HMI World | Forum | May-June 2003

HMI and Asan Medical Center are planning a joint symposium in Seoul, Korea entitled “Nanotechnology in Biology and Medicine.” Nanotechnology is a word heard throughout science and business circles lately, but is its real impact on medicine is still in its infancy. Here, HMI World takes a look at some of the nanotechnology research in the works and how this new field may change medicine.

The definition of nanotechnology is simple: the science and engineering of structure on a nanoscale (10^-9 meters or 1/100,000th the width of a human hair), which is made possible by technologies that allow us to view, study, and manipulate matter on the level of individual atoms and molecules. In reality, the applications of nanotechnology merge with existing work on a microscale, and the two are often used interchangeably in small-scale science. Biologists, chemists, and physicists have always studied tiny structures—the difference now is that the refinement of techniques to detect small-scale phenomena and engineer miniscule devices has finally brought science down to the level of the processes it is studying.

For many people in the clinical world, nanotechnology is still just a buzzword, and its practical implications are unclear. But behind the hype, this nascent field is devising several applications that have the potential to change the way medicine is practiced. While it may take several years for these new advances to reach most doctors’ offices, nanotechnology is already creating devices and tools that will make diagnosis, analysis, therapeutics, and detection faster, cheaper, and more precise than ever before.

One of the first fruits of small-scale engineering in biology has been DNA chips, which capture an unprecedented amount of information about all the genes being expressed in a cell. “It’s really one of the success stories of micro/nanotechnology,” said Dr. Mehmet Toner, professor of surgery at Massachusetts General Hospital and a speaker at the June conference. “The implications are tremendous for fundamental science, and include diagnostics, prognostics, and therapeutics.” Right now the chips are expensive to use, but someday, just like computer chips, they will become much more widely available. One of the biggest challenges for science is interpreting all the information that the chips yield; Toner said that bioinformatics techniques must develop in parallel with nanotechnology, which currently is a technology-driven field. “We create too much information with these new tools and techniques, and we don’t know what to do with it. It’s the nature of how things happen,” Toner said.

The next step, he added, is to use the technology of microfluidics—designing chips that are etched with tiny capillaries that allow fluid flow in picoliter-sized volumes—to bring just about any biological assay that works on a molecular level into a chip. This so-called “lab-on-a-chip“ approach could greatly speed cumbersome reactions, and allow scientists to more precisely control the accuracy of the tests. Eventually a chip could include several layers of parallel reactions, allowing, for instance, many different assays on a small sample of genetic material or fluid.

One of Toner’s research projects is to try to incorporate living cells into chips, allowing researchers to isolate single cells on an array and test how each cell responds to various stimuli. The results of such studies would be far more precise. “You can actually run ten thousand experiments on the chip at once,” he said. “Every cell is the same cell but exposed to ten thousand different combinations of stimuli.” Since cells are natural environmental sensors, cells that are embedded in chips could also be used as biosensors to detect chemical agents.

Goodbye to labs
Eventually these micro and nanofabricated chips could replace just about any kind of blood test that would normally need to be done in a laboratory with a cheap, disposable chip. Already chips can be used to test for specific genetic mutations in individuals, but are not widely available. The ability to perform several laboratory tests right in a doctor’s office will speed many aspects of medical practice and greatly reduce administrative costs. Furthermore, if the cost of these chips goes down, such tests would be a boon to developing countries and rural areas that do not have access to expensive laboratory equipment.

Sensitive screening
Dr. Charles Lieber’s lab at Harvard University has developed a nanowire that can detect levels of prostate-specific antigen (PSA) much more sensitively than current blood tests. “You have this naturally high sensitivity working at the nanoscale,” said Lieber, Hyman professor of chemistry. The concept, he said, is simple. The detection device capitalizes on the fact that proteins and molecules in the body carry natural electric charges. When the device that measures a reaction is on a nanoscale, it is sensitive enough to pick up the positive and negative charges that chemical reactions give off—in this case, when PSA antibodies on the wire bind with PSA in the blood. Because the device is measuring a change directly, there is no need to use extra dyes or labels to serve as a proxy for what is being measured, as in current techniques.

