Posts tagged chemicals
Articles and news from the latest research reports.
Brain Damage in Children—The Result of Too Many Chemicals?
A new report is sounding the alarm of a “silent epidemic” of childhood neurological disorders linked to neurotoxic compounds.
While genetics is known to play a role in neurological problems, only 30 to 40 percent of neurodevelopmental disorders can be definitively tied to family history. “There are a lot of chemicals out there that have been shown to have the capability to injure the developing brain,” says study coauthor Philip Landrigan, MD, professor and chair of the department of community and preventive medicine at Mount Sinai School of Medicine in New York City and one of the world’s foremost authorities on children’s environmental health. “And we’re very concerned that a number of chemicals in everyday products have never been properly tested to determine whether they’re toxic to the human brain.”
In the new report, Dr. Landrigan and his coauthor identified six chemicals that have been discovered, within the past seven years, to trigger brain damage in children. In 2006, he and other researchers ID’d lead, methylmercury, arsenic, polychlorinated biphenyls (PCBs), and toluene as known contributors to rising rates of neurodevelopmental disorders like autism, attention-deficit hyperactivity disorder, and learning disabilities.
Stem cells reprogrammed using chemicals alone
Scientists have demonstrated a new way to reprogram adult tissue to become cells as versatile as embryonic stem cells — without the addition of extra genes that could increase the risk of dangerous mutations or cancer.
Researchers have been striving to achieve this since 2006, when the creation of so-called induced pluripotent (iPS) cells was first reported. Previously, they had managed to reduce the number of genes needed using small-molecule chemical compounds (1, 2), but those attempts always required at least one gene, Oct4.
Now, writing in Science, researchers report success in creating iPS cells using chemical compounds only — what they call CiPS cells.
Hongkui Deng, a stem-cell biologist at Peking University in Beijing, and his team screened 10,000 small molecules to find chemical substitutes for the gene. Whereas other groups looked for compounds that would directly stand in for Oct4, Deng’s team took an indirect approach: searching for small-molecule compounds that could reprogram the cells in the presence of all the usual genes except Oct4.
Then came the most difficult part. When the group teamed the Oct4 replacements with replacements for the other three genes, the adult cells did not become pluripotent, or able to turn into any cell type, says Deng.
Fine-tuning
The researchers tinkered with the combinations of chemicals for more than a year, until they finally found one that produced some cells that were in an early stage of reprogramming. But the cells still lacked the hallmark genes indicating pluripotency. By adding DZNep, a compound known to catalyse late reprogramming stages, they finally got fully reprogrammed cells, but in only very small numbers. One further chemical increased efficiency by 40 times. Finally, using a cocktail of seven compounds, the group was able to get 0.2% of cells to convert — results comparable to those from standard iPS production techniques.
The team proved that the cells were pluripotent by introducing them into developing mouse embryos. In the resulting animals, the CiPS cells had contributed to all major cell types, including liver, heart, brain, skin and muscle.
“People have always wondered whether all factors can be replaced by small molecules. The paper shows they can,” says Rudolf Jaenisch, a cell biologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who was among the first researchers to produce iPS cells. Studies of CiPS cells could give insight into the mechanisms of reprogramming, says Jaenisch.
The frog’s secret
The achievement could even help regenerative biologists to work out how amphibians grow new limbs. Deng’s group found that one gene indicative of pluripotency, Sall4, was expressed much earlier in the CiPS-cell reprogramming process than in iPS-cell reprogramming. The same Sall4 involvement is seen in frogs that regenerate a lost a limb: before the regeneration, cells in the limb de-differentiate, a process akin to reprogramming, and Sall4 is active early in that process.
The discovery “provides an important framework to decipher the signalling pathways leading to Sall4 expression” in regulating limb regeneration, says Anton Neff, who studies organ regeneration at Indiana University in Bloomington.
Sheng Ding, a reprogramming researcher at the Gladstone Institutes in San Francisco, California, says that the study marks “significant progress” in the field, but notes that chemical reprogramming is unlikely to be used widely until the team can show that it can work for human cells, not just mouse ones. Other strategies, including one that uses RNA, can complete reprogramming with less risk of disturbing the genes than the original iPS-generation method, and are already in use in humans. Indeed, clinical trials with iPS cells derived through such means are already being planned.
Deng has made some progress towards using his method in human cells, but it will require tweaks. ”Maybe some additional small molecules are needed,” he says.
If it the technique is found to be safe and effective in humans, it could be useful for the clinic. It does not risk causing mutations, and the compounds themselves seem to be safe — four of them are in fact already in clinical use. The small molecules can easily pass through cell membranes, so they can be washed away after they have initiated the reprogramming.
