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Parkinsn Current Topics
News on the Parkinson's Front
The search for the elusive Parkinson's Family curesinclude not only "Classic Parkinson's", but theParkinson's Plus syndromes and Essential Tremor disabilities aswell.
Where would we be at this stage, if the NationalInstitutes of Health hadn't funded in part, Dr. JosephJankovich's studies on the etiology of Parkinson's families ofdisabilities or for that matter, the work of Dr. Jonahs Salk?
Dry research in the clinic or the laboratory, wheneconomic benefit to the profit makers is still unclear, isnecessary for break-throughs.
It has been a relatively short period of time sincethe discovery that levodopa therapy would alleviate the symptomsof the "Classic Parkinson's" patient, verifying thediagnosis, short of an autopsy.
Jankovich's latest work suggests that 30% of person'sdiagnosed with a familial essential tremor will eventuallydevelop Parkinson's. Previous works had estimated only about 10%probability.
Prior to 1968, when the link between levodopatreatment and "Classic Parkinson's" was discovered,those who had been subjectively diagnosed as having familialessential tremor by the family doctor or the neurologist, weremisdiagnosed, 30% of the time.
Today, neurologists and family doctors are stillmaking the same mistake, basing their diagnosis on familyrecollection of tremor in their ancestors, and the patient's lackof resources to get the expensive MRIs or CAT scans to rule outbrain stem anomalies.
Now days, it takes several thousands of dollars and ayear or more to finally arrive at the Parkinson's diagnosis,taking one step at a time in the treatment algorithm. We allreceive the death sentence from birth. Levodopa therapy gives the"Classic Parkinson's" patient a parole for a period oftime. The mis-diagnosis of familial essential tremor gives nosuch parole since the present day drugs used to treat ET areineffective in 60% of the patients. Essential tremor isdegenerative also. Logic would indicate earlier levodopa trialsin patients diagnosed with familial essential tremor who lackresources for further diagnostic testing.
In the United States, 30% of the population has noaccess to neurological medical care. It is only possible toreceive care for "life threatening" conditions. Thislack of access keeps the number of diagnosed Parkinson's patientsartificially low, thusly, keeping Parkinson's as one of the"step-children" at pie serving time.
The following was in the paper over the weekend.
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NIH budget Cuts.
The National Institutes of Health, which have enjoyedstrong bipartisan support, now face significant budget cuts forthe first time.
The health institutes calculate that their budget,$11.3 billion this year, could be cut 10 percent to 25 percentunder the Senate's fiscal plan. The agency is telling Congressthat such cuts would severely slow research on Alzheimer's,cancer, cystic fibrosis and other diseases.
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These cuts could mean shortening Dr. Carol Tanner'sTwins Study or the elimination of Dr. Shirley Bayer'sdevelopmental neurobiology studies if their grants are reduced.
Dr. Bayer's project is to use the weaver mutant mouseas an animal model of human Parkinson's disease. The same neuronsthat die in Parkinsonian patients also die in these animals. Sheis trying to find out more about the neurons that die byanalyzing their developmental history. Perhaps some of thesefindings may provide a dating transduction in a variety of celltypes.
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The following is an article on the discovery of agenetically altered mouse that help in the finding of a cure toAlzheimer's disease. It looks surprisingly similar to Dr. Bayer'swork.
