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Absinthe

Evidence of the pale-green liqueur’s toxicity eventually extinguished the fin-de-siècle infatuation with absinthe. The drink’s history began, however, long before the 19th century

Vincent van Gogh shot himself on the afternoon of July 27, 1890, in Auvers-sur-Oise, France; he died in the early morning two days later. Paul F. Gachet, the doctor who attended van Gogh during the last two months of his life, planted a thuja tree on the artist’s grave. The gesture was probably inspired by van Gogh’s admiration of thuja trees and his inclusion of their flamelike images in some of his Auvers paintings.

Gachet’s choice of a grave ornament was unwittingly pathetic. The thuja tree is a classical source of the chemical thujone, a constituent and indeed the toxic principle of the alcoholic drink known as absinthe. There is good evidence to indicate that van Gogh was addicted to absinthe, that his psychosis was exacerbated by thujone and that his fits with hallucinations contributed to his suicide.

In his fondness for absinthe van Gogh was by no means alone. The drink was enormously popular in the late 19th century, particularly in France. French soldiers fighting in the Algerian conflicts of the 1840’s had spiked their wine with wormwood extract (ostensibly to ward off fevers), and on their return to France their acquired taste was satisfied by absinthe, which contained a variety of essential oils including that of wormwood. Absinthe’s popularity with the soldiers spread among their compatriots from all walks of life; some of the most creative people of the time were its devotees. Absinthe was said to evoke new views, different experiences and unique feelings.

It could also wrack the drinkers’ brains. The disease known as absinthism was recognized in the 1850’s; its victims evinced a dazed condition) and intellectual enfeeblement and experienced terrifying hallucinations. The symptoms and extent of the damage from excessive consumption of absinthe could not be attributed to alcohol alone. Other culpable chemicals came from the leaves and flowers used in the drink’s preparation. But manufacturers, governments and the public, enamored of profits, tax revenues and titillation, respectively, were slow to heed the warning signs. Absinthe was not banned until the 20th century.

There may have been a subtler reason for the reluctance to abandon this favorite spirit. Some of the plants that gave absinthe its distinctive taste were stock remedies from herbal lore; they had been exploited for thousands of years with results that were often meritorious, sometimes innocuous and rarely sinister. Even after the liqueur’s fall from grace, investigations of the chemistry and the physiological effects of its constituents, as well as those of related chemicals, contributed to medical practices and to the development of effective drugs.

Thujone occurs in a variety of plants, including tansy (Tanacetum vulgare) and sage (Salvia officinalis), as well as in all trees of the arborvitae group, of which the thuja (Thuja occidentalis), or white cedar, is one. It is also characteristic of most species of Artemisia, a genus within the Compositae, or daisy, family. Wormwood (Artemisia absinthium) and Roman wormwood (Artemisia pontica) were the main sources of the thujone in absinthe.

Wormwood (in French, absinthe; in German, Wermut) is an herb with a perennial root system from which arise branched, firm, leafy stems that are almost woody at the base and reach a height of two to three feet. Its flowers are tiny, greenish-yellow and globular, and its indented leaves have a silvery-gray sheen. The species was cultivated from the Middle Ages to the early part of the 20th century.

The earliest recorded use of wormwood comes from the Ebers Papyrus, copies of which date from 1550 B.C. but which include writings from 3550 B.C. To the Egyptians, wormwood, or a closely related species, had religious as well as medicinal significance. The “wormwood” that is mentioned seven times in the King James’ version of the Bible was probably not Artemisia absinthium, but Artemisia judaica. Pliny’s Historia Naturalis, written in the first century A.D., describes extracts of wormwood as being of great antiquity (even then!) and having longstanding utility against gastrointestinal worms (hence the name). Thujone does indeed stun roundworms, which are then expelled by normal peristaltic action of the intestine. 

Wormwood was fully described in Dioscorides’ De Materia Medica
, an influential book that was completed in about A.D. 65 and was considered the final authority in pharmacy for the next 1,500 years. Both Pliny and Dioscorides included several applications for wormwood in addition to its anthelmintic properties. Anointing arms and legs with the plant’s juice helped to repel gnats and fleas, and attaching leaves to stored garments protected them from moths. These “virtues” have been substantiated, but the authors go on to list others that have not.

