The search for the elusive Parkinson's Family cures include not only "Classic Parkinson's", but the Parkinson's Plus syndromes and Essential Tremor disabilities as well. Where would we be at this stage, if the National Institutes of Health hadn't funded in part, Dr. Joseph Jankovich's studies on the etiology of Parkinson's families of disabilities or for that matter, the work of Dr. Jonahs Salk? Dry research in the clinic or the laboratory, when economic benefit to the profit makers is still unclear, is necessary for break-throughs. It has been a relatively short period of time since the discovery that levodopa therapy would alleviate the symptoms of the "Classic Parkinson's" patient, verifying the diagnosis, short of an autopsy. Jankovich's latest work suggests that 30% of person's diagnosed with a familial essential tremor will eventually develop Parkinson's. Previous works had estimated only about 10% probability. Prior to 1968, when the link between levodopa treatment and "Classic Parkinson's" was discovered, those who had been subjectively diagnosed as having familial essential tremor by the family doctor or the neurologist, were misdiagnosed, 30% of the time. Today, neurologists and family doctors are still making the same mistake, basing their diagnosis on family recollection of tremor in their ancestors, and the patient's lack of resources to get the expensive MRIs or CAT scans to rule out brain stem anomalies. Now days, it takes several thousands of dollars and a year or more to finally arrive at the Parkinson's diagnosis, taking one step at a time in the treatment algorithm. We all receive the death sentence from birth. Levodopa therapy gives the "Classic Parkinson's" patient a parole for a period of time. The mis-diagnosis of familial essential tremor gives no such parole since the present day drugs used to treat ET are ineffective in 60% of the patients. Essential tremor is degenerative also. Logic would indicate earlier levodopa trials in patients diagnosed with familial essential tremor who lack resources for further diagnostic testing. In the United States, 30% of the population has no access to neurological medical care. It is only possible to receive care for "life threatening" conditions. This lack of access keeps the number of diagnosed Parkinson's patients artificially low, thusly, keeping Parkinson's as one of the "step-children" at pie serving time. The following was in the paper over the weekend. --------------------------------------------------------------------------- NIH budget Cuts. The National Institutes of Health, which have enjoyed strong bipartisan support, now face significant budget cuts for the first time. The health institutes calculate that their budget, $11.3 billion this year, could be cut 10 percent to 25 percent under the Senate's fiscal plan. The agency is telling Congress that such cuts would severely slow research on Alzheimer's, cancer, cystic fibrosis and other diseases. --------------------------------------------------------------------------- These cuts could mean shortening Dr. Carol Tanner's Twins Study or the elimination of Dr. Shirley Beyer's developmental neurobiology studies if their grants are reduced. Dr. Beyer's project is to use the weaver mutant mouse as an animal model of human Parkinson's disease. The same neurons that die in Parkinsonian patients also die in these animals. She is trying to find out more about the neurons that die by analyzing their developmental history. Perhaps some of these findings may provide a dating transduction in a variety of cell types. -------------------------------------------------------------------------- The following is an article on the discovery of a genetically altered mouse that help in the finding of a cure to Alzheimer's disease. It looks surprisingly similar to Dr. Beyer's work. -------------------------------------------------------------------------- Scientists create mouse with Alzheimer's Sally Lehrman OF THE EXAMINER STAFF Thursday, Feb. 9, 1995 Bay Area scientists have created a mouse that exhibits the same brain abnormalities as humans with Alzheimer's, offering an important new tool for understanding the disease and developing a treatment. "This mouse is a real breakthrough . . . providing the first real hope we can progress toward meaningful drugs," said John Groom, president and chief executive of Athena Neurosciences, the South San Francisco company that led the collaborative project. Alzheimer's is one of the top killers of Americans, with at least 100,000 people dying of the disease each year. The condition is marked by a progressive loss of memory, dementia, and eventually death. Researchers have found it difficult to pinpoint the cause of Alzheimer's, how the brain changes as it loses memory, and how to go about fixing it. The lack of an animal that developed anything like the disease has made it especially hard to study. Mice with rodent versions of cystic fibrosis, obesity and other conditions have become valuable tools for scientists to learn about these diseases and the ways drugs can interfere. Scientists have tried for many years to engineer an Alzheimer's mouse through genetic manipulation, but never have been able to achieve changes in the brain that mimic the disease. In the Thursday issue of Nature magazine, Athena, its partner Eli Lilly and Co. and their collaborators describe a mouse that develops remarkably similar characteristics to humans with Alzheimer's. The animal develops plaque in its brain, abnormal nerve fibers that surround the plaque like a