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Scientists create mouse withAlzheimer's
Sally Lehrman OF THE EXAMINER STAFF
Thursday, Feb. 9, 1995
Bay Area scientists have created a mouse that exhibitsthe same brain abnormalities as humans with Alzheimer's, offeringan important new tool for understanding the disease anddeveloping a treatment. "This mouse is a real breakthrough .. . providing the first real hope we can progress towardmeaningful drugs," said John Groom, president and chiefexecutive of Athena Neurosciences, the South San Franciscocompany that led the collaborative project. Alzheimer's is one ofthe top killers of Americans, with at least 100,000 people dyingof the disease each year. The condition is marked by aprogressive loss of memory, dementia, and eventually death.Researchers have found it difficult to pinpoint the cause ofAlzheimer's, how the brain changes as it loses memory, and how togo about fixing it. The lack of an animal that developed anythinglike the disease has made it especially hard to study. Mice withrodent versions of cystic fibrosis, obesity and other conditionshave become valuable tools for scientists to learn about thesediseases and the ways drugs can interfere. Scientists have triedfor many years to engineer an Alzheimer's mouse through geneticmanipulation, but never have been able to achieve changes in thebrain that mimic the disease. In the Thursday issue of Naturemagazine, Athena, its partner Eli Lilly and Co. and theircollaborators describe a mouse that develops remarkably similarcharacteristics to humans with Alzheimer's. The animal developsplaque in its brain, abnormal nerve fibers that surround theplaque like a web, inflammatory cells and deterioration of theconnections between its nerve cells. The problems arise in twokey areas of the brain related to spatial memory and associativelearning. Later this year, the Athena scientists intend to testthe animals in a complicated maze and see whether they havememory difficulties just like humans. "I would be shocked ifthese animals weren't impaired," said Dr. Ivan Lieberburg,an author of the Nature report. Lieberburg said the mouse, whichdeveloped the brain changes after a single gene change, helpsprove the theory that amyloid plaque formation is the cause ofAlzheimer's. Now scientists can study its precise effects.
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The following is a recent newspaper story that putstogether the genetic science as we know it today with the plightof two boys.
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Boys' Illness Leads Medical Sleuth onGenetic Hunt
Charles Petit, Chronicle Science Writer
Nearly 20 years ago, two young boys with elfin facesand a baffling set of ailments were brought by their parents to aDenver hospital. Puzzled physicians asked a young researcher, Dr.Edward McCabe, to take a look. The boys were mentally retardedand small, and they had weak muscles. A few years earlier, countywelfare officials had taken the older boy away, suspecting childabuse because the tot suffered so many broken bones. The parentsgot him back when the foster family found his bones keptbreaking. Then the couple had a second boy with the sameproblems. McCabe, then being trained in children's metabolicdisorders, embarked on an odyssey of medical detective work andintimate involvement with the family. That fixation helped leadto an announcement last week by a team of Italian, American,German and British researchers of the final step in theatom-by-atom identification of the genetic errors found in thetwo youngsters. The scientific report in the journal Naturedescribes the gene for a disease called adrenal hypoplasiacongenita, one of at least three closely related geneticdisorders those Colorado boys had. This constellation of diseasesis so rare that the full description of the genes responsiblewill not, by itself, much alter the lives of many people. But thelong voyage of discovery illustrates the strides made by geneticscience in just two decades. Broadly, the results are part of theglobal effort called the Human Genome Project, which is aimed atunraveling the mysterious tapestry of human heredity. In thewings is not only the ability to detect and diagnose hundreds andperhaps thousands of inherited diseases, but also the knowledgeto prevent them or, through gene therapy, perhaps eventually curemany of them. In an interview last week, McCabe, now chief ofpediatrics at the University of California at Los Angeles Schoolof Medicine, described the chance encounter with the family inColorado and what followed. ``I was just called in to work up thecase,'' he said. ``They were honest, sort of unsophisticatedcountry people who lived up north of Denver. They were goodparents, but the kids were sick.'' Medical tests showed that bothboys had oddly high levels of glycerol in their blood. Glycerol,commonly used in hand lotions, should only exist in traces inhuman tissue. After eliminating such possible sources as glycerolsuppositories, McCabe concluded that a derangement in the boys'metabolism of fat was at work. With two brothers and reports fromthe family of an uncle who had died suddenly as a child inNebraska with similar problems, a genetic defect was clearly theculprit. ``But back then, we had practically no way to find thegene responsible and wouldn't know what to do about it even if wehad.'' Further study showed that the boys actually had threediseases. The first, previously