Major Scientific Advances In 1997

By David N. Leff

Companies (at least publicones) customarily produce annual reports for share-holders and potential investors. Hereis BioWorld’s annual report of newsworthy milestone advances (but not –with one exception – true “breakthroughs“) in biotechnology research anddevelopment during 1997. The selected items, set forth alphabetically by disease or othercategory, are keyed primarily to coverage in BioWorld Today. Date of issue –all from 1997; all on page 1, unless otherwise noted – follows item in parentheses.

Allergies:

A whiff of pollen, or acat in the room, gives some people spasms of hay fever or asthma. Other individuals ignorethese allergens. How come?

• Immunologist TalalChatila at Washington University, St. Louis, Mo., identified a gene mutation in theinterleukin-4 (IL-4) receptor that imparts susceptibility to allergies “aroundtenfold“ higher than affects people carrying the normal IL-4 receptor gene. Hisreport in the New England Journal of Medicine, dated Dec. 11, 1997, was titled:“The association of atopy [inherited hypersensitivity to allergens] with again-of-function mutation in the subunit of the interleukin-4 receptor.“ (Dec. 11)

• A mutated interleukin-9(IL-9) gene, on human chromosome 5, is another susceptibility prospect, pinpointed byscientists at Magainin Pharmaceuticals Inc., in Plymouth Meeting, Pa. Their reportin the Proceedings of the National Academy of Sciences, dated Nov. 5, 1997, wastitled: “Interleukin 9: A candidate gene for asthma.“

Molecular geneticist RoyLevitt directs Magainin’s Institute of Molecular Medicine. To define IL-9’s rolein asthma, he dosed 150 mice with asthma simulating bronchoconstrictors, then geneticallymapped their varied responses. IL-9 proved to up-regulate, among other targets, an enzyme,tryptase, against which Magainin is now developing a small-molecule antagonist. (Nov. 25)

• Tristan da Cunha, aremote island in the South Atlantic, is home to some 300 inhabitants. Thirty percent ofthem suffer from asthma, as compared with five percent in the U.S. These islandersprovided a ready-made research sample to Sequana Therapeutics Inc., of La Jolla,Calif., which reported cloning the first mutant gene guilty of causing asthma. (May 21)>

Diabetes:

• Biotechstart-ups and big pharma alike are redoubling their efforts to make oral insulin areality. “I’m not aware of any other groups than ours with results in humans atthe moment.“ So said Michael Flynn, president and research and development directorof Cortecs International Ltd., an Anglo-American company based in London.

His firm completed a Phase IIclinical trial of its orally ingestible insulin, Macrulin. The trial’s main purpose,he explained, “was to get insulin from the intestine to the liver, where it ispresumed to act. We wanted to avoid what happens with injected insulin, of which 80percent acts in the periphery.“

Flynn also wants to avoid“a flood of diabetics thinking that next year they’re going to have oralinsulin. That’s a few years away – if everything goes well.“ (Dec. 15)

• French diabetologistCharles Thivolet designed an oral vaccine consisting of recombinant human insulin hookedup to a portion of the Cholera vibrio toxin. Its aim is not to replace theneedle-injected hormone, but to mobilize the body’s mucosal immune defenses againstautoimmune cells run amok.

His article in the Proceedingsof the National Academy of Sciences, dated April 29, l997, was titled: “A choleratoxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes.“Thivolet and his team fed a minute dose of their insulin-toxin vaccine to non-obesediabetes-prone mice. Fifteen weeks later, only two of them had developed diabetes, ascompared with seven of 16 control animals. (May 6) >

CANCER

Angiogenesis:

• Taking a leaffrom plaque-blocked coronary arteries that starve heart muscle to death, a paper in theJan. 24, 1997, Science reported: “Tumor infarction in mice byantibody-directed targeting of tissue factor to tumor vasculature.“ (Tissue factor isclotting factor III, a.k.a. thromboplastin.) The approach, said the paper’s seniorauthor, Philip Thorpe, killed off cancer-bound arterioles, venules and capillaries bydamming them with blood clots. Immunopharmacologist Thorpe is at the University ofTexas Southwestern Medical Center, in Dallas. He expects this mouse-proven method towork against virtually all solid tumors in humans, and foresees clinical trials within thenext two years. (Jan. 24)

• Some fortunatesurvivors of cancer surgery, radiation and chemotherapy experience remissions that maylast for years. Then one day their tumors reappear.

