The invention of a technique known as two-photon microscopy was awarded the 2015 Brain Prize for revealing the structure of cells and networks in a living brain.
The world’s most valuable prize for neuroscience research was awarded today (March 9) to four German and American scientists who invented a microscopy technique that reveals the finest structures of the brain, in both health and disease.

Living Brain
Credit: ROBERT LUDLOW, UCL INSTITUTE OF NEUROLOGY, LONDON; WELLCOME TRUST
This image of a living human brain taken during surgery won the 2012 Wellcome Trust Award for biomedical photography.
American scientists Karel Svoboda and David Tank and German scientists Winfried Denk and Arthur Konnerth shared the $1.08-million (1 million euro) Brain Prize for the invention and development of two-photon microscopy, a technique to create detailed images of brain cells and the connections, or synapses, between them, in action.

Leaf of Lavender
Credit: ANNIE CAVANAGH AND DAVID MCCARTHY; WELLCOME TRUST
This false-coloured scanning electron micrograph (SEM) shows a lavender leaf (Lavandula) imaged at 200 microns. The surface of the leaf is densely coveredwith fine hair-like outgrowths made from specialised epidermal cells called non-glandular trichomes.
This new technique gives scientists the ability to study the function of individual brain cells, and how these cells communicate with each other as part of brain networks. [Beauty and Brains: Award-Winning Medical Images]
“Thanks to these four scientists, we’re now able to study the normal brain’s development and attempt to understand what goes wrong when we’re affected by destructive diseases such as Alzheimer’s and other types of dementia,” Povl Krogsgaard-Larsen, chairman of the Grete Lundbeck European Brain Research Foundation, which awards The Brain Prize, said in a statement.

Frog Oocytes
Credit: VINCENT PASQUE, UNIVERSITY OF CAMBRIDGE; WELLCOME TRUST
This confocal micrograph shows stage V-VI oocytes (800-1000 micron diameter) of an African clawed frog (Xenopus laevis), a model organism used in cell and developmental biology research. Each oocyte is surrounded by thousands of follicle cells, shown in the image by staining DNA blue. Blood vessels, which provide oxygen to the oocyte and follicle cells, are shown in red. The ovary of each adult female Xenopus laevis contains up to 20 000 oocytes. Mature oocytes are approximately 1.2 mm in diameter, much larger than the eggs of many other species.
Denk was the “driving force” behind the invention of two-photon microscopy in 1990, prize representatives said. Along with Tank and Svoboda, Denk used the technique to image the activity of dendritic spines, the fundamental signaling units of neurons. Konnerth took the technique further by using it to measure the activity of thousands of synapses in living animals, and Svoboda used the method to study how brain networks change when animals learn new skills.

A Cancer Cell Divides
Credit: KUAN-CHUNG SU AND MARK PETRONCZKI, LONDON RESEARCH INSTITUTE, CANCER RESEARCH UK; WELLCOME TRUST
This composite confocal micrograph uses time-lapse microscopy to show a cancer cell (a HeLa cell derived from the cancer of a woman named Henrietta Lacks) undergoing cell division (mitosis). The DNA is shown in red, and the cell membrane is shown in cyan.
Light travels in tiny packets called photons. Two-photon microscopy is an advanced form of fluorescence microscopy, a technique that involves labeling parts of cells with molecules that glow, or fluoresce, when light of a certain wavelength shines on them (typically ultraviolet light). Normally, high-energy (short-wavelength) UV light spreads throughout the tissue and makes some areas glow more than others, making it hard to see specific parts of cells. In addition, the UV light can’t penetrate very far into the tissue because it exhausts the fluorescent molecules.

Stunning Seedling
Credit: FERNAN FEDERICI AND JIM HASELOFF; WELLCOME TRUST
This confocal micrograph shows the tissue structures within the leaf of an Arabidopsis thaliana seedling. The sample was fixed and stained with propidium iodide, which labels DNA, but was imaged four years later. Different oxidation of the staining chemical in different tissues allows researchers to investigate the structures within.
In contrast, two-photon microscopy uses infrared (longer-wavelength) lasers, pulsed over a specific area so only that area emits light. “It’s like the difference between looking at a movie in daylight, and looking at a movie in a dark hall: If you take away the unwanted light you can see what you want to see much better,” Dr. Maiken Nedergaard, a professor of neurosurgery and neurobiology at the University of Rochester Medical School, in New York, said in the statement.