unrecognized, was dubbed glycerolkinase deficiency. The second, the cause of the muscle weakness,closely resembled the well-known disease, Duchenne musculardystrophy. The third was discovered a short time later, after theolder boy suddenly died within a day of a minor operation on hiseyes. ``The parents insisted on an autopsy,'' McCabe said. ``Theyremembered the child abuse charges and did not want anybodythinking they had hurt their son.'' The autopsy revealed theboy's adrenal glands, atop his kidneys, to be small andmalformed. The glands provide many of the hormones, such asnatural steroids, that provide the body with the ability to copewith shock. McCabe ordered the surviving brother protected frommajor stress, and he was put on a regular dose of steroids tocompensate for his medical problems. Scientifically, thecoincidence of the three diseases in two brothers indicated thatthe boys had somehow inherited a defect that damaged threeneighboring genes. McCabe kept working on the ailment at BaylorCollege of Medicine in Texas. By the mid-1980s, it was clear thatthe three genes were on the X-chromosome, a long string of geneswhose roles include determination of sex characteristics. Hefound himself heading a group at Baylor competing with groups inGreat Britain to clone, or copy and fully map, the gene forglycerol kinase deficiency, and wound up in a three-way tie. Twoof the teams, including McCabe's, then set their sights on thethird of the linked defective genes, the one that stunts adrenalglands. That scientific rivalry turned to fruitful cooperation,thanks to the intervention of Giovanna Camerino, a geneticsresearcher at the University of Sassari in Italy. She calledMcCabe and his chief competitor, Anthony Monaco of John RadcliffeHospital in Oxford, to suggest that they cooperate with her groupand with a fourth team led by Thomas Meitinger in Munich,Germany, to define the molecular sequence of the remaining genefor the adrenal disorder. During the past two years, linkedlargely by fax and electronic computer mail, the four teamslaboriously put together the full sequence of molecules. Now, 18years after meeting the two sick little boys, McCabe knows indetail what was wrong with them. The damaged genes that causeDuchenne muscular dystrophy, glycerol kinase deficiency andadrenal hypoplasia lie next to one another on what geneticistslabel the short arm of the X-chromosome. Something had knockedout the middle gene in the two boys and damaged the two flankinggenes. Their mother had a 50-50 chance of passing the disease toany son, and a 50-50 chance of passing the defective genes to anydaughters who, while well, could pass it on to their sons. Theresearch has produced tests to detect the defects in developingfetuses, allowing girls and women in affected families to be toldwhether they carry the gene. Knowledge of the genes' structuresshould lead to better therapies that could block some of thesigns of the disease. The third gene discovered, for adrenalhypoplasia, also may be involved in a host of other criticalfunctions, including proper brain development. So far, McCabe hasdiagnosed about 50 boys with the same group of ailments. Whileretarded and vulnerable to many diseases, they are affectionateand active. He also has kept in close touch with the family inColorado and the surviving son. While extremely retarded, he is acheerful young man and has finished special education classes.``We talk in medicine about taking information from the bench(laboratory) to bedside and back,'' McCabe said. ``In this case,we have done it.''
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In light of recent lobbying on behalf of increasedfunding for Parkinson's research, the following story seems toindicate that NIH is positioning itself into the profit streamwhich may indicate a shift away from research on less profitablediseases.
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Broad Gene Therapy Patent
Washington
The government has won a broad patent on the first wayto perform human gene therapy, a method that covers 60 percent ofthe genetic experiments approved in the United States. Thepatent, awarded yesterday to the National Institutes of Health,covers any method of genetically altering human cells outside thebody and then inserting those cells back into a patient to fightdisease. That process is called ex vivo gene therapy. The NIH haslicensed the patent exclusively to Genetic Therapy Inc., aMaryland research company that collaborates with NIH. GTI willuse the patent rights to develop, and license other companies todevelop, products necessary to move gene therapy from thelaboratory to doctors' offices. ``I'm thrilled,'' said genetherapy pioneer Dr. W. French Anderson, the patent's maininventor. ``It comes at a very timely point -- investments inbiotech and gene therapy are at rock bottom. This is a shot inthe arm to get some money back out of sporting goods andfast-food establishments and back into biotech.'' Numerous genesthemselves have been patented by their discoverers, and theUniversity of Michigan has patented a specific treatment forcystic fibrosis where genetic changes are wrought inside thelungs, a process called in vivo gene therapy, Anderson explained.But yesterday's patent is the broadest yet, classified as a``pioneering'' patent because the experiment on which it wasbased proved for the first time that gene therapy could work. Itcovers any future gene therapy done outside the body.