Pliny also mentioned a wine known as absinthites that was fortified with extract of wormwood. From the first to the 15th century, however, the selection of wormwood, tansy and other plants as additives to foods and beverages was supposedly based on their characteristic taste rather than on their ability to intoxicate. With the development of steam distillation in the 16th century (described in the books Hieronymus Brunschwig published in 1500 and 1512), relatively innocuous decoctions were replaced by powerful essences derived from the same plants. In the 17th century, tansy became popular in a baked dish of the same name that was made with eggs and cream. Artemisia maritima was used to make purl, a fortified ale that was popular in 17th- and 18th­century Ireland and England. Purl is mentioned in The Merry Wives of Windsor, and wormwood is mentioned in three other Shakespearean plays.

The production of grain alcohol by distillation of fermented cereals heralded the invention of liqueurs, and toward the end of the 18th century the formulation of absinthe evolved in Switzerland. The recipe found its way to Henri-Louis Pernod, who in the early 1800’s opened a factory in Pontarlier, France. Several competitive companies were subsequently founded in France and Switzerland, and for the next 100 years absinthe production was a significant industry.

Rue is said to be the most bitter plant known, but wormwood is a close second. The bitterness is due to a compound called absinthin (C30H4006), the complex structure of which was not solved until the 1950’s. The bitterness threshold for pure absinthin is one part in 70,000: one ounce can be detected in 524 gallons of water.

To overcome the bitter taste of absinthe, it was customary to add a sweetener. The most genteel manner involved mounting a cube of sugar in a silver sieve (an absinthe spoon) that was placed across the top of a glass containing a small amount of absinthe. Cold water was then poured over the sugar cube into’ the glass. Dilution turned the clear green of the liqueur to a yellow opalescence. Men and women became enthralled with this ritual of presentation as well as with the appearance, taste and excitement of the liqueur.

The aesthetics of absinthe drinking may account in part for the aura that soon enveloped it. In the cheerful atmosphere of recovery that followed the Franco-Prussian War (1870-1871), l’heure verte (“the green hour”) became an established daily event; some Parisian clubs and cafes were dedicated to the liqueur. Images of absinthe are immortalized in paintings such as Edouard Manet’s The Absinthe Drinker (1859), Edgar Degas’ L’Absinthe (1876) and Henri de Toulouse-Lautrec’s pastel of van Gogh with a glass of absinthe, which was completed in 1887. The same year van Gogh himself did a still life with a glass of absinthe and a carafe.

The incisive graphic work of Honore Daumier addressed the subject with social commentaries such as the lithographs entitled “Beer-never ... it takes absinthe to revive a man” and “Absinthe ... the first glass ... the sixth glass,” which were published in Le Charivari in 1863. Absinthe Drinkers, an 1881 canvas by Jean-Francois Raffaelli, has subjects that are more mellow than depressed, and the two glasses are truly opalescent. Pablo Picasso created Absinthe Drinker in 1901 and The Poet Cornuty-Absinthe in 1903. Eleven years later he constructed six abstract glasses of metal and ceramic topped with absinthe spoons—one artist’s response to increasing legislative attempts to ban absinthe in France. 

Charles Baudelaire, poet and a close friend of Manet, included absinthe in his list of vices; he advised, “Be drunk, always,” but went on to say, some lines later, “With wine, with poetry, or with virtue, as you please,” which gives a more wholesome choice than is typically attributed to the author. Paul Verlaine often awaited inspiration over a glass and then wrote in tones rampant, coarse and sensual within the same verse. Arthur Rimbaud, whose brilliant poetic career was finished by the time he was 20, was in his cups for most of that brief time. The English poet Ernest Dowson punned on an aphrodisiacal rumor: “I understand that absinthe makes the tart grow fonder.” The enigmatic surrealist playwright Alfred Jarry insisted that rational intelligence was inferior to hallucinations and relied on absinthe to ensure a steady supply of the latter. In the bistros of the rue de Seine, Guillaume Apollinaire, poet and friend of Picasso and Gertrude Stein, came under the spell of both Jarry and the ever-present absinthe.