Such devices, Lieber said, will allow clinicians to “detect or screen for diseases with unprecedented sensitivity. And at the same time they will be able do very broad scope screening“—for instance, screening for several possible disease markers at once.

All of these small-scale devices add up to medicine that is more comprehensive and much more personalized than ever before. Dr. Lynn Jelinski, president of Sunshine Consultants, International and keynote speaker at the Asan-HMI conference, said, “In the future, with nanotechnology and gene chips we could analyze your DNA and find the risk of diseases for you. One could imagine individualized risk-appropriate prevention plans. Furthermore, if you had a disease we could figure out from your genes the best therapies to use.” When it becomes easy enough to assay a person’s entire genome or run a thousand possible tests at once during a visit to the doctor, it suddenly becomes possible for every person find out his or her genetic susceptibilities using a single drop of blood.

This capability carries heavy impacts, choices, and changes for society. Do we really want to know that we might get a disease before we even have symptoms? How can patients keep such information private, and protect themselves against potential discrimination from insurers and employers? “This is a technology that has to go hand in hand with ethics and societal issues,” said Jelinski. But ultimately, she said, it has the promise of greatly reducing health care costs and bringing a new focus to preventive medicine tailored to the individual.

Building new organs
The field of tissue engineering is also developing much more sophisticated abilities based on microfabrication and nanofabrication techniques. Cells need to be placed on a scaffold that gives them structure before they can be coaxed to forming tissues. “We know we can control cell structure and function by fine control of the scaffold that cells lie on,” said Dr. Joseph Vacanti, John Homans professor of surgery at HMS. With the ability to devise more precise scaffolds, tissue engineers can create tissues that are more complex and have a built-in blood supply.

Over the past 20 years, Vacanti said, the tissue engineering field has managed to create viable skin, bone, cartilage, bladders, and blood vessels. Muscle tissue is currently under development in his lab, including heart muscle, and more complex structures based on bone and cartilage. But the ultimate goal is building large pieces of tissue and whole organs, with the aim of solving the organ shortage problem, which keeps many people waiting for donor organs that are in very short supply.

But creating organs is no easy task, and requires a detailed understanding of the underlying biology, as well as the ability to manipulate many factors in the cells. “My opinion is that right now the real limiter to building a whole organ is the problem of ordering all the cells in a thick living structure,” Vacanti said. It is difficult to provide larger structures with the steady flow of oxygen and nutrition they need to survive. “Our approach to this barrier is using microfabrication technology to create an entire blood supply to the tissue as we’re building it.”

“The field now is growing exponentially,” Vacanti added, and students and young researchers are interested in tackling these problems.

From research to reality
When will these technologies be moving out of labs and into clinics? Most experts are hesitant to commit to a timeline. “In some cases nanotechnology certainly has been overhyped. We have to be very realistic about what will be delivered,” said Jelinski. The initial buzz around nanotechnology in industry has softened as private funding sources have tightened their belts. Companies are now looking at specific products they can sell rather than committing resources to research.

But in academic research labs, the field is gaining ground, and has seen some exciting new changes in a way that brings basic biology and chemistry together with engineering and physics. “You’re merging two areas that were in the past pretty incompatible,” said Lieber. He notes that the students in his lab now come from widely varied backgrounds and work together on projects, rather than keeping to their disciplines.

“I find the highly interdisciplinary nature of it very exciting,” added Jelinski. She began in the academic world as a chemist and eventually studied the biophysical properties of spider silk; now she has her own consulting company and moves between academics, government, and industry, and across physical sciences, engineering, and medicine. This impetus to work across disciplines may have effects beyond the nanotechnology tools that are being developed, because it will bring in some diverse perspectives to tackling problems in medicine, and ideally some innovative solutions to medical challenges of the future.