DAY: WEDNESDAY DATE: 3/22/95-------------------------------------------------------------------------
Perhaps this story on BioTech will further enlighten.
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Biotech: Teaming up to survive andthrive
Ralph T. King Jr. Monday, April 24, 1995
TO WALL STREET, most of the biotechnology industry isabatch of long-shot, underfinanced wannabe drug makers --and itis no place to put your hard- earned money. Yet bigpharmaceutical companies are lining up to pour money into thebiotechs. Do they know something the Street doesn't? Drugcompanies, of course, have long kept a close eye on what thebiotechs are doing, investing in a few that seemed particularlypromising. But lately their interest has turned red hot. Dealsbetween pharmaceutical giants and biotech firms more than doubledin value last year and numbered nearly 200. Drug companies,especially European ones, are combing for prospects and promotingtheir partnership appeal with an ardor that astounds biotechexecutives, who are used to having to fight for every dollar offunding. Chiron Corp. of Emeryville (Top 100 No. 74) was sweptoff its feet in November when Switzerland's Ciba-Geigy AG boughta half interest for $2.1 billion, a 96 percent premium over thestock price. In January, Affymax NV of Palo Alto found four eagerbidders for its novel yet unproven drug- discovery technology.The company, for which earnings are still a fond dream, solditself to Glaxo PLC for more than half a billion dollars.
Research revolution
What is happening is that the drug industry is rushingto join the DNA generation. Gene-based analysis andcomputerization are transforming biological research. Sometime-honored techniques for creating drugs are rapidly becomingobsolete, and an array of new methods indispensable. Among themare automated methods to make and screen millions of drugcandidates in the time it takes a chemist using old-schoolmethods to process a handful. These are the kind of skills a drugcompany can gain access to fast by sinking a chunk of money intoa struggling biotech. Meanwhile, the world is awash in high-techbiotech shops with great ideas but questionable ability to bringthem to fruition. Buying such little companies outright risksdousing their entrepreneurial fire. But forming an alliance,usually involving fees based on progress toward goals, enablesthe pharmaceutical giants to convert some fixed research costs tovariable ones and diversify risk. The result is that the drug andbiotech industries, competitors a few years ago, increasinglylook like natural partners. "This is a strategicredefinition of the pharmaceutical industry," says SteliosPapadopoulos, a managing director at Paine Webber Inc."They're walking away from early- stage, in-house researchand relying heavily on small biotech companies." Jean-PierreGarnet, chairman of Smith Kline Beecham PLC's drug division,says, "Nobody wants to be left behind." Nobody exceptWall Street. The bear market in biotech stocks drags on.
