By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Hippocrates (circa 460-377 B.C.E.) prescribed brewing a tea from the bark of the willow tree (botanical genus Salix) to treat headache and fever.
Lo! The legendary ¿Father of Medicine¿ had discovered the active ingredient of aspirin two millennia before German chemists in the mid-19th century obtained salicylic acid. This is now the most popular drug of all time, with over 10,000 tons of the stuff consumed annually in the U.S. alone. In recent years, enterically coated aspirin tablets have curbed its gastrointestinal irritation.
Throughout the 1800s, powders and potions were the physician¿s pharmacological mainstay, followed by pills and capsules in the 1900s. Late in that century, liposomes and polymer microspheres came on the drug-delivery scene, while oral and inhaled insulin began moving in on the traditional injection needle.
Now a one-page review article titled ¿Drugs on target,¿ in an issue of Science released June 25, 2001, surveys the future of pharmaceutical delivery in the present millennial century. Its author is biomaterials inventor Robert Langer, an endowed professor of chemical and biomedical engineering at Massachusetts Institute of Technology in Cambridge.
¿The field of drug delivery is advancing rapidly,¿ Langer averred. ¿By controlling the precise level and/or location of drug in the body, side effects are reduced, lower doses are often needed, and new therapies are possible ¿ with major benefits to patients.¿
He cited novel controlled-release systems for anticancer therapy, growth hormone, Ritalin and oral heparin and insulin through the lungs, ¿in final stage clinical trials. Sales of advanced drug delivery systems in the U.S.,¿ Langer noted, ¿are approaching $20 billion annually.¿
A sampling of what the MIT expert also foresees:
¿ To avoid the toxicity of polymers for gene therapy delivery, cationic b¿cyclodextrin-based polymers have been synthesized that complex DNA.
¿ To overcome the roadblock of delivering proteins orally, an enteric coating enables the drug to transit the stomach unharmed, as well as use of protease inhibitors, which spare protein destruction by digestive enzymes.
¿ The biggest challenge here will be to pass a drug through the GI tract into systemic circulation.
¿ ¿In the future, the intersection between nanotechnology and drug delivery may see exciting developments. Microelectrical mechanical systems or microarrays are being studied. For example, chips containing nanosized drug reservoirs might be able to deliver pharmaceuticals for long time periods in a controlled manner.¿ (See BioWorld Today, Jan. 28, 1999, p. 1.)
Flaws In Stem Cell Cloning Reported Variously In Science, Washington Post, BioWorld Today
An article in Science dated July 6, 2001, titled ¿Epigenetic instability in ES [embryonic stem] cells and cloned mice,¿ reached Page 1 of the same day¿s Washington Post, headlined: ¿Clone Study Casts Doubt On Stem Cells.¿
The Post¿s account observed, ¿The work shows for the first time that embryonic stem cells ¿ which are at the center of an escalating political and ethical debate as President Bush decides whether federal funds should be spent to study them ¿ are surprisingly genetically unstable, at least in mice.¿
The senior author of the Science paper is biologist Rudolph Jaenisch, a member of the Whitehead Institute for Biomedical Research and on the faculty of MIT, both in Cambridge, Mass. He led off by observing, ¿Cloning by nuclear transfer (NT) is an inefficient process in which most clones die before birth and survivors often display growth abnormalities.¿ In the experiments he and his co-authors described, ¿Many of the animals survived to adulthood despite widespread gene dysregulation, indicating that mammalian development may be rather tolerant to epigenetic aberrations of the genome. Our results indicate,¿ Jaenisch concluded, ¿that even apparently healthy cloned animals can have gene expression abnormalities that are not severe enough to impede development to birth but that may cause subtle physiological abnormalities which could be difficult to detect.¿
As it happens, a brief item on page 5 of BioWorld Today, dated July 2, 2001, carries the heading: ¿Why, at 1 percent, is cloning of farm animals so inefficient? One short answer: Mismethylation.¿
To Scope Stem Cell Leukemia Gene, Hulking Pufferfish, Tiny Zebrafish Genomes Fill Bill
The stem cell leukemia (SCL) gene regulates the formation of both blood (hemopoiesis) and blood vessels (vasculogenesis). The latter is a current hot topic of anti-angiogenesis strategies to thwart the growth and metastasis of nascent malignant tumors.
SCL has a pattern of expression that is highly conserved across vertebrate species from mammals to fish. To identify the full complement of regulatory elements in the SCL gene, amid the vast tract of noncoding mammalian DNA, research hematologists at the University of Cambridge, UK, enlisted the genomes of two piscine species ¿ the huge, venomous pufferfish (Fugu rubripes) and the minnow-sized zebrafish (Brachydanio rerio).
Their paper, in the Proceedings of the National Academy of Sciences (PNAS), dated June 5, 2001, bears the title: ¿Regulation of the stem cell leukemia (SCL) gene: A tale of two fishes.¿
¿One potentially powerful approach,¿ the co-authors recounted of their experiments, ¿takes advantage of the observation that the pufferfish genome is about 8-fold smaller than that of humans, yet contains a similar number of genes. Analysis of pufferfish DNA therefore provides an attractive strategy for identification of SCL regulatory elements . . . which are highly conserved from mammals to teleost fish.¿
However, they added, ¿pufferfish do not provide a tractable experimental system for in vivo studies. By contrast, the zebrafish is a powerful model organism for studies of vertebrate development, including hemopoiesis.¿ They combined the genomes of both species.