One explanation for suchunexpected relapses comes from oncologist Michael O’Reilly, at Children’sHospital, Boston. His paper in Nature, dated Nov. 25, 1997, bore the title:“Antiangiogenic therapy of experimental cancer does not induce acquired drugresistance.“

Angiogenesis is theproliferation of new blood vessels to feed hungry tumor cells. O’Reilly’sinhibitor of this process starves tumors down to microscopic, but still living specks.“We think,“ he said, “that this is the first model for studying why, insomeone who has a cancer treated, and is apparently disease-free for a number of years,the tumor comes back.“ (Dec. 3)

• Two growth factors, anagonist and an antagonist, “are the yin and yang of angiogenesis,“ observedGeorge Yancopoulos, senior vice president of research at Regeneron Pharmaceuticals Inc.,in Tarrytown, N.Y. “What ties these two blood-vessel-promoting moleculestogether,“ he explained, “is their common receptor, which protrudes beyond thewalls of the endothelial cells that make up capillaries, veins and arteries.“

He reported the company’sdiscovery in Science dated July 4, 1997. “Curbing angiogenesis,“Yancopoulos pointed out, “could kill a solid tumor by starving it of blood-bornenutrients, and perhaps make coronary bypass surgery unnecessary.“ (July 7)>

Colorectal:

• According to NationalCancer Institute (NCI) mortality statistics, colorectal cancer (CRC) comes in secondto lung cancer in the U.S., with an estimated 56,000 deaths in 1994. NCI indicts dietaryfat, red meat and alcohol among the main causes of CRC. The chemotherapeutic agent offirst and last resort is 5 fluorouracil (5FU), which helps only about 20 percent ofadvanced CRC cases. The other 80 percent fail 5FU therapy, said oncologist Robert Coffey,of Vanderbilt University, in Nashville, Tenn., because their cancers harbor adisabled p53 tumor suppressor gene. This mutation exposes them to the toxicity of oxygenfree radicals.

Vitamins and veggies are theantioxidant antidotes of choice against the wanton oxygen ions. Nature Medicine forNovember 1997 described Coffey’s in vivo test of these remedies, under thetitle: “Antioxidants enhance the cytotoxicity of chemotherapeutic agents inCRC.“ The Vanderbilt team treated mice carrying human CRC tumors with 5FU plus twoantioxidants. This cohort experienced complete tumor regression, whereas the cancers grewso large in control mice that the animals had to be sacrificed. (Nov. 18)

• Jews of Ashkenazi(Eastern European) descent make up more than 95 percent of American Jewry, and arestatistically prone to cancer of the colon and rectum. It’s linked to a mutation inthe human APC gene, as reported in the Dec. 15, 1997, issue of the journal CancerResearch. The paper, by molecular oncologists Bert Vogelstein and Kenneth Kinzler, atthe Johns Hopkins University, in Baltimore, was titled: “Familial colorectalcancer in Asheknazim due to a hypermutable tract in APC.“

Individuals with a familyhistory of breast and/or ovarian cancer are also predisposed to colorectal tumors, butit’s not caused by that APC gene, according to a paper in that same issue of CancerResearch, titled: “The ... APC mutation does not predispose to colorectalcancer in Jewish Ashkenazi breast and breast ovarian cancer kindreds.“ (Dec. 16)

Prostate:

• Althoughimmunologist John Frelinger’s transgenic mice are born with the gene for humancancer-causing PSA (prostate-specific antigen), they raised T cells that killed identicalantigens growing in implanted human tumor cells. These animals “promise to provide aworkbench for devising immunotherapies and perhaps gene therapies against prostatecancer,“ observed Frelinger, at the University of Rochester, N.Y., cancercenter.

