Ellison Medical Foundation
One-Day Symposium
www.ellison-med-fn.org

Differential Gene Expression in Development and Aging

Wednesday, October 11, 2000; 8:00 AM - 5:00 PM

Beckman Institute Auditorium
California Institute of Technology
Pasadena, California

Program

Prof. Joshua Lederberg 8: 45 AM "Welcoming Remarks" -- Prof. Joshua Lederberg, President Emeritus and Nobel Laureate; Rockefeller University; New York, NY

Prof. David Baltimore 8:50 AM "The Basic Science of Aging" -- Prof. David Baltimore, President and Nobel Laureate; California Institute of Technology; Pasadena, CA

Prof. Richard Weindruch 9:45 AM "Gene Expression Profile of Aging and Its Retardation by Caloric Restriction" -- Prof. Richard Weindruch, University of Wisconsin; Madison, WI

Prof. Joseph Takahashi 11:00 AM "Circadian Clock Genes in Mammals" -- Prof. Joseph Takahashi, Northwestern University; Chicago, IL

Prof. David Botstein 1:00 PM "Genome Wide Gene Expression in Cancer" -- Prof. David Botstein, Stanford University; Stanford, CA

Dr. Andre Nussenzweig 1:45 AM "The Role of DNA Double Strand Repair in Genomic Stability and Tumorigenesis" -- Dr. Andre Nussenzweig, National Cancer Institute, NIH; Bethesda, MD

Prof. Norman Davidson 4:00 PM Prof. Norman Davidson and Prof. Melvin Simon Prof. Melvin Simon of CalTech
Drs. Craig Venter and David Baltimore Dr. Craig Venter, CEO of Celera Genomics and CalTech President David Baltimore at the Professor Norman Davidson Lecture: "Sequencing the Human Genome" -- Dr. J. Craig Venter, Founder, CEO, and Chief Scientist of Celera Genomics Corp.; Rockville, MD

Highlights

Prof. Joshua Lederberg A. Prof. Lederberg suggested that in addition to the human Genome (including the mtDNA in mitochondria) and the human Proteome (the collection of all human proteins), there needs to be a third category called the human microbiome (the DNA descriptions of all species of natural flora and parasites -- both beneficial and pathological -- that attend our being -- both interior and exterior).

There are known to be at least 200 species living on/in the average human -- 80 species in the mouth alone. The types of creatures include both transient and resident viruses (e.g., herpes), bacteria (like E-coli which out-compete their neighbors for this prime real estate [but one shouldn't sterilize them with a potent antibiotic unless it's essential, since otherwise the patient may become infected with an opportunistic organism {a pathological yeast (thrush) or fungal (aspergillosis) superinfection, for example} that is not susceptible to that particular antimicrobial treatment -- sort of like shooting yourself in the foot.]. Some species of E-coli, in improperly cooked meat, are pathological), normal fungus, yeast, protozoa (like amoeba), nematodes (worms), mites, lice, ticks, and other assorted parasites that may have humans only as an incidental host during just one particular phase of their life cycle.

The absolute numbers of the different types of microorganisms are staggering. Prof. Lederberg strongly recommends as the best source to learn more about this obscure category of knowledge a now out-of-print book by Theodor Rosebury (which he called a "cult favorite"). A review of this 1969 book can be found in the New Scientist Magazine and is reproduced here [modulo substitutions of American for British spelling/punctuation/capitalization].

B. Prof. David Baltimore made the observation that all the evidence points to the aging process as being a programmed event. Therefore, clocks and their success or failure at synchronization may be extremely important. Cell stress responses (such as Adrenal Cortical Response to ACTH) and the P50, P51, and P65 genes that may regulate apoptosis could lead to severe adverse inflammatory effects. NF Kappa B and Tumor Necrosis Factor (TNF) appear to play a central "alarm" role in the cell. The elucidation of the common pathways of apoptosis will be crucial to our understanding of how growth factors stimulate quiescent embryonic stem cells to undertake repair of damaged tissues.

C. Prof. Richard Weindruch suggested that Caloric Restriction may cause a metabolic shift that exposes premature death secondary to tumors. In the question period, it was unclear whether the CR effect could actually be related to a decline in gut flora (bacteria) that results in less of a chronic inflammatory response than in ad lib fed animals. This has not yet been investigated except in the case of germ-free mice, which is a special case.

D. Prof. Joseph Takahashi described a wide network of circadian clocks that pervade the organism from the highest endocrine level to the lowest cellular level (Per, Tim, and Clk genes). During the question period, he mentioned that the recent work reported in Science describing melatonin synchronization to a 24-hour cycle by shining a light on the back of the knee could not be reproduced. Secondly, the work with melatonin and synchronization of the blind, however, appears to be valid. Thirdly, he also mentioned that it is now known that laboratory mice to not make melatonin at all (because they are nocturnal animals, it was suspected that they inverted the "melatonin switch" to make themselves vigilant with the onset of melatonin rather than sleepy, as it is with humans); so how could the work of Pierpaoli with his pineal transplants between young and old mice be valid?
[Ref. Vladimir A. Lesnikov and Walter Pierpaoli, "Pineal Cross-Transplantation (Old-to-Young and Vice Versa) as Evidence for an Edogenous 'Aging Clock.'" pp. 456-460, Walter Pierpaoli, William Regelson, and Nicola Fabris, Eds., The Aging Clock: The Pineal Gland and Other Pacemakers in the Progression of Aging and Carcinogenesis: Third Stomboli Conference on Aging and Cancer (Vol. 719, Annals of the New York Academy of Sciences, New York; May 31, 1994)].

E. Prof. David Botstein said that his approach to gene expression microarray chips was "to place antibodies on glass," as distinguished from the approach of Affymetrix, Inc. of Santa Clara, California.

F. Dr. J. Craig Venter stated in his lecture that 40 different species' genomes have been published so far (including various bacteria, yeast, and fruit flies), and there are more than 100 species that will be completed in the next five years (including numerous mammals). He took the opportunity to announce (concurrent with a press release scheduled for the next day) that Celera has completed the sequencing of the mouse genome (three different passes over three strains of mice, each with 9.3 billion base pairs over 21 chromosomes). They found 67 percent homology with human genes (the function of ~ 50 percent of the genes has not yet been identified, however). And now that they have completed the Human Genome sequence along with the public (NIH/Welcome) effort (announced at the end of June 2000) -- which will be published jointly both in Science and in Nature at the beginning of 2001-- he was prepared to make two observations: (1) Surprisingly, there are fewer than 50,000 human genes!; and (2) there are [2.5 - 3.0] million SNPs (Single Nucleotide Polymorphisms)[the 0.1 percent of the human genome that makes us look different from one another] of which Celera has a data base of 2.8 million candidates so far.

Next, Celera is going to focus its efforts on "proteomics." They expect to do protein-expression analysis using microarray chips and to process one million protein sequences per day using a collection of Time-of-Flight Mass Spectrometers. He expects that Celera's approach will lead to a significant jump on the problem of drug discovery and therapeutics for a wide variety of diseases.

LA-GRG Members Attending the Ellison Foundation Meeting
LA-GRG Members
Rear (from Left): Tom O'Sullivan, Steve Kaye, Steve Coles, Bob Nathan
Front (from Left): Aubrey de Grey (Cambridge University and our October Speaker), Stan Primmer, and Johnny Adams.