Companies (at least public ones) customarily produce annual reports for shareholders and potential investors. Here is BioWorld Today s annual report of newsworthy milestone advances in biotechnology research and development during 1998. The selected items, set forth alphabetically by disease or other category, are keyed primarily to coverage in BioWorld Today. Date of issue all from 1998, all on page 1 unless otherwise noted follows each item in parentheses.


Multiple Sclerosis

A promising therapy for MS is a cytokine called human transforming growth factor beta (TGF-b). But TGF-b s promise in patients was hedged by unacceptable side-effects. The reason: That cytokine never got to first base because a latency protein kept it in check. So Jeanette Thorbecke, at New York University, turned to gene therapy in a mouse model of the disease. It has an MS-mimicking affliction called experimental allergic encephalomyelitis (EAE). Like MS, EAE sends T-cells of the immune system to attack the myelin basic protein that protectively sheaths nerve cells. Thorbecke s T cells gave that latency protein the slip, allowing TGF-b to get in its therapeutic licks. (Oct. 14)

Excessive uric acid in the body attacks the big-toe joints to cause gout, a disorder that hits far more men than women. The reverse is true of MS. Acting on the set-a-thief-to-catch-a-thief principle, immunologists at Thomas Jefferson University, in Philadelphia, dosed MS-mimicking mice with uric acid. Eighty percent of them lived for 24 days; all control animals were dead by day 16.

Then the researchers checked the medical records of 20,212,505 Medicare and Medicaid patients. Of this number, 36,733 had gout; 34,607, MS. Statistical analysis predicted that 62 should have incurred both diseases; in fact, only four did. They conclude that oral uric acid might prove a useful therapy for MS. (Jan. 22)

Rheumatoid Arthritis

As a therapeutic to alleviate RA symptoms, immunologist Sharon Wahl places her bets on a molecule in the immune system called human transforming growth factor-beta (TGF-b) This cytokine switches on inflammatory cells as needed by the body, and calls off that inflammation after it s done its job.

Wahl, who directs the oral infection and immunity branch at the National Institute of Dental Research, in Bethesda, Md., had shown that if we put TGF-b directly into the arthritic joints of rodents, we made their arthritis worse. If we gave it systemically into the bloodstream, it made their symptoms better. She then turned to gene therapy as a strategy for getting the rats to make their own TGF-b. Wahl and her team planted the growth factor s naked DNA in a circular bacterial plasmid, and injected the construct into the rats muscle. A single 300-microgram shot produced a striking reduction in the number of arthritic joints, and in the disabling swelling and deformity. Inflammation subsided, and no cartilage or bone loss occurred.

This is the first evidence, Wahl pointed out, that one can administer the growth factor as a naked DNA gene, at a site different from the inflammation, and see a biologically active effect. (June 17)



As part of his decades-long campaign to starve tumor cells to death, Harvard Medical School surgeon Judah Folkman announced on April 1, 1998, a gene-therapy assault on the cancer s blood supply. It was no April Fool s hoax, but triggered a media frenzy.

Members of Folkman s lab told the annual meeting of the American Association for Cancer Research that they had transferred and expressed in mice two proteins that block angiogenesis. The senior author of their presentation was Philippe Leboulch, chief scientific officer of Genetix Pharmaceuticals Inc., in Cambridge, Mass., which collaborated with the Harvard scientists.

Their anti-angiogenesis product was a gene sequence encoding a fusion protein of angiostatin and endostatin, which stop blood-vessel proliferation. Inserted into nude mice bearing human neuroblastoma cells, it strongly inhibited growth of those tumors. (Apr. 7, p. 3)

Holding a fertilized hen s egg up to the light reveals on its large end a fine web of red blood vessels. They will nourish the growing chick during its 21-day incubation.

Malignant tumors too gorge themselves on blood pumped into them by angiogenesis the spread of veins, arteries and capillaries. Efforts to strangle tumors in their cradle, as it were, have spawned a spreading anti-angiogenesis movement among molecular biologists and oncologists, among others.

