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Aug 21

Reported by Veronique Greenwood in Discover Magazine, 18th August2011.

Pills... by psyberartist / flickr

What’s the News: For all the testing we do, drugs are still mysterious things—they can activate pathways we never connected with them or twiddle the dials in some far-off part of the body. To see if drugs already FDA-approved for certain diseases could be used to treat other conditions, scientists lined up two online databases and discovered two drugs that, when tested in mice, worked against diseases they’d never been meant for, suggesting that mining of such information could be a fertile strategy for finding new treatments.

How the Heck:

What’s the Context:

  • Searching FDA-approved drug databases for effects that can be brought to bear on other illnesses isn’t that unusual in chemistry. Many scientists begin studies this way.
  • But what’s nice about this study is that one of the databases, the Omnibus, is crowdsourced: researchers have been adding information to it, bit by bit, for decades, and it’s available for free. Generally, free databases that have accreted over time aren’t considered the most reliable datasets, but as this study shows, they can get the job done.
  • Having the two databases pull from each other is a nice touch as well—most studies are just looking to work on a single, specific disease, but here, any combination of drug and disease is up for investigation.

Not So Fast: These particular drugs would need quite a bit more testing to see if they could be useful for these illnesses in humans. As one computational chemical biologist said to ScienceNOW, “Topiramate hits quite a lot of targets and has complex side effects, while the doses needed for functional effects for cimetidine seemed high,” though he still praised the study’s goals: “This is a really important concept; it is almost like they are looking for an antidote to a disease.”

The Future Holds: Unfortunately, through a quirk of the incentive system in pharmaceuticals, it’s unlikely that companies that first developed these drugs will invest the time and money required to test them for new uses: their patents have expired, so the companies don’t stand to profit from it. But perhaps drugs still under patent, or drugs just beginning to be tested, could be explored this way. With new drugs few and far between these days, re-purposing old ones could be a way for drug companies to fund further research.

Reference: Dudley et al. Computational Repositioning of the Anticonvulsant Topiramate for Inflammatory Bowel Disease. Science Translational Medicine. 17 August 2011: Vol. 3, Issue 96, p. 96ra76 DOI: 10.1126/scitranslmed.3002648

Sirota et al. Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data. Science Translational Medicine. 17 August 2011: Vol. 3, Issue 96, p. 96ra77. DOI: 10.1126/scitranslmed.3001318

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Apr 09

Reported by Ewen Callaway in Nature News, 6 April 2011 (doi:10.1038/news.2011.215).

Mouse cells have been coaxed into forming a retina, the most complex tissue yet engineered.

Here's lookin' at you kid. M. Eiraku and Y.Sasai at RIKEN Center for Developmental Biology

A retina made in a laboratory in Japan could pave the way for treatments for human eye diseases, including some forms of blindness.

Created by coaxing mouse embryonic stem cells into a precise three-dimensional assembly, the ‘retina in a dish’ is by far and away the most complex biological tissue engineered yet, scientists say.

“There’s nothing like it,” says Robin Ali, a human molecular geneticist at the Institute of Ophthalmology in London who was not involved in the study. “When I received the manuscript, I was stunned, I really was. I never though I’d see the day where you have recapitulation of development in a dish.”

If the technique, published today in Nature1, can be adapted to human cells and proved safe for transplantation — which will take years — it could offer an unlimited well of tissue to replace damaged retinas. More immediately, the synthetic retinal tissue could help scientists in the study of eye disease and in identifying therapies.

The work may also guide the assembly of other organs and tissues, says Bruce Conklin, a stem-cell biologist at the Gladstone Institute of Cardiovascular Disease in San Francisco, who was not involved in the work. “I think it really reveals a larger discovery that’s coming upon all of us: that these cells have instructions that allow them to self-organize.”

Cocktail recipe

In hindsight, previous work had suggested that, given the right cues, stem cells could form eye tissue spontaneously, Ali says. A cocktail of genes is enough to induce frog embryos to form form eyes on other parts of their body2, and human embryonic stem cells in a Petri dish can be coaxed into making the pigmented cells that support the retina, sheets of cells that resemble lenses and light-sensing retinal cells themselves3.

However, the eye structure created by Yoshiki Sasai at the RIKEN Center for Developmental Biology in Kobe and his team is much more complex.

The optic cup is brandy-snifter-shaped organ that has two distinct cell layers. The outer layer — that nearest to the brain — is made up of pigmented retinal cells that provide nutrients and support the retina. The inner layer is the retina itself, and contains several types of light-sensitive neuron, ganglion cells that conduct light information to the brain, and supporting glial cells.

To make this organ in a dish, Sasai’s team grew mouse embryonic stem cells in a nutrient soup containing proteins that pushed stem cells to transform into retinal cells. The team also added a protein gel to support the cells. “It’s a bandage to the tissue. Without that, cells tend to fall apart,” Sasai says.