Notwithstanding the veneration of absinthe that pervaded this entire artistic epoch, one wonders how much the “doors of perception” (to borrow from Aldous L. Huxley’s 1954 essay) were opened for these creative people. The artists were not constantly intoxicated, and indeed, there is good evidence to indicate that those works regarded as outstanding were usually created in lucid moments. On the other hand, the novel experiences of relative sizes, shapes and colors perceived under the influence of absinthe could have been recalled later and incorporated in a new font, palette or composition.

Oil of wormwood and alcohol were the standard ingredients of absinthe. The flavor and color of the drink were augmented with extracts of various plants: anise, fennel, hyssop, melissa (lemon balm) and, to a lesser extent, angelica, dittany of Crete, juniper, nutmeg, star anise and veronica—to name but a few. Specifications varied with the region and the maker. The general procedure for making absinthe involved steeping the mixture of herbs in a strong alcohol solution and then distilling the alcohol together with volatile constituents. Absinthe was also made by adding individual essential oils to grain alcohol, a method more convenient for concoction on demand. George Saints bury, a fin-de­sieècle English literary critic and commentator on matters alcoholic, wrote that “almost every French chemist [pharmacist] in every small town had a liqueur of his own which was sovereign for digestion and other things.”

The high ethanol content was not the special health hazard of absinthe, because it was diluted with water; the concentration of alcohol in diluted absinthe was certainly no greater than that in drinks containing brandy, whiskey, gin or rum. The main function of the alcohol concentration was to keep the oil constituents in solution. The louche, or turbidity, resulting from dilution was caused by the terpenes in absinthe, which came out of solution when the alcohol concentration was lowered and formed a colloidal suspension. These terpenes included thujone, fenchone, pinocamphone and citral. Modern methods of analysis, employing gas chromatography coupled with mass spectrometry, have identified several additional terpenes and other chemicals in the essential oils that were incorporated into absinthe.

Some batches of absinthe contained questionable ingredients. Whereas the green coloration of properly prepared absinthe came from chlorophyll, there were reports of copper salts being added to inferior batches to improve the tint. On the bases of color and solubility the most likely adulterant was normal cupric acetate. Other reports pointed to occasional contamination with methanol and alcohols higher than ethanol, although the same could be said of other liqueurs. A report of antimony in some batches prompted a medical annotation in the Lancet in 1873 speculating, with better intentions than wisdom, that tartar emetic was also added in an attempt to make the drink less toxic. That salt, however, is only sparingly soluble in alcohol. A better candidate is antimony trichloride, which is poisonous. It is soluble in alcohol and produces a creamy precipitate on dilution with water and most likely was added to get a better louche effect. 

Such malpractices certainly added insult to injury for the absinthe consumer, but even the “best” of absinthe was toxic enough. Several of the early herbals warn against excess, but it is Johan Lindestolophe’s De Venenis (“On Poisons”), published in 1708, that states clearly for the first time that continued use of Artemisia absinthium will lead to “great injury of the nervous system.” The author and his commentator Christianus Stenzelius attested to the narcotic and debilitating effects of the herb from personal experience.

In 1859 Auguste Motet completed his thesis for the medical degree, “On Alcoholism and the Poisonous Effects Produced in Man by the Liqueur Absinthe.” The title was prophetic, but given the vehicle the report probably did not reach the audience it deserved. In 1864, however, one of the leading journals of the day published a short note in which Louis Marce of the Bicetre, the famous hospital in Paris, described experiments with dogs and rabbits given essence of absinthe. The treated animals had suffered convulsions, involuntary evacuations, abnormal respiration and foaming at the mouth. Marce juxtaposed these symptoms with those experienced by absinthe drinkers. He clearly understood the “double action” of absinthe intoxication: the separate effects caused by alcohol and thujone.

