He considered the issue. “It might not hurt if we somehow suggested what Victor Gendeg concluded ... God provided us with the means for our defense."
"Touchy subject,” Indira noted. “A month ago I would have called that superstition. Now?"
"A month ago I might have agreed. This message will not be to mollify our population. This will be directed at the Achirdians. If we can plant the idea our God is stronger than their God, maybe they'll realize their God is false.” Tuekakas made a face. “Ehhh! I'm ashamed I said that. Dr. Sariskal is right. Politicians are the same everywhere."
"Maybe their religion is not the fault.” Indira turned and smiled gently. “The Christians always talk about their forgiving God. The Muslims say God is merciful. And I recall the Hindu tale of Lord Krishna, or maybe it was Shiva, who once cut off the head of an enemy, but then forgave him and gave him the head of a goat. In India, we would consider that an improvement, you know! I think their religion, or religions, very likely also value forgiveness."
"So, we tell them ... what? ‘God has taught us to forgive those who trespass against us. But He did not teach us to be stupid. Don't try that again.’”
Indira pondered. “Neighbors, you have made a very serious mistake. You failed, and in that failure taught us how to build a similar weapon. The Creator has taught us to be forgiving, and we will not retaliate unless we see that you have attacked us again. We wish for peace, but if you choose war we will respond with a fury that will assure your destruction."
"Wyakin, you could have been a diplomat.” Tuekakas thought for a moment and smiled, “I'll bet you never thought your first message to another race would be anything like this."
"Noooo, not at all what I had in mind, all these many years."
Tuekakas put his hands in his pockets and looked down. “We are going to do it. We are going to travel to the stars. Make new homes. Colonize new worlds. Just one thing still bothers me,” he said. “I hope I am not remembered as a new Columbus."n Copyright © 2009 Tom Ligon
In memory of Dr. Robert W. Bussard, August 11, 1928 to October 6, 2007.
The author would like to again thank Dr. H. Paul Shuch of The SETI League, for permission to use the name of the organization, and for great background details. Special thanks to William Gleason, Roy Gray, and Juliette Wade for their valuable advice, and the forum at analogsf.com for their input.
(EDITOR'S NOTE: This story is a sequel to “El Dorado” [October 2007].)
* * * *
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[Back to Table of Contents]
Science Fact: PRESERVING THE MEMORY by Janet Freeman
Alzheimer's disease is a fearsome problem, but sometimes problems can be solved by breaking them into smaller problems.
* * * *
Over five million Americans have it, including nearly half of those over age 85. Ten million Baby Boomers will develop it. It is now the sixth leading cause of death in the US. The worldwide societal cost is estimated at over $400 billion.
It is Alzheimer's disease (AD), a thief that destroys the brain and replaces the person you know with a stranger. AD usually affects people older than 65 (known as late-onset AD) although people have been diagnosed in their 40s and 50s. Patients initially display problems with memory. As the disease progresses, they struggle with communicating, learning, thinking, reasoning, and motor skills, and may exhibit behavior and personality changes. People with AD typically survive eight to ten years after diagnosis (some have lasted 20) and usually die from complications such as accidents, malnutrition, dehydration, and infection, often pneumonia.
There is no cure. Yet.
Billions of dollars have been spent trying to change that. For the past four years, the National Institute on Aging has spent about $644 million per year on AD and sponsored about 30 Alzheimer's Disease Research Centers at prestigious institutions. Other government agencies also provide funding. Private agencies such as the Alzheimer's Association have awarded hundreds of millions in international grants. Outside the US, major research efforts exist in Japan, the United Kingdom, and Europe.
Scientific consensus says AD is caused by a combination of genetic and environmental factors. Current AD research focuses on the following, in hopes of developing therapies that may delay, prevent, or even reverse AD:
* Understanding the role played by the protein plaques and tangles characteristic in the AD brain,
* Using imaging and other biomarkers for earlier diagnosis and tracking the disease process,
* Identifying AD-associated genes and what they do,
* Determining how other physiological processes relate to AD, and
* Developing treatments.
* * * *
Unraveling plaques and tangles
The loss of brain cells is one obvious characteristic of AD (see Figure 1). Examine brain tissue of a typical AD patient and you will find the other two: protein structures that Dr. Alois Alzheimer dubbed senile plaques and neurofibrillary tangle
s (see Figure 2).
* * * *
Figure 1: A normal brain (left) vs. advanced AD brain with severe loss of neurons. [Credit: Jannis Productions, Stacy Jannis.]
