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SEPTEMBER / OCTOBER 2004

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Fourth Asan-HMI symposium highlights nanotechnology

Two of the most promising and controversial areas of research, nanotechnology and stem cells, shared the stage at a June symposium in Seoul, Korea, showing international progress and directions for the near future. The Fourth Asan–HMI Joint International Symposium, titled “Nanotechnology in Biology and Medicine,” focused on promising areas of drug design and delivery, nano-based diagnostics and therapies, tissue engineering, “lab-on-a-chip” devices, and genomics. Hosted at Asan Medical Center and organized jointly by Asan and Harvard Medical International, the symposium drew experts from Korea and the United States.

Lynn Jelinksi: Nanotechnology has the potential to “change the quality of the human condition.”

In her keynote address, Lynn Jelinski, a chemist, former Cornell professor, and now president of Sunshine Consultants International in Florida, said that nanotechnology and genomics are “definitely going to change the quality of the human condition.” One of nanotechnology’s attractions is that nanoscale clusters of molecules have different physical properties, as in conductivity, strength, and optical transport, than the same material on a bulk scale. So it is possible to develop novel circuits and to find new uses for familiar substances. Jelinski explained that in 2000, the World Technology Evaluation Center (sponsored by multiple federal research agencies) projected that the worldwide impact of nanotechnology by 2015 would top a trillion dollars per year.

But gaps in our knowledge remain. “Do we understand the toxicity of nanostructures?” Jelinski asked. Not entirely. She said it is up to scientists to examine the real dangers and to develop public understanding of the technology to avoid a backlash similar to that against genetically modified food and other organisms.

Mehmet Toner: Exploring the impact of nanosystems on tissue engineering.

Framing the situation of nanotechnology vis-à-vis the public, Mehmet Toner, professor of biomedical engineering at Massachusetts General Hospital (MGH) and Harvard Medical School and director of the Microsystems Bioengineering Laboratory at MGH, said that nanotech seems to have a relative lack of support and understanding in the public mind.

Further confusion surrounds the prefix nano. Strictly speaking, nano refers to billionths of a meter, and nanotechnology applies to methods of manipulating objects 100 nanometers or smaller in size. But few people speak strictly about the nano scale. What is important is that nanotechnology enables intervention on the scale at which biological systems actually operate.

Tissue engineering
One of the aspects of nanotech that Toner addressed was the impact of nanosystems on tissue engineering. The field makes use of microfabrication techniques to produce functional tissue in both two and three dimensions.

Toner described studies in which tiny engineered surfaces, some with islands of binding or nonbinding molecules, control cell shape and differentiation. “Cell shape can … regulate stem cell lineage commitment,” Toner said, suggesting an area where nanotech and stem cell research may converge for generating certain adult cells for medical applications.

Lab-on-a-Chip
Small, portable lab-on-a-chip and microelectromechanical systems (MEMS) devices can also combine molecular, cellular, and fluidic analyses for applications like diagnosis at the point of care and work in drug discovery.

Since lab-on-a-chip and MEMS techniques are well established, reliable, and economical, the chips are amenable to use in poorer countries. The devices can be made for cents, Toner said, and they are still very accurate.

As the CEO of Digital Bio Technology in Korea, Jun-Keun Chang is developing lab-on-a-chip and other devices for world markets. Also an assistant professor of electrical engineering and computer science at Seoul National University, Chang presented at the conference, describing fluidics-based devices that enable single-molecule and single-cell manipulation and detection. “We can look into multiple events within living cells simultaneously by real-time monitoring and fluorescence measurement at the single-cell level,” he said. Chang said that lab-on-a-chip devices like his could potentially be used prenatally, replacing amniocentesis with a noninvasive blood test.

Peter Park: Looking for relationships between genomic data from microarrays and patient data, in order to predict patient survival based on molecular profiles.

All of these tiny-tech instruments and approaches generate data, but in many cases, methods for gleaning reliable information from it prove to be inadequate. Peter Park, instructor in pediatrics at Children's Hospital, Boston and associate director of bioinformatics at the Harvard Medical School–Partners Center for Genetics and Genomics, is devising statistical and computational methods for interpreting data from a variety of high-throughput technologies like microarrays, genomic sequences, and protein–protein interactions. One of his interests is finding relationships between genomic data from microarrays and patient data, in order to develop methods for predicting patient survival based on molecular profiles. Microarray studies still have bugs, Park said, which prevent them from being used for clinical care. A major problem is a lack of agreement among studies for the same disease.

