We are excited about viruses, viewing them either as chemical entities whose intriguing facility of proliferation is fascinating, or as horrifying infectious agents causing appalling diseases in their host. Accordingly, research in our laboratory can roughly be divided into two general topics: viral replication and genetics at the cellular level, and mechanisms of viral pathogenensis in a host organism.

Our research focuses on RNA viruses, particularly picornaviruses, whose prototype is poliovirus. Picornaviruses, are estimated to infect 6 billion humans per year, cause a bewildering array of disease syndromes (paralysis, meningitis, heart disease, hepatitis, common cold, etc).

Paul, 2002

Picornaviruses contain a plus-stranded RNA genome that functions as mRNA as soon as the viral particle enters the cell. The viral proteins, which are synthesized, recruit cellular factors. Together, they provide a menu for genome replication and genome encapsidation. Topics studied in the laboratory are the control of translation independently of a capping group (mediated by the Internal Ribosomal Entry Site, IRES), RNA replication and viral genetics. We can reproduce the entire replication process in a cell-free extract.

Paul, 2002

Molecular mechanisms by which a virus causes disease in a host organism are complex and multi level. We have focused on poliovirus, a virus known for nearly 100 years that in nature infects humans only but can also cause disease in primates and transgenic mice. Poliovirus replicates somewhere in the orogastrointestinal tract (Peyer's patches?) from which it can migrate to the central nervous system where it targets motor neurons. Destruction of motor neurons causes irreversible paralysis or death, a disease called poliomyelitis. The human receptor for poliovirus (CD155) is the key for pathogenesis as it is the gate for viral entry into cells. Therefore, the interaction of CD155 with poliovirus, its role in viral spread in the host organism, and its non-pathogenic cellular function(s) are all topics studied in the laboratory. In addition, we are investigating how genetic elements of the viral genome influence neurovirulence.

Viruses are viewed to reside at the threshold between dead and living matter. This definition is flawed, however, because humans have not come to a consensus about the definition of life. When we chemically synthesized poliovirus according to its genomic sequence in the absence of natural template (Cello et al., 2002) we have shifted the definition of viruses towards non-living matter.

Indeed, we view poliovirus as a chemical that has the empirical formula for its organic matter (Molla et al., 1991):

C_332,652 H_492,388 N_98,245 O_131,196 P₇₅₀₁ S₂₃₄₀

Rapid progress in DNA synthesis and sequencing allows genetic alterations of viruses at the level of whole genome synthesis. Since genome synthesis is independent of the natural template it allows modifications of the genetic information to an extent not possible before. As our first experiment in "synthetic biology" we have synthesized infectious poliovirus by chemical means and in the absence of a natural template. More recently we have synthesized several totally new variants of poliovirus that preserved the amino acid sequence of the wt virus but differed in the use of synonymous codon pairs. Changes in codons or codon pairs lead to virus attenuation, a hallmark of live anti-viral vaccines.