* * * *
"The $64,000 question is: what's the relation between those two pathologies?” asks Thomas Bird, MD, Professor of Medicine, Neurology, and Medical Genetics at the University of Washington. “How and why do you get both? Why is this occurring relatively simultaneously? What's the connection between them?"
Their presence makes them prime suspects in the murder of brain cells, but their guilt has not been proven. Researchers are investigating how they form, how they affect neurons and brain tissue, their role in AD (are they a cause, a symptom, or a byproduct?), and how to remove them or prevent them from occurring.
Neuritic plaques (as senile plaques are now called) are spherically shaped masses of beta-amyloid peptide (Ab), dotted with debris from dead neurons. Small amounts of other proteins are found in plaque as well. Ab is made in nerve cells from a larger protein called amyloid precursor protein (APP), which is found in the fatty membrane surrounding nerve cells. AD either causes brain cells to make too much Ab or not dissolve enough of it. The neurons excrete Ab into the area between cells where it forms clumps of plaque. One particular form, Ab42 (it has 42 amino acids) is very sticky stuff and abounds in plaque.
People who have Alzheimer's tend to have lower blood levels of soluble Ab in their cerebral spinal fluid blood than those who do not display dementia, suggesting that Ab somehow accumulates in the brain, although this mechanism has not been proven. The frustrating thing is that plaque can be found in the brains of people who never developed dementia, and some AD brains showed relatively little plaque formation. Numerous correlation studies failed to demonstrate a clear relationship between the severity of dementia and Ab in the human AD brain.
Working to understand the normal function of APP and Ab is essential to uncovering the mysteries of plaque. Some studies found APP is a key regulator of structure and function of neuromuscular synapses. A synapse is the interface at which one nerve cell transmits a signal and the adjacent cell receives it. Ab may also have a role in synaptic functioning. Both proteins are intense areas of research.
Beta-secretase and gamma-secretase are the two enzymes involved in snipping Ab from APP. Inhibiting their function is a focus for new plaque-fighting drugs.
* * * *
Figure 2: Neuritic plaques (cloudy masses between cells) and neurofibrillary tangles (deformed dark triangles) are characteristic in the AD brain. [Credit: Jannis Productions, Stacy Jannis.]
* * * *
Research in the past few years indicates that smaller particles of soluble Ab, rather than insoluble plaque, impair synaptic function. People with AD appear to have soluble Ab dimers (two Ab molecules bound together) and trimers (three Ab molecules) in their brains, while those without AD don't, even when they do have plaque. Ab dimers may mediate processes that affect dendritic spines. Dendrites are the branches off the main body of a nerve cell that connect the cell to other nerve cells. Dendritic spines are small protrusions from dendrites that form one-half of a synapse. One study found excessive levels of calcium in dendrites of mice with plaques. When a synapse fires its signal to the next nerve cell, calcium levels along the dendrite should vary, but in these calcium-laden nerve cells, it didn't. In a separate study, Ab dimers reduced the density of dendritic spines by 47%.
Another study found Ab dimers in the hippocampus disrupted nerve cell long-term potentiation, the mechanism that underlies memory and learning. An Ab antibody applied to the region bound the dimers and restored long-term potentiation. This suggests an immunological approach to fighting Ab might be successful.
Sixty percent of AD cases, as well as other dementing disorders such as Parkinson's disease, have brain plaques based on another protein, alpha-synuclein, which clumps together inside neurons to form Lewy bodies. Alpha-synuclein may enhance the release and toxicity of Ab and is another area of study.
Neurofibrillary tangles are made of tau, a microtubule-associated protein. Its regular job is to help stabilize the microtubules that form the neuron's flexible interior scaffolding, assist in establishing various microcompartments within the cell, and facilitate transport of molecules from one part of the cell to the next. In AD pairs of tau filaments bind together into helices. These pairs cling to each other and form what looks like a bundle of sticks, called tangles. In brain samples tangles appear as triangles, the insoluble gravestones of dead neurons. Most of the tau in tangles is hyperphosphorylated (lots of phosphate groups attached). The more tangles one has, the more demented one becomes.
Why does this happen to tau? The “amyloid cascade hypothesis” claims Ab induces tangles. One scenario suggests Ab causes inflammation that injures neurons and results in oxidative stress. This disrupts normal neuron metabolism and causes enzymes to hyperphosphorylate tau; the phosphate-laden tau forms tangles, which causes the neuron to malfunction; eventually the neuron dies.
However, tau tangles appear in more than a dozen forms of neurogenetic degenerative diseases without plaque (prominently in familial frontal lobe dementia and Pick's disease), so the cascade model isn't the whole story. Some studies show soluble tau peptides, rather than the large insoluble tangles, cause damage to the cell.
