[naturenews] from [nature.com]
[Nature News]
Published online 21 August 2009 | Nature | doi:10.1038/news.2009.848
News
Sugar hit triggers bug's drug slug
An engineered bacterium can deliver a therapeutic protein straight to the gut when fed with xylan.
Mico Tatalovic
A gut-dwelling bacterium has been genetically engineered to deliver a dose of therapeutic protein on demand.
Protein production in the engineered bacterium is switched on only when its host eats the complex sugar xylan. Tests on mice that had colonies of the bacteria in their guts showed that the expressed protein can successfully treat an inflammatory bowel disease called colitis.
The research, to be published in the journal Gut1, has potential as an alternative method for delivering drugs to the colon. Drugs taken orally are often broken down into inactive forms before they reach their target in the digestive system.
In 2000, Lothar Steidler, then at the University of Ghent, Belgium, and his colleagues showed that Lactococcus lactis bacteria that were engineered to secrete mouse interleukin-10 anti-inflammatory protein were effective at treating colitis in mice2. But those bacteria generated the protein non-stop, without the ability to regulate how much was produced.
Now, microbiologist Simon Carding of the Institute of Food Research in Norwich, UK, and his team have engineered the gut bacterium Bacteroides ovatus to carry a gene that encodes the therapeutic protein keratinocyte growth factor-2, which has a crucial role in maintaining and repairing the intestinal lining. Crucially, the protein is expressed only when the bacteria are fed with xylan.
The team found that the protein-expressing bacteria reduced rectal bleeding, accelerated healing of the gut lining and reduced gut inflammation in the mice. The protein could also prevent development of the disease in the first place. "There were no side effects, none at all. We were amazed how well it worked given the small amount of bacteria administered," says Carding.
Because B. ovatus is a natural inhabitant of the mucus within the colon, the team thinks that the protein is being delivered specifically to the damaged cells that line the gut. "A major goal of drug treatment for any disease is to target it to the site of disease activity and to be able to control its levels in the body," Carding explains.
"The system we have developed is a means of delivering proteins to the colon, and it could be used to deliver a variety of proteins for a variety of purposes, including vaccine antigens," adds Carding. His team is currently testing about a dozen bacterial strains that express different proteins, including one that limits tumour growth by restricting blood-vessel formation.
Gérard Eberl, a microbiologist from the Pasteur Institute in Paris, says that "it would probably be very easy to make this work in humans as well, since human and mouse intestinal bacterial communities are very similar".
Francisco Guarner, a gut researcher at the Vall d'Hebron University Hospital in Barcelona, Spain, is more cautious. Although there has been a lot of interest in the idea since Steidler's research was published in 2000, the field has not developed as quickly as expected, he says.
Promising studies have shown that L. lactis that are engineered to deliver therapeutic drugs could be safe in humans. But Guarner says that it may be difficult to translate gut research in mice into a human clinical setting — not least because of unknown effects from the zoo of other bacteria fighting for space in our guts.
References
1. Hamady, Z. Z. R. et al. Gut (in the press).
2. Steidler, L. et al. Science 289, 1352-1355 (2000).
3. Braat, H. et al. Clin. Gastroenterol. Hepatol. 4, 754-759 (2006).
[Nature News]
Published online 21 August 2009 | Nature | doi:10.1038/4601068a
News
Japan relaxes human stem-cell rules
But scientists fear it is too late to regain lost ground.
David Cyranoski
A long-sought loosening of Japan's guidelines on human embryonic stem-cell research came into effect on 21 August. But some say the new rules are too little, too late for a struggling field that was once a source of national pride.
On the surface the previous guidelines, set in 2001, were permissive. They allowed scientists to derive new human embryonic stem (ES) cell lines and research both home-grown and imported cell lines. But that could be done only after the research was approved, and the approval process was the stumbling block. Proposed projects needed to be approved twice — first by a local institutional review board and then by a science-ministry committee. And researchers working on human ES cells had to use separate facilities from other stem-cell research.
The upshot was a slowing down of research, some say. Roughly 50 groups have passed the application process, says Hirofumi Suemori of Kyoto University's Institute for Frontier Medical Sciences. But that is only about a quarter of the number that he estimates originally wanted to use human ES cells, based on the number of groups that work with mouse ES cells or request materials derived from human ES cells.