At the Scripps Research Institute, in La Jolla, Calif., one such investigator, David Cheresh, showed how an enzyme that promotes angiogenesis can be cleaved to produce a fragment that inhibits this process. The fragment, PEX by name, that he tested in hens eggs seeded with human tumors, curbed tumor growth and cut down on blood-vessel density. (Feb. 10, p. 3)


Glioma, a highly aggressive form of brain cancer, is the leading killer of children with cancer. It strikes 15,000 to 20,000 victims a year in the U.S. alone. Chemotherapy and radiation are the only treatments; after such therapy the average patient s life expectancy is 12 months.

Some years ago, researchers discovered a molecule in glioma cells that they called brain-enriched, hyaluronan-binding (BEHAB) protein. This year, Yale University neurobiologist Susan Hockfield discovered that BEHAB alone doesn t turn glial cells malignant. Rather, she and her colleagues have apprehended a cleaved fragment of the BEHAB sequence as the tumorigenic culprit.

In pursuit of better treatments for glioma tumors, Hockfield cites three therapeutic targets: block BEHAB; block the enzyme that cleaves its cancer-causing fragment; find the factor in the brain that induces glial cells to make BEHAB. (Apr. 2)


Multiple polyps in the large intestine are a likely early stage of adult colon cancer. One variant is juvenile polyposis (JP) in children and teen-agers, which often progresses to gastrointestinal malignancy. JP can be familial, with a strong family history of the disease, or sporadic, with no apparent inheritance pattern.

Surgical oncologist James Howe, at the University of Iowa School of Medicine, in Iowa City, focussed on an extended family of 46 members, 13 of them with JP. He and his crew detected germ-line mutations on a gene involved in cell growth. They found this mutant gene in all 13 JP members of the family, in none of their spouses, and in four of 26 individuals at 50 percent risk of contracting colorectal cancer. Howe advises genetic counseling for JP families that harbor this gene mutation. (May 15)

Aspirin, of all things, turns out to be a tumor suppressor. It puts down the accumulation of gene mutations that cause hereditary nonpolyposis colorectal cancer. Between 15 and 30 percent of colorectal cancers have a hereditary origin, half of which involve germ-line mutations of the human DNA-mismatch repair genes. The unlucky people thus endowed inherit one good copy of the repair gene from one parent, and a bad copy from the other. Later in life, if the good copy in one cell suffers mutation, the cancer can take off. Researchers at Thomas Jefferson University, in Philadelphia, determined that aspirin lowers the rate at which such mutations occur. (Sept. 15)


Detecting the presence of a solid tumor in a patient suspected of cancer often involves radio-imaging or tissue biopsy. Thus, mammograms seek out breast cancer; colonoscopy goes after tumors of the large intestine; a rise in prostate-specific antigen may signal malignancy in that gland.

A simple blood test is in the works to replace these more invasive diagnostic procedures. It s based on the concept that as solid tumors grow, they shed millions of their malignant epithelial cells into the bloodstream. There, oncological immunologist Jonathan Uhr, at the University of Texas Southwestern Medical Center, in Dallas, separates out those tumor cells by means of ferromagnetic spheres coated with antibodies directed at the tumor cells. Collected in a cell-sorter, these then confirm the malignancy by inspection under the microscope.

Uhr and his colleagues verified their blood-test rationale in patients with breast cancer, and plan to apply it routinely in breast and prostate cases at the Dallas clinic, to further refine the test. (Apr. 16)


Before the immune defense s killer T cells can mow down upstart cancerous cells, they have to recognize that malignant target for what it is. Presenting wannabe tumors to these surveillance patrols is the mission of human lymphocyte antigen (HLA) molecules. But cancer risk factors, such as flawed genes, viruses, cigarettes, toxic chemicals and UV radiation, allow the odd proto-tumor to elude surveillance.

Steven Rosenberg, chief of surgery at the National Cancer Institute, has cloned the genes for the tumor antigens by which T lymphocytes recognize melanomas. As the tumor-associated target antigen for their anti-melanoma vaccine, they chose one, glycoprotein-100, and chemically enhanced its ability to bind those HLA molecules. Then they added to the vaccine mix a cytokine, interleukin-2, which boosts the growth of T lymphocytes, and injected this vaccine into 31 melanoma patients. In 13 of them 42 percent their tumors shrank by 50 percent or more. (Mar. 9)


The strongest risk factor for prostate cancer (PC), aside from maleness is blackness. Latest figures show 520 black men per million die of the disease, compared with 236 per million whites.

