Dr. Ronald Crystal tells young researchers about gene therapy revolution

Dr. Ronald Crystal, professor of medicine at Cornell Medical College, delivers the keynote address at the convocation April 22 for the Undergraduate Research Forum. Nicola Kountoupes/University Photography

By David Brand

The use of gene therapy to treat both hereditary and acquired diseases will be a reality, a leading researcher told Cornell students last week. "We in the gene therapy field, although we have not cured anyone, believe that this is a revolution that will occur in medicine," he told the undergraduates.

Dr. Ronald Crystal, professor of medicine at Cornell Medical College and one of the world's leading authorities on what he describes as "using genes as drugs," was the keynote speaker at the 12th annual Cornell Undergraduate Research Forum on April 22. The forum is a celebration of undergraduate research in science and the humanities from nearly every college in the university. About 90 students presented research from a wide range of study, from the molecular structure of spider silk to "The Subversion of Arthur Miller," during all-day sessions.

Crystal's talk centered on his ground-breaking research in using genes to treat cystic fibrosis, the hereditary disease of the respiratory tract, and atherosclerosis, which is responsible for 72 percent of all cardiovascular deaths in the United States. In both cases, Crystal and his colleague Dr. Todd Rosengart have used the adenovirus, one of the causes of the common cold and "the gold standard of the gene therapy field," to attempt to halt the diseases.

Crystal explained that there are two basic strategies for treating disease by changing the genetic repertoire of somatic cells. The first is ex vivo, taking cells out of the body, modifying them genetically in a test tube and returning them to the body. The second is in vivo, where Crystal and his colleagues are focusing their research, in which the altered virus is introduced directly into the body.

The adenovirus is altered with conventional molecular technology by removing the "brains" of the virus that tell it where to replicate. The human or animal gene is then inserted into the virus. The challenge, then, said Crystal, is to get the virus, called the vector, into the cell. "In the gene therapy field there is a fantasy of injectible vectors, and that may occur some day. In reality in human studies the way we get our vector to the cell is to put it directly into the organ."

In 1993 Crystal's group for the first time used an altered virus vector in vivo in a human subject. Their target was the epithelial cells that carry the genetic mutations that result in cystic fibrosis, the most common lethal hereditary disorder of Caucasians, he said. The goal was to put the normal gene in the epithelial cells and replicate it in 5 percent of the cells. This was achieved, but the effect did not last. Host defenses against the virus removed the altered cells within weeks.

"The challenge of gene therapy is that we are at the point that now we know we can get normal levels to cure genetic disease, the problem is we can't get it to persist," Crystal said.

What is needed, he said, is a strategy to modify the virus to emulate the stealth bomber and enter the cells without the body's host defenses being aware.

About three years ago, the Crystal team began considering gene therapy to treat an acquired disease, in particular cardiovascular disease, which represents 42 percent of all death in the United States. Crystal and Rosengart targeted cardiac ischemia, or atherosclerosis, in which there is insufficient blood flow to the heart muscle. The idea was to make new blood vessels to bypass the vascular obstruction.

To do this they inserted a gene protein called vascular endothelial growth factor in an adenovirus. And on Dec. 17 of last year they performed the first human gene therapy in the human heart. To date a total of seven patients have been injected with the altered virus.

"The expectations are that this will build new vessels," said Crystal.

Following Crystal's talk, senior Daniel Klein, a 1998 Marshall Scholarship winner, discussed how he began his research at Cornell by integrating the fields of linguistics, computer science and mathematics.

The undergraduate research forum is sponsored by the Cornell Undergraduate Research Board (CURB). Assistant Dean Marilyn Williams of the College of Arts and Sciences works with students seeking to do undergraduate research at Cornell.

Said undergraduate Mary Goll, a major in genetics and development and a co-chair of CURB, "I began working in a laboratory on campus my sophomore year and have probably gained more from this experience than any other. Applying classroom knowledge gives a true understanding and appreciation of what is learned."

