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Each month brings new investigative tools, as well as commercial and therapeutic applications of existing technologies. No one can predict which of today�s discoveries will most shape tomorrow�s industries, but these synopses describe recent research that warrants attention.
The Express Difference
RNA interference can select for bad genes alone.
Context: In the last three years, RNA interference (RNAi) has become a standard tool to silence genes in early drug development, and the technology�s promise as a therapeutic has spawned several startups. But serious questions remain about whether RNAi can block expression of problem genes without interfering with expression of essential ones. Diseases like Huntington would be especially challenging; it occurs when one of the two copies of the gene for a particular protein is defective. Nonetheless, the nearly identical normal gene must be expressed for proper cell function (except for sperm and eggs, human cells have two copies of each gene, one from each parent). Miller et al. at the University of Iowa have found that RNAi can stop expression of disease-causing versions of such genes selectively—even when the two versions differ by only one nucleotide.
Lipinski Still Rules
In drug development, compounds with high molecular weights are the most likely to fail.
Context: Drug designers generally agree on the chemical requirements of orally administered drugs. Many of these notions derive from decades of empirical observations that predict whether or not a drug can reach and act on its target tissue. These observations have been codified in the 1997 analysis by Christopher Lipinski, Ph.D., putting forth the so-called rule of five, which specifies properties for suitable drug candidates in terms of molecular weight, the number of hydrogen bond donors and acceptors, and lipophilicity (a measure corresponding roughly to greasiness). Dr. Lipinski�s analysis has been questioned because the findings may reflect earlier, simpler drugs and, thus, may be a historical artifact. Wenlock et al. now update Dr. Lipinski by examining molecules currently in various stages of drug development (Phase I, II, III, preregistration, and marketed), as well as those that have been dropped from these stages.
Hot off the Press
Researchers show how the pain receptor adapts.
Context: The protein that responds to capsaicin (the chemical that makes peppers taste hot) conveys both heat and pain. When temperatures get hot enough to damage tissues, this protein, called the capsaicin receptor, causes nerve cells to send messages to the brain. If tissue becomes more vulnerable to damage (as after a sunburn), the receptor becomes more sensitive to heat and responds at lower temperatures. Prescott and Julius describe how a small molecule known as PIP2 (phosphatidylinositol-4,5-bisphosphate) regulates the receptor so that it fails to respond to safe levels of heat and chemicals but responds to dangerous ones with pain messages. The findings could contribute to treatment for chronic pain.
Aging Too Fast
Progeria linked to spontaneous gene mutations.
Context: After a long, hard search, two research teams have identified the gene responsible for progeria, an extremely rare disease that causes victims to develop symptoms of old age quickly and die in their teens of heart disease and stroke. The LMNA gene, which codes for a protein called lamin A, is the culprit; mutations in it are implicated in many other disorders of the muscular and skeletal system. The protein forms part of a complex web of proteins inside the nuclear membrane, and its misfunction is believed to wreak havoc in cell division. A third team has created mice with a very similar condition.
Old DNA Tales
Changes in DNA predict prostate cancer.
Context: Prostate cancer is the most common form of cancer in the United States and, for men, the second most fatal. According to the National Cancer Institute, prostate cancer is the second most prevalent cancer, after skin cancer, in men. One reason mortality is so high is that often the cancer is not detected until it has spread to many parts of the body. Scientists have now developed a prostate DNA test that can distinguish between tissue from older men (ages 55 to 80) and tissue from younger men (ages 16 to 36), as well as between prostate cancer restricted to the prostate and cancer that has spread to other parts of the body.
Monkeying with Mental Functions
Certain types of loss in vision can be reversed.
Context: Sometimes vision and hearing problems in older people are due to the parts of their brains that process sight and sound: older brains seem less able to filter out distractions. Scientists have noted, specifically, that as monkeys age, neurons in the primary visual cortex lose their ability to respond selectively to various patterns of lines and movement. This kind of loss was generally considered irreversible. But researchers have shown that a neurotransmitter called GABA (γ-aminobutyric acid) can restore much of this ability in the neurons of older monkeys.
Oöcytes to See
Embryonic stem cells can form green eggs (no ham).
Context: Embryonic stem (ES) cells can form many types of tissue, including beating heart cells, neurons, and bone- and blood-forming cells. But these cells had never been observed to form germ cells, that is eggs and sperm. Now H�bner et al. provide strong evidence that mouse ES cells can become egg cells, also known as oöcytes. If this turns out to be the case, obtaining eggs for therapeutic cloning, research, and even in vitro fertilization might become much easier.
Unzipping Cells
Bacterial peptides align.
Context: The bacteria Staphylococcus aureus and Streptococcus pyogenes cause a host of diseases, including pneumonia and sepsis. By entering host cells, these bacteria avoid the immune system and antibiotics, cross through the cells that line blood vessels, and spread through the body. To penetrate cells, the bacterial cell wall attaches to the host protein fibronectin, which is involved in cell adhesion. Schwarz-Linek et al. have deduced a 3D structure of host and bacterial proteins in contact.
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