His paper in the June 10,1997, Proceedings of the National Academy of Sciences, bore the title:“Tissue-specific expression of the human prostate-specific antigen in transgenicmice: Implications for tolerance and immunotherapy.“ (June 12)

• Anotherprostate-tumor-inducing gene (PTI-1), recently discovered, shows potential inunmasking prostate cancers, and monitoring their home-based growth and metastatic spread. PTI-1may someday harness antisense technology to reverse that cancer in its tracks, suggestedmolecular biologist Paul Fisher, at Columbia University’s College of Physicians& Surgeons in New York. He reported discovery of PTI-1 in the Jan. 1, 1997,issue of Cancer Research. Its title: “Human prostatic carcinoma oncogene PTIis expressed in human tumor cell lines and prostate carcinoma patient bloodsamples.“ (Jan. 8)

Telomeres:

These are DNA sequencesthat cap the tip ends of human chromosomes. They normally shorten with age, whittled awayby the enzyme telomerase. When this cell life span limiting enzyme is missing, thechromosomes divide indefinitely, essentially becoming immortal – that is, malignant.Hence, the widening quest by anticancer researchers to restore telomerase function:

• Nobelist Thomas Cech, Universityof Colorado, Boulder, reported in Science dated Aug. 15, 1997, cloning of thegene for the human telomerase catalytic protein, and how it may be deployed against tumorsand diseases of aging. His paper bore the title: “Telomerase catalytic subunithomologs from fission yeast and humans.“

One week later, on Aug. 22,1997, Cell reported finding the identical gene, under the title: “hEST2, theputative human telomerase catalytic subunit gene, is up regulated in tumor cells andduring immortalization.“ Its senior author is molecular biologist Robert Weinberg, ofthe Whitehead Institute for Biomedical Research, at the Massachusetts Instituteof Technology, in Cambridge.

Cech’s commercialpartner, Geron Corp., of Menlo Park, Calif., is pursuing both the cancer andsenescence markets opened wider by the telomerase gene discovery. (Aug. 15, pp. 1 and 4)

• In the December 1997issue of Nature Genetics, two scientists at Geron reported “the firstdemonstration of reconstitution of the [telomerase] enzyme from its RNA and protein.“They added: “Geron has produced telomerase activity in normal, mortal human cells,using the gene for the human telomerase catalytic protein that we cloned recently.“(Dec. 3)

Tumor Suppression:

• Last year, aprotein called p53 starred as the ranking suppressor of tumors (See the BioWorldBiotechnology State of the Industry Report 1997, p. 11). This year, other suchmolecules have moved onto center stage, notably p73.

Both Cell dated Aug.22, 1997, and Nature for Sept. 11, reported on the similarities and differencesbetween the newly discovered p73 and well known p53 proteins.

Molecular biologist WilliamKaelin, of Boston’s Dana Farber Cancer Institute, said: “Our paper in Naturefocused on the question: Could the p73 gene act like p53?“ His answer: “Atleast when overproduced, the protein products of p73 could in fact activate transcriptionof genes normally regulated by p53, and itself act as a tumor suppressor.“ (Sept. 11)

• Described as “thefirst documentation of [a gene] ... involved in cancer progression by actual causativerelationship to the tumor,“ PEG-3 adds new knowledge to the murky mechanism oftumor metastasis. Molecular biologist Paul Fisher, at Columbia University’sCollege of Physicians and Surgeons, in New York, reported the discovery in the Proceedingsof the National Academy of Sciences for Aug. 19, 1997. The paper’s title:“Subtraction hybridization identifies a transformation progression-elevated gene PEG-3with sequence homology to a growth arrest and DNA-damage-inducible gene.“ (Sept. 2)

• A different newfoundgene, expressed at abnormally high levels in the tumor cells of most breast cancerpatients, unveils “a crucial metabolic pathway linked to the growth and progressionof human breast cancer.“ Paul Meltzer, at the National Human Genome ResearchInstitute in Bethesda, Md., reported this discovery in Science dated Aug. 15,1997. It involves the estrogen pathway, which also affects ovarian and prostate cancer.(Aug. 18) >

CLONING

Dolly:

• The journal Science,in its year-end issue dated Dec. 19, 1997, acclaimed Dolly as “Breakthrough of theYear.“ Scientists concurred, but bioethicists were less sanguine.