Chemical Makes Blind Mice See; Compound Holds Promise for Treating Humans
ScienceDaily (July 25, 2012) — A team of University of California, Berkeley, scientists in collaboration with researchers at the University of Munich and University of Washington, in Seattle, has discovered a chemical that temporarily restores some vision to blind mice, and is working on an improved compound that may someday allow people with degenerative blindness to see again.
Mice with a genetic disease that causes blindness regained some sight after injection with a chemical “photoswitch.” The eye of the untreated mouse on the left shows no response to light, while the pupil of the mouse on the right, which was injected with the chemical, contracts in light. (Credit: Image courtesy of University of California - Berkeley)
The approach could eventually help those with retinitis pigmentosa, a genetic disease that is the most common inherited form of blindness, as well as age-related macular degeneration, the most common cause of acquired blindness in the developed world. In both diseases, the light sensitive cells in the retina — the rods and cones — die, leaving the eye without functional photoreceptors.
The chemical, called AAQ, acts by making the remaining, normally “blind” cells in the retina sensitive to light, said lead researcher Richard Kramer, UC Berkeley professor of molecular and cell biology. AAQ is a photoswitch that binds to protein ion channels on the surface of retinal cells. When switched on by light, AAQ alters the flow of ions through the channels and activates these neurons much the way rods and cones are activated by light.
"This is similar to the way local anesthetics work: they embed themselves in ion channels and stick around for a long time, so that you stay numb for a long time," Kramer said. "Our molecule is different in that it’s light sensitive, so you can turn it on and off and turn on or off neural activity."
Because the chemical eventually wears off, it may offer a safer alternative to other experimental approaches for restoring sight, such as gene or stem cell therapies, which permanently change the retina. It is also less invasive than implanting light-sensitive electronic chips in the eye.
"The advantage of this approach is that it is a simple chemical, which means that you can change the dosage, you can use it in combination with other therapies, or you can discontinue the therapy if you don’t like the results. As improved chemicals become available, you could offer them to patients. You can’t do that when you surgically implant a chip or after you genetically modify somebody," Kramer said.
"This is a major advance in the field of vision restoration," said co-author Dr. Russell Van Gelder, an ophthalmologist and chair of the Department of Ophthalmology at the University of Washington, Seattle.
Kramer, Van Gelder, chemist Dirk Trauner and their colleagues at UC Berkeley, the University of Washington, Seattle, and the University of Munich will publish their findings on July 26, in the journal Neuron.
The blind mice in the experiment had genetic mutations that made their rods and cones die within months of birth and inactivated other photopigments in the eye. After injecting very small amounts of AAQ into the eyes of the blind mice, Kramer and his colleagues confirmed that they had restored light sensitivity because the mice’s pupils contracted in bright light, and the mice showed light avoidance, a typical rodent behavior impossible without the animals being able to see some light. Kramer is hoping to conduct more sophisticated vision tests in rodents injected with the next generation of the compound.
"The photoswitch approach offers real hope to patients with retinal degeneration," Van Gelder said. "We still need to show that these compounds are safe and will work in people the way they work in mice, but these results demonstrate that this class of compound restores light sensitivity to retinas blind from genetic disease."
From optogenetics to implanted chips
The current technologies being evaluated for restoring sight to people whose rods and cones have died include injection of stem cells to regenerate the rods and cones; “optogenetics,” that is, gene therapy to insert a photoreceptor gene into blind neurons to make them sensitive to light; and installation of electronic prosthetic devices, such as a small light-sensitive retinal chip with electrodes that stimulate blind neurons. Several dozen people already have retinal implants and have had rudimentary, low vision restored, Kramer said.
Eight years ago, Kramer, Trauner, a former UC Berkeley chemist now at the University of Munich, and their colleagues developed an optogenetic technique to chemically alter potassium ion channels in blind neurons so that a photoswitch could latch on. Potassium channels normally open to turn a cell off, but with the attached photoswitch, they were opened when hit by ultraviolet light and closed when hit by green light, thereby activating and deactivating the neurons.
Subsequently, Trauner synthesized AAQ (acrylamide-azobenzene-quaternary ammonium), a photoswitch that attaches to potassium channels without the need to genetically modify the channel. Tests of this compound are reported in the current Neuron paper.
New versions of AAQ now being tested are better, Kramer said. They activate neurons for days rather than hours using blue-green light of moderate intensity, and these photoswitches naturally deactivate in darkness, so that a second color of light is not needed to switch them off.
"This is what we are really excited about," he said.
Source: Science Daily