* * * *
Diagnosis and Disease Monitoring
People usually see a doctor about AD only when they start having significant memory problems. At that point doctors can diagnose AD correctly up to 90% of the time using a health history, mental status exam, physical exam, neurological exam, lab tests, and a brain scan. When other dementing conditions are ruled out, the diagnosis is Alzheimer's. The diagnosis can only be 100% certain by examining brain tissue and finding plaques and tangles—not something most people want done when they're still alive.
However, overwhelming evidence indicates brain changes start years or even decades before symptoms of mild cognitive impairment (MCI) appear. Having the means to identify more accurately those at risk for AD or in its very early stages might enable doctors to delay or prevent further damage, or even reverse damage that's been done. The hunt is on for AD biomarkers, ways to measure and evaluate objectively the Alzheimer's disease process.
Brain imaging helps us see inside the living AD brain and understand which of its regions are physically damaged or not functioning properly. Initially AD starts in the hippocampus, which is essential for retrieving short-term and spatial memories and for laying down most new memories. From there it spreads to the cerebral cortex, the wrinkled, specialized outer layer of the brain. Some cortices known to be affected include:
*The parietal lobe, which controls language comprehension and aspects of time and space comprehension;
*The temporal lobe, involved in problem solving, interpreting sensory input, and movement;
*The frontal lobe, the origin of insight, foresight, personality formation, and various executive functions; and
*The amygdala, involved in memory and emotion.
Two types of brain imaging provide gray-scale pictures of internal body brain structures. They can detect abnormalities like blood clots, fractures, tumors, infections, and cerebral atrophy. Computerized Axial Tomography (CT or CAT) shoots x-rays through the body to create its images. Magnetic Resonance Imaging (MRI) uses magnetism and radio waves to excite the hydrogen nuclei in the body's water molecules, then capture the radio waves those molecules emit. MRI is better suited than CT for imaging non-calcified tissue, and provides better contrast between different tissue types. MRI measurement of structural atrophy of the hippocampus and entorhinal cortex is a sensitive indicator of AD.
The other three types of brain imaging show brain function by recording the neuron's oxygen or sugar intake. Neurons don't have internal oxygen or glucose reserves for energy, so when they fire, they must immediately obtain more energy. Functional MRI (fMRI) provides a color picture indicating levels of oxygen used by the brain as
its owner performs a task, such as counting or reading aloud. fMRI works by measuring the magnetic change in hemoglobin when it becomes deoxygenated, thus indicating which areas of the brain are consuming the most oxygen and therefore are most active.
Positron Emission Tomography (PET) measures gamma rays emitted when positrons from the short-lived radioactive tracer (injected into the patient) annihilate nearby electrons. It produces 3D images whose colors reflect levels of tracer activity. The most common tracer, sugar fluorodeoxyglucose (FDG), shows where blood sugar is being consumed during a task. Other tracers can be used to image different molecular processes.
Single Photon Emission Computed Tomography (SPECT) measures gamma rays to produce a 3D color image, but uses a tracer that emits gamma radiation directly. While PET has higher resolution, SPECT is more widely available and less expensive. SPECT is about as accurate as clinical criteria for diagnosing AD, and is superior in differentiating AD from other dementias. Some SPECT tracers can reflect neurotransmitter activity.
An exciting development for AD revolves around a new PET tracer, Pittsburgh Compound-B (PiB). PiB appears to bind almost exclusively to Ab42 or Ab40 and vascular Ab deposits, permitting imaging of Ab plaque in living bodies.
Researchers are striving to find biomarkers like proteins and enzymes in blood or cerebrospinal fluid (CSF) samples. For example, lower-than-normal soluble Ab levels and higher-than-normal tau levels in CSF have been used to diagnose AD with a sensitivity of 92%. Some studies have shown highly elevated CSF levels of beta-secretase, the APP-snipping enzyme, is an excellent indicator as to whether someone with MCI will go on to develop AD.
The Alzheimer's Disease Neuroimaging Initiative (ADNI), announced in 2004, is striving to build a standardized set of AD imaging and biomarker techniques. The study tracks over 800 people—cognitively normal, MCI or AD—by recording biomarkers and cognitive abilities over time. ADNI data is freely accessible to researchers from their own computers. The study, which runs through 2010, is the most expensive the National Institutes of Health have ever funded. Efforts similar to ADNI now exist in Australia, Japan, Europe, and China. In addition to identifying sensitive methods for earlier detection of AD and providing a centralized biomarker database, ADNI results will hopefully simplify and speed the assessment and comparison of different research and therapy approaches.
Analog SFF, July-August 2009 Page 17