Until February 1997,scientific wisdom and common knowledge alike held that cloning a large mammal from itsfully developed, adult “mother’s“ DNA would never be possible. In fact, theodds against such a feat turned out to be 277 to one.

That’s how many cells theScottish scientists at the Roslin Institute near Edinburgh, and its affiliatedbiotechnology company, PPL Therapeutics plc, had to process before achieving thebirth of their healthy demonstration model – the brown-eyed, white-nosed, bleatingDolly. They presented the six-month-old ewe to the world in Nature dated Feb. 26,1997. (See BioWorld Today, Feb. 25, 1997)

Their unorthodox butsuccessful technique, nuclear transfer, featured removing the nucleus from an ovine ovumand replacing it with the nucleus of a cultured udder cell from an adult ewe, thenjump-starting the odd couple with a jolt of electricity.

Dolly was a great act tofollow.

Her Scottish creators didfollow her, with Polly and Molly, two cloned ewes engineered to produce a high-valueprotein, Factor IX, in their milk. Their report in Science, also dated Dec. 19,bore the title: “Human Factor IX transgenic sheep produced by transfer of nuclei fromtransfected fetal fibroblasts.“ Until Dolly came along, somatic cells were thoughtincapable of reproducing the range of genes necessary for cloning a whole creature.

In all, the team obtained ninetransgenic fetuses, of which two contained the Factor IX transgene. When these grow tolactating age, they will presumably produce the anti-hemophilia protein in their milk.

Alan Colman of PPL, aco-author of the Science paper, pointed out: “If we have a cell with aparticular gene in a particular place, we could actually make all the animals we need inthe first generation, instead of having to wait several generations. We could, forexample, make an instant herd of transgenic cows or sheep, pumping out a therapeuticprotein, and this might be enough animals to meet the world demand for that product.“(See BioWorld International, Dec. 24, 1997).

Tobacco Pharming:

• As molecularbiologists worldwide vied to produce high-value human proteins in the milk of cows, sheep,goats and pigs, French scientists came up with proof-of-principle quantities of humanhemoglobin from tobacco plants (Nicotiana tabacum). An item in Nature datedMarch 6, 1997, reported this demonstrator model cloning feat under the title: “Humanhemoglobin from transgenic tobacco.“ One of the paper’s senior co-authors,biophysicist Michael Mardan, at INSERM, (France’s National Institute ofHealth and Medical Research), in Paris, explained that the main motivation of the projectwas to avoid “possible contamination in transfused blood from existing sources –human donors with AIDS or hepatitis, and bovine or eventually porcine bloodproducts.“ (Mar. 6) >

GENE THERAPY

Gene Targeting:

• Instead ofpedigree analysis and positional cloning, molecular geneticist Thaddeus Drya takes thesought-after gene as his point of departure, not endpoint. Drya, at the HarvardUniversity-affiliated Massachusetts Eye and Ear Infirmary, in Boston, describedhis approach: “You have a gene of interest, which is expressed only in the eye. Soyou reason that someone in the world probably has a mutation in that gene. And that personmust have some defect of vision.“

His paper in the Oct. 28,1997, Proceedings of the National Academy of Sciences, was titled: “Gene-basedapproach to human gene-phenotype correlations.“ Drya views this gene-orientedstrategy as an alternative to classical gene-mapping, not a replacement. (Nov. 5)

DNA Delivery:

Gene therapists arestill searching for the ideal gene delivery system. Viral vectors have their shortcomings;DNA injected naked or shot from guns leaves much to be desired; liposome microcarriersstill need work:

