Secrets of a cell
Peering in at a near-nano level could spark medical breakthroughs
Drawing the shades in his eighth-floor office at Harvard Medical School, Ulrich von Andrian offers a visitor a private screening of one of his recent gore-spattered spectacles.
"It's a snuff flick," he says.
The digital images projected onto the wall show T-cells - a type of white blood cell that performs SWAT duty for the immune system - hunting tainted cells that may carry disease.
The action unfurls in a lymph node. There's a chase, there's a killing. And cytoplasm drains from the "corpse" of the intruder like blood from a street punk who crossed Dirty Harry.
In leading laboratories in Boston and beyond, a revolution is afoot in the way scientists visualize cells. Pioneering microscope techniques are allowing researchers to dramatically zoom in the focus on infinitesimal structures and events occurring in living tissue - and, most critically, they are increasingly able to do so without harming the organism. Until now, the finest-resolution images depended on the use of toxic radiation or chemicals.
"The science is becoming gentle, used in a way that is compatible with life to study processes fundamental to life," said Xiaowei Zhuang, a Harvard chemist and Howard Hughes Medical Institute investigator whose Cambridge lab is at the forefront of the new wave of imaging.
"If you want to understand the inner workings of the cell, you need to see - really see - how molecules interact with each other," she said. "No more straining to guess at the purpose of some blurry dot."
Researchers predict live visualization at the near-nano level will yield powerful new diagnostic tools, highly targeted medicines, and super-precise surgery for an array of afflictions, from clogged arteries to cancer.
The technology is still at its dawn, but already scientists have made important discoveries about how, for example, immune cells capture an invading pathogen - a virus, say - in the lymph nodes and chop up the prey to fashion custom antibodies. Such work could give clues on how to make vaccines.
Work by Harvard's X. Sunney Xie, meanwhile, shows how just one molecule can initiate long sequences of activity - invisible until now - that might explain the role of individual genes in sickness or health.
Other recent findings have shed light on the precise mechanisms used by viruses to invade cells; how cells transport material and relay signals from outside the cell to within; and how brain neurons fight for territory and prune back unnecessary tendrils to make for a well-ordered web.
"This is the ultimate reality check for medical research," said von Andrian, a Harvard pathology professor whose lab was the first to video a T-cell killing another cell. "We are peering in on cellular processes as they really are, as they occur against the backdrop of all the other activity in the cell. . . . The cell isn't a quiet place. It's a teeming city. Science has barely begun exploring it."
In forging a new future, cell biology is returning to its roots. At the center of the research is the centuries-old laboratory workhorse known as the optical, or light, microscope, which uses visible light to visualize its subjects.
Anton van Leeuwenhoek, the 17th century lens grinder often hailed as the father of microscopy, would hardly recognize his descendents - they have been tricked out with lasers and teamed up with computers able to gather and collate vast quantities of information into real-time three-dimensional images.
Von Andrian's $1.2 million microscope system floats on a cushion of air; otherwise, minute vibrations carried by the research center's structural steel would ruin his eensy images.
Until recently, light microscopes were seen as inferior to newer deep-peering technologies because of a fundamental constraint: At a point called the diffraction barrier, light waves begin to interfere with one another, blurring images below the size of a human cell to fuzzy blobs.
So for close-up examination of smaller bits - protein clusters, viruses, DNA - scientists of the past 50 or 60 years relied heavily on electron microscopes and other imaging tools that bombarded lifeless, "fixed" cells with X-rays, chemicals, magnetic fields, and radio waves.
The results were spectacular, but static - like studying a beautifully mounted bald eagle in a museum display instead of watching the plunging raptor snatch a salmon from a roiling river.
Now light is making a comeback thanks to giant steps in the use of fluorescent molecules - like those that impart glow to certain species of jellyfish. Using various techniques, these molecules can be inserted in cells and then activated to outline live subcellular structures down to the level of a few nanometers. A nanometer is one-billionth of a meter, barely larger than an atom; a dust mite measures about 200,000 nanometers.
"Lens-based microscopy has toppled a barrier that was thought would stand forever," said Stefan W. Hell, director of Germany's Max Planck Institute of Biophysical Chemistry and a leader in the new field.
Hard-nosed medical researchers play down the wow factor, but there is plenty of cool captured in images emerging from top labs.
Here, limned by Zhuang's imaging system at her lab in Cambridge, a mitochondrion hunches on a microtubule - a sort of highway within the cell - looking for all the world like an inchworm on a twig. But the microtubule has a diameter 2,000 times narrower than the finest human hair.
Here, biological engineers at the Massachusetts Institute of Technology have started tracking the rise of precancerous mutations within cells.
And there, caught in the crosshairs by Harvard cell biologist Tomas Kirchhausen, what appear to be bubbles forming on the seething surface of an alien planet are actually vesicles - orbs produced on the cell's constantly churning outer membrane to carry nutrients and other materials to the deep interior.
"I've worked 25 years to understand this process," Kirchhausen said quietly, almost disbelievingly. "Until very recently, the ability to see what we are seeing now was nearly inconceivable."
In Kirchhausen's lab, the focus is on figuring out how molecules enter and exit cells. A constant flow of nutrients is needed for life processes. But viruses and other shifty characters trick cells - by use, it seems, of the biological equivalent of a secret handshake - to sneak past the gates.
"Learning how viruses gain access will be the critical step in figuring out how to block their entry," Kirchhausen said.
Older imaging techniques have yielded wondrous mug shots of DNA, individual proteins, and other structures. Meanwhile, thanks to genomic advances, scientists have excellent inventories of the cell's vital parts.
If the past half-century has been largely dedicated to cataloging what lies within the cell, the next span of decades will focus increasingly on grasping the complex choreography of the cell.
"In ballet, a dancer can fumble a step without ruining the production," said Stephen Harrison, director of Harvard's Center for Molecular and Cellular Dynamics, but the origins of many fearsome diseases may lie in subtle missteps of cellular processes.
"If a cell misses a single beat, the result can be catastrophic," he said. "That's why it's so critical to go beyond identifying the cell's working parts to watching those parts hard at work."
Colin Nickerson can be reached at Nickerson.colin@gmail.com. 