This colorized negative stained transmission electron micrograph (TEM) depicts some of the ultrastructural morphology of the A/CA/4/09 swine flu virus. (Credit: CDC/C. S. Goldsmith and A. Balish)
Marine Biological Laboratory (2009, May 21). Swine Flu: Influenza A (H1N1) Susceptibility Linked To Common Levels Of Arsenic Exposure. – The ability to mount an immune response to influenza A (H1N1) infection is significantly compromised by a low level of arsenic exposure that commonly occurs through drinking contaminated well water, scientists at the Marine Biological Laboratory (MBL) and Dartmouth Medical School have found.
Joshua Hamilton, the MBL’s Chief Academic and Scientific Officer and a senior scientist in the MBL’s Bay Paul Center; graduate student Courtney Kozul of Dartmouth Medical School, where the work was conducted; and their colleagues report their findings in the journal Environmental Health Perspectives.
“When a normal person or mouse is infected with the flu, they immediately develop an immune response,” says Hamilton, in which immune cells rush to the lungs and produce chemicals that help fight the infection. However, in mice that had ingested 100 ppb (parts per billion) arsenic in their drinking water for five weeks, the immune response to H1N1 infection was initially feeble, and when a response finally did kick in days later, it was “too robust and too late,” Hamilton says. “There was a massive infiltration of immune cells to the lungs and a massive inflammatory response, which led to bleeding and damage in the lung.” Morbidity over the course of the infection was significantly higher for the arsenic-exposed animals than the normal animals.
Respiratory infections with influenza A virus are a worldwide health concern and are responsible for 36,000 deaths annually. The recent outbreak of the influenza A H1N1 substrain (“swine flu”)⎯which is the same virus that Hamilton and his colleagues used in their arsenic study to date has killed 72 people in Mexico and 6 in the United States.
“One thing that did strike us, when we heard about the recent H1N1 outbreak, is Mexico has large areas of very high arsenic in their well water, including the areas where the flu first cropped up. We don’t know that the Mexicans who got the flu were drinking high levels of arsenic, but it’s an intriguing notion that this may have contributed,” Hamilton says.
The U.S. Environmental Protection Agency considers 10 ppb arsenic in drinking water “safe,” yet concentrations of 100 ppb and higher are commonly found in well water in regions where arsenic is geologically abundant, including upper New England (Massachusetts, New Hampshire, Maine), Florida, and large parts of the Upper Midwest, the Southwest, and the Rocky Mountains, Hamilton says.
Arsenic does not accumulate in the body over a lifetime, as do other toxic metals such as lead, cadmium, and mercury. “Arsenic goes right through us like table salt,” Hamilton says. “We believe for arsenic to have health consequences, it requires exposure day after day, year after year, such as through drinking water.”
Arsenic exposure not only disrupts the innate immune system, as the present study shows, it also disrupts the endocrine (hormonal) system in an unusually broad way, which Hamilton’s laboratory discovered and first reported in 1998.
“Most chemicals that disrupt hormone pathways target just one, such as the estrogen pathway,” he says. “But arsenic disrupts the pathways of all five steroid hormone receptors (estrogen, testosterone, progesterone, glucocorticoids, and mineralocorticoids), as well as several other hormone pathways. You can imagine that just this one effect could play a role in cancer, diabetes, heart disease, reproductive and developmental disorders-all the diseases that have a strong hormonal component.”
At this point, Hamilton thinks arsenic disrupts the innate immune system and the endocrine system through different mechanisms. “Arsenic may ultimately be doing a similar thing inside the cell to make these effects happen, but the targets are likely different,” he says. The proteins that mediate hormone response are different than the proteins that mediate the immune response. “We don’t yet know how arsenic disrupts either system at the molecular level. But once we know how it affects one system, we will have a pretty good idea of how it affects the other systems as well.”
Presently, Hamilton’s lab is focused on understanding the unusual “biphasic” effect that arsenic has on the endocrine system. At very low doses, arsenic stimulates or enhances hormone responses, while at slightly higher doses (still within the range found in drinking water), it suppresses these same hormone responses.
“Why we see that dramatic shift (from hormone enhancement to suppression) over such a narrow dose range is quite fascinating and totally unknown,” Hamilton says. “Our principal focus is to figure out this switch. We think that will help us understand why arsenic does what it does in the body.”