web, inflammatory cells and deterioration of the connections between its nerve cells. The problems arise in two key areas of the brain related to spatial memory and associative learning. Later this year, the Athena scientists intend to test the animals in a complicated maze and see whether they have memory difficulties just like humans. "I would be shocked if these animals weren't impaired," said Dr. Ivan Lieberburg, an author of the Nature report. Lieberburg said the mouse, which developed the brain changes after a single gene change, helps prove the theory that amyloid plaque formation is the cause of Alzheimer's. Now scientists can study its precise effects. ------------------------------------------------------------------------- The following is a recent newspaper story that puts together the genetic science as we know it today with the plight of two boys. -------------------------------------------------------------------------- Boys' Illness Leads Medical Sleuth on Genetic Hunt Charles Petit, Chronicle Science Writer Nearly 20 years ago, two young boys with elfin faces and a baffling set of ailments were brought by their parents to a Denver hospital. Puzzled physicians asked a young researcher, Dr. Edward McCabe, to take a look. The boys were mentally retarded and small, and they had weak muscles. A few years earlier, county welfare officials had taken the older boy away, suspecting child abuse because the tot suffered so many broken bones. The parents got him back when the foster family found his bones kept breaking. Then the couple had a second boy with the same problems. McCabe, then being trained in children's metabolic disorders, embarked on an odyssey of medical detective work and intimate involvement with the family. That fixation helped lead to an announcement last week by a team of Italian, American, German and British researchers of the final step in the atom-by-atom identification of the genetic errors found in the two youngsters. The scientific report in the journal Nature describes the gene for a disease called adrenal hypoplasia congenita, one of at least three closely related genetic disorders those Colorado boys had. This constellation of diseases is so rare that the full description of the genes responsible will not, by itself, much alter the lives of many people. But the long voyage of discovery illustrates the strides made by genetic science in just two decades. Broadly, the results are part of the global effort called the Human Genome Project, which is aimed at unraveling the mysterious tapestry of human heredity. In the wings is not only the ability to detect and diagnose hundreds and perhaps thousands of inherited diseases, but also the knowledge to prevent them or, through gene therapy, perhaps eventually cure many of them. In an interview last week, McCabe, now chief of pediatrics at the University of California at Los Angeles School of Medicine, described the chance encounter with the family in Colorado and what followed. ``I was just called in to work up the case,'' he said. ``They were honest, sort of unsophisticated country people who lived up north of Denver. They were good parents, but the kids were sick.'' Medical tests showed that both boys had oddly high levels of glycerol in their blood. Glycerol, commonly used in hand lotions, should only exist in traces in human tissue. After eliminating such possible sources as glycerol suppositories, McCabe concluded that a derangement in the boys' metabolism of fat was at work. With two brothers and reports from the family of an uncle who had died suddenly as a child in Nebraska with similar problems, a genetic defect was clearly the culprit. ``But back then, we had practically no way to find the gene responsible and wouldn't know what to do about it even if we had.'' Further study showed that the boys actually had three diseases. The first, previously unrecognized, was dubbed glycerol kinase deficiency. The second, the cause of the muscle weakness, closely resembled the well-known disease, Duchenne muscular dystrophy. The third was discovered a short time later, after the older boy suddenly died within a day of a minor operation on his eyes. ``The parents insisted on an autopsy,'' McCabe said. ``They remembered the child abuse charges and did not want anybody thinking they had hurt their son.'' The autopsy revealed the boy's adrenal glands, atop his kidneys, to be small and malformed. The glands provide many of the hormones, such as natural steroids, that provide the body with the ability to cope with shock. McCabe ordered the surviving brother protected from major stress, and he was put on a regular dose of steroids to compensate for his medical problems. Scientifically, the coincidence of the three diseases in two brothers indicated that the boys had somehow inherited a defect that damaged three neighboring genes. McCabe kept working on the ailment at Baylor College of Medicine in Texas. By the mid-1980s, it was clear that the three genes were on the X-chromosome, a long string of genes whose roles include determination of sex characteristics. He found himself heading a group at Baylor competing with groups in Great Britain to clone, or copy and fully map, the gene for glycerol kinase deficiency, and wound up in a three-way tie. Two of the teams, including McCabe's, then set their sights on the third of the linked defective genes, the one that stunts adrenal glands. That scientific rivalry turned to fruitful cooperation, thanks to the intervention of Giovanna Camerino, a genetics researcher at the University of