Research

Fred H. Gage, a professor in the Laboratory of Genetics, concentrates on the adult central nervous system and unexpected plasticity and adaptability to environmental stimulation that remains throughout the life of all mammals. His work may lead to methods of replacing or enhancing brain and spinal cord tissues lost or damaged due to Neurodegenerative disease or trauma.

Gage's lab showed that, contrary to accepted dogma, human beings are capable of growing new nerve cells throughout life. Small populations of immature nerve cells are found in the adult mammalian brain, a process called Neurogenesis. Gage is working to understand how these cells can be induced to become mature functioning nerve cells in the adult brain and spinal cord. They showed that environmental enrichment and physical exercise can enhance the growth of new brain cells and they are studying the underlying cellular and molecular mechanisms, that may be harnessed to repair the aged and damaged brain and spinal cord.

"Differences arise at every level of the brain's astonishingly intricate architecture, leading to variances in how we think, learn and behave and in our propensity for mental illness. Jumping genes may explain how some of these differences arise, even in identical twins."

Variations in the genes we inherit from our parents ensure that each of our brains is wired differently. But even identical twins, who inherit the same set of genes, can differ markedly in their mental functioning, behavioral traits and risk of mental illness or neurodegenerative disease. From where do these differences arise?

Gage's laboratory has identified a likely suspect in the hunt for an explanation for this mysterious variability in brain function: jumping genes. Such genes (also known as "retrotransposons") can insert copies of themselves into other parts of the genetic code, making one neuron function very differently than its neighbor. Many such insertions may create a mosaic of cells possessing varying genetic operating instructions, which in turn could influence cognitive abilities, personality traits and susceptibility to neurological problems.

To better understand how jumping genes play a role in brain function, Gage and his colleagues have investigated the genetic underpinnings of Rett syndrome, a rare neurodevelopmental disease that affects mostly girls and is considered one of the autism spectrum disorders. Typical features of the disorder include loss of speech, stereotypic movements, mental retardation and social behavioral problems. Although almost all cases are caused by a mutation in the MeCP2 gene, how severely people are affected by the symptoms of Rett syndrome varies widely.

Gage's team found that a mutation in the MeCP2 gene mobilizes the L1 retrotransposons in brain cells of Rett syndrome patients, reshuffling their genomes. Their research showed that the mutation in the brains of mice with Rett syndrome resulted in a significant increase in numbers of L1 insertions in their neurons, suggesting that the jumping genes might account for some of the effects of the MeCP2 mutation. Using stem cell reprogramming techniques, the researchers generated neurons from skin cells of Rett syndrome patients, which they could then study in the laboratory. Similar to the findings in mice, these human neurons possessed high numbers of L1 copies, which might explain the variability in symptoms seen in people with the disorder.

Gage's findings may not only explain how a single mutation can cause the baffling variability of symptoms typical of Rett syndrome but also shed new light on the complexity of molecular events that underlie other psychiatric disorders, such as autism and schizophrenia.

Top row, left to right: Jenny Erwin, Apua Paquola, Anthony Simone, David Husband, Cedric Bardy, Dane Clemenson, Matthew Ellis, Mark Van Den Hurk, Ruben Hernandez, Krishnan Padmanabhan, Roberto Jappelli, Arianna Mei, Vicki Sciorra, Wei Deng, Yangling Mu

Middle row, left to right: Mohamedi Kagalwala, Tiago Goncalves, Julia Wrin-Piper, Michael McConnell, Benjamin Lacar, Fernando Flores, Eunice Mejia, Christopher Tse, Jinju Han, Jun Yao, Ahmet Denli, Bilal Kerman, Hyung Joon Kim, Yongsung Kim, Iryna Gallina

Front row, left to right: Ngoc Tran, Kristen Brennand, Leah Boyer, Inigo Narvazia, Yanelli Nunez, Elmar Malek, John Jepsen, Fred. H. Gage, Benjamin Campbell, Elisa Nabel, Diana Yu, Lynne Moore, Isabelle Guimont, Carol Marchetto, Ruth Keithley, Star Lee, Tithi Baul, Cheyenne Butcher, Yan Li, Chunmei Zhao