This research was funded by the Dartmouth Toxic Metals Research Program Project by a grant from NIH-NIEHS and its Superfund Basic Research Program (grant P42 ES007373).
- 1. Kozul et al. Low Dose Arsenic Compromises the Immune Response to Influenza A Infection in vivo. Environmental Health Perspectives, Online May 20, 2009; DOI: 10.1289/ehp.0900911
Marine Biological Laboratory (2009, May 21). Swine Flu: Influenza A (H1N1) Susceptibility Linked To Common Levels Of Arsenic
Karyotype for trisomy Down syndrome. Notice the three copies of chromosome 21. (Credit: Image courtesy of Talking Glossary of Genetics, NIH/National Human Genome Research Institute)
Research In Mice And Human Stem Cells Suggests New Therapeutic Targets
ScienceDaily.com, May 21, 2009 – Most cancers are rare in people with Down syndrome, whose overall cancer mortality is below 10 percent of that in the general population. Since they have an extra copy of chromosome 21, it’s been proposed that people with Down syndrome may be getting an extra dose of one or more cancer-protective genes.
The late cancer researcher Judah Folkman, MD, founder of the Vascular Biology Program at Children’s Hospital Boston, popularized the notion that they might be benefiting from a gene that blocks angiogenesis, the development of blood vessels essential for cancer’s growth, since their incidence of other angiogenesis-related diseases like macular degeneration is also lower.
A study from Children’s now confirms this idea in mice and human cells, and identifies specific new therapeutic targets for treating cancer.
Publishing online May 20 in the journal Nature, cancer researcher Sandra Ryeom, PhD, and colleagues from Children’s Vascular Biology Program show that a single extra copy of Dscr1 (one of the 231 genes on chromosome 21 affected by trisomy, with three copies rather than two) is sufficient to significantly suppress angiogenesis and tumor growth in mice, as well as angiogenesis in human cells. The team also found its protein, DSCR1, to be elevated in tissues from people with Down syndrome and in a mouse model of the disease.
Further study confirmed that DSCR1 acts by suppressing signaling by the angiogenesis-promoting protein vascular endothelial growth factor (VEGF). In a mouse model of Down syndrome, endothelial cells (which make up blood vessel walls) showed a decreased growth response to VEGF when they had an extra copy of Dscr1. An extra copy of another chromosome 21 gene, Dyrk1A, also appeared to decrease cells’ response to VEGF.
Finally, Ryeom and colleagues showed that these extra genes suppress VEGF signaling via a specific signaling pathway inside endothelial cells — the calcineurin pathway. Until now, Ryeom says, little has been known about the internal pathways VEGF activates once it binds to cellular receptors; most existing anti-VEGF drugs work by simply binding to VEGF (like Avastin) or blocking its ability to bind to its cellular receptors.
“We’re now moving further downstream by going inside the cell,” Ryeom says. “When we targeted calcineurin, we suppressed the ability of endothelial cells to grow and form vessels. While it’s likely not the only pathway that’s involved, if you take it out, VEGF is only half as effective.”
Ryeom and her group next validated the mouse findings in human cells. In collaboration with George Daley, MD, PhD, and colleagues in the Stem Cell program at Children’s, she worked with induced pluripotent stem cells (iPS cells) created from skin cells from a patient with Down syndrome — one of 10 disease-specific lines recently developed in Daley’s lab.
Knowing that iPS cells tend to induce tumors known as teratomas when inserted into mice, Ryeom guessed that teratomas grown from iPS cells with an extra chromosome 21 would have far fewer blood vessels than teratomas from iPS cells with the normal number of chromosomes. She was right: blood vessels budded in the Down teratomas, but never fully formed.
“The studies in the iPS cells helped validate and confirm that the suppression of angiogenesis that we saw in mouse models also holds true in humans,” says Ryeom. “It suggests that these two genes might point to a viable cancer therapy.”
Ryeom’s group has identified which part of the DSCR1 protein blocks calcineurin and is testing to see whether that fragment can be delivered specifically to endothelial cells, to prevent them from forming new blood vessels, without affecting calcineurin pathways in other cells and causing side effects. “Immunosuppressive drugs also target calcineurin in T-cells,” Ryeom notes. “We think that Dscr1 blocks calcineurin specifically in endothelial cells, without affecting T-cells, but we need to check.”
