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UC Davis Health System

UC Davis Health System

When tiny is big

 photo of the Nanoscale Interdisciplinary Research Team
The Nanoscale Interdisciplinary Research Team is made up of (from left, front row) Susan Kauzlarich, Satya Dandekar, (from left, back row) Majorie Longo, Jacquelyn Gerbay-Hauge and Gang-Yu Liu.

Posted July 5, 2006

Nanotechnology isn't as complicated as it sounds. You just have to think small. Really, really small. Then even smaller than that.

If you can wrap your mind around it, think in the range of one billionth of a meter. That's about the size of 10 hydrogen atoms lined up. It takes about 1,000 of these nanometers to total the diameter of a typical biological cell.

That's so small that it requires a whole new set of tools just to investigate this teensy biological frontier and a whole new vocabulary to describe it. To name just a few of the terms coined by this study of the infinitesimal, there's nanoparticles, nanocrystals, nanoplatforms, nanomaterials, nanografting, nanofabrication, nanophases, and, researchers hope, nanotherapy.

It's this latter possibility — nanotherapy — that has captured the attention of a group of basic scientists at UC Davis who come from faculties of the School of MedicineCollege of Letters and Science and the School of Engineering. These five researchers — incidentally all women — and their labs are hoping to use synthetically engineered nanoparticles as a decoy that would block the human immunodeficiency virus that causes AIDS from infecting human cells.

This is no mean feat.

Worldwide, the HIV epidemic is showing little sign of abating. By the end of 2001, 40 million people were carrying the virus: 940,000 in America, While most of those infected in America can trace their infection to the use of illicit injectable drugs, internationally its primary cause is clear: unprotected sex.

Medical research has made great strides in treating HIV infection, but its toll continues to astound the epidemiologists who total the numbers. Just last year, 3 million died from HIV; 1.1 million were women and more than a half a million were under the age of 15. Ninety-five percent of the 40 million living with HIV are in developing countries. In sub-Saharan Africa, for example, 28.1 million are infected with HIV — numbers that threaten the very survival of whole nations.

Among the hotbeds of AIDS research, UC Davis holds a prominent position. As early as the late '80s, Davis researchers had already identified simian and feline immunodeficiency viruses whose similarities to HIV greatly advanced understanding retroviruses. Now, under the auspices of the Northern California Center for AIDS Research, headed by medical school virologists Satya Dandekar, an ambitious collaboration among three chemists, a chemical engineer and material scientist and Dandekar is poised to make further important breakthroughs in understanding and, perhaps, preventing HIV infection.

This collaboration, funded by a National Science Foundation grant that encourages interdisciplinary basic science research, features principal investigator and chemistry professor Jacquelyn Gervay Hague, associate chemistry professor Gang-Yu Liu, chemistry professor Susan Kauzlarich, associate chemical engineering and material science professor Marjorie Longo, and Dandekar, professor and chair of the medical school's Department of Medical Microbiology and Immunology. Together with the students and fellows in their labs, the women have formed the Nanoscale Interdisciplinary Research Team.

 photo of nanotech instrument
Technology enables researchers to create synthetic drugs atom by atom.

“We are targeting our study at the way the virus infects the cells that line the mucosal membranes of the rectal and vaginal tracts,” said Dandekar, who has been investigating the mechanism of mucosal infection and immunity since joining the medical school in 1983 following a postdoctoral fellowship at the National Institutes of Health. “That is clearly the most common way HIV is transmitted, even though most Americans seem to contract the virus through IV drug use. But if you want to really attack the spread of this virus, these mucosal membranes have to be the target.”

Like all viruses, HIV carries proteins on its surface. One of these — GP120 — recognizes and binds to a component of the surface membrane of the mucosal cell it is targeting, specifically the carbohydrate molecule known as Galacosyl ceramide, or Galcer, for short.

“That interaction between GP120 and Galcer can either be a weak interaction or a strong one,” said Longo, the chemical engineer on the team. “Part of our quest is to understand how you get one or the other.”

Making nanoparticles

To manufacture the diminutive synthetic particles the researches are using, UC Davis chemist Susan Kauzlarich uses inorganic quantum dots, which are semiconductors such as silicon.