Caffeine Crystal
Credit: ANNIE CAVANAGH AND DAVID MCCARTHY; WELLCOME TRUST
This false-coloured scanning electron micrograph shows caffeine crystals. Caffeine is found occurring naturally in plants, where its bitterness serves as a defense mechanism.
Normally, a single photon of infrared light doesn’t have enough energy to make a molecule fluoresce. But in a two-photon microscope, the pulsed laser shines enough light on a sample that, occasionally, two photons will hit at the same time, causing the molecule to give off light.
Unlike conventional fluorescence microscopy, two-photon microscopy doesn’t exhaust the fluorescent molecules. The infrared can penetrate much deeper into the tissue, enabling researchers to peer hundreds of micrometers (several times the width of a human hair) beneath the surface of a living, active brain.
Crown Prince Frederik of Denmark will present the prize to the four researchers on May 7 in Copenhagen.

Chicken Embryo
Credit: VINCENT PASQUE, UNIVERSITY OF CAMBRIDGE; WELLCOME TRUST
This fluorescence micrograph shows the vascular system of a developing chicken embryo (Gallus gallus), two days after fertilization.

Moving Cancer Cells
Credit: SALIL DESAI, SANGEETA BHATIA, MEHMET TONER AND DANIEL IRIMIA, KOCH INSTITUTE FOR INTEGRATIVE CANCER RESEARCH, MIT; WELLCOME TRUST
Taken in the course of research into how cancer cells move and spread, this Wellcome honoree shows cancer cells traveling through spaces a tenth the width of a human hair.

Moth Fly
Credit: KEVIN MACKENZIE, UNIVERSITY OF ABERDEEN; WELLCOME TRUST
This false-colored image of a moth fly reveals the insect’s fuzzy body and compound eyes.

Hole in the Heart
Credit: Henry De’Ath, Royal London Hospital | Wellcome Trust
This photograph shows the repair of a traumatic ventricular septal defect (VSD). A VSD is a hole between the right and left ventricles of the heart, and is usually seen as a congenital condition, known as a ‘hole in the heart’. This picture was taken in theatre to document the unusual injury and its subsequent repair; the VSD is seen at the bottom of this image, and a bovine patch is being stitched and parachuted into place to seal the defect.

Bacteria Biofilm
Credit: Fernan Federici, Tim Rudge, PJ Steiner and Jim Haseloff | Wellcome Trust
This micrograph photo was taken as part of a synthetic biology project and shows Bacillus subtilis, a Gram-positive, rod-shaped bacterium that is commonlyfound in soil. Distinct lineages of bacteria expressing different fluorescent proteins were initially mixed randomly on a petri dish. As the bacteria grow, they organize themselves into reproducible patterns and shapes that can be predicted with mathematical models.

Loperamide Crystals
Credit: Annie Cavanagh and David McCarthy | Wellcome Trust
This false-coloured scanning electron micrograph shows crystals of loperamide, which is a drug used to treat diarrhea; loperamide works by slowing down the movement of the intestine and reducing the speed at which the contents of the gut pass through. Food remains in the intestines for longer and water can be more effectively absorbed back into the body. This results in firmer stools that are passed less often.

Microneedle Vaccine
Credit: Peter DeMuth | Wellcome Trust
This scanning electron micrograph shows an array of ‘microneedles’ made from a biodegradable polymer. Researchers have shown these materials can be used to deliver vaccines and therapeutics to the outer layers of the skin in a safe and painless way.
Desmid Alga
Credit: Spike Walker | Wellcome Trust
This photomicrograph shows Micrasterias, a type of green alga called a desmid, which usually inhabits the acidic waters associated with peat bogs. These particular desmids are flat, plate-like single cells made up of two halves, which are mirror images of each other with highly ornamented edges.
Cool Connective Tissue
Credit: Anne Weston, LRI, CRUK | Wellcome Trust
This false-colored scanning electron micrograph shows connective tissue removed from a human knee during arthroscopic surgery. Individual fibers of collagen can be distinguished and have been highlighted by the creator using a variety of colors.
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