Folkman’s interest in why patients with Down syndrome have such a reduced risk for cancer focused on endostatin, an anti-angiogenic compound made by the body. Discovered in the Folkman lab, endostatin is a fragment of collagen 18 — whose gene is also on chromosome 21. People with Down syndrome reportedly have almost doubled levels of endostatin because of the extra copy of the gene.
“I think there may be four or five genes on chromosome 21 that are necessary for angiogenesis suppression,” says Ryeom. “In huge databases of cancer patients with solid tumors, there are very few with Down syndrome. This suggests that protection from chromosome 21 genes is pretty complete.”
The study was funded by the Howard Hughes Medical Institute, the Harvard Stem Cell Institute and the NIH Director’s Pioneer Award (supporting George Daley, MD, PhD); as well as the Smith Family Medical Foundation, the Garrett B. Smith Foundation and Annie’s Fun Foundation (supporting Sandra Ryeom, PhD). Kwan-Hyuck Baek, PhD, of Children’s Vascular Biology program was the paper’s first author.
The Expedition 19 crew participates in a toast aboard the International Space Station.
StraitsTimes.com, May 21, 2009 –HOUSTON — Cheers to Recycled urine! At the
international space station, it was one small sip for man and a giant gulp of recycled urine for mankind.
Astronauts aboard the space station celebrated a space first on Wednesday by drinking water that had been recycled from their urine, sweat and water that condenses from exhaled air. They said ‘cheers’, clicked drinking bags and toasted NASA workers on the ground who were sipping their own version of recycled drinking water.
‘The taste is great,’ American astronaut Michael Barratt said.
Then as Russian Gennady Padalka tried to catch little bubbles of the clear water floating in front of him, Barratt called the taste ‘worth chasing’. He said the water came with labels that said: ‘drink this when real water is over 200 miles away’.
The urine recycling system is needed for astronaut outposts on the moon and Mars. It also will save NASA money because it won’t have to ship up as much water to the station by space shuttle or cargo rockets.
It’s also crucial as the space station is about to expand from three people living on board to six.
The recycling system had been brought up to the space station last November by space shuttle Endeavour, but it couldn’t be used until samples were tested back on Earth and a stuck valve was fixed on Monday.
So when it came time to actually drink up, NASA made a big deal of it. The three-man crew stood holding their drinks and congratulated engineers in two NASA centres that worked on the system.
‘This is something that had been the stuff of science fiction,’ Barratt said before taking a sip.
NASA deputy space shuttle manager LeRoy Cain called it ‘a huge milestone.’ On the Russian side of the space station, moisture in the air – not urine – is turned into drinking water.
The new system takes the combined urine of the crew from the toilet, moves it to a big tank, where the water is boiled off, and the vapour collected. The rest of contaminants – the yucky brine in the urine – is thrown away, said Marybeth Edeen, the space station’s national lab manager who was in charge of the system.
The water vapour is mixed with water from air condensation, then it goes through filters, much like those put on home taps, Ms Edeen said.
When six crew members are aboard it can make about 6 gallons (22 litres) from urine in about six hours, Ms Edeen said.
Some people may find the idea of drinking recycled urine distasteful, but it is also done on Earth, but with a lot longer time between urine and tap, Ms Edeen said. In space, it takes about a week, she said.
The technology NASA developed for this system has already been used for quick water purification after the 2004 Asian tsunami, Ms Edeen said.
Artificial chromosomes like these could be used as Trojan horses to sneak useful new traits into the human genome.
Bioengineers will likely control the future of humans as a species.
DiscoverMagazine.com, Spring 2009, by Jane Bosveld — “There are no shortcuts in evolution,” famed Supreme Court justice Louis Brandeis once said. He might have reconsidered those words if he could have foreseen the coming revolution in biotechnology, including the ability to alter genes and manipulate stem cells. These breakthroughs could bring on an age of directed reproduction and evolution in which humans will bypass the incremental process of natural selection and set off on a high-speed genetic course of their own. Here are some of the latest and greatest advances.