Sassari in Italy. She called McCabe and his chief competitor, Anthony Monaco of John Radcliffe Hospital in Oxford, to suggest that they cooperate with her group and with a fourth team led by Thomas Meitinger in Munich, Germany, to define the molecular sequence of the remaining gene for the adrenal disorder. During the past two years, linked largely by fax and electronic computer mail, the four teams laboriously put together the full sequence of molecules. Now, 18 years after meeting the two sick little boys, McCabe knows in detail what was wrong with them. The damaged genes that cause Duchenne muscular dystrophy, glycerol kinase deficiency and adrenal hypoplasia lie next to one another on what geneticists label the short arm of the X-chromosome. Something had knocked out the middle gene in the two boys and damaged the two flanking genes. Their mother had a 50-50 chance of passing the disease to any son, and a 50-50 chance of passing the defective genes to any daughters who, while well, could pass it on to their sons. The research has produced tests to detect the defects in developing fetuses, allowing girls and women in affected families to be told whether they carry the gene. Knowledge of the genes' structures should lead to better therapies that could block some of the signs of the disease. The third gene discovered, for adrenal hypoplasia, also may be involved in a host of other critical functions, including proper brain development. So far, McCabe has diagnosed about 50 boys with the same group of ailments. While retarded and vulnerable to many diseases, they are affectionate and active. He also has kept in close touch with the family in Colorado and the surviving son. While extremely retarded, he is a cheerful 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.'' -------------------------------------------------------------------------- In light of recent lobbying on behalf of increased funding for Parkinson's research, the following story seems to indicate that NIH is positioning itself into the profit stream which may indicate a shift away from research on less profitable diseases. --------------------------------------------------------------------------- Broad Gene Therapy Patent Washington The government has won a broad patent on the first way to perform human gene therapy, a method that covers 60 percent of the genetic experiments approved in the United States. The patent, awarded yesterday to the National Institutes of Health, covers any method of genetically altering human cells outside the body and then inserting those cells back into a patient to fight disease. That process is called ex vivo gene therapy. The NIH has licensed the patent exclusively to Genetic Therapy Inc., a Maryland research company that collaborates with NIH. GTI will use the patent rights to develop, and license other companies to develop, products necessary to move gene therapy from the laboratory to doctors' offices. ``I'm thrilled,'' said gene therapy pioneer Dr. W. French Anderson, the patent's main inventor. ``It comes at a very timely point -- investments in biotech and gene therapy are at rock bottom. This is a shot in the arm to get some money back out of sporting goods and fast-food establishments and back into biotech.'' Numerous genes themselves have been patented by their discoverers, and the University of Michigan has patented a specific treatment for cystic fibrosis where genetic changes are wrought inside the lungs, 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 was based proved for the first time that gene therapy could work. It covers any future gene therapy done outside the body. DAY: WEDNESDAY DATE: 3/22/95 ------------------------------------------------------------------------- Perhaps this story on BioTech will further enlighten. -------------------------------------------------------------------------- Biotech: Teaming up to survive and thrive Ralph T. King Jr. Monday, April 24, 1995 TO WALL STREET, most of the biotechnology industry is abatch of long-shot, underfinanced wannabe drug makers --and it is no place to put your hard- earned money. Yet big pharmaceutical companies are lining up to pour money into the biotechs. Do they know something the Street doesn't? Drug companies, of course, have long kept a close eye on what the biotechs are doing, investing in a few that seemed particularly promising. But lately their interest has turned red hot. Deals between pharmaceutical giants and biotech firms more than doubled in value last year and numbered nearly 200. Drug companies, especially European ones, are combing for prospects and promoting their partnership appeal with an ardor that astounds biotech executives, who are used to having to fight for every dollar of funding. Chiron Corp. of Emeryville (Top 100 No. 74) was swept off its feet in November when Switzerland's Ciba-Geigy AG bought a half interest for $2.1 billion, a 96 percent premium over the stock price. In January, Affymax NV of Palo Alto found four eager bidders for its novel yet unproven drug- discovery technology. The company, for which earnings are still a fond dream, sold itself to Glaxo PLC for more than half a billion dollars. Research revolution What is happening is that the drug industry is rushing to join the DNA generation. Gene-based analysis and computerization are transforming biological research. Some time-honored techniques for creating drugs are rapidly becoming obsolete, and an array of new methods indispensable. Among them are automated methods to make and screen millions of drug candidates