Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Sweet success in targeting sugar molecules to cells in living animals

19.08.2004


New tool offers scientists great flexibility



Howard Hughes Medical Institute researchers have successfully targeted unnatural sugar molecules with chemically unique functional groups onto the surfaces of cells in living animals without altering the animals’ physiology.
The achievement is a significant advance in the promising new field of metabolic engineering because it provides a new tool with which researchers can label specific cells in whole animals so that they can differentiate one cell from another.

The researchers said the new approach to marking cell-surface sugars could lead to improved understanding of fundamental cellular processes where sugars are known to play an important role, such as in interaction with pathogens, and in mediating inflammation and disease. The research may also make it possible to target the delivery of chemical agents to specific cell types in living organisms more precisely.



Led by Howard Hughes Medical Institute Medical Institute investigator Carolyn R. Bertozziat the University of California, Berkeley, the researchers published their findings in the August 19, 2004, issue of the journal Nature.

"The method introduced by Bertozzi and colleagues is remarkable as a chemical process," wrote David A. Tirrell of the California Institute of Technology in an accompanying News and Views article in Nature. "The fact that specific chemical transformations can now be accomplished with spatial and temporal control in live animals is a major step forward for chemistry."

Glycosylation is the addition of carbohydrate (sugar) groups to a molecule. It has long been known that the glycosylation patterns of sugar molecules on cell surfaces can influence their interaction with other cells. "Glycobiologists have known that cancer cells, for example, exhibit changes in glycosylation patterns when compared with their normal healthy tissue counterparts," said Bertozzi. "And there are changes in glycosylation of blood vessels at sites of chronic inflammation that are characteristic of disease. There are even some reports in changes of glycosylation in the brains of people who have prion disease or Alzheimer’s disease," she said.

Additional studies suggest that glycosylation patterns on embryonic cells may serve as developmental markers because they change as the embryo grows. Thus, studying changes in glycosylation could improve understanding of embryonic development.

But studying the role of cell surface sugar chains, called polysaccharides, in disease is best done in the context of multiple cells, said Bertozzi. "All the interesting biology we want to study takes place at the level of whole organisms. This is a general feature of glycobiology; polysaccharides exert their function largely at the systems level," she said. This is in contrast to many proteins, such as enzymes, whose function can be studied by purifying and analyzing individual molecules.

Despite the promise of these studies, researchers faced a major challenge in finding the means to target sugars with specific markers for biological study to the surface of cells. Sugars are synthesized by complex metabolic pathways, and it was thought that integrating a marker into a specific sugar molecule would inevitably disrupt its processing in the cell.

To overcome these problems, Bertozzi and her colleagues developed a chemical technique to tag sugars in a way that does not disrupt a cell’s biology and is highly specific. The technique involves "feeding" a cell a slightly modified sugar with a chemical group called an azide attached. Such sugars are not normally found on cells, but are processed by the cell’s metabolic pathways similarly to normal sugars and are incorporated into the cell-surface polysaccharides. The researchers can then tag the resulting "azido sugar" on the cell surface by treating it with a molecule called a phosphine to which any desired molecule, such as a probe for visualization, can be attached.

This reaction, called the Staudinger ligation, is "bio-orthogonal," said Bertozzi -- meaning that it does not affect the cell’s biology; and the components form a covalent bond with one another in a highly selective manner.

In the research reported in Nature, Bertozzi and her colleagues describe the first use of their cell-surface engineering technique in living animals. Previously, they had only applied it to cultured cells.

They injected the azido sugar into mice and used the Staudinger ligation to attach a phosphine molecule that carried a distinctive tag that would enable the scientists to detect whether attachment to the cell surface had occurred.

The researchers found that the azido sugar made its way into the mouse organs, was chemically processed similarly to the normal sugar, and appeared on the cell surface. They also found that the unnatural sugar caused no adverse physiological effects, even at the largest doses.

"We weren’t particularly surprised at the lack of toxicity because unnatural sugars are not known for high toxicity," said Bertozzi. "And at the highest dose, the amount of sugar we gave the animals was about that contained in a can of soft drink. Also, the azide component is already used in clinically approved drugs, such as AZT, which is taken at much higher dosages," said Bertozzi.

The scientists’ analyses revealed that the azido sugars were most concentrated in the heart, kidney and liver, with much lesser amounts in the brain and thymus. These findings indicate it may be able to apply this tagging technique to study the biology of other organs and to look for changes in organs that occur in diseases as cancer.

According to Bertozzi, advancing the technique to living animals will have important research and clinical implications. "From our point of view, one of the most exciting implications of this work is the prospect for imaging glycosylation in real time within living organisms," she said. "We hope to be able to witness changes in the pattern of glycosylation in a tissue as an animal develops through the embryonic stages, as a disease develops, or as tumors become metastatic. Until now, there has not been a technique to do such imaging."

Bertozzi and her colleagues are working on probes that could be attached to a phosphine, including those that can be used in magnetic resonance imaging, positron emission tomography and single photon emission computed tomography. They are also developing new bio-orthogonal ligation reactions with azides that will give them additional sugar-tagging techniques.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>