Wall Street remains wary
Many stock investors, burned by failed promises andcapital losses, refuse to get sucked in. In a stock group thathas seen steep spikes two or three times during the past decade,some analysts claim to see a familiar pattern of hype asinvestment bankers promote mergers in the group.But in a way,Wall Street and the drug industry may both be right. Someanalysts suggest that issuing public equity may be a poor way tofinance ventures as speculative as biotech companies; of the 240that are public, at least half have only enough cash to continuefor 18 months, according to Recombinant Capital, a San Franciscoconsulting firm. These classic biotech shops that bet everythingon a few molecules make drug giants wary, too. It is the biotechswith broadly enabling technology, rather than a few intriguingcompounds, that are the hot tickets. And some don't even chafe atthe idea of losing their independence. Alejandro Zaffaroni,founder of Affymax, says, "My goal from the very beginningwas to transform our company into a lead discovery center for bigpharma." Affymax is an example of a biotech offering an"arrow" technology -- often contrasted with those thathave "target" technologies. An arrow technology mightoffer ways to guide drugs to a given site within the body, orways to concoct and test a vast number of drug recipes. WhatGlaxo got by buying Affymax was access to a disposable microchip,crammed with a million fragments of DNA, that acts like acomputerized test tube. When partial DNA extracted from blood issquirted on the chip, it attaches to the one spot in a millionthat is its chemical complement; there it emits a light, which isscanned by laser and processed by computer. The chip can revealin minutes how an experimental drug might interact with, say, thegene that causes cystic fibrosis, or tell whether a patient is acarrier of that gene. The so-called target companies go afterbody sites involved in disease, providing methods to pinpointmolecular locations at which a drug could intervene. Human GenomeSciences compiles inventories of new sites and clues to theirfunctions. Onyx Pharmaceuticals Inc. of Richmond, having foundtargets along cancer's metabolic pathway, penned a $75 millioncollaboration with Bayer AG in May 1994. The deal is similar tomost such pharmaceutical-biotech alliances, in which the biotechpartner contributes a proprietary technology or drug candidate inexchange for upfront or equity payments and research funding,plus milestone payments based on key results in the clinic.Royalties or profit sharing loom on the back end. Drug companyinterest runs deep The depth of drug-company interest intechnology purveyors is evident at biotech gatherings, whichinvariably swarm with pharmaceutical executives orrepresentatives. In January, Hambrecht & Quist's annualhealth care conference in San Francisco drew 165 of them, up 30percent from the year before. Bayer is a good example. The Germanaspirin maker's research chief flew in to meet with a group ofstart-up company scientists in February at a Lake Tahoe retreatattended by seven of his counterparts at other drug firms. Bayerhas its biotechnology center in Berkeley, where it is building a$100 million manufacturing plant and has 20 specialists devotedto scouting out potential partners. Last year it signed up two,and this year it expects to recruit up to half a dozen others.Its $70 million deal with Arris Pharmaceutical Corp. of South SanFrancisco involves a technique for attacking inflammation suchasasthma, allowing Bayer to drop similar work internally. Fivedrug giants besides Bayer, all European, have taken front-rowseats in the San Francisco area, the largest concentration ofbiotech firms. One advantage European firms have is that many areclosely held and don't face the kind of short-term earningspressure American rivals do. The chance to cherry-pick promisingbut cash-poor biotech firms lures even some biotech companies --the big ones. Genentech Inc. (Top 100 No. 57) is pouring moneyinto Scios Nova Inc. of Mountain View for a shot at half theprofits from a kidney-failure treatment, and AmgenInc. snapped upa bunch of drug leads by buying Synergen Inc. Any big drugcompany can offer some of the things most biotechs lack, such asthe ability to shepherd drugs through clinical trials, deviselarge-scale production processes and market worldwide.
The ultimate bait
Of course, money is the ultimate bait. Drug companiesspend about $4 billion a year on basic research, 20 percent of itfor external projects in either the biotech sector or academia.That portion will double in five years, predicts Viren Mehta, ananalyst with Mehta & Isalyin New York. With all thisdrug-company money flowing into the biotechs -- and occasionallya takeover popping at a fat premium -- why shouldn't stockinvestors go along for the ride? Unfortunately, the drug firms'interest hasn't really made it easier to decide what aspeculative, development-stage biotech should sell for. DeniseGilbert, Affymax's chief financial officer, says she tried invain to value technology-based companies during her previouscareer as a biotech analyst. The $539 million price Glaxo paidwas based not on any earnings projection but on the estimatedcost of duplicating Affymax's skills.
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All of this preoccupation with profits, pre-emptingyour competitors by patenting genes has caused opposition.Parkinsonians, look at both sides and the grey areas of theirarguments. Is the controversy, GREED vs Right? What ever side hasthe most money vs the loudest voice will prevail and in the end,our medications will either increase or decrease in number andeither way, they will cost more.
Here is the other viewpoint, from the paper again.