Embryos From the Palm of Your Hand
In as little as five years, scientists may be able to create sperm and egg cells from any cell in the body, enabling infertile couples, gay couples, or sterile people to reproduce. The technique could also enable one person to provide both sperm and egg for an offspring-an act of “ultimate incest,” according to a report from the Hinxton Group, an international consortium of scientists and bioethicists whose members include such heavyweights as Ruth Faden, director of the Johns Hopkins Berman Institute of Bioethics, and Peter J. Donovan, a professor of biochemistry at the University of California at Irvine.
The Hinxton Group’s prediction comes in the wake of recent news that scientists at the University of Wisconsin and Kyoto University in Japan have transformed adult human skin cells into pluripotent stem cells, the powerhouse cells that can self-replicate (perhaps indefinitely) and develop into almost any kind of cell in the body. In evolutionary terms, the ability to change one type of cell into others-including a sperm or egg cell, or even an embryo-means that humans can now wrest control of reproduction away from nature, notes Robert Lanza, a scientist at Advanced Cell Technology in Massachusetts. “With this breakthrough we now have a working technology whereby anyone can pass on their genes to a child by using just a few skin cells,” he says.
Studies in cell cultures showed the cells were able to find and kill cells from lung,
squamous, breast and cervical cancer (left). — PHOTO: INSTITUTE OF MOLECULAR AND CELL
GoogleNews.com,ScienceDaily.com, StraitsTimes.com, May 21, 2009 —
Researchers in London have demonstrated the ability of adult stem cells from bone marrow (mesenchymal stem cells, or MSCs) to deliver a cancer-killing protein to tumors.
The genetically engineered stem cells are able to home to the cancer cells, both in culture and in mouse models, and deliver TNF-related apoptosis-inducing ligand (TRAIL), destroying the tumor cells while sparing normal cells.
The research was presented on May 19, at the American Thoracic Society’s 105th International Conference in San Diego.
“Present oncological therapies are limited by host toxicity,” said Michael Loebinger, M.D., M.A, who, along with S. M. Janes, M.D., Ph.D., conducted the research at the Centre for Respiratory Research at the University College of London. “They are also limited by cancer resistance and may not destroy cancer stem cells.”
With these experiments, the investigators combined two disparate areas of research that they believed held promise for treating cancer. Studies had shown that MSCs can be used as vectors to deliver anti-tumor therapy, while other studies found that TRAIL killed cancer cells, but not normal cells.
For their experiments, Drs. Loebinger and Janes identified those cells likely to be resistant to therapies (cancer cells that have characteristics of stem cells) and found that they were just as likely to be destroyed as tumor cells by this novel therapy.
In culture, the stem cells caused lung, squamous, breast and cervical cancer cells to die (all p< 0.01), even at low stem cell/tumor cell ratios (1:16).
In mice, the researchers showed that the stem cells could reduce the growth of subcutaneous breast tumors by approximately 80 percent (p< .0001). The stem cells could also be injected intravenously as therapy for mice with lung metastases and could eliminate lung metastases in 38 percent of mice compared to control mice, all of which still had metastases (p=0.03).
It is the first study to intravenously introduce MSCs that have been genetically modified to deliver TRAIL. Drs. Loebinger and Janes chose the breast cancer cells for both models because in their in vitro experiments, the MSCs “demonstrated a particularly strong homing to breast cancer cells.”
“Breast cancer tumors are a good model of metastases,” added Dr. Loebinger, “but our plan is to test the engineered stem cells with other models, including lung cancer.”
While not fully understood, Dr. Loebinger added, the homing of the engineered cells appears to be a characteristic of MSCs themselves.
The authors conclude that, “this is the first study to demonstrate a significant reduction in tumor burden with inducible TRAIL-expressing MSCs in a well-controlled and specifically directed therapy.”
They believe that human trials of TRAIL-expressing MSCs could begin in two or three years.
Funding for this research was provided by the Medical Research Council UK.
Image: David Scharf/Photo Researchers
DiscoverMagazine.com, May/June 2009 — The strawberry is a member of the Rosaceae family, the same as the common rose. This image from a scanning electron microscope clearly reveals the seeds-and hairlike strands-on the berry’s surface. Strawberries are known as accessory fruits because they are not derived exclusively from the plant’s ovaries-the seeds are the actual “fruit.”
Strawberries have plenty of health benefits when consumed, but they can also help with hygiene. A crushed strawberry mixed with baking soda can whiten teeth, thanks to the stain-fighting effects of the fruit’s malic acid.