During the morning, afternoon and evening, undergraduate presenters and their sessions and topics were:

All About Biology
·Elliot Bernstein: "Quantifying Bird Migration Patterns"
·John Beaber: "Autoinducer Analogs that normally inhibit Agrobacterium tra gene expression are strongly stimulatory in a strain that overexpresses TraR"
·Rachel Keats: "Spatial Variability in the Distribution of Aquatic Macroinvertebrates in a Pristine 2nd-order Stream"
·Rebecca Smart: "How a Star is Born: The Search for the Causative Agent in Tetrahymen Thermophila Star Formation"
·Sandra Irlen: "Scotopic Sensitivity/Irlen Syndrome: Identifying Risk Factors for Discontinued Use of Irlen Filters"
·Rebecca Murcek: "Altered-Function Mutants of Agrobacterium Tumefaciens OccR"

Spiders, Students and Influence Lines
·George LaVerde: "Studying the Molecular Structure of Spider Silk (Nephila lavipes) using Nuclear Magnetic Resonance: the effect of Water on the Glycine in the Silk"
·Tina Shiau: "A Re-estimation of the Returns to Attending an Elite University"
·David Warner: "Does Church Attendance Matter? Religious Participation, Well-Being, and Social Integration in the Later Half of the Life Course"

·Sarah Vickers: "The Regulation of Fas Antigen Expression in Cultured Bovine Granulosa Cells"
·Elayne Heisler: "Moving to a Continuing Care Retirement Community: Does Distance Moved Matter for Social Integration and Health?"

Poster Session
·Christopher DiMattina, Professor Bruce McNaughton (U. of Arizona): "Modeling Hippocampal-Cortical Interplay "
·Gina Weibel: "Atomic Force Microscopy: Study of Fluoronated Polymers
·Greg Aloe, Josh Freeh, Lance Hazer, Rowin Andruscavage, Rami Sabanegh, Partick Florit: "Binary and Flat Plate Impact Properties of Small Spheres"
·Gregory J. Fulchiero Jr.: "Diameter measurement of Nephila clavipes dragline silk by Fraunhofer Diffraction, using a modified 256 gray-scale hand scanner"
·Jamie Critelli: "Dynamics within a Hydroponics Pond"
·Jessica Wetcher and Andrew Rafal: "Face Memory: Gender Differences in Face Processing and Memory"
·Joseph Lee: "Extracellular Polymer Kinetics of Pseudomonas putida G7"
·Matthew Goldman: "Use of an In-Vitro Digestion/CACO-2 Cell Culture Model to assess Food Iron Availability and Characterization"
·Michael Ivan: "Protein-Polymer Conjugates: Synthesis"
·Rachel A. Saxer: "Effects of Exogenous Insulin Like Growth Factor-I on Chondrocyte Autocrine/Paracrine Axis Function in Monolayer Culture"
·Rajeev R. Shah: "Vibration Induced Droplet Atomization"
·Sarah J. Graznak: "The molecular analysis of a Vivipary gene in barley"
·Scott Aaronson: "Optimal Demand-Oriented Topology for Hypertext Systems"
·Meredith Agle and Laura Zimmer: "Quality and Safety of Apple Cider"
·Clara Ling and Eyal Oren: "The effects of a spatial learning task on the sleep onset period"
·Kenneth Harris: "Dendrochronological Study of an Early Bronze Age Settlement in North Italy"; "Trace-Element Analysis of Selected Tree-Rings"

It All Starts With Perception
·Kenneth Millman: "A Neural Network Strategy for Discovering the Structure of Natural Scenes"
·Melissa Hergan: "A Comparison Between Subjective and Objective Measurements of Monochromatic Aberrations of the Eye"
·Lisa Barcelo: "Marital Communication and the 'Illusion of Transparency'"
·Matthew West: "Students' Perceptions of Creativity as a Function of Media Use in Professorial Presentations"
·Sara Lederman: "The Illusion of Transparency in Emotional Expressions"

Science And Its Impact On Society
·Hunt Howell: "The Whisperer in Darkness: Eugenics and the Works of H.P. Lovecraft"
·Ryan Oettinger: "The Relationship Between Knowledge and Training"
·Xandra Rarden: "The Social Construction of Scientific Evidence: A Case Study of the Silicone Breast Implant Controversy"
·Alisa Greenstein: "What Kids Can Tell Us: An Interview Assessment Protocol"

Our Nation Our Future
·Juan Felipe Rincón: "Conflicting Visions on the National Information Infrastructure"
·Lena Entin: "Child Care in the Wake of Welfare Reform"
·Meredith Chaiken: "A Study of the Economic Mechanism of Local Currency: Ithaca Hours"
·Allison Kavey: "Significant Factors Affecting Adolescent Pregnancy in Broome County, NY, in 1993 and 1996"
·Meghan O'Sullivan and Darren Scott: "Hotel Forecasting Methods"