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80 Church Groups Ask Banon Gene Patents /They decry `marketing human life'
Louis Freedberg, Chronicle Washington BureauWashington
Opening a far-reaching debate that pits scienceagainst religion, leaders from every major religious denominationin the United States called yesterday for imposing an immediatemoratorium on patents for human genes and genetically engineeredanimals. ``Marketing human life is a form of genetic slavery,''said Richard Land, executive director of the Christian LifeCommission of the Southern Baptist Convention. ``Instead of wholepersons being marched in shackles to the market block, humancell- lines and gene sequences are labeled, patented and sold tothe highest bidders.'' Land, along with representatives of 80denominations that are often at odds with each other on suchcontroversial issues as school prayer and abortion, called onCongress to hold hearings on the matter and to revise the lawthat leaves it up to the U.S. Office of Patents and Technology tolicense gene-related products. Representatives of thebiotechnology industry, however, said a moratorium would halt thedevelopment of life-saving drugs. Without the incentive of patentrights, they said, companies would be reluctant to invest thetens of millions of dollars needed to bring drugs to themarketplace, often to benefit patients with such life-threateningdiseases as AIDS, cancer and diabetes. ``This would be absolutelyterrible for our industry,'' said Kirk Robb, president ofGenentech in South San Francisco. ``Some small companies would goout of business. Others would drastically reduce what they aredoing.'' Genentech, one of the two largest biotechnologycompanies in the nation, has developed gene-related products likehuman insulin; Factor 8, used for treating children withhemophilia; and TPA, known as a ``clot buster'' to stop heartattacks. Genentech now has close to 1,000 patents, not all ofwhich are gene related. Industry representatives say thereligious leaders misunderstand what gene patenting is all about.They insist that owning a patent, which grants exclusive rightsto market a genetic invention for 17 years, does not mean that acompany owns the gene. ``A patent on a gene does not conferownership of that gene to the patent holder,'' said CarlFeldbaum, president of the Biotechnology Industry Organization.``It only provides temporary legal protections against attemptsby other parties to commercialize the patent holder's discoveryor invention.'' He said that virtually all biotechnology firmsare small, have no products on the market and need to raise fundsfrom investors to conduct research that leads to new drugs.Without the incentive of patent protection, raising the necessaryventure capital would be nearly impossible. Jeremy Rifkin,president of the Foundation on Economic Trends in Washington, themain organizer of the statement signed by religious leaders,declared that argument to be ``nonsense.'' ``There are thousandsof successful product on the market, including drugs, medicalprocedures and farm products which are not protected bypatents,'' he said. After the Supreme Court ruled in 1980 thatExxon Corp. was entitled to patent a genetic product used totreat oil spills, the U.S. Patent and Trademark Office hasroutinely awarded patents on human genes. Yesterday, the officeissued a statement saying that it simply follows the law inissuing patents, citing the high court ruling that patent lawsprovide protection for ``literally anything under the sun knownto mankind'' involving human intervention. ``The Patent andTrademark Office does not have the authority to deny a patent onany subject matter that the patent laws and the federal courtsdeem to be patentable,'' the statement read. Those statementsavoided what to many is at the root of a discussion about thenature of life. ``This issue is going to dwarf the pro-lifedebate within a few years,'' said Land. ``I think we are on thethreshold of mind-bending debates about the nature of human lifeand animal life. We see altering new life forms as a revoltagainst God's sovereignty and the attempt by humankind to usurpGod and be God.'' But Susanne Huttner, director of the Universityof California's Research and Education Program, said that aperson or an animal is made up of billions of cells organizedinto complex tissues and organs. ``An individual gene and theprotein it encodes are important but insufficient for `life'judged as a complex organism,'' she said. Outside the room wherethe religious leaders held their press conference, ahealthy-looking Paul Lieberman, 59, of Stratford, Conn.,dissented strongly with one of his own leaders, Rabbi DavidSaperstein, director of the Reform Action Center of ReformJudaism. Lieberman said that four years ago he began taking thegene-related drug Cladrabine when he was diagnosed as having aspecialized case of ``hairy cell'' leukemia. He said the drugworked. ``As a liberal Jew, I always felt that healing people wasmore important than ethics,'' said Lieberman, who was inWashington at the request of Orthobiotech, the drug'smanufacturer. ``If we follow the Talmud, to save one life is tosave the world.''