in the time it takes a chemist using old-school methods to process a handful. These are the kind of skills a drug company can gain access to fast by sinking a chunk of money into a struggling biotech. Meanwhile, the world is awash in high-tech biotech shops with great ideas but questionable ability to bring them to fruition. Buying such little companies outright risks dousing their entrepreneurial fire. But forming an alliance, usually involving fees based on progress toward goals, enables the pharmaceutical giants to convert some fixed research costs to variable ones and diversify risk. The result is that the drug and biotech industries, competitors a few years ago, increasingly look like natural partners. "This is a strategic redefinition of the pharmaceutical industry," says Stelios Papadopoulos, a managing director at Paine Webber Inc. "They're walking away from early- stage, in-house research and relying heavily on small biotech companies." Jean-Pierre Garnet, chairman of Smith Kline Beecham PLC's drug division, says, "Nobody wants to be left behind." Nobody except Wall Street. The bear market in biotech stocks drags on. Wall Street remains wary Many stock investors, burned by failed promises and capital losses, refuse to get sucked in. In a stock group that has seen steep spikes two or three times during the past decade, some analysts claim to see a familiar pattern of hype as investment bankers promote mergers in the group.But in a way, Wall Street and the drug industry may both be right. Some analysts suggest that issuing public equity may be a poor way to finance ventures as speculative as biotech companies; of the 240 that are public, at least half have only enough cash to continue for 18 months, according to Recombinant Capital, a San Francisco consulting firm. These classic biotech shops that bet everything on a few molecules make drug giants wary, too. It is the biotechs with broadly enabling technology, rather than a few intriguing compounds, that are the hot tickets. And some don't even chafe at the idea of losing their independence. Alejandro Zaffaroni, founder of Affymax, says, "My goal from the very beginning was to transform our company into a lead discovery center for big pharma." Affymax is an example of a biotech offering an "arrow" technology -- often contrasted with those that have "target" technologies. An arrow technology might offer ways to guide drugs to a given site within the body, or ways to concoct and test a vast number of drug recipes. What Glaxo got by buying Affymax was access to a disposable microchip, crammed with a million fragments of DNA, that acts like a computerized test tube. When partial DNA extracted from blood is squirted on the chip, it attaches to the one spot in a million that is its chemical complement; there it emits a light, which is scanned by laser and processed by computer. The chip can reveal in minutes how an experimental drug might interact with, say, the gene that causes cystic fibrosis, or tell whether a patient is a carrier of that gene. The so-called target companies go after body sites involved in disease, providing methods to pinpoint molecular locations at which a drug could intervene. Human Genome Sciences compiles inventories of new sites and clues to their functions. Onyx Pharmaceuticals Inc. of Richmond, having found targets along cancer's metabolic pathway, penned a $75 million collaboration with Bayer AG in May 1994. The deal is similar to most such pharmaceutical-biotech alliances, in which the biotech partner contributes a proprietary technology or drug candidate in exchange 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 company interest runs deep The depth of drug-company interest in technology purveyors is evident at biotech gatherings, which invariably swarm with pharmaceutical executives or representatives. In January, Hambrecht & Quist's annual health care conference in San Francisco drew 165 of them, up 30 percent from the year before. Bayer is a good example. The German aspirin maker's research chief flew in to meet with a group of start-up company scientists in February at a Lake Tahoe retreat attended by seven of his counterparts at other drug firms. Bayer has its biotechnology center in Berkeley, where it is building a $100 million manufacturing plant and has 20 specialists devoted to 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 San Francisco involves a technique for attacking inflammation such asasthma, allowing Bayer to drop similar work internally. Five drug giants besides Bayer, all European, have taken front-row seats in the San Francisco area, the largest concentration of biotech firms. One advantage European firms have is that many are closely held and don't face the kind of short-term earnings pressure American rivals do. The chance to cherry-pick promising but cash-poor biotech firms lures even some biotech companies -- the big ones. Genentech Inc. (Top 100 No. 57) is pouring money into Scios Nova Inc. of Mountain View for a shot at half the profits from a kidney-failure treatment, and AmgenInc. snapped up a bunch of drug leads by buying Synergen Inc. Any big drug company can offer some of the things most biotechs lack, such as the ability to shepherd drugs through clinical trials, devise large-scale production processes and market worldwide. The ultimate bait Of course, money is the ultimate bait. Drug companies spend about $4 billion a year on basic research, 20 percent of it for external projects in either the biotech sector or academia. That portion will double in five