• Melanoma biologist JohnPawelek at Yale University, in New Haven, Conn., and his partners at nearby VionPharmaceuticals Inc., also in New Haven, eyed the notorious pathogen, Salmonellatyphomurium, as a putative vector. As detailed in the Oct. 15, 1997, issue of CancerResearch, they made the microorganism less toxic to mice, and inserted a geneconstruct, designed to kill whatever tumors the bacteria bumped into. “We entered thevector into the mouse bloodstream,“ Walker recounted, “and it could find all thetumors in the animal.“ His Proceedings of the National Academy of Sciencespaper is titled: “Tumor-targeted Salmonella as a novel anticancer vaccine.“(Oct.15)

• A newly patentednonviral vector started Phase I clinical trials this year in the U.S. and Europe. The U.S.patent, No. 5,676,954, issued to inventor pulmonologist Kenneth Brigham, of VanderbiltUniversity, in Nashville, was headed “Method of in vivo delivery offunctioning foreign genes.“

Michael Fons of GeneMedicineInc., The Woodlands, Texas, the university’s licensee, said, “The patentcovers any cationic lipid complexed to DNA that’s injected or inhaled to delivergenes to cells in the body.“ (Oct. 15)

• An adeno-associatedvirus, injected into muscle tissue, delivered and expressed a self-regulated gene ofinterest. A report in the March 1997 issue of Nature Medicine bore the title:“Recombinant adeno-associated virus for muscle directed gene therapy.“ Itssenior author is noted gene therapist James Wilson, at the University of Pennsylvania,in Philadelphia. Industrial co-authors were from Philadelphia-based Genovo Inc.,which Wilson founded, and Ariad Pharmaceuticals Inc., of Cambridge, Mass.

Topping Wilson’s list oftherapeutic proteins being prepped for the new gene therapy paradigm is human Factor IX,to treat hemophilia. “Our goal,“ Wilson said, “is to get it into humanswithin 12 months or sooner.“ (Mar. 13) >

INFECTIOUS DISEASES

AIDS/HIV:

In 1997, AIDSresearchers nailed down the finding, announced at the tail end of 1996, that HIV needsmore than one or even two receptors in order to break and enter their human target cells.One such co-conspirator is the CCR5 coreceptor:

• A sexually activehomosexual man in Australia seemingly disproved the recent finding that people who lackthe front-line receptor for HIV won’t get AIDS. A paper in the March 1997 NatureMedicine reported “HIV-infection in an individual homozygous for the CCR5deletion allele.“ That is, he had inherited from both parents a mutation that deletesa 32-base-pair sequence from his CCR5 gene, thus rendering it helpless to smuggle the HIVinto its initial target cells.“ (Mar. 4, p. 4)

• How does HIV infectbrain cells? An answer appeared in the Feb. 13, 1997, issue of Nature, titled:“CCR3 and CCR5 are coreceptors for HIV-1 infection of microglia.“ Its seniorauthor, neurologist Dana Gabuzda, observed: “There was no clear role for CCR3; nobodyhad ever really looked in the brain.“ She called her team’s finding “thefirst evidence that CCR3 is an important receptor to allow HIV infection in the body. Soit may require different forms of therapy. (Feb. 13)

• Before the AIDS viruscan break and enter its target cell – typically, a T lymphocyte or macrophage –the viral particle must make contact with its cellular victim, and merge their two outerlipid bilayers. This piece of burglary is the job of gp41, a surface glycoprotein on thevirion.

At the MassachusettsInstitute of Technology, in Cambridge, structural biologist Peter Kim resolved afragment of gp41’s crystal structure. “This is the first time,“ he said,“that anybody has been able to get a high-resolution structure of any part of the HIVenvelope protein. It’s the major target that the human immune systemcounterattacks.“ Kim’s report appeared in the April 18, 1997, issue of Cell.(April 22)

• Immunologist BruceWalker, at Boston-based Massachusetts General Hospital, fights the AIDS virus by“forcibly educating immune-system killer T cells that don’t know how torecognize HIV to find and kill virus-infected T cells and macrophages.“ He pursuesthis strategy jointly with Cell Genesys Inc. of Foster City, Calif. His paper inthe Proceedings of the National Academy of Sciences, dated Oct. 14, 1997, wastitled: “Lysis of HIV-infected cells and inhibition of viral replication by universalreceptor T cells.“ (Oct. 21)