Now clinical oncologists at McGill University, in Montreal, have unveiled what they describe as the strongest predictor of contracting PC yet found. It s a protein in blood called insulin-like growth factor (IGF). They compared the IGF plasma levels of 152 U.S. physicians who got PC in the years since 1992 with those of 152 controls who did not. The former had 4.3 times as much of the protein as did the latter. (Jan. 23)

Once a prostate cancer tumor has broken out of its capsule wall and begun to metastasize to other organs, the preferred treatment is palliative rather than curative. Castration, surgical or chemical, cuts off production of testosterone, the male androgen hormone, which drives the tumor s growth. Diethylstilbestrol, a synthetic form of the female hormone, estrogen, also targets the testosterone receptor, which acts as a transcription growth factor.

Oncologists at the University of Rochester, in New York, found that estrogen activated that receptor in human prostate cancer cells, in the presence of a co-activator they discovered. Virtually every patient who succumbs to PC 40,000 men each year dies of a disease that initially was stimulated by androgens, said cancer surgeon Edward Messing, who chairs the urology department at the university. This discovery, he added, is the first demonstration that an estrogen can switch on the androgen receptor, and also turn on genes that normally only respond to androgen stimulation. (May 12)



In January 1998, a 25-year-old woman became the sixth fatality of avian virus flu in Hong Kong. Health authorities halted the outbreak by overseeing the slaughter of more than 1.5 million chickens and other fowl populating the island territory. Virologists at the U.S. Centers for Disease Control (CDC) isolated the Hong Kong virus from its first victim, a 3-year-old boy. Should this viral strain begin to spread human-to-human, for lack of a chicken vector, pending discovery and production of a vaccine, the lead CDC virologist observed, mankind would not be entirely defenseless, as it was in the 1918 influenza pandemic. (Jan. 16)

When that great influenza pandemic of 1918 started killing millions of people worldwide, the governor of Alaska proclaimed a total quarantine, prohibiting all ships from entering the territory s ports, to protect Alaskans from the infection. He overlooked one loophole: the U.S. Postal Service. A lone letter carrier came ashore at a small coastal harbor, bringing the mail and the virus.

At a nearby mission community of some 90 Eskimos, 90 percent were dead within a week. Their bodies, buried in the permafrost, were exhumed in 1997 by a retired pathologist, who sent lung tissue from one victim to the Armed Forces Institute of Pathology s Jeffery Taubenberger, in Washington, D.C. He had sequenced DNA from two U.S. soldiers who died in 1918 at the height of the pandemic. That Eskimo tissue, Taubenberger said, allows us to compare it to the sequence we generated from the first case, then look for genetic variations of the virus. (Feb. 9)


For three decades, parasitologist Ruth Nussenzweig, at New York University, has been constructing vaccines aimed at bringing down the deadly Plasmodum falciparum, pathogen of malaria. So far the score is 1-0, favor P. falciparum. Her latest strategy involved two vaccines, delivered in sequence. Both plasmids encoded immunogenic proteins of the parasite s sporozoite stage. The first, a recombinant influenza virus vector, could express only the essential fragment of the sporozoite protein, namely a B-cell epitope, eliciting an antibody response, and a cytotoxic lymphocyte (CTL) epitope, triggering a T-cell attack. The second vaccine embodied a highly virulent vaccinia virus vector, roomy enough to express the entire sporozoite surface protein.

First, Nussenzweig injected mice with the flu-virus package containing the CTL target antigen. Three weeks after, the potentially lethal vaccinia construct was injected into the animals brains. A fortnight later they were alive and without any trace of vaccinia virus in their brains. It was a very striking protection, Nussenzeig observed. (Apr. 7)

Vaccinologists at Vical Inc., a San Diego, Calif., firm, teamed with parasitologists at the U.S. Naval Medical Center, in Bethesda, Md., to design and test a naked-DNA vaccine, which expressed the full-length circumsporozoite gene from P. falciparum. The Phase I trial enlisted 20 healthy volunteers. A majority of them developed killer T-cell responses. Designers of the vaccine explained that naked DNA may side step the obstacle in conventional vaccines of individuals variability to specific antigen recognition and response. (Oct. 16)


Just over half a century ago, a new antibiotic, isoniazid, turned the statistics of TB infection and death around. It was a one-pathogen, anti-TB drug, and it worked for a while. But as early as 1954, that germ, Mycobacterium tuberculosis, wised up to isoniazid, and developed drug resistance. Nowadays isoniazid barely works unless reinforced by two or more additional antibiotics.

