General Course Information:


Wednesday 11:00A-12:50P



Instructor Information:


Office Address: 749 Fairchild

Telephone Number: (212) 854-2409


Office Hours: TBA



New for 2003:

1] The readings will be extensively updated. Courseworks will have the latest syllabus on line.

2] The papers required for readings will be available at the Courseworks website for downloading as high resolution (PDF) files. You will be expected to download and print your own copies.


Introduction: Human diseases fall into three broad categories according   to our understanding of their origins: genetic, infectious, and indeterminate.   While the second category seemed until recently to be shrinking, and the last   category is certainly getting smaller, the first is growing rapidly, not due   to increased incidence of genetic disease, but due to a fast moving front of   new knowledge about disease-associated human alleles. The isolation and characterization   of multiple alleles for thousands of other disease-associated genes is on the   way. This course is designed to give students an opportunity learn on the some   of the many molecular mechanisms of diseases caused by novel alleles, while   not losing sight of other causes, in particular emergent infectious agents.


Discussion papers: these will be handed out at least one week in advance   of each class. In the first class, on January 22, I will review the syllabus,   hand out some background material and the papers to be discussed in the following   class, and introduce those papers. In subsequent classes, students will spend   the first half presenting the papers I had introduced in the previous week,   and then I will introduce the following week's papers.


Presentations: I expect that every student will be able to lead to a   detailed, critical discussion of the data and conclusions of the papers, so   I will choose the discussion leader for each class at the beginning of that   class, and not before. In any case I will steer the discussion to the molecular   cause or mechanism underlying a disease or condition, and links of that mechanism   to a set of consequent symptoms.


Background material: Stryer, Biochemistry; Darnell, Lodish and Baltimore,   Molecular Cell Biology; Kandel, E., et al, 2000. Principles of Neural Science;   and two books of mine: Pollack: (1994), Signs of Life, and (1999) The Missing   Moment. These are on reserve in the Biology library, on the sixth floor of Fairchild.


Grading: Each student will choose a new [2000 at the oldest] paper published   in a selective journal [Cell, Nature (in all its variations), Science, PNAS,   and JAMA are such journals], and submit two essays on it. Please use wide margins,   double-spaced lines, and numbered pages. The first essay, a 1-2 page rationale   will be due, at the very latest, in class Wednesday October 29. This brief midterm essay will allow me to forestall a poor choice   of paper.


The final paper will be due at the last class, Wednesday December 3. Final grade  will depend on class performance and the final paper.


Requirements:  Students from all divisions of the University are welcome. The prerequisite for BIOL 4065 is completion of a 3000-level course at Columbia or Barnard, either in biochemistry or genetics. Columbia College seniors and first-year graduate students meeting this prerequisite may register without permission. All other students must request permission in advance from the professor, at






   Lecture         Date       Class Subject and Readings


  1              Wednesday,      Introduction to the seminar;

                 September 3       introduction to genetic medicine.




                               Cargill, M., et. al., 1999.

                               Characterization of

                               single-nucleotide polymorphisms in

                               coding regions of human genes.

                               Nature Genetics 22: 231.


                               Humans as the world's greatest

                               evolutionary force, 2001. Science

                               293: 1786.




                               Holtzman, N., et. al., 1997.

                               Predictive genetic testing: from

                               basic research to clinical practice.

                               Science 278: 602.


                               Martindale, D., 2001. Pink slip in

                               your genes. Scientific American:

                               January, 19.


                               Adams, M., et. al., 1995. Initial

                               assessment of human gene diversity

                               and expression patterns based upon

                               83 million nucleotides of cDNA

                               sequence. Nature 377: 3.


                               Class lecture (Pollack):


                               Introduction to single-allele

                               difference in phenotype-



  2              Wednesday,      The first human mutation:

                 September 10       Alkaptonuria.




                               Garrod, A., 1902. The incidence of

                               alkaptonuria: a study in clinical

                               individuality. Lancet 2: 1616-1620.


                               Fernandez-Canon, J. et. al., 1996.

                               The molecular Basis of alkaptonuria.

                               Nature genetics 14:19.






                               Class lecture (Pollack):


                               Intro to genetic resistance.


  3              Wednesday,      Resistance: Vancomycin resitance and the Adenosine Deaminase deficiency

                 September 17        .




                               Hirschhorn, E., et. al., 1996.

                               Spontaneous in vivo reversion to

                               normal of an inherited mutation in a

                               patient with adenosine deaminase

                               deficiency. Nature Genetics 13: 290.


                               Chiosis, G., et. al., 2001.

                               Selective cleavage of d-lac-d-lac by

                               small molecules: Re-sensitizing

                               resistant bacteria to Vancomycin.

                               Science 293:1484.






                               Class lecture (Pollack):


                               Intro to Biofilms.