Marce’s student and collaborator, Valentin Magnan, carried those studies forward at the Saint Anne Asylum, focusing on the different effects engendered by absinthe as opposed to alcohol alone. Magnan and his colleagues observed that absinthe could cause hallucinations (both auditory and visual) in human beings, and they also induced them in experimental animals. For example, dogs given absinthe would posture toward a blank wall as if confronting imaginary foes. A single dose, albeit a fairly large one, caused convulsions mimicking those of epilepsy. Oil of wormwood elicited all the hallmarks of absinthism, and controlled experiments excused other essences within absinthe.

The 1865 edition of Dictionnaire de Medecine, by M. P. Emile Littre and Charles P. Robin, listed absinthism as a variety of alcoholism but emphasized that the special neurological effects were attributable to something other than alcohol. In 1868 Robert Amory, one of Magnan’s students, gave a summary on absinthism to the Boston Medical and Surgical Journal, which is now the New England Journal of Medicine. In 1874 Magnan reviewed his papers on the subject in the Lancet.

The scientific warnings eventually reached the popular press, but they were matched by denials from those with an economic interest in the liqueur. Men and women caught up in the industrial revolution enjoyed the release absinthe provided and strove to convince themselves that the risks were small. Consumer reaction at the turn of the century ranged from mild restraint in drinking the spirit to complete disdain for the medical allegations that had been leveled against it.

In the period from 1875 to 1913, the annual consumption of absinthe per French inhabitant increased 15-fold. France imbibed about 10.5 million gallons of absinthe in 1913. There were regional differences: in and around Aries, for example, the rate was four times the national average. Statistics showed significant positive correlations between per capita absinthe consumption by region and the incidences of neurological disorders, stillbirths and rejections of army conscripts because of psychoses. Heinous crimes were blamed on absinthe intoxication.

Several attempts at reducing consumption of absinthe by increasing taxation were to no avail, and so in 1912 the French government demanded that the concentrations of both alcohol and essential oils be lowered. Consumers merely modified the ratio of water to absinthe. The unregulated sale of essences and powders of wormwood under trade names and the availability of cheap (and possibly contaminated) alcohol routed the legislative exercise. A prohibition on both the sale and manufacture of absinthe in France was formalized in 1915, but there was some vacillation, and the ban was not reasonably enforced until some years later. Belgium, Switzerland, the U.S. and Italy took similar actions between 1905 and 1913. 

In 1901 Raoul Ponchon, bon vivant and commentator on all elements of Parisian life, wrote a poem called Absinthe and the Guinea Pig, after a report that the deputy chief of the municipal laboratory had injected an animal with 10 milliliters of absinthe to illustrate the mortal toxicity of the poet’s favorite drink. The “scientific” demonstration had been intended more for dramatic effect than for accurate simulation of the human habit, but the poet picked up on the concept of dosage and remarked that he would have to drink a liter of the beverage at a single sitting in order to match the guinea pig’s “binge.”

Although Ponchon’s skepticism became less organized as the poem progressed, his initial point is well taken. It is still not clear how much absinthe was too much. The human dose-response relation is difficult to assess from available data. The binge drinker experienced hallucinations from acute intoxication; the chronic imbiber suffered some irreversible brain damage to an extent dependent on the amount of absinthe and the frequency of consumption as well as the age, nutritional status and general health of the imbiber. Upset stomachs were common in habitual drinkers, particularly those whose diets were less than adequate.

The correct chemical structure of thujone was published in 1900 by the German chemist Friedrich W. Semmler, and by 1916 European and American scientists had documented its pharmacodynamics. The compound causes marked excitement of the autonomic nervous system, followed by unconsciousness and convulsions. The involuntary and violent muscular contractions are at first clonic (rapid and repeating with intervening relaxation) and then tonic (continuous and unremitting). The effects of thujone are practically identical with those of camphor. Camphor- and thujone-induced convulsions were studied as a model for epilepsy; a number of research papers describing these studies appeared in the neurology and psychiatry journals during the 1920’s and 1930’s.

