Spot cancer before it starts with nanoscale microscopy

DEEP in the heart of the cell, your DNA may be undergoing subtle changes that could lead to a devastating disease several years down the line. New microscopy techniques are now lifting the lid on this inner world, potentially offering an early-warning system for cancer or Alzheimer's long before the diseases begin to bite.

Full-blown disease may be preceded by a long build-up. For example, a change in chromatin - the complex of DNA and proteins that packages DNA into the cell nucleus - is one of the earliest events to occur after exposure to carcinogens or ultraviolet rays.

Changes sometimes happen years before symptoms of a tumour manifest themselves. However, tracking those changes has been frustratingly beyond the reach of medicine. They involve tweaks to structures that are less than 400 nanometres across, which is smaller than the wavelength of the visible light used in ordinary optical microscopy.

"When you have two structures that are smaller than the wavelength of light, you can't really tell them apart and everything is merged into one big blur," says Vadim Backman of Northwestern University in Evanston, Illinois. "We're missing all that complexity."

To make sense of the blur, Backman has ditched standard microscopes in favour of a method called partial wave spectroscopic (PWS) microscopy.

PWS looks at how a light beam interacts with a cell. As the beam travels through the cell it reflects off different structures within according to their density. The pattern from the reflected light is used to reconstruct the nanoscale detail inside the cell. "It's almost like you have a cat in a black box. Instead of trying to X-ray it, you hear it miaow and so you know it is a cat," says Backman, who presented his work at the Frontiers in Cancer Prevention Research meeting in Boston last month.

PWS is one of many new techniques for studying cells at the nanoscale (see "A nanoscopic study in scarlet"). It is particularly good at detecting changes in density in complexes like chromatin. So far, Backman has used PWS to show that apparently healthy cells taken from people with lung, colon, pancreatic, ovarian and oesophageal cancer have unusual chromatin densities not seen in cells from people who are cancer-free.

What's more, such changes are relatively easy to detect because they often occur in normal cells as well as those that are or will become cancerous. For example, Backman used PWS to identify which of 135 smokers had lung cancer and which were cancer-free by analysing cells swabbed from the inside of the cheek (Cancer Research, DOI: 10.1158/0008-5472.can-10-1686). Similarly, he found that a swab of rectal cells could identify people with colon cancer, and a cervical swab could detect women with ovarian cancer.

"It is a very creative and promising method," says Igor Sokolov of Clarkson University in Potsdam, New York, who is using another nanoscale technique called atomic force microscopy to look for differences between healthy and cancerous cervical cells. "Anything that provides new information about cellular structure at the nanoscale will potentially be advantageous for both diagnostics and further understanding of diseases."

The hope is that PWS could be used to screen the general population for early signs of cancer. Backman also has preliminary evidence that PWS could be used to diagnose autoimmune diseases such as inflammatory bowel syndrome and to investigate the changes in cells that cause Alzheimer's disease to develop.

A nanoscopic study in scarlet

Tiny changes in the structure of cells can make a big difference to your health. Gabriel Popescu and his colleagues at the University of Illinois at Urbana-Champaign are studying how light is scattered off red blood cells in order to diagnose diseases such as malaria, sickle-cell anaemia and an age-related disease called anisocytosis, in which the size of the cells begins to change.

Popescu's technique, called quantitative phase microscopy, measures the intensity of scattered light close to a cell and compares this with the distance the light has travelled through the cell, in order to detect tiny undulations in the cell's surface. Deformed cells glow an unusual shade of red, which can be detected by the microscope (Biomedical Optics Express, DOI: 10.1364/boe.2.003259). "The shades of red are telling us how sick the cell is," says Popescu.

Vadim Backman of Northwestern University in Evanston, Illinois, is impressed. "He's not looking at the small things inside the cell, but at small differences in cell thickness, which he can detect beautifully with nanoscale precision."

So far, Popescu has discovered a characteristic light signature for anisocytosis and hopes to do the same for malaria.

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