Until two years ago, no one knew how isoniazid got in its anti-TB licks. Then Clifton Barry at the National Institute of Allergy and Infectious Diseases, in Hamilton, Mont., discovered that the antibiotic moved in on a bacterial enzyme involved in making the pathogen s cell wall, thus killing the cell.

Then Jim Musser at Baylor College of Medicine, in Houston, figured out the genetics by which the bacterium produced strains resistant to isoniazid. Whereupon, enzymologist Kirk McMillan at Pharmacopaeia Inc., in Princeton, N.J., joined with Barry to develop a fast assay that in a few hours can identify inhibitors of cell-wall biosynthesis such as isoniazid. We intend to screen one-million-plus compounds, looking for novel anti-tuberculars, McMillan said. (June 8)

Antibiotics such as isoniazid lock the TB barn door after their horse is stolen. What s needed is an effective preventive vaccine. A few years ago, two immunologists, Michael Brenner and Steven Porcelli, at Harvard-affiliated Brigham and Women s Hospital, in Boston, discovered a third immune-system antigen-presenting pathway, managed by the CD1 molecule. They showed, for the first time, that CD1 added immunogenic lipids (fats) to the protein and peptide targets thus far known.

In guinea-pig models of TB infection, the animals immune systems recognized infective antigens from M. tuberculosis, and elicited T cell responses. These specific T lymphocytes were programmed to break and enter the lung-infecting macrophages in which the pathogen holes up, sheltered from antibodies, and kill it dead. Brenner and Porcelli are co-inventors of a U.S. patent, which their hospital has licensed to Aquila Biopharmaceuticals Inc., in Worcester, Mass. The firm is developing the TB vaccine, based on the researcher s ongoing in vivo preclinical experiments. (June 16)


Alzheimer s Disease

In postmenopausal women, estrogen replacement therapy fends off osteoporosis, but at a heightened risk of uterine cancer. Now there s evidence that estrogen also slows down or wards off the neural degeneration by amyloid-beta peptides that are pathological hallmarks of Alzheimer s disease (AD).

Biochemist and cell biologist Sam Gandy, at New York University and the Nathan Kline Institute, in Orangeburg, N.Y., treated fetal human brain neurons with estrogen. Compared to untreated neurons, the hormone lessened output of amyloid-beta (a precursor of AD s senile neuritic plaques) by half.

If all goes well, the researchers predicted, it will mean that estrogen may be recognized as a lead compound in designing drugs against AD. (Apr. 8)

Drug Addiction

An enzyme named cytochrome P2A6 (CYP2A6) is mostly involved in ridding the human body of nicotine. Two mutations occur in the structural, or coding, region of the CYP2A6 gene, pointed out molecular pharmacologist Rachel Tyndale, at the University of Toronto. Both express an inactive product. A fortunate fraction of the population harbors these defective proteins.

The active enzyme removes nicotine slowly, so smokers have to restock their levels of the drug at greater intervals. Hence they smoke fewer cigarettes. When people are learning to smoke, Tyndale explained, nicotine levels stick around for a longer time, but cause dizziness and nausea, for example, in a non-tolerant beginner. And we think that in the people who are slower at getting rid of these effects because they harbor an inactive enzyme that tips the balance toward them not wanting to smoke.