• In heterosexualintercourse, the AIDS virus takes passage as a stowaway on sexually transmitted diseases(STD) cells. A paper in the Lancet, dated July 28, 1997, documented this seminalfinding in a report titled: “Reduction of concentration of HIV-1 in semen aftertreatment or urethritis: Implications for prevention of sexual transmission ofHIV-1.“

The report, co-authored byteams at the University of North Carolina, in Chapel Hill, and in the East AfricanRepublic of Malawi, concluded: “the diagnosis and treatment of STDs, especiallygonorrhea, in patients with HIV infection, should be a key component of HIV-1 preventionprograms.“

Epidemiologist Rachel Royce, aco-author, stated: “This is a very important finding, because it is the first one togive the biological evidence ... that sexually transmitted infections have an impact onthe probability of acquiring and transmitting HIV.“ (July 2)

• Triple-drug treatmentfor HIV-positive patients got a resonant endorsement in mid-year from a mixed panel ofexperts. It drafted guidelines recommending that all people with certified AIDS receive acostly but potent combination of three medications, including two antiretrovirals and aprotease inhibitor. (June 30)

Drug Resistance:

YaleUniversity Nobelist Sydney Altman developed a nucleic-acid weapon for disabling thedrug-resistance genes by which infectious pathogens are threatening to disarm more andmore antibiotics. He reported in the Proceedings of The National Academy of Sciences datedAug. 5, 1997, having devised strings of synthetic DNA sequences that encode catalyticoligonucleotides. These enzyme-like molecules target messenger RNA and prevent it fromexpressing the drug-resistance factors. (Aug. 5)

• Malaria, once readilykept at bay by drugs such as chloroquine and atabrine, is now defying these and othertherapeutic compounds, almost as fast as they are introduced. Plasmodium, the mainmalarial parasite, harbors in its cells an organelle called the apicoplast. Molecularparasitologists at the University of Pennsylvania, in Philadelphia, reported in Naturedated Nov. 27, 1997, that this maverick particle succumbs to a broad-spectrumantibiotic, ciprofloxacin. What’s more, when apicoplast gets clobbered, so does thewhole parasite.

“Our results,“ theauthors wrote, “directly link apicoplast functions with parasite survival, validatingthis intriguing organelle as an effective target for parasiticidal drug design.“(Dec. 29, p. 2) >

Flu:

• As virologistsand public health authorities in Hong Kong and beyond circle their wagons against thechicken-spread “bird flu,“ an 80-year-old specimen of lung tissue from a U.S.Army private helped settle the viral etiology of the great 1918 flu pandemic. RNA geneticanalysis, reported in Science, dated March 25, 1997, revealed the genes “aremost closely related to pig virus, not avian.“ (March 21)

NEUROLOGICAL DISEASES

Alzheimer’s:

• Creeping loss ofmemory is a cardinal feature of Alzheimer’s disease (AD), and a focus of muchneurological research. In 39 rats, Daniel Alkon, at the National Institute ofNeurological Disorders and Stroke, discovered “a critical molecular step thatoccurs during learning and memory.“ He reported this finding in the Sept. 2, 1997, Proceedingsof the National Academy of Sciences, as having potential application in diagnosing andtreating AD. His paper’s title: “Late memory-related genes in the hippocampusrevealed by RNA fingerprinting.“ (Sept. 10)

• APOE-4, a genepreviously thought to account for up to half of the cases in late-onset AD, actuallyreflects only the much smaller population of early-onset patients. This finding wasreported in the January 1997 issue of Neurology under the title: “ApoE-4 andage at onset of Alzheimer’s disease.“ (Feb. 19)

• Amyloid plaques, thealleged – but unproven – perpetrators of AD, had a few more items added to theirprofile rap sheet. When polymer physicist H. Eugene Stanley, at Boston University,turned his attention and his instruments on the plaque puzzle, he determined theseparticles, which cluster tightly around neurons, are porous, not solid. And they arecapable of deaggregating as well as aggregating, with therapeutic implications.