years, predicts Viren Mehta, an analyst with Mehta & Isalyin New York. With all this drug-company money flowing into the biotechs -- and occasionally a takeover popping at a fat premium -- why shouldn't stock investors go along for the ride? Unfortunately, the drug firms' interest hasn't really made it easier to decide what a speculative, development-stage biotech should sell for. Denise Gilbert, Affymax's chief financial officer, says she tried in vain to value technology-based companies during her previous career as a biotech analyst. The $539 million price Glaxo paid was based not on any earnings projection but on the estimated cost of duplicating Affymax's skills. -------------------------------------------------------------------------- All of this preoccupation with profits, pre-empting your competitors by patenting genes has caused opposition. Parkinsonians, look at both sides and the grey areas of their arguments. Is the controversy, GREED vs Right? What ever side has the most money vs the loudest voice will prevail and in the end, our medications will either increase or decrease in number and either way, they will cost more. Here is the other viewpoint, from the paper again. --------------------------------------------------------------------------- 80 Church Groups Ask Ban on Gene Patents /They decry `marketing human life' Louis Freedberg, Chronicle Washington Bureau Washington Opening a far-reaching debate that pits science against religion, leaders from every major religious denomination in the United States called yesterday for imposing an immediate moratorium on patents for human genes and genetically engineered animals. ``Marketing human life is a form of genetic slavery,'' said Richard Land, executive director of the Christian Life Commission of the Southern Baptist Convention. ``Instead of whole persons being marched in shackles to the market block, human cell- lines and gene sequences are labeled, patented and sold to the highest bidders.'' Land, along with representatives of 80 denominations that are often at odds with each other on such controversial issues as school prayer and abortion, called on Congress to hold hearings on the matter and to revise the law that leaves it up to the U.S. Office of Patents and Technology to license gene-related products. Representatives of the biotechnology industry, however, said a moratorium would halt the development of life-saving drugs. Without the incentive of patent rights, they said, companies would be reluctant to invest the tens of millions of dollars needed to bring drugs to the marketplace, often to benefit patients with such life-threatening diseases as AIDS, cancer and diabetes. ``This would be absolutely terrible for our industry,'' said Kirk Robb, president of Genentech in South San Francisco. ``Some small companies would go out of business. Others would drastically reduce what they are doing.'' Genentech, one of the two largest biotechnology companies in the nation, has developed gene-related products like human insulin; Factor 8, used for treating children with hemophilia; and TPA, known as a ``clot buster'' to stop heart attacks. Genentech now has close to 1,000 patents, not all of which are gene related. Industry representatives say the religious leaders misunderstand what gene patenting is all about. They insist that owning a patent, which grants exclusive rights to market a genetic invention for 17 years, does not mean that a company owns the gene. ``A patent on a gene does not confer ownership of that gene to the patent holder,'' said Carl Feldbaum, president of the Biotechnology Industry Organization. ``It only provides temporary legal protections against attempts by other parties to commercialize the patent holder's discovery or invention.'' He said that virtually all biotechnology firms are small, have no products on the market and need to raise funds from investors to conduct research that leads to new drugs. Without the incentive of patent protection, raising the necessary venture capital would be nearly impossible. Jeremy Rifkin, president of the Foundation on Economic Trends in Washington, the main organizer of the statement signed by religious leaders, declared that argument to be ``nonsense.'' ``There are thousands of successful product on the market, including drugs, medical procedures and farm products which are not protected by patents,'' he said. After the Supreme Court ruled in 1980 that Exxon Corp. was entitled to patent a genetic product used to treat oil spills, the U.S. Patent and Trademark Office has routinely awarded patents on human genes. Yesterday, the office issued a statement saying that it simply follows the law in issuing patents, citing the high court ruling that patent laws provide protection for ``literally anything under the sun known to mankind'' involving human intervention. ``The Patent and Trademark Office does not have the authority to deny a patent on any subject matter that the patent laws and the federal courts deem to be patentable,'' the statement read. Those statements avoided what to many is at the root of a discussion about the nature of life. ``This issue is going to dwarf the pro-life debate within a few years,'' said Land. ``I think we are on the threshold of mind-bending debates about the nature of human life and animal life. We see altering new life forms as a revolt against God's sovereignty and the attempt by humankind to usurp God and be God.'' But Susanne Huttner, director of the University of California's Research and Education Program, said that a person or an animal