She and her team looked for defective CYP2A6 genes in the chromosomes of 428 present and former cigarette smokers. Those who had inherited a mutant gene (allele) from only one parent consumed 129 smokes a week, whereas those with two active genes from both parents had a weekly cigarette usage of 159. These findings, Tyndale concluded, provide further support for the fact that nicotine is indeed an addictive drug, which smokers are very carefully replenishing on a daily basis. (June 25)

A person who tries to give up smoking is punished by two kinds of withdrawal agony. The somatic or physical costs of quitting cold turkey may include sweating, dizziness, racing heart, tremor, and hunger hence increased body weight. But the emotional signs of drug withdrawal, observed psychopharmacologist Athina Markou, at the Scripps Institute, in La Jolla, Calif., such as anxiety, irritability, inability to concentrate, and depression-like symptomology, are longer-lasting than the somatic aspects.

Markou interprets backsliding as the would-be quitter is self-medicating his or her withdrawal symptoms with nicotine. When a nicotine-addicted rat is abruptly cold-turkeyed, Markou said, the findings of its withdrawal have been so far limited to somatic signs gasping for breath, writhing, teeth-chattering. She has demonstrated in rats that emotional more than somatic withdrawal from nicotine, and other drugs of abuse as well, stimulate demand for euphoria by a jolt of electricity directly to the brain s reward center in the hypothalamus. (May 11)

What cholesterol does to the heart i.e., starve it of oxygen cocaine seems to do to the brain. Human volunteers who shot up high and low doses of pure cocaine in a double-blind trial experienced transient narrowing of the cerebral arteries that nourish the brain.

A research neuropharmacologist at Harvard-affiliated McLean (Psychiatric) Hospital in Belmont, Mass., scanned the brains of the volunteers with magnetic resonance angiography twice just before and just after getting their cocaine fix. Five of the eight high-dose recipients showed constricted cerebral blood vessels, suggestive of the strokes that hit a small percentage of cocaine users.

Most of them don t even know they ve had a stroke, which may cause loss of memory, and attention, and other cognitive effects. Alan Leshner, director of the National Institute on Drug Abuse, observed: If these users are compromised in their cognitive functions, they may be far less able to adhere to treatment programs designed to reduce or stop their drugs. (Feb. 5)

Often described as the brain s own morphine, endorphin is released by the brain s opioid system to relieve pain, and fulfill the cravings of narcotic addicts. Seeking a molecular basis for why some people use drugs of abuse and others are indifferent to them, molecular geneticist Lei Yu and neuroscientist Mary Jeanne Kreek, at the University of Cincinnati screened 113 former heroin addicts, now on methadone, and 39 control individuals. By DNA analysis, they discovered in one human opioid receptor molecule five single-nucleotide polymorphisms, which alter endorphin activity. One in particular seemed to correlate with drug-seeking behavior, which, Kreek observed, may eventuate at some future time into addiction treatments, including gene therapy. (Aug. 4)

Nerve Trauma

The universally accepted dogma that human brain cells can t regenerate has taken a qualified hit. Generations of neurologists have long known, and taught, that the 100 billion neurons in the human brain begin dying off soon after birth, and can never be replaced. They associated this accelerated cell demise in old age with the onset of neurodegenerative diseases.

Neuroscientist Fred Gage, at the Salk Institute for Biological Studies, in La Jolla, Calif., has found evidence to the contrary. His postgraduate student discovered a clinical study of throat cancer cases at Sweden s G teborg University Hospital. Those terminal patients received a marker drug, bromodeoxyuridine (BrdU, to assay the growth of brain neurons. (BrdU decorates the nuclei of cells that have undergone division.)

The Salk team gained permission from five terminal patients to look for signs of possible new neuron growth in their brain autopsies. They found such signs in the hippocampus. Gage s report of this discovery concluded that cell genesis occurs in human brains as in rodents and retains the potential for self-renewal throughout life. But he added that Practical implications of this counter-dogma finding are fairly theoretical at this point. (Nov. 18)

Parkinson s Disease

Since 1988, some 200 Americans with Parkinson s disease (PD) have received transplanted human fetal brain cells, to replace their lost dopamine-producing neurons. Neurosurgeon Curt Freed, at the University of Colorado in Denver, pioneered these still-experimental transplants. Now he and his collaborators are cloning such dopamine-rich tissue in embryonic calves.