Camphor was subsequently employed by Laszlo J. von Meduna and his colleagues at the National Hospital for Nervous and Mental Diseases in Budapest in convulsive therapy for certain cases of schizophrenia. Early difficulties in dosage regulation and the side effects of intramuscular camphor injections were avoided by substituting first intravenous pentylenetetrazole and then inhalation of hexaflurodiethyl ether. Although electroconvulsive therapy has replaced these chemical approaches, it is still remarkable to note that the beneficial effect of such therapies is brought about by the convulsion itself rather than by the compound administered or the flow of current. In this area thujone and camphor played positive roles in the evolution of an important medical practice.

From the first to the 18th century, Chinese scholars extolled the virtues of the qing-hao plant (Artemisia annua) in the treatment of malaria. The efficacy of decoctions of this species was reconfirmed in 1971, and the active principle was identified the next year: it is an unusual sesquiterpene lactone peroxide named qinghaosu. Derivatives of the compound that are more effective have since been synthesized; their utility against otherwise resistant strains of the malarial parasite is an exciting development. Malaria was common around the Mediterranean region in the 19th century, and for a time I wondered whether the French troops of the 1840’s might have arrived at a preventive medicine when they added wormwood to their daily wine. But it turns out that Artemisia absinthium does not contain enough qinghaosu to make it a significant source of the compound.

Artemisia species have been praised as sources of insect repellants, anthelmintics and antimalarials. Thujone and its chemical cousin camphor played roles in basic research on epilepsy and convulsive therapy that were judged positive and constructive. Absinthe tippling, on the other hand, was judged to be negative and destructive, and in retrospect, the interdiction was tardy but surely justified. Opinions to the contrary have beenexpressed in the past 20 years, but they seem to be based on romantic and wishful thinking. After the ban on absinthe a substitute containing no wormwood and additional anise was offered on the Continent; two of the proprietary names are Ricard and Pernod. 

PR
Stem cell therapy counters muscular dystrophy in mice: study
 
Stem cell cultures are held up in a US lab.  Scientists have ...
Stem cell cultures are held up in a US lab. Scientists have demonstrated that a combination of stem cell and gene therapy can be used to correct the devastating hereditary disease of muscular dystrophy, according to a new study published Wednesday.

Scientists have demonstrated that a combination of stem cell and gene therapy can be used to correct the devastating hereditary disease of muscular dystrophy, according to a new study published Wednesday.

Working with mice but using human cells, a team led by Yvan Torrente of the University of Milan, Italy showed that they could spark the most common form of the muscle-wasting disease, Duchenne muscular dystrophy (DMD), and then reverse it, offering hope to millions of sufferers world-wide.

They also showed that a DMD sufferer's own cells might be used for the therapy, reducing the possibility of rejection.

DMD is a hereditary affliction in which the gene which helps synthesize the key muscle protein dystrophin is mutated. Dystrophin is essential to preventing damage to the muscles as they are used, and so with the presence of the defective gene, its production is disturbed and the muscles deteriorate.

In their experiment, Torrente and his team obtained muscle stem cells, labelled CD133+, from human DMD patients. The cells were implanted into mice where they generated defective muscle tissue resembling that in the human DMD patients.

The researchers then took more muscle stem cells from the humans and repaired the damaged dystrophin gene in them, so that dystrophin production would be normalized.

Those cells were implanted in the same mice, and began producing healthy muscle tissue, helping the mice begin to recover from the induced DMD.

"These data demonstrate that genetically engineered blood or muscle-derived CD133+ cells represent a possible tool for future stem cell-based autograft applications in humans with DMD," Torrente said in a summary of the research.

"Additional research will substantially enhance our understanding of the mechanisms underlying this effect, and may lead to the improvement of gene and cell therapy strategies for DMD," he added.

The research is published in the December issue of the journal Cell Stem Cell.

Mysterious Mud Waves Found on Arctic Seafloor 

Along parts of the Arctic Ocean floor, currents have driven mud into huge piles, with some "mud waves" nearly 100 feet across.

Around the world, strong currents can produce these features, piling up sediments from the ocean floor to create a wavy surface, but researchers had thought the Arctic was too calm to produce the mud waves.

The Arctic mud waves were discovered on recent expeditions to map the ocean bottom with sonar, which can view layers of sediment up to 1,000 feet below ground.