{“These irrational guidelines have done and will probably continue to do great damage to all related research fields in Japan.”}
Some charge that the regulations cost the country leadership in the field. It was Shinya Yamanaka of Kyoto University who, in 2006, created induced pluripotent stem (iPS) cells for the first time (K. Takahashi and S. Yamanaka Cell 126, 663–676; 2006) — produced from normal adult cells, iPS cells have the potential, like ES cells, to generate any cell type in the body. But it soon became clear that expertise with ES cells was essential for advancing iPS-cell technology, and further experiments such as comparing the properties of iPS cells and ES cells were done outside Japan. Even in the United States, where until this year federal funding was limited to ES-cell lines derived by August 2001, ES-cell research moved ahead, says Suemori. "Researchers there were able to press forward, and with that as the foundation, they also stole the lead in iPS-cell research," he says.
The Japanese government has been slowly trying to change the restrictions. In April, a new section in the explanatory material for the old guidelines erased the requirement for separate facilities. The latest guidelines also remove the secondary approval step for working with ES cells: a local review committee must still approve the work, but researchers then need only notify the science ministry of this.
Yet some burdensome restrictions remain, says Suemori. For example, the notification must include "word-for-word" minutes of the local review committee's meeting.
And the two-stage approval process remains for deriving new cell lines. Norio Nakatsuji, director of Kyoto University's Institute for Integrated Cell-Material Sciences, who created all five of Japan's human ES-cell lines, has given up plans to make any more. "I would summarize the change as being from absurd to excessively strict," he says. "These irrational guidelines have done and will probably continue to do great damage to all related research fields in Japan."
Last December, Yamanaka was widely quoted for remarks made at a science-ministry assembly in which he appraised Japan's 2008 record against other iPS-cell research groups, mostly in the United States: "One win, and about 10 losses," he said.
The new regulations were pushed through by the Council for Science and Technology Policy, a 15-person group chaired by the prime minister that stands as the country's highest science-policy body. Junichi Iwata, of the science ministry's life-science division, says the changes were targeted at the use of human ES cells and not their derivation, explaining that only two groups are licensed to derive such cells.
Asked why the reform didn't go further in addressing researchers' criticisms, he says: "The new guidelines just went into effect, so we'll see how things go. If need be, we'll change them again."
But it might be too late to make a difference. Most of Japan's stem-cell researchers have already been pushed into iPS-cell research through targeted funding programmes and are unlikely to go back to the ES-cell basics. "I do not expect a dramatic increase in ES-cell research," says Shin-Ichi Nishikawa, a stem-cell researcher at the RIKEN Center for Developmental Biology in Kobe.
Suemori likewise sees little change and fading hope. "It will be very difficult for us to catch up now," he says.
[Nature News]
Published online 21 August 2009 | Nature | doi:10.1038/news.2009.848
News
Sugar hit triggers bug's drug slug
An engineered bacterium can deliver a therapeutic protein straight to the gut when fed with xylan.
Mico Tatalovic
A gut-dwelling bacterium has been genetically engineered to deliver a dose of therapeutic protein on demand.
Protein production in the engineered bacterium is switched on only when its host eats the complex sugar xylan. Tests on mice that had colonies of the bacteria in their guts showed that the expressed protein can successfully treat an inflammatory bowel disease called colitis.
The research, to be published in the journal Gut1, has potential as an alternative method for delivering drugs to the colon. Drugs taken orally are often broken down into inactive forms before they reach their target in the digestive system.
In 2000, Lothar Steidler, then at the University of Ghent, Belgium, and his colleagues showed that Lactococcus lactis bacteria that were engineered to secrete mouse interleukin-10 anti-inflammatory protein were effective at treating colitis in mice2. But those bacteria generated the protein non-stop, without the ability to regulate how much was produced.
Now, microbiologist Simon Carding of the Institute of Food Research in Norwich, UK, and his team have engineered the gut bacterium Bacteroides ovatus to carry a gene that encodes the therapeutic protein keratinocyte growth factor-2, which has a crucial role in maintaining and repairing the intestinal lining. Crucially, the protein is expressed only when the bacteria are fed with xylan.
The team found that the protein-expressing bacteria reduced rectal bleeding, accelerated healing of the gut lining and reduced gut inflammation in the mice. The protein could also prevent development of the disease in the first place. "There were no side effects, none at all. We were amazed how well it worked given the small amount of bacteria administered," says Carding.
Because B. ovatus is a natural inhabitant of the mucus within the colon, the team thinks that the protein is being delivered specifically to the damaged cells that line the gut. "A major goal of drug treatment for any disease is to target it to the site of disease activity and to be able to control its levels in the body," Carding explains.
"The system we have developed is a means of delivering proteins to the colon, and it could be used to deliver a variety of proteins for a variety of purposes, including vaccine antigens," adds Carding. His team is currently testing about a dozen bacterial strains that express different proteins, including one that limits tumour growth by restricting blood-vessel formation.