At first, the stem cells formed blobs of early retinal cells. Then, over the next week, the blobs grew and began to form a structure, seen early in eye development, called an optic vesicle. Just as it would in an embryo, the laboratory-made optic vesicle folded in on itself over the next two days to form an optic cup, with its characteristic brandy-snifter shape, double layer and the appropriate cells.

Even though the optic cups look and develop like the real thing, “there may be differences between the synthetic retina and what happens normally,” Ali says.

Sasai’s team has not yet tested whether the optic cups can sense light or transmit impulses to the mouse brain. “That’s what we are now trying,” he says. However, previous studies have suggested that embryonic retinas can be transplanted into adult rodents4, so Sasai is hopeful.

Sasai, Ali and others expect that human retinas, which develop similarly to those of mice, could eventually be created in the lab. “In terms of regenerative medicine, we have to go beyond mouse cells. We have to make human retinal tissue from human embryonic stem cells and investigation is under way,” Sasai says.

The eyes have it

Synthetic human retinas could provide a source of cells to treat conditions such as retinitis pigmentosa, in which the retina’s light-sensing cells atrophy, eventually leading to blindness. In 2006, Ali’s team found that retinal cells from newborn mice work when transplanted into older mice5. Synthetic retinas, he says, “provide a much more attractive, more practical source of cells”.

David Gamm, a stem-cell biologist at the University of Wisconsin, Madison, says that transplanting entire layers of eye tissue, rather than individual retinal cells, could help people with widespread retinal damage. But, he adds, diseases such as late-stage glaucoma, in which the wiring between the retina and brain is damaged, will be much tougher to fix.

When and whether such therapies will make it to patients is impossible to predict. However, in the nearer term, synthetic retinas will be useful for unpicking the molecular defects behind eye diseases, and finding treatments for them, Sasai says. Retinas created from reprogrammed stem cells from patients with eye diseases could, for instance, be used to screen drugs or test gene therapies, Ali says.

Robert Lanza, chief scientific officer of the biotechnology company Advanced Cell Technology, based in Santa Monica, California, says the paper has implications far beyond treating and modelling eye diseases. The research shows that embryonic stem cells, given the right physical and chemical surroundings, can spontaneously transform into intricate tissues. “Stem cells are smart,” Lanza says. “This is just the tip of the iceberg. Hopefully it’s the beginning of an important new phase of stem-cell research.”

  • References
    1. Eiraku, M. et al. Nature 472, 51-56 (2011). | Article |
    2. Zuber, M. E., Gestri, G., Viczian, A. S., Barsacchi, G. & Harris, W. A. Development 130, 5155-5167 (2003). | ArticlePubMedISIChemPort |
    3. Osakada, F. et al. Nature Biotechnol. 26, 215-224 (2008). | Article |
    4. Tansley, K. J. Exp. Biol. 22, 221-233 (1946). | PubMedISIChemPort |
    5. MacLaren, R. E. et al. Nature 444, 203-207 (2006). | ArticlePubMedISIChemPort |
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Dec 10

Reported by by Kate McAlpine in New Scientist, 09 December 2010

Doctors could one day instantly detect cancers by photographing patients with a digital camera.

Mammograms take time (Image: Image Source/Getty)

Jeppe Seidelin Dam and colleagues at the Technical University of Denmark in Roskilde are developing a device that can convert infrared radiation into visible light. Attached to a digital camera fitted with an infrared flash, it could detect tumours by recording the telltale pattern of infrared light they reflect.

“This would allow a surgeon to quickly determine if the entire tumour has been removed before finishing an operation,” he says.

At the heart of the system is a multilayered crystal of potassium titanium oxide phosphate in which the infrared photons from the object to be imaged interfere with photons from an infrared laser, also fired into the crystal. The interaction shifts the wavelength into the visible spectrum while preserving the image information, allowing it to be captured by a normal camera.

Mirror amplifiers

The idea was first explored in the 1970s, but improvements to methods for growing crystals since then have improved the resolution of the device 300-fold. By placing a pair of mirrors on either side of the crystal so that the laser light reflects back and forth, the team increased the odds of its photons interfering with infrared photons from the object.

“We pass the same photons through the crystal up to 100 times,” says Dam. The crystal was able to capture an infrared panorama with a resolution of 200 by 1000 pixels, the team says.

The device could be placed in front of a digital camera lens like a filter, and be used to take thermal photographs or video. Shrinking it down to a size suitable for everyday use should not be difficult, says Dam. “These are basically the same components that are in green laser pointers.”

While current infrared colour imagers need to run at -200°C and cost around $100,000, Dam says that an upconversion imager would run at room temperature and cost about $10,000.

Stefano Bonora of the University of Padua, Italy, calls the upconversion technique “really interesting” for its potential to generate infrared images at room temperature. Such detectors are lacking at the moment, he says.

Journal reference: Optics Letters, DOI: 10.1364/OL.35.003796

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