Probing the Micro and Macro Extremes
·Hong Tat: "Extinction Method of Determining Distances to Planetary Nebulae"
·Amy Snyder: "Evaluating the Scientific Merit of NASA's Current Planetary Exploration Program"
·Ryan Williams: "Surreal Numbers and Data Compression"
·David Rosenberg: "Growth Kinetics of Bacterium Pseudomonas putida G7"
·Nathaniel Cady: "A Microcontact Printed Biosensor for the Detection of E. coli 0157:H7"

Four Continents Four Perspectives
·Dorian Fougères: "Contemporary Aboriginal Land Management in and around The Atherton Tablelands, Queensland, Australia"
·Oscar Vazquez: "A Historical Study of Health Care in Latin America"
·Sarah Megan Heller: "Romance in Kathmandu"
· Kenann McKenzie-Conley: "Antebellum Black Press"

History and Its Methods
·Alyssa Goulian: "An Irrevocable Decision: Greenville District South Carolina, 1859-1860"
·Amit Chhabra: "American Military Aid to Pakistan in 1954: Breakthrough or Breakdown?"
·Hilary Krieger: "The Subversion of Arthur Miller"
·Thanos Pantazis, Melissa Loewenstern: "Trace-Element Analysis of Selected Tree-Rings" and "Dendrochronological Study of an Early Bronze Age Settlement in North Italy"

Question of Identity
·Michael Levy: "Talmudic Responses to the 'Problem of Hell'"
·Ho-Shyuan Wu: "Ethnic Identity Attitudes Among Asian American College Students"
·Rebecca Churchill: "Self-Esteem, Appraisals and Emotions"
·Noelina Arciniegas: "The Development of a Racialized Dominican Identity as Represented Through the Works of Major Poets"

Environmentality
·Matthew Myers: "A Brief Examination of How Native American Sovereignty is affected by the Implementation of Federal Environmental Law"
·Ianthe Nelson: "Detection of Floridian Sinkholes Using Ground Penetrating Radar"
·Kim Chan: "Input Parameters for Modeling the Peace Bridge"
·Nazaneen Grant: "The Health Conditions of Nicaraguan Miskito Lobster Divers: An Interdisciplinary Perspective"
·Ivy Kwong: "Breaking Waves Over Porous Structure"

Healthy Blend of Chemistry and Physics
·Kevin Cavicchi: "Dissolution Rates of Polymer Blends"
·Jacob Lipcon: "Robust Control of High-Dimensional Systems"
·Errol Laub (presenter), Siew Ying Ngiam (co-author), Taryn Williams (co-author): "Behind the Scenes of a Concrete Fracture Testing Project"
·Scott Yewell: "Reduction of Sub-Woofer Nonlinearities Using Feedback Control"
·David Wasserman, Colin Benoit, Glenn Goldenberg and Rafael Zayas: "Autonomous Airship"
·Andrew S. Aggarwala and the SAE Air Cargo Team "Design, Test, and Competition of a Heavy-Lift Radio-Controlled Model Airplane"

Microbes, et al.
·Ellena Cronquist: "The Role of Platelet Activating Factor in Bovine Embryo Development"
·Daniel Bernstein: "Neural Network Model of the Lamprey Brain and Spinal Cord"
·Tracy Allaman: "Biotechnology in the Media"
·Eric Nelson: "Opportunistic Bacterial Disease of Tropical Marine Fish Embryos"
·Julie Pactovis: "Probing Issues of Modularity in Williams Syndrome"

More of the Microworld
·Jennifer Rosen: "Fluorgenic PCR-based Assay for the Detection of Human Enteroviruses"
·Mathew Abraham: "Effect of Antisense and Sense Oligonucleotides on the Production of the Alzheimer Amyloid Peptide Precursor in COS-7 Cells and COS-7 Cells Bearing the Beta-APP-141 Hammerhead Ribozyme"
·Todd Twersky: "Effect of PCBs on TSH and Prolactin Secretion in Canine Pituitary Glands"
·Scott Showalter: "Simulation of Phosphorylation in Src's SH2 Domain: Mutant Y213E"