“These are very small-sized particles of elemental silicon on which we can modify and put the Galcer that binds with HIV's GP120,” said Kauzlarich, who has been at UC Davis for 15 years. “The process involves synthetic chemistry which takes advantage of new approaches to make nanoparticles that are stable. Because they emit light, or luminesce, we can tell exactly how certain ligands inhibit the attachment of virus to cell walls. And what we're hoping to do is actually image this process.”

Silicon is an attractive possibility because unlike many other chemicals that carry harmful byproducts, silicon is a nontoxic biocompatible element.

“That means if I want to introduce silicon into a human being, it won't cause harm,” said Kauzlarich, an inorganic materials chemist whose lab is using solution chemistry in an inert atmosphere to develop the nanoparticles.

Chemist Gang-Yu Liu uses a process called nanografting to engineer the GP120 binding sites, which measure no larger than 2 x 4 nanometers onto the surfaces. To accomplish this, her group has employed sharp probes, known as atomic force microscope cantilevers, to shave away molecules from planar surfaces and the silicon nanoparticles and thus create room for the synthetic ligands to attach.

“We can also image the particles so we can see the individual proteins one by one,” said Liu, who Kauzlarich calls the ringleader of the research team because she saw how all the scientists' work fit together.

Imaging includes the use of total internal reflectance fluorimetry and atomic force microscopy. Principal investigator and chemist Jacquelyn Gervay Hague has successfully manufactured the pertinent nanoparticles and has shown them to bind to the HIV and inhibit infection, but only at a rate of 60 to 70 percent.

“We believe by using nanotechniques we can make artificial particles that are better capable of binding the virus than even the natural cells,” said Gervay-Hague,” and we believe we can achieve 100 percent inhibition of viral replication using them. That's our goal.”

To explore this attachment of GP120 to Galcer, the Davis scientists are manufacturing synthetic nanoparticles that are covered in specific numbers of Galcer molecules. The diminutive particles can vary not only in the quantity of Galcer present but also in its mobility. By determining which Galcer-laden nanoparticles are the most attractive to HIV, the researchers believe they will be able to create a particle so tantalizing to HIV it would, if given the choice, choose the synthetic particles rather than the mucosal cells to infect.

“This is a project,” said the medical school's Dandekar, “that combines and uses modern technology to study very basic science questions that have the potential to answer important clinical needs. We believe that by focusing on this very important first step in the infection process, we can block its ability to enter the cell and wreak havoc.

“But I am not a chemist or an engineer. I am a virologist. I know how to grow virus, infect cells, manipulate viral genomes and study all the effects viral infection has on host cells and hosts in general. I have a very good understanding of what it does to cause AIDS. But I have no idea how to put nanoparticles together. I can't make the decoys. I can't image them. I can't manipulate them. So I need the work these other researchers are doing. I provide the biological model — the human cells — that can test the efficacy of their work.”

Indeed, it is this total collaboration, as Dandekar so aptly calls it, that distinguishes the work of these five Davis faculty women and their respective labs.

 photo of Satya Dandekar and Elizabeth Reay
Satya Dandekar and Elizabeth Reay check the viability of cytopathic effect of synthetic drugs in cultured cells.

“We bring deep and diverse experience to this project,” said Dandekar. “But there is no way that any one disciple alone could do the work of this project. We each need the others.”

Already having achieved promising results, the group expects to publish within a year and is hopeful that their synthetic Galcer nanoparticles could be added to such commonly available products as KY Jelly.

“We know that to control the spread of HIV infection we need both good educational outreach and the availability of easy-to-use, readily available preventives that can block infection,” said Dandekar. “We believe this approach may fit that bill.

“We also believe that through this collaboration, which we expect will continue beyond the four years of this first grant, our approach will be applicable in other mucosal infections, such as E.coli, salmonella and Valley Fever.”

PI Gervay Hague is also excited because the interdisciplinary collaboration is giving the graduate students and fellows in all five of the labs the opportunity to learn about other disciplines.

“It really is an extremely rich environment for the young scientists who are working on this project, particularly the students,” she said. “It's the advantage of five completely different labs coming together to work on the same problem and it will prepare them well for the future.”