is made up of billions of cells organized into complex tissues and organs. ``An individual gene and the protein it encodes are important but insufficient for `life' judged as a complex organism,'' she said. Outside the room where the religious leaders held their press conference, a healthy-looking Paul Lieberman, 59, of Stratford, Conn., dissented strongly with one of his own leaders, Rabbi David Saperstein, director of the Reform Action Center of Reform Judaism. Lieberman said that four years ago he began taking the gene-related drug Cladrabine when he was diagnosed as having a specialized case of ``hairy cell'' leukemia. He said the drug worked. ``As a liberal Jew, I always felt that healing people was more important than ethics,'' said Lieberman, who was in Washington at the request of Orthobiotech, the drug's manufacturer. ``If we follow the Talmud, to save one life is to save the world.'' DAY: FRIDAY DATE: 5/19/95 -------------------------------------------------------------------------- In closing, there have been two stories worth adding to this long collage. One involves finding a gene that turns on other cells, which may be useful in regenerating neurons. The other is the discovery of the gene which determines the sex of child. -------------------------------------------------------------------------- Gene found that keys nervous system growth Warren King Tuesday, May 16, 1995 SEATTLE -- Scientists have discovered a gene that is key to the development of the nervous system, a finding that eventually could lead to treatments for diseases such as Alzheimer's and Parkinson's. The gene, named "NeuroD," helps switch on other genes to form some of the cells most basic to life. If it is as important as researchers suspect, it could someday be used to replace nerve cells damaged by devastating neurological diseases. "Many pieces have yet to be put together to understand the pathway (of development)," said Lauren Snider, a member of a research team at Fred Hutchinson Cancer Research Center in Seattle. "We have to know more of that story." Snider said the research, conducted mostly on frog embryos, found that the NeuroD gene was involved in the very earliest stages of life, when cells are differentiating to form the basic body systems. Genes provide a sort of blueprint for the making of these basic proteins and cells. 05/16/95 17:50 PST ------------------------------------------------------------------------- Scientists Find How Boys Will Be Boys / A genetic switch governs gender of an embryo Washington Researchers have isolated a genetic switch that separates the boys from the girls. It turns off the female in the human embryo and starts biological changes that eventually put hair on the chest. Dr. Michael Weiss of the University of Chicago said the new study advances the understanding of the complex cascade that determines whether people are male or female and sheds new light on how this process can sometimes go awry. In their research, to be published today in the journal Science, Weiss and his team used sophisticated imaging techniques to explore on an atomic level the biological pathway to manhood. Their research report traces the development of maleness, from the turning on of the SRY gene, which is on the Y chromosome, to the work of another gene, called MIS, that removes the female parts of the original embryo. Weiss said science has long known that everybody at conception is female, but the precise biological mechanism that changes an embryo to male is still incompletely understood. Solving the puzzle on the molecular level may answer questions about other basic cellular changes, such as the development of cancer. ``If we can understand the general switches involved in sex determination, then we could possibly relate that to other basic processes, such as how organs differentiate or how cancer arises,'' he said. For the first weeks after conception, all mammal embryos start forming the basic female structures -- uterus, fallopian tubes and vagina. ``The embryo destined to become a boy begins as a female,'' Weiss said in an interview. ``It lays down first female structures and not male structures at a phase when the embryo looks like a recognizable mammal, with toes, fingers and eyes and a heart. This is 35 to 40 days into human gestation.'' After that, he said, a gene called SRY switches on to start the embryo on its way toward manhood. The new study shows that SRY also triggers the work of another gene, called MIS, that dissolves the female parts of the original embryo. ``SRY is the master switch,'' said Weiss. ``For the first time we have shown that SRY can activate a male specific pattern of gene expression leading to activation of MIS, which is the key signaling molecule for half of the male pathway.'' Sex determination in mammals originates with the chromosome of the sperm that fertilizes the egg. Male sperm can carry one of two chromosomes, X or Y. The Y chromosome is the male element that carries the SRY gene. The female egg has an X chromosome. If the egg is fertilized with the father's X chromosome, then the embryo continues its development as a female. But if the egg is fertilized with Y, then the SRY gene sets off a series of changes that eventually creates a male. ``The XY embryo (containing the X chromosome from the mother's egg and the Y chromosome from the father's sperm) has two critical tasks to accomplish,'' said Weiss. ``The first is to build male organs. The second is to cause the female structures to go away.'' John Cottingham NEW ADDRESS: [log in to unmask]