  4              Wednesday,      Biofilms.

                 September 24


                               Goldman, M., et. al., 1997. Human

                               defensin is a

                               salt-sensitive antibiotic in lung

                               that is inactivated

                               in CF. . Cell 88: 553.


                               Pier, G., et. al., 1997. Cystic

                               fibrosis transmembrane

                               conductance regulator is an

                               epithelieal cell receptor

                               for the clearance of P. aer. from

                               the lung. Proc. Nat. Acad. Sci. 94:





                               Smith, J., et. al. 1996. Cystic

                               fibrosis airway

                               epithelia fail to kill bacteria

                               because of abnormal

                               airway surface fluid. Cell 88: 229.


                               Class lecture (Pollack):


                               Intro to infectious proteins.


Wednesday October 1, no class


  5              Wednesday,      Infectious proteins.

                 October 8




                               Manuelides, L., et. al., 1997.

                               Evolution of a strain of CJD that

                               induces BSE-like plaques. Science

                               277: 94.


                               Priola, S. et al, 2000. Porphyrin

                               and phthalocyanin antiscrapie

                               compounds. Science 287: 1503.




                               Birkett, C., et. al., 2001. Scrapie

                               strains maintain biological

                               phenotypes on propagation in a cell

                               line culture. EMBO Journal 20: 3351.


                               Paushkin, S., et. al., 1997. In

                               vitro propagation of the prion-like

                               state of yeast Sup35 protein.

                               Science 277: 381.


                               Klein, et al, 1997. A crucial role

                               for B cells in neuroinvasive

                               scrapie. Nature 390: 687.


                               Jackson, G. et al, 1999. Reversible

                               conversion of monomeric human prion

                               protein between native and

                               fibrilogenic configurations. Science

                               283: 1935.


                               Class lecture (Pollack):


                               Intro to the difference between an

                               animal model and the clinic.


  6              Wednesday,      Difference between an animal model

                 October 16       and the clinic: Cyclosporin A.




                               Van den Borne, B., et. al., 1998. No

                               increase of malignancies and

                               mortality in Cyclosporin A-treated

                               patients with rrheumatoid arthritis.

                               Arth and Rheum 41: 1930.


                               Hojo, M., et. al., 199. Cyclosporine

                               induces cancer progression by a cell

                               autonomous mechanism. Nature 397:





                               Crabtree, Cell 1999


                               Kiani et al, Immunity 2000


                               Class lecture (Pollack):


                               Intro to Influenza.


  7              Wednesday,      Influenza.

                 October 22




                               Gibbs, M., et. al., 2001.

                               Recombination in the hemagglutinin

                               gene of the 1918 "Spanish Flu."

                               Science 293: 1842.


                               Hatta, M., et. al., 2001. Molecular

                               basis for high virulence of Hong

                               Kong H5N1 Influenza A viruses.

                               Science 293: 1840.




                               Lederberg, J., 1997. Infectious

                               disease as an evolutionary paradigm.

                               Emerging Infectious diseases 3: 417.


                               Class lecture (Pollack):


                               Intro to inherited differences in

                               susceptibility to infection.



                               Inherited differences in

  8              Wednesday,    susceptibility to infection: HIV and

                 October 29       AIDS.




                               Dean, M., et. al., 1996. Genetic

                               restriction of HIV-1 infection and

                               progression to AIDS by a deletion

                               allele of the CKR5 structural gene.

                               Science 273: 1856.


                               Risch. N., et. al., 1995. Genetic

                               analysis of idiopathic torsion

                               dystonia in Ashkanazi Jews and their

                               recent descent from a small founder

                               population. Nature Genetics 9: 152.




                               Levin, B., et. al., 2001.

                               Epidemiology, evolution and the

                               future of the HIV/AIDS epidemic.

                               Emerging Infectious Diseases 7: 505.


                               Martinson, H., et. al., 1997. Global

                               distribution of the CCR5 gene

                               32-basepair deletion. Nature

                               Genetics 16:100.


                               Class lecture (Pollack):


                               Intro to anticipation by triplet



  9              Wednesday,      Anticipation by triplet repeat:

                 November 5        Huntington's Disease




                               Rubinsztein, D., et. al., 1994.

                               Mutational Bias provides a model for

                               the evolution of Huntington's

                               disease and predicts a general

                               increase in disease prevalence.

                               Nature Genetics 7: 525.


                               Duyao, M., et al., 1993.

                               Trinucleotide repeat length

                               instability and age of onset in

                               Huntington's Disease. Nature

                               Genetics 4: 387-392.




                               Ona, V., et al, 1999. Inhibition of

                               caspace-1 slows disease progression

                               in a mouse model of Huntington's

                               disease. Nature 399: 263.


                               Leeflang, E., et. al., 1999.