Salk News Releases

• The neuroscience of finding your lost keys
  March 21, 2013
• Salk scientists develop faster, safer method for producing stem cells
  December 3, 2012
• What can the water monster teach us about tissue regeneration in humans?
  September 25, 2012
• Neurons derived from cord blood cells may represent new therapeutic option
  July 16, 2012
• Salk scientist receives distinguished NIH award for transformative research
  September 28, 2011
• Salk Institute scientist garners international esteem on two continents
  June 20, 2011
• Patients' own cells yield new insights into the biology of schizophrenia
  April 13, 2011
• Stem Cell Leader Awarded $2.3 Million Grant for Parkinson's
  February 3, 2011
• Rett syndrome mobilizes jumping genes in the brain
  November 17, 2010
• Modeling autism in a dish
  November 11, 2010
• Work-life balance: Brain stem cells need their rest, too
  July 1, 2010
• American Philosophical Society inducts Fred H. Gage
  April 27, 2010
• Salk scientist has been elected a member of the European Molecular Biology Organization
  October 22, 2009
• Newborn brain cells show the way
  July 9, 2009
• Newborn brain cells "time-stamp" memories
  January 28, 2009
• A novel human stem cell-based model of ALS opens doors for rapid drug screening
  December 3, 2008
• Newborn neurons in the adult brain can settle in the wrong neighborhood
  November 10, 2008
• Salk Scientist Fred H. Gage to Receive the Keio Medical Science Prize
  October 15, 2008
• Salk researchers reprogram adult stem cells in their natural environment
  July 1, 2008
• UC San Diego and Salk Institute Establish Center to Study the Origin of Humans
  March 4, 2008
• Newborn brain cells modulate learning and memory
  January 30, 2008
• Newborn neurons like to hang with the in-crowd
  May 7, 2007
• Life and death in the hippocampus: what young neurons need to survive
  August 16, 2006
• Finding a cellular Neverland: How stem cells stay childlike
  June 27, 2006
• Human embryonic stem cells integrate successfully into mouse brain
  December 12, 2005
• "Jumping genes" contribute to the uniqueness of individual brains
  June 14, 2005
• Salk scientist Rusty Gage elected to American Academy of Arts and Sciences; Awardees also include sculptor, actor and Supreme Court Chief Justice
  May 4, 2005
• Current Human Embryonic Stem Cell Lines Contaminated With Potentially Dangerous Non-Human Molecule, UCSD/Salk Team Finds
  January 24, 2005
• New Findings Reopen Debate About Adult Stem Cell Plasticity
  July 21, 2004
• Stem Cell Regulator Could Hold Key to Staving Off Age-related Brain Changes
  January 30, 2004
• Gene Therapy Postpones Lou Gehrig's Disease Symptoms
  August 7, 2003
• Salk Professor Fred H. Gage Elected to National Academy of Sciences
  April 29, 2003
• Salk Scientists Demonstrate For The First Time That Newly Born Brain Cells Are Functional In The Adult Brain
  February 27, 2002
• Neural Progenitor Cells Recovered From Postmortem And Adult Tissue
  May 2, 2001
• Exercise Makes Mice Smarter, Salk Scientists Demonstrate
  November 8, 1999
• Running Boosts Number Of Brain Cells, According To New Salk Study
  February 22, 1999
• Human Brains Do Sprout New Cells According To New Salk Study
  November 1, 1998
• An Enriched Environment Stimulates An Increase In The Number Of Nerve Cells In Brains Of Older Mice
  April 24, 1997

Awards and Honors

• Fellow of the National Academy of Sciences
• Fellow of the Institute of Medicine of the National Academy of Sciences
• Fellow off the American Academy of Arts and Sciences
• Bristol-Myers Squibb Neuroscience Research Award, 1987
• IPSEN Prize in Neuronal Plasticity, 1990
• Charles A. Dana Award for Pioneering Achievements in Health and Education, 1993
• Christopher Reeve Research Medal, 1997
• Max Planck Research Prize, 1999
• The Robert J. and Claire Pasarow Foundation Award, 1999
• President, Society for Neuroscience, 2001
• Vi and John Adler Professor on Age-related Neurodegenerative Diseases, 2001
• MetLife Award for Medical Research, 2002
• Klaus Joachim Zulch-Preis through the Max Planck Society, 2003

Links

Gage lab

Gage technologies available for licensing

Patients' own cells yield new insights into the biology of schizophrenia

March 17, 2011

After a century of studying the causes of schizophrenia-the most persistent disabling condition among adults-the cause of the disorder remains unknown. Now induced pluripotent stem cells (iPSCs) generated from schizophrenic patients have brought researchers from the Salk Institute for Biological Studies a step closer to a fundamental understanding of the biological underpinnings of the disease. Read more>>