Stanley reported thesefindings in the Proceedings of the National Academy of Sciences, dated July 8,1997, jointly with neurologist Brad Hyman, who directs the Alzheimer Research Unit at MassachusettsGeneral Hospital, in Boston. (July 9)

Drug Addiction:

• Every cigarettesmoker quits 365 times a year – while asleep at night. When he awakes, the firstsmoke of the morning feels far more pleasurable than all the cigarettes that follow duringthe day. Why?

At Baylor College ofMedicine, in Houston, neurophysiologist John Dani offered this answer, distilled fromhis paper in the Nov. 27 issue of Nature:

“Nicotine does not existnaturally in the brain, but when it is obtained from tobacco, it can activate receptors onthe mid-brain dopamine-secreting neurons. If the nicotine hangs in there for many minutesor hours, the neurons become numb, desensitized. So the burst of firing that they firstdisplayed goes away, and the neurons need to have the nicotine go away so they can recoverand respond again to the drug – as after a nighttime of abstinence fromcigarettes.“ (Dec. 9)

• Among the bodily duesthat heavy cigarette smokers pay is emphysema, the disease that cripples the lung alveoli,which swap carbon dioxide for oxygen during breathing. The protein that keeps thosetissues supple is elastin; cigarette smoke brings on an enzyme, elastase, which destroyselastin. But not in heavy smoking knockout mice deprived of the elastase gene. Controlmice, carrying that protease, developed lung conditions resembling human emphysema. As forthe transgenics, recounted cell biologist Steven Shapiro, at Washington University,in St. Louis, Mo., “It didn’t touch ’em.“ Science dated Sept.26, 1997, reported his experiment in a paper titled: “Requirements for macrophageelastase for cigarette smoke-induced emphysema in mice.“ (Sept. 26)

• French knockout micethat lack the dopamine receptor gene (which honchos feelings of reward and pleasure) mightbe useful for treating many cases of human narcotic addiction. Tarek Samad is co-author ofa paper in Nature dated Aug. 6, 1997, which documents the loss of interest inopiates by the dopamine-deprived animals. Its main finding, he observed, “might beuseful for treating a lot of human addicts. Adding a ligand for the receptor willeliminate the reward, and so the addiction.“ (Aug. 7)

Nerve Regeneration:

Except in very youngchildren, dying or damaged brain and spinal-cord nerve cells never regenerate. However,beyond the central nervous system (CNS) serving head and spine, peripheral neurons thatactuate the body’s muscles can and do put out new axons to replace those lost toinjury:

• But at Case WesternReserve University, in Cleveland, neuroscientist Jerry Silver has tested in laboratoryanimals the possibility of CNS regeneration by an end run around a “glial scar,“which blocks neuronal renewal. “Our report [in the Dec. 18, 1997, Nature]suggests for the very first time,“ Silver said, “that once the nerve fibers arepast the area of glial scar, there’s an enormous potential for the regeneration ofthe adult CNS.“ (Dec. 18)

• NeuroscientistFrederick Livesey, at Trinity College, Dublin, Ireland, is also pursuing the samegoal, as he reported in the same Dec. 18, 1997, Nature. “The fundamentalbiology of how [CNS neurons] regenerate,“ he said, “is core information we musthave before we can understand how to make other types of neurons regenerate.“ (Dec.18)

• The human bcl-2gene teaches embryonic nerve cells of the CNS how to regenerate their axons duringprenatal development. About the end of the first trimester of gestation, that tutorialgene shuts down for good.