DAY: FRIDAY DATE: 5/19/95
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In closing, there have been two stories worth addingto this long collage. One involves finding a gene that turns onother cells, which may be useful in regenerating neurons. Theother is the discovery of the gene which determines the sex ofchild.
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Gene found that keysnervous system growth
Warren King Tuesday, May 16, 1995
SEATTLE -- Scientists have discovered a gene that iskey to the development of the nervous system, a finding thateventually could lead to treatments for diseases such asAlzheimer's and Parkinson's. The gene, named "NeuroD,"helps switch on other genes to form some of the cells most basicto life. If it is as important as researchers suspect, it couldsomeday be used to replace nerve cells damaged by devastatingneurological diseases. "Many pieces have yet to be puttogether to understand the pathway (of development)," saidLauren Snider, a member of a research team at Fred HutchinsonCancer Research Center in Seattle. "We have to know more ofthat story." Snider said the research, conducted mostly onfrog embryos, found that the NeuroD gene was involved in the veryearliest stages of life, when cells are differentiating to formthe basic body systems. Genes provide a sort of blueprint for themaking of these basic proteins and cells.
05/16/95 17:50 PST
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Scientists Find How BoysWill Be Boys / A genetic switch governs gender of an embryo
Washington
Researchers have isolated a genetic switch thatseparates the boys from the girls. It turns off the female in thehuman embryo and starts biological changes that eventually puthair on the chest. Dr. Michael Weiss of the University of Chicagosaid the new study advances the understanding of the complexcascade that determines whether people are male or female andsheds new light on how this process can sometimes go awry. Intheir research, to be published today in the journal Science,Weiss and his team used sophisticated imaging techniques toexplore on an atomic level the biological pathway to manhood.Their research report traces the development of maleness, fromthe turning on of the SRY gene, which is on the Y chromosome, tothe work of another gene, called MIS, that removes the femaleparts of the original embryo. Weiss said science has long knownthat everybody at conception is female, but the precisebiological mechanism that changes an embryo to male is stillincompletely understood. Solving the puzzle on the molecularlevel may answer questions about other basic cellular changes,such as the development of cancer. ``If we can understand thegeneral switches involved in sex determination, then we couldpossibly relate that to other basic processes, such as how organsdifferentiate or how cancer arises,'' he said. For the firstweeks after conception, all mammal embryos start forming thebasic female structures -- uterus, fallopian tubes and vagina.``The embryo destined to become a boy begins as a female,'' Weisssaid in an interview. ``It lays down first female structures andnot male structures at a phase when the embryo looks like arecognizable mammal, with toes, fingers and eyes and a heart.This is 35 to 40 days into human gestation.'' After that, hesaid, a gene called SRY switches on to start the embryo on itsway toward manhood. The new study shows that SRY also triggersthe work of another gene, called MIS, that dissolves the femaleparts of the original embryo. ``SRY is the master switch,'' saidWeiss. ``For the first time we have shown that SRY can activate amale specific pattern of gene expression leading to activation ofMIS, which is the key signaling molecule for half of the malepathway.'' Sex determination in mammals originates with thechromosome of the sperm that fertilizes the egg. Male sperm cancarry one of two chromosomes, X or Y. The Y chromosome is themale element that carries the SRY gene. The female egg has an Xchromosome. If the egg is fertilized with the father's Xchromosome, then the embryo continues its development as afemale. But if the egg is fertilized with Y, then the SRY genesets off a series of changes that eventually creates a male.``The XY embryo (containing the X chromosome from the mother'segg and the Y chromosome from the father's sperm) has twocritical tasks to accomplish,'' said Weiss. ``The first is tobuild male organs. The second is to cause the female structuresto go away.''
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