Gérard Eberl, a microbiologist from the Pasteur Institute in Paris, says that "it would probably be very easy to make this work in humans as well, since human and mouse intestinal bacterial communities are very similar".
Francisco Guarner, a gut researcher at the Vall d'Hebron University Hospital in Barcelona, Spain, is more cautious. Although there has been a lot of interest in the idea since Steidler's research was published in 2000, the field has not developed as quickly as expected, he says.
Promising studies have shown that L. lactis that are engineered to deliver therapeutic drugs could be safe in humans. But Guarner says that it may be difficult to translate gut research in mice into a human clinical setting — not least because of unknown effects from the zoo of other bacteria fighting for space in our guts.
References
1. Hamady, Z. Z. R. et al. Gut (in the press).
2. Steidler, L. et al. Science 289, 1352-1355 (2000).
3. Braat, H. et al. Clin. Gastroenterol. Hepatol. 4, 754-759 (2006).
[Nature News]
Published online 21 August 2009 | Nature | doi:10.1038/4601068a
News
Japan relaxes human stem-cell rules
But scientists fear it is too late to regain lost ground.
David Cyranoski
A long-sought loosening of Japan's guidelines on human embryonic stem-cell research came into effect on 21 August. But some say the new rules are too little, too late for a struggling field that was once a source of national pride.
On the surface the previous guidelines, set in 2001, were permissive. They allowed scientists to derive new human embryonic stem (ES) cell lines and research both home-grown and imported cell lines. But that could be done only after the research was approved, and the approval process was the stumbling block. Proposed projects needed to be approved twice — first by a local institutional review board and then by a science-ministry committee. And researchers working on human ES cells had to use separate facilities from other stem-cell research.
The upshot was a slowing down of research, some say. Roughly 50 groups have passed the application process, says Hirofumi Suemori of Kyoto University's Institute for Frontier Medical Sciences. But that is only about a quarter of the number that he estimates originally wanted to use human ES cells, based on the number of groups that work with mouse ES cells or request materials derived from human ES cells.
{“These irrational guidelines have done and will probably continue to do great damage to all related research fields in Japan.”}
Some charge that the regulations cost the country leadership in the field. It was Shinya Yamanaka of Kyoto University who, in 2006, created induced pluripotent stem (iPS) cells for the first time (K. Takahashi and S. Yamanaka Cell 126, 663–676; 2006) — produced from normal adult cells, iPS cells have the potential, like ES cells, to generate any cell type in the body. But it soon became clear that expertise with ES cells was essential for advancing iPS-cell technology, and further experiments such as comparing the properties of iPS cells and ES cells were done outside Japan. Even in the United States, where until this year federal funding was limited to ES-cell lines derived by August 2001, ES-cell research moved ahead, says Suemori. "Researchers there were able to press forward, and with that as the foundation, they also stole the lead in iPS-cell research," he says.
The Japanese government has been slowly trying to change the restrictions. In April, a new section in the explanatory material for the old guidelines erased the requirement for separate facilities. The latest guidelines also remove the secondary approval step for working with ES cells: a local review committee must still approve the work, but researchers then need only notify the science ministry of this.
Yet some burdensome restrictions remain, says Suemori. For example, the notification must include "word-for-word" minutes of the local review committee's meeting.
And the two-stage approval process remains for deriving new cell lines. Norio Nakatsuji, director of Kyoto University's Institute for Integrated Cell-Material Sciences, who created all five of Japan's human ES-cell lines, has given up plans to make any more. "I would summarize the change as being from absurd to excessively strict," he says. "These irrational guidelines have done and will probably continue to do great damage to all related research fields in Japan."
Last December, Yamanaka was widely quoted for remarks made at a science-ministry assembly in which he appraised Japan's 2008 record against other iPS-cell research groups, mostly in the United States: "One win, and about 10 losses," he said.
The new regulations were pushed through by the Council for Science and Technology Policy, a 15-person group chaired by the prime minister that stands as the country's highest science-policy body. Junichi Iwata, of the science ministry's life-science division, says the changes were targeted at the use of human ES cells and not their derivation, explaining that only two groups are licensed to derive such cells.
Asked why the reform didn't go further in addressing researchers' criticisms, he says: "The new guidelines just went into effect, so we'll see how things go. If need be, we'll change them again."
But it might be too late to make a difference. Most of Japan's stem-cell researchers have already been pushed into iPS-cell research through targeted funding programmes and are unlikely to go back to the ES-cell basics. "I do not expect a dramatic increase in ES-cell research," says Shin-Ichi Nishikawa, a stem-cell researcher at the RIKEN Center for Developmental Biology in Kobe.
Suemori likewise sees little change and fading hope. "It will be very difficult for us to catch up now," he says.
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