The expeditions were looking mainly for signs of the ancient ice sheets that once covered the Arctic and found evidence of massive scrapes in the ocean bottom about half a mile (1 kilometer) deep. Sonar images clearly showed these grooves running in parallel, plus boulders and other debris were revealed, left by the giant ice sheets.

In the continental shelf north of Greenland, sonar found deep scours that were undoubtedly left by ancient ice, the scientists said.

"It shows very, very clearly iceberg scours," said expedition scientist Martin Jakobsson of Stockholm University in Sweden.

The mud waves, however, were an unexpected surprise. The scientists aren't sure what formed them.

"The mud waves could be caused by tidal fluctuations," said expedition scientist Leonard Polyak of Ohio State University. "But that’s really just speculation at this point." 

Not So Tall Tale: Why Pygmies Evolved to Be Shorter

Their smaller-than-average size may be tied to maximizing reproduction 

pygmy 
SHORT ON STATURE (AND LIFE): The Aeta and other pygmies have the highest mortality rates among all human populations; their small body size evolved as a life history consequence of early death.

Pygmies, the most well-known group of diminutive humans, whose men on average grow to a maximum of five feet tall and their women about a half foot shorter, were thought to be endowed with their characteristic small body sizes due to poor nutrition and environmental conditions.

But the theories did not hold up, given that these populations—primarily hunter–gatherers—are found mostly in Africa but also in Southeast Asia and central South America, and thereby are exposed to varying climates and diets. Further, other populations who live under conditions of low sustenance, such as Kenya's Masai tribes, are among the world's tallest people.

So what could account for these pockets of people who grow so small?

According to University of Cambridge researchers, the key is the pygmies' life expectancy. "After going to the Philippines and interviewing the pygmies, I noticed this very distinctive feature of the population: very high mortality rates," says Andrea Migliano, a research fellow at Cambridge's Leverhulme Center for Human Evolutionary Studies and co-author of a new study published in Proceedings of the National Academy of Sciences USA. "Then, going back to life history theory, we noticed that their small body size was really linked to high mortality."

Migliano and her colleagues began their study by comparing the growth rates of two Filipino pygmy groups (the Aeta and the Batak) with data from African pygmies as well as from East African pastoralist (livestock-raising) tribes like the Masai and the lower echelon of the U.S. growth distribution (in essence, malnourished Americans). All these groups have low nutritional status but reach significantly different average height levels. The U.S. population showed the greatest growth rate, whereas both the pygmies and African pastoralists lagged behind. Although the pygmies plateaued around 13 years of age, the pastoralists kept growing, reaching their cessation point into their early twenties. Because the pygmy growth rate approximated the taller pastoralists, but had an earlier end point, the researchers concluded that their growth was not nutritionally stunted.

The group next examined the incredibly low life expectancy of different pygmy populations, ranging from roughly 16 to 24 years of age. (Pastoralists and other hunter–gatherer populations experience expectancies that are nearly one to two decades longer—a number that is still low, especially when compared with the 75- to 80-year life span expected of Americans.) Pygmies also reach their age of last reproduction a few years earlier than their taller counterparts, although there are many more pastoralist women than pygmies who reach this age at all.

Looking at fertility curves, the researchers noted Aeta appeared to reproduce on average when they were around 15 or 16 years old, which is about three years earlier than other hunter–gatherers. The tallest of these populations actually appeared to reproduce the latest. By having an early onset of reproductive abilities, the scientists say, the pygmies appear to trade off time spent growing, allowing them to continue on in the face of low life expectancy.

"Although the challenges posed by thermoregulation, locomotion in dense forests, exposure to tropical diseases, and poor nutrition do not account for the characteristics of all pygmy populations," the authors wrote, "they may jointly or partially contribute to the similarly high mortality rates in unrelated pygmy populations."

This research centered around women, but Migliano expects an analysis of males to mirror that of females, partly because the fertility of one would affect the other. Further, life history theory is anchored to the female because of the importance of reproduction as a variable. She adds that this paradigm could be used to help better understand the evolution of Homo floresiensis, the so-called "hobbit" found on the Indonesian island Flores in 2003.

