General Course Information:
BIOL W4065.001
MOLECULAR BIOLOGY OF DISEASE
Wednesday 11:00A-12:50P
1000 FAIRCHILD
Instructor Information:
ROBERT ELLIOT,
POLLACK
Office Address:
749 Fairchild
Telephone Number:
(212) 854-2409
E-mail: pollack@columbia.edu
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
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
Lecture Date Class Subject and
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.
Background:
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.
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-
alkaptonuria.
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.
Background:
none.
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.
Background:
none.
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:
12088.
Background:
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.
Backgound:
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:
530.
Backgound:
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.
Background:
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.
Background:
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
repeats.
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
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.
Background:
Ona, V., et al,
1999. Inhibition of
caspace-1 slows disease progression
in a mouse model of
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
414:_225.
Sellman, B., et. al., 2001.
Dominant-negative mutants of a toxin
subunit: an approach to therapy of
anthrax. Science 292:_695
Backgound:
Vaccines for Biodefense: A system in
distress. 2001. Science 294: 498.
Panniter, A., et. al. 2001.
structure of the anthrax lethal
factor.
Nature 414:_229.
Class lecture
(Pollack):
Introduction to
maternal
inheritance.
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:
212.
Background:
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.
Background:
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.
Background:
Amit, et al,
2000. Clonally Derived
Human Embryonic
Stem Cell Lines
Maintain Pluripotency and
Prolifierative Potential for
Prolonged
Periods of
Culture. Developmental Biology 227:
271.
Lanza, R., et. al.,
2000. Extension
of cell life-span and
telomere-length in animals cloned
from senescent somatic cells.
Science 288:
665.
Wilmut,
offspring derived from fetal and
adult mammalian cells. Nature
385:810.
Pollack, 2001. Stem Cells,
Therapeutic Cloning, and the Soul.
The George C.
Marshall Foundation
Roundtable,
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.
Background:
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.