                               Analysis of Germline Mutation

                               Spectra at the Huntington's Disease

                               Locus Supports a Mitotic Mutation

                               Mechanism. Human Molec Gen 8: 173.


                               Class lecture (Pollack):


                               Introduction to Anthrax.


  10             Wednesday,      Anthrax.

                 November 12




                               Bradley, K. et. al., 2001.

                               Identification Of the cellular

                               receptor for anthrax toxin. Nature



                               Sellman, B., et. al., 2001.

                               Dominant-negative mutants of a toxin

                               subunit: an approach to therapy of

                               anthrax. Science 292:_695




                               Vaccines for Biodefense: A system in

                               distress. 2001. Science 294: 498.


                               Panniter, A., et. al. 2001. Crystal

                               structure of the anthrax lethal

                               factor. Nature 414:_229.


                               Class lecture (Pollack):


                               Introduction to maternal



  11             Wednesday,      Maternal inheritance: mitochondrial

                 November 19        loss of function.




                               Ballinger, S. et al, 1992.

                               Maternally transmitted diabetes and

                               deafness associated with a 10.4 kb

                               mitochondrial DNA deletion. Nature

                               genetics 1: 11-15.


                               Taylor, R. 1997. Selective

                               inhibition of mutant mitochondrial

                               DNA replication in vitro by peptide

                               nucleic acids. Nature genetics 15:





                               Jenuth, J., et. al., 1996. Random

                               genetic drift in the female germline

                               explains the rapid segregation of

                               mammalian mitochondrial DNA. Nature

                               genetics 14: 146-151.


                               Class lecture (Pollack):


                               Introduction to aging.


  12             Wednesday,      Aging

                 November 26




                               Schächter, F., et. al., 1994.

                               Genetic associations with human

                               longevity at the APOE and ACE loci.

                               Nature genetics 6: 29.


                               Lee, C-K, et al, 1999. Gene

                               expression profile of aging and its

                               retardation by caloric restriction.

                               Science 285: 1390.




                               Puca, A., et. al., 2001. A

                               genome-wide scan for linkage to

                               human exceptional longevity

                               identifies a locus on chromosome 4.

                               Proc. Nat. Acad. Sci. 98: 10505.


                               Sohal, R., et. al., 1997. Oxidative

                               stress, caloric restriction, and

                               aging. Science 273: 59.


                               Class lecture (Pollack):


                               Intro to clonal replacement vs.

                               germ-line therapies.


  13             Wednesday,      Clonal replacement vs. Germ-line

                 December 3       therapies.




                               Verlinsky, Y., et. Al., 1992.

                               Preconception and preimplantation

                               diagnosis for cystic fibrosis.

                               Prenatal Diagnosis 12: 103.


                               Rideout, W. et al, 2002. Correction

                               of a Genetic Defect by Nuclear

                               Transplantation and Combined Cell

                               and Gene Therapy, Cell 109: 17.




                               Amit, et al, 2000. Clonally Derived

                               Human Embryonic Stem Cell Lines

                               Maintain Pluripotency and

                               Prolifierative Potential for

                               Prolonged Periods of

                               Culture. Developmental Biology 227:



                               Lanza, R., et. al., 2000. Extension

                               of cell life-span and

                               telomere-length in animals cloned

                               from senescent somatic cells.

                               Science 288: 665.


                               Wilmut, I., et. al., 1997. Viable

                               offspring derived from fetal and

                               adult mammalian cells. Nature



                               Pollack, 2001. Stem Cells,

                               Therapeutic Cloning, and the Soul.

                               The George C. Marshall Foundation

                               Roundtable, Washington D.C., October

                               17, 2001.


                               Munsie, M., et. al., 2000. Isolation

                               of pluripotent embryonic stem cells

                               from reprogrammed aduly mouse

                               somatic stem cell nuclei. Current

                               Biology 10: 989.


                               Class lecture (Pollack):


                               Intro to possible psychiatric

                               consequences of infectious diseases.


  14             Friday,      Possible psychiatric consequences of

                 December 5         infectious diseases.




                               Kandel, E. 1999. Biology and the

                               future of psychoanalysis: a new

                               intellectual framework for

                               psychiatry revisited. Am J.

                               Psychiatry 156: 505.


                               Karlsson, H., et. al., 2001.

                               Retroviral RNA identified in the

                               cerbrospinal fluids and brains of

                               individuals with schizophrenia.

                               Proc. Nat. Acad. Sci. 98: 4634.




                               Mohn, A., et al, 1999. Mice with

                               reduced NMDA receptor expression

                               display behaviors related to

                               schizophrenia. Cell 98: 427.


                               O'Callaghan, E., et. al., 1991.

                               Schizophrenia after prenatal

                               exposure to 1957 A2 influenza

                               epidemic. Lancet 337: 1248.