"I think there is a great potential to use the theory to understand changes in body size during hominid evolution, such as the size of the hobbits and the relatively larger size of erectus," Migliano says. "But my main objective is to apply the theory to the understanding of the current human diversity."

Researcher: Cause and Treatment for Parkinson's "In Our Sights"

Scientists optimistic after discovering genetic link to loss of dopamine-producing neurons 

neuron 
NEED FOXA2 TO LIVE: Scientists find that insufficient copies of the gene FOXA2 cause dopamine neurons, which die off during Parkinson's disease, to spontaneously degenerate.

A successful treatment for Parkinson's disease, a neurodegenerative disorder that affects 1 percent of the world's population and (an estimated 500,000 people in the U.S.) aged 60 years and over, may be "in our sights now," says Ronald McKay, a researcher at the National Institutes of Health (NIH).

McKay's optimism stems from new research that shows that a gene, known as forkhead box A2 (FOXA2), is responsible for the differentiation and spontaneous destruction of neurons that secrete the neurotransmitter dopamine, a cell population that is progressively lost in Parkinson's disease, which is characterized by tremors, loss of muscle control and speech difficulties.

"We have the cells; we know what controls their birth and death—we're on our way," says McKay, a senior molecular biology investigator. "It looks like we've got this disease in our sights now. We will understand Parkinson's disease relatively soon."

McKay and colleagues (at the NIH's National Institute of Neurological Disorders and Stroke in Bethesda, Md., and at Northwestern University's Feinberg School of Medicine in Chicago) report in the journal PLoS Biology that they tested candidate cells in the brain of embryonic mice to determine which ones produce the enzyme tyrosine hydroxylase, a compound manufactured by dopamine neurons to help convert amino acids into precursors of the neurotransmitter.

The team found that such cells are created at the floor plate, a tubular cluster of cells located near the spinal cord, which organizes the developing brain by signaling immature, precursor cells to differentiate into neurons that play a particular role.

"The floor plate gives rise directly to dopamine neurons; it isn't just an organizer, but it's also itself a precursor cell," McKay says.

While examining the floor plate to determine when new dopamine neurons are created (and thereby when tyrosine hydroxylase signals can be detected), researchers also discovered high levels of FOXA2, the transcription factor coded by the FOXA2 gene.

"If you increase the expression [effect] of FOXA2, you get more dopamine neurons in the lab," McKay says, noting that when they upped the amount of FOXA2 in a tissue culture it triggered the creation of six times as many dopamine-producing nerve cells as normally present.

In addition, researchers observed spontaneous degeneration of dopaminergic neurons in the substantia nigra (a midbrain region associated with both pleasure and movement) in transgenic mice created without the usual two copies of the FOXA2 gene. (Animals normally receive a copy of the gene from each parent.) Substantia nigra nerve cells send dopamine to the striatum, another midbrain structure, which regulates the planning of movement. The erosion of these cells began after the mice turned 18 months old, which is akin to the age at which Parkinson's most often strikes humans.

Just as in humans, the loss of cells was unequal in the two brain spheres, resulting in asymmetric motor difficulties, such as stiffness on the right side but not the left.

"In the case of Parkinson's, although we know 10 genes involved in the disease, we don't have a good experimental model that is like the cell loss that you see in Parkinson patients," McKay says. "In these animals we do see this, we see a spontaneous loss of the same dopaminergic neurons that are seen in Parkinson's disease."

Serge Przedborski, co-director of Columbia University's Center for Motor Neuron Biology and Disease, praised the findings but noted that the new model was more useful in some circumstances than in others, An expert in Parkinson's mouse models induced by a toxin known as MPTP—which causes Parkinsonian symptoms when injected into animals—he believes the new model will be more useful in studying plasticity (the strengthening and weakening of neuronal connections) in a neurodegenerative brain. If a researcher wants to study the mechanism of cell death, he adds, an MPTP model should suffice.

McKay says that combining the toxin and genetic models may be the best way to "generate a comprehensive understanding of the disease" The bottom line, he says: "I think there's reason to be optimistic here."

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