Freed s group implanted the resulting bovine fetal cells into the brains of rats rendered parkinsonian by a chemical that poisoned their dopamine-producing neurons. Such PD rodent models rotate in aimless circles, as a measurable sign of their surrogate disease. They then received cerebral infusions of the cloned bovine dopaminergic neurons. One month later, these animals showed significant and persistent remissions of their rotational behavior.

The use of cloned tissue, Freed commented, is an improvement over existing animal transplantation technologies, because it provides us with large quantities of identical cells. While this early-stage research shows promising results, it will be some time before we begin human studies. (May 4)


Genome Sequencing

Amid the rising tide of organisms with genomes totally sequenced in 1998, these three stand out as relevant to biotech research:

Heart Disease

Two divergent approaches, one surgical, one non-surgical, have tackled cardiovascular disorders. A 60-year-old man with coronary artery disease received 10 injections into his heart during bypass surgery at Cornell University Medical College in New York. The gene therapy consisted of genes expressing endothelial growth factor, delivered by a disarmed adenovirus.

Simultaneously, Collateral Therapeutics, of La Jolla, Calif., announced plans to treat atherosclerosis by threading a catheter through a femoral artery into a coronary artery, and there deliver the gene therapy package well inside the heart muscle, to stimulate the growth of collateral blood vessels. (Jan. 7)

About 30,000 Americans a year suddenly drop dead because their hearts start beating erratically. This hereditary disorder is called idiopathic ventricular fibrillation (IVF). Molecular geneticist Jeffrey Towbin, at Baylor College of Medicine, in Houston, set out to find the genes responsible. But, he observed, it s hard to get blood from a dead person. So he and his colleagues drew blood from living members of three families with a high number of IVF deceased. Storing these samples enabled them to track the suspect genes.

Instead of just extracting the DNA and RNA from the white blood cells, they immortalized those cells, using Epstein-Barr virus, so they could grow indefinitely on their own. The investigators knew that certain mutant ion-channel genes occurred in cases where ventricular arrhythmias were present. They found three different mutations, one in each family s DNA. This finding permits an immediate preventive measure indwelling, automatic defibrillators and eventually, drug therapy that works on those defective ion channels. (Mar. 19)

Regular moderate consumption of alcoholic beverages is good for the heart, according to popular (and some scientific) belief. It s supposed to lower cholesterol levels. Cardiologist Vincent Figueredo, at the University of New Mexico proposes a second mechanism, which supports a finding that people who imbibe a little ethanol daily are more likely to survive a heart attack. He suggests that alcohol blocks the transport of adenosine, which dilates blood vessels feeding the heart. (July 10)


Missing blood-clotting factors VIII and IX are the principal causes of hemophilia A and B respectively. When a victim of this hereditary, males-only affliction suffers a bleeding episode, (usually internal), he receives transfused VIII or IX, depending on his specific form of the disease.

But upstream of these two coagulation-cascade proteins is factor VII, which is thought able to bypass VIII or IX altogether. Sometimes a hemophiliac s immune system stops recognizing factor VIII. In such a life-threatening crisis, high-dose, high-cost recombinant factor VII is transfused as a stopgap measure.

Coagulation factors all work by binding to a receptor-like molecule that s exposed only when bleeding breaks open the cell s plasma membrane. Biochemist Gary Nelsestuen, at the University of Minnesota, in St. Paul, has altered two amino acids in factor VII s protein sequence, which makes it bind to the docking site with higher affinity, hence greater efficiency, and presumably lower dosage. Clinical trials may be in the offing. (Apr. 21)

One of the cruelest Catch-22s that afflict a patient with hemophilia A absence of a functioning factor VIII gene is that his na ve immune system sees and rejects replacement factor VIII as non-self. The only therapeutic countermeasure is enormously stepped-up dosage of the coagulant protein, to outgun the anti-VIII antibodies and T cells. (This same rejection danger threatens many other gene-therapy products.)

Richard Morgan, who directs gene transfer at the National Human Genome Research Institute, in Bethesda, Md., took aim at this factor VIII paradox in knockout mice lacking the factor s gene. His strategy would teach the animals blood-forming stem cells, which produce the immune system s T cells and B cells, to perceive the factor VIII protein as self.