Transgenic mice possessing anextra copy of the bcl-2 gene experience nerve regeneration failure, when bcl-2is turned off. Gerald Schneider, of the Massachusetts Institute of Technology, inCambridge, reported in Nature, dated Jan. 30, 1997, “Bcl-2 promotesregeneration of severed axons in the mammalian central nervous system.“ He is workingwith other academic collaborators on “genetic engineering to put the genes intoadults, the next major step toward therapeutic treatment of spinal trauma.“ (Jan. 30)

OBESITY

• A mammalian genethat diverts mitochondria from their sole job – supplying energy for cell functioning– to burning off calories in the form of excess body fat was reported in the March1997 Nature Genetics. The gene’s discoverer, molecular geneticist CraigWarden, University of California at Davis, said his group is “actively lookingfor the human sequence variants of the gene, and asking whether these are associated withobesity.“ (Mar. 5)

• Molecular geneticistFarid Chehab, at the University of California at San Francisco, brain-washed femalemice into thinking they were fat. “We took young female mice with no external signsof puberty,“ he recounted, “and treated them with leptin. This tricked theirbrains into believing they were obese, and triggered earlier reproduction than in controlanimals, treated with saline placebo.“ His report appeared in the Jan. 3, 1997, issueof Science. (Jan. 7)

REPRODUCTION

• A newlydescribed “fertilization antigen“ works both sides of the street –infertility and family planning. In initial human trials, it corrected a form of maleinfertility. In preclinical in vivo studies, the molecule showed the makings of acontraceptive vaccine. Its discoverer, Rajesh Naz, is research director at the MedicalCollege of Ohio, in Toledo.

His report appeared in the Proceedingsof the National Academy of Sciences. dated April 29, 1997, titled: “Fertilizationantigen-1: cDNA cloning, testis-specific expression, and immunocontraceptiveeffects.“ (April 30, p. 3)

• Contraception and itsopposite, infertility, are the main lines of research into human reproduction, but sexualintercourse itself sparked one inquiry into the changes in the mammalian brain broughtabout by copulation. Psychologist S. Marc Breedlove, at the University of California atBerkeley, subjected rats to four weeks of controlled mating. He then delineated themotor neurons that control penile erection and ejaculation, and found that they shrank.“Copulatory experience,“ he observed, “can alter the size of neurons. Hisreport in the Oct. 23, 1997, issue of Nature, bore the title: “Sex on thebrain.“ (Oct. 23)

• What is aquintessentially female hormone like estrogen doing in the male testis? The answerappeared in Nature, dated Dec. 4, 1997, in an article titled: “A role foroestrogens in the male reproductive system.“ Endocrinologist Kenneth Korach pointedout: “As we become more worried about estrogen-like compounds in the environment andworkplace, this paper offers the first real evidence that estrogen has an important rolein male reproduction.“ Its key finding: “Estrogen is extremely important tomaturation of sperm.“ Korach is scientific director of the environmental disease andmedicine program, at the National Institute of Environmental Health Sciences, inTriangle Park, N. C. (Dec. 4)

• Reports of infertilityin male mice – and men – who lack active follicle stimulating hormone (FSH) mayhave been greatly exaggerated. In women, absent FSH function does spell absoluteinfertility. An article in the February 1997 Nature Genetics reported: “Menhomozygous for an inactivating mutation of [FSH] receptor gene present variablesuppression of spermatogenesis and fertility.“

Another paper in the sameissue of the journal found that in mice, “FSH is required for ovarian folliclematuration but not male fertility.“ (Feb. 13)

GENOME MAPS:

• Since 1995, some14 microorganisms have had their complete genomes sequenced. Of these, the following ninewere announced in 1997, twice as many as in ‘95 and ‘96 combined.

GENOME COMMON NAME SIZE (Mb)
Saccharomyces cerevisiae Yeast 1.83
Helicobacter pylori Ulcer pathogen 1.66
Escherichia coli Gram+ bacterium 4.60
Methanobacterium Extremophile thermoautotrophicum 1.75
Bacillus subtilis Gram+ bacterium 4.20
Archeoglobus fulgidus Archeobacterium 2.18
Borellia burgdorferi Lyme disease bacteria 1.44
Aquifex aeolicus Aerobic oxygen reducer 1.50
Treponema pallidum Syphilis pathogen 1.14

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