Drug delivery
One particularly promising area of nanotechnology is drug delivery. Nanotech devices for delivering drugs have numerous advantages over their macroscale counterparts, said Nicholas Peppas, the Fletcher S. Pratt chair of engineering at the University of Texas, Austin. He spoke about an investigation he is involved in that is the first successful in vitro study of oral delivery of interferon-beta 1a, used for multiple sclerosis.

Nicholas Peppas: Nanotech devices offer numerous advantages in the area of drug delivery.

The study tested oral delivery of peptides and proteins, including interferon-beta 1a, through a hydrogel carrier. Engineered on a nano scale and composed of crosslinked polymers, the pH-sensitive hydrogels incorporated the drug and then released it at variable rates, depending on the pH of the surrounding environment. The research suggests that these nanoparticle carriers may protect drugs from being broken down in the body until they can reach the small intestines.

Underscoring the promise of engineered technologies to deliver medications, Sang-Yoon Kim, professor of otolaryngology at Asan Medical Center and its teaching affiliate, the University of Ulsan College of Medicine, presented his work on microspheres loaded with all-trans-retinoic acid (atRA) to treat head and neck squamous cell carcinoma, an aggressive epithelial malignancy. Clinical application of atRA is limited due to retinoid resistance and toxicity. His team’s study showed that unlike daily oral doses, biodegradable microspheres that were injected under the skin maintained plasma concentration of the drug in the therapeutic range for a long period.

Looking into the future, Peppas said that these and other technologies may be used to construct smart diagnostic and therapeutic systems. He visualizes giving people an injection containing microparticles or nanospheres, which have been imprinted to recognize disease-associated compounds like glucose, angiotensin, and cholesterol. The “stealth” particles would circulate in the blood, and when they recognized an enemy compound, would capture it, and through biodegradation, trigger the release of an appropriate therapeutic drug.

Stem cell controls
In his work on the natural systems that regulate adult hematopoietic stem cells, David Scadden, professor of medicine at MGH and HMS, co-director of the Harvard Stem Cell Institute (see Forum), and director of the Center for Regenerative Medicine and Technology at MGH, has identified for the first time elements of the microenvironment that control the behavior of mammalian stem cells. He and his colleagues discovered that mineral components are important to stem cell localization; matrix components are important to constraint of stem cells; and bone-forming osteoblasts, to the support and proliferation of stem cells.

More specifically, Scadden commented that the calcium-sensing receptor, located on the surface of hematopoietic stem cells and other cells, is critical to stem cells finding their niche. If stem cells are in an environment of low ionic calcium, the receptor is downregulated. “In the blood bank, that’s exactly the way we store stem cells,” Scadden said. “So, in fact, our method of storage may be working against us … We are now working with the blood bankers to see if methods of storage can be used which could possibly change this expression and enhance engraftment.”

Mi-Jung Kim, an assistant professor of laboratory medicine at the Asan Institute for Life Sciences, University of Ulsan College of Medicine, also is investigating hematopoietic stem cells to improve their therapeutic value. Kim has conducted recent studies on the integration and proliferation of transplanted bone marrow cells in the recipient ’s body.

Mitchell Spellman: “These lectures and the promise and the power of nanotechnology have already or will very soon obliterate or obscure the distinction between what we’ve called pure science and applied science.”

Promise and power
The symposium was opened by Kun-Choon Park, president of Asan Medical Center and professor of surgery at the University of Ulsan College of Medicine, who said that nanotechnology “can lead via improved biodevices to a better quality of life, improved wealth creation, and a stronger base for our new knowledge-based economy.”

In closing the conference, Mitchell Spellman, director of academic alliances and international exchange programs at HMI, described a paradigm shift put in motion by work at the nano scale, the level at which biological systems function. “These lectures and the promise and the power of nanotechnology have already or will very soon obliterate or obscure the distinction between what we’ve called pure science and applied science,” he said.

Robert K. Crone, president and CEO of HMI, pointed out that each Asan-HMI symposium has been multicultural and multidisciplinary. “Each event has been a learning experience for the faculty as well as the audience, enabling even those who are experienced in their subject to look at their research from a different perspective.”