Morgan and his team transformed the mouse stem cells with the gene encoding human factor VIII. Then, they transplanted the resulting factor-positive bone marrow into a second factor-negative mouse, after wiping out the recipients own bone marrow by irradiation. Half of these reconstituted mice, Morgan recounted, did not develop anti-factor-VIII immune responses, while every one of the controls did produce lots of antibodies. And one-half represents a good result for this experimental gene therapy. (May 14)

Organ Transplantation

An organ transplant recipient pays a price for his or her donor graft, beyond the cost in dollars. It s a lifelong blackmail debt called immunosuppression, payable to the immune system to avoid rejection of the alien implanted tissue. Cyclosporine, the most-used immunosuppressive drug, poses a constant threat of infection, not to mention such side effects as excessive hairiness, high blood pressure, tremor, gum overgrowth and kidney dysfunction.

While transplant surgeons work to develop new and improved immunosuppressants, a team of Japanese transplant immunologists at Kansai Medical University, in Osaka, is bent on doing away with such drugs altogether. Instead, they seek to create a state of immune tolerance between the donor graft and the recipient s immune system. They report achieving this peaceable-kingdom effect in mice, and more recently in pigs, which are putative candidates for xenotransplantation. (June 10)

Transplant surgeons have great expectations that the common pig can become an organ donor for human recipients. But virologists now warn that prospective porcine donors harbor retroviruses that may infect graft recipients. In three breeds of swine from 12 sites in four European countries, a German group detected porcine retrovirus in every sample of skin, liver, lung and aortic endothelial cells. Co-cultivation of the aortic cells with human embryonic kidney cells led to their infection with the pig virus.

However, at Sweden s Karolinska Institute, 10 diabetic patients received 400 million to two billion insulin-secreting islets of Langerhans from fetal pig tissue. In five of them, the xenografts survived and functioned for up to a year. (Aug. 31)


Your average healthy male puts out some 200 million sperm cells a day. Only a fraction of that output gets as far as ejaculation, much less fertilization. The sperm assembly line goes through quality control and culling en route from cell generation to maturation. Whether this rejection process takes the form of simple necrosis (lethal damage) or programmed cell death (apoptosis) is a subject of lively research.

Developmental geneticist Grant MacGregor and his colleagues at Emory University, in Atlanta, went looking for genes involved in male gametogenesis. One putative payoff for male contraception was finding a drug to block such a gene s protein product. Another spinoff would be molecular mechanisms to abrogate testicular cancer.

In sterile mice, the team identified two mutually antagonistic genes. They act like a control center for apoptosis, MacGregor explained, meaning that its gene would be expressed in places where one might wish cells to survive. (Mar. 10)

When research cardiologist Randall Moreadith, at the University of Texas, inserted a pigment-forming gene along with a target site into albino mice, he hoped he could see that the transgene had gone in by changing the rodent s coat color back to normal pigmentation. Instead, he accidentally came up with an animal model of human male infertility

Moreadith noticed that when he bred the transgenes, male progeny with two copies of the gene, one on each chromosome, were sterile; they couldn t form sperm cells. At six months of age, all the sperm-producing cells were dead, and testicles had shrunk to one-third of their normal size. Some infertile men display similar symptoms.

The researchers propose that the gene conferring this condition might be useful not only as a diagnostic but possibly as an infertility therapeutic. Conversely, they point out, something that could inhibit this gene or its protein product would be a good male contraceptive. (Nov. 25)

Stem Cells

At the instant of fertilization, the maternal and paternal founder cells join to launch the cascade of differentiation that will turn all-purpose cells downstream into single-minded specialists in the embryo-to-be. Until it starts differentiating, that mother-of-all-stem-cells is a pluripotent free agent.

To a developmental biologist, the holiest of all grails is to wrap his or her hands around a human embryonic stem cell. Now one such scientist, James Thomson at the University of Wisconsin, in Madison, has done just that. A university spokesman observed that Thomson is the first of many scientists in hot pursuit of the human embryonic stem cell to come up with the trophy.

