Navigating the mysterious world of nano-medicine
A Fantastic Voyage
Most discussions of the future of medicine tend to revolve around genetic manipulation, personalised pharmaceuticals, and putting off death as long as possible.
Yet the work that's going on in research labs in Basel, Switzerland, home of two of the world's biggest drug companies isn't about any of that. Instead, they are building on atomic force microscopy (AFM) to image and study the smallest structures in the human body with a view to working at the molecular level: nanomedicine.
More the 1966 movie Fantastic Voyage, less the 1997 movie Gattaca or the reconstruction of an entire Supreme Being from a few cells of 1997's Fifth Element.
"The long-term goal is to draw one drop of blood and have it analysed in minutes at the bedside," said Patrick Hunziker, a doctor with the intensive care unit at University Hospital Basel. That sounds like Gattaca, in which parents chose the genetic makeup of their babies before conception and people punched in at work with a drop of blood for DNA identification.
Then Hunziker turns to AFM images of collagen fibers forming the plaques of atherosclerosis, which eventually kills more than 50 per cent of Europeans. Fantastic Voyage, after all; in fact, Hunziker includes a still from the movie among his slides.
The movie was silly enough in concept: a team of doctors and a submarine were shrunk to micrometer size by a miniaturising ray gun and injected into the bloodstream of a comatose patient to go turn a laser beam on a blood clot that needed to be removed from his brain. In one hour. Before the miniaturisation wore off. But the visual imagery of their journey through the human body was startling enough to make most viewers forget, at least temporarily, the many logical flaws.
The history of medicine is a long series of developments allowing doctors to see better and more clearly into the human body: X-rays, MRI scans. Now, the notion of being able to see all the way down to the molecular level promises much earlier detection and much finer control. A different technique, X-ray phase contrast imaging, passes X-rays (either from ordinary tubes or from a synchrotron) through a series of tiny gratings, or arrays of slits, and from builds a detailed, three-dimensional picture of soft tissues from the reflections at much finer resolutions than is possible today.
Christian David, explaining the technique at the Paul Scherrer Institute, predicts many applications: distinguishing semtex and cocaine from cheese and chocolate inside luggage, product inspection, and mammography. Also heart disease: looking at the heart using today's methods requires contrast dyes, which are almost immediately flushed out. This technique does not require dyes.
Nor does it produce the kind of tissue damage familiar from traditional X-rays. "Radiography needs tissue damage to get an image," he said. "Phase contrast does not require any photons to be absorbed. You look at the change in direction of the wave but don't need to deposit harmful energy."
That lack of damage should be a selling point. "The question is, can we get this into hospitals?" he said. The technique needs more work with ordinary X-ray tubes instead of PSI's near-by synchrotron, the Swiss Light Source, and doctors and technicians need to be convinced. Medical equipment manufacturers seem the most likely conduit.
Martin Stoltz, a doctor at Biozentrum is exercised by a completely different question: "What's the point of living past 130," he said, "if for the last 20 years of your life you can't get out of bed because your joints don't work?" His target is arthritis, which is on the rise everywhere, and his tool is AFM, which his team has developed into a technique they call Arthroscan, which he predicts will be the most widely used detection device worldwide by 2015.
On the nanometer scale, he said, the difference in elasticity between a knee's healthy cartilage and cartilage showing early signs of osteoarthritis is startling. In his image, the first looked like loosely scattered strands of spaghetti, the second like twigs forming a bird's nest. Today's MRIs give only limited information and "No early detection," he said. "Precise diagnosis at the nanometer scale will enable effective healing of cartilage disease."
A third approach is sensors built of tiny cantilevers that can detect microorganisms in 90 minutes rather than the 20 hours it takes a colony to grow to sufficient size in a Petri dish. Coating the cantilevers with antibodies, said Christoph Gerber, allows multiple protein detection. The personalised medicine of so many mass media stories could be enabled by this type of nanomechanical sensor.
All of these ideas – and also those of cancer researcher Marija Plodinec – converge on the notion of being able to detect warning signals at the molecular level and to treat individual cells before they can cause too much damage. Nanocarriers made of polymers of the kind already safely in use in the human body could carry drugs that first detect a condition and then turn themselves on to treat only the target cells, an approach Hunziker called "theragnostics".
Hunziker himself has had some good results, but they're not ready for clinical trials – and when they are, probably the atherosclerosis patients he sees most won't be first in line. Typically, very new treatments, after animal testing, are most likely to be tried on humans whose chances for survival are bad already. Cancer, therefore, is a more likely first target.
He almost sounds wistful, therefore, when he says: "I would like to cure atherosclerosis by the time of my retirement." He is 43.
Busting up atherosclerosis plaques might be more similar to busting up a clot, but Hunziker's work's real similarity to Fantastic Voyage is in the emphasis on making things – drugs, devices – small enough to interact on the same scale as human cells. As Hunziker says, there is a fundamental size mismatch between today's microscopic tools and any attempt to fix problems at the cellular level – and the cellular level, as Stoltz noted, is where all diseases start.
One must hope, though, that no one uses a miniaturising ray to get to that level. Because no one ever explained, at the end of Fantastic Voyage, why the atoms that made up the submarine, abandoned in a blood vessel, didn't explode the patient when they returned to full size. ®