Those cells, Thomson said, are different from every other human stem cell isolated to date. As the source of all cell types, they hold great promise for use in transplantation medicine, drug discovery and development. The Geron Corp., of Menlo Park, Calif., holds worldwide exclusive licenses to Thomson s issued and pending patents. (Nov. 6)

Because Thomson s technology, and the stem-cell lines, are under patent protection, said Norman Fost, director of the university s medical ethics program, all uses of the technology will require a license. This will not be granted if the user intends to use the cells for cloning human beings, or germ-line manipulation of humans.

In that the cells can t simply be implanted into a woman s uterus and become a human life, the technology does an end run around many ethical questions associated with human embryo research. (Nov. 6, p. 2)

DNA Microchip Arrays

The genome of a chimpanzee (Pan troglodytes) is 98.5 percent the same as that of a human (Homo sapiens). But a breast-cancer gene mutation s sequence is 99.2 percent identical. Molecular geneticists at the NIH s National Human Genome Research Institute (NHGRI) and Affymetrix Inc., of Santa Clara, Calif., teamed up to make the genomic comparison in seven subhuman primate species plus the dog (genomic identity 83.5 percent).

It was the first time DNA microchips had been used to sequence nucleotides from nonhuman primates. Their thumbnail-size array was paved with some 48,000 DNA fragments that added up to the 3.4 kilobases of exon II on the breast-cancer BRCA-1 gene. (Jan. 27)

Scanning an entire genome on a single chip is the goal of molecular geneticist Vivian Cheung, at the Children s Hospital of Philadelphia. As a demo model, she set out to track down the chromosomal whereabouts of a gene for hyperinsulinemia (HI), a rare, inherited disease affecting mainly Ashkenazi Jews and Arabs. Conventional linkage analysis had already traced HI to a region of human chromosome 11 s short arm.

Her group took blood from nine HI patients, extracted the DNA and isolated the shared regions. They then hybridized those fluorescence-labeled, genomic not complementary DNA fragments onto glass slides arrayed with known DNA clones. Beyond this proof-of-principle exercise as a better way than genotyping, the group is now making chromosome X and Y chips. Then, Cheung concluded, we ll march down the rest of the human genome. (Mar. 5)


Twenty years ago, in the (then) Soviet city of Sverdlovsk, a mysterious epidemic killed 96 people. Authorities claimed that the anthrax outbreak was caused by people eating bad meat they bought from private butchers.

Now, DNA forensic technology has confirmed that Bacillus anthracis was the killer. Moreover, the molecular biologists at Los Alamos National Laboratories, in New Mexico, and Northern Arizona University, in Flagstaff, detected not one but five strains of the pathogen in the autopsied tissue samples from 11 of the 96 casualties.

To find multiple strains in victims all at the same time, the scientists pointed out, was inconsistent with a natural outbreak. They concluded that a biowarfare facility in Sverdlovsk released these anthrax strains, presumably by accident, and that the cocktail might have been assembled for greater efficacy in a missile payload. (Feb. 3)

While the U.S. Defense Department is developing a vaccine against anthrax attack, it is also testing antidotes, including an emulsion called BCTP. This proprietary product was developed by Novavax Inc., in Columbia, Md. The company reported that mice carrying simulated wounds infected by Bacillus anthracis, then treated with BCTP, had skin lesions and swellings reduced by 95 percent, while 80 percent of control animals died. (Oct. 5, p. 3)

DNA Paternity Testing

Just as Dolly, the cloned sheep, was the media blockbuster of 1997, so a research paper in Nature, dated Nov. 5, 1998, beat out all other biotech-related news items in 1998. Its simple title told the whole story: [Thomas] Jefferson fathered slave s last child. The article s lead author was professor of pathology Eugene Foster, retired from the University of Virginia, in Charlottesville which, incidentally, Jefferson founded.

The DNA forensic analysis that Foster and his co-authors reported reached the conclusion that Jefferson fathered at least one child with his slave, Sally Hemings. Genetic linkage tracked back to the mother s fifth offspring, Eston Hemings Jefferson. The key genomic indicator was the maleness Y chromosome.

As the index for Thomas Jefferson s Y chromosomal DNA, the co-authors used DNA from the living descendants of the former president s paternal uncle. They found that this ancestor shared the same Y chromosome that passed down the generations from Sally s son, Eston, to 52-year-old John Jefferson, now residing in Norristown, Pa. (Nov. 4)

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