Gareth Howell, Ph.D.
Assistant Research Professor
Jackson Laboratory, Bar Harbor, Maine
Bio from time in John Lab
I received a Bachelor's degree in Molecular Biology from the
University of Manchester, UK. I went on to join The Wellcome Trust
Sanger Institute, Cambridge, UK where I studied for my Ph.D. in
comparative genomics and bioinformatics. In 2003 I joined the
laboratory of Dr. John Schimenti, at The Jackson Laboratory, as a
Postdoctoral Fellow, gaining hands-on experience using mice to study
genes contributing to developmental disease. I returned to the UK, to
train with Dr. Stuart Wilson and Dr. Marysia Plazcek at The University
of Sheffield, in powerful new methods for gene-silencing.
to The Jackson Laboratory as an Associate Research Scientist in October
2005, working closely with Simon John to understand the neurobiology of
glaucoma and to develop clinically relevant neuroprotective treatments.
Under the strong mentorship of Simon, I received my first independent
grant in 2006 and was subsequently promoted to Research Scientist.
During my time with Simon, I have applied my bioinformatics and other
experience in a number of different areas including identifying early
stages of glaucomatous neurodegeneration. A second major focus is the
refinement of a radiation-based neuroprotective treatment that
completely prevents optic nerve damage in DBA/2J mice. More recently,
because of my strong genomics background, I am leading a major
initiative to identify glaucoma-relevant genes in humans. We are using
cutting edge sequencing technology to identify potential disease-causing
variants in human glaucoma patients.
My time with Simon has been invaluable as a final training ground before
beginning my independent career. My program covers both glaucoma and
Alzheimer’s Disease (AD). For glaucoma, I am continuing to conduct
experiments to understand the role of both the complement and endothelin
systems. For AD, it has become clear to me that we can harness the
power of mouse genetics and genomics to contribute a great deal to the
understanding of this debilitating disease.
Kayrat Saidas (Sai) Nair, Ph.D. Sai Nair Ph.D
Department of Ophthalmology
UCSF, School of Medicine
Bio from time in John Lab
I received my Ph.D. in Biochemistry from the University of Mumbai,
India. From there I became a Postdoctoral Fellow in the laboratory of
Dr. Vladlen Slepak at the University of Miami. My research focused on
factors regulating phototransduction. With the advent of human/mouse
genome sequencing, and emphasis shifting towards translational research,
I felt it both timely and important to shift my research to examining
ways to solve complex problems related to human diseases. With a
background and interest in vision research, it was only appropriate to
study ocular diseases. I joined the John Laboratory as a Postdoctoral
Fellow in 2005. I have since progressed to a Research Scientist
position, which allows me more independence, as well as the training and
experience needed in preparation to become a PI. The goals of my
projects are to understand genetic factors controlling intraocular
pressure (IOP) elevation and glaucoma.
One of my projects focuses on understanding the genetic complexity
underlying elevated IOP and glaucoma, using the DBA/2J mouse as a model.
Using the power of mouse genetics, our goal is to identify genetic
mutations and their interactions that confer susceptibility towards
glaucoma. It is challenging to identify contributing casual genes in
complex, late-age onset diseases. We have been able to achieve this
utilizing a specific gene mapping strategy that has been refined and
well-proven in the John Lab. Our mapping efforts have led to
identification of 7 genetic loci that contribute to IOP elevation in
this system. These loci interact with one another and modulate IOP
elevation. Of these 7 loci, we have already identified three causal
mutations. Understanding how these mutations and loci influence
pathogenesis will help us identify pathways that govern susceptibility
to glaucoma. Potentially, this could lead to new avenues to treat the
disease in humans. Additionally, this work has allowed us to gain
insight into factors determining disease severity and penetrance.
Success in this work is possible, because of the great expertise in
ocular disease and in mechanistically dissecting complex diseases using
mouse genetics in the John Lab. The great support provided by John Lab
members and the general Jackson Laboratory environment are also
Another project involves characterizing a much needed animal model that
recapitulates features of angle closure glaucoma. Angle closure glaucoma
(ACG) is a subset of glaucoma affecting 16 million people. ACG is
estimated to blind more people worldwide than other common forms of
glaucoma, with 4 million people being bilaterally blind. The genetic and
molecular mechanisms of IOP elevation in ACG are not understood but a
reduced ocular size is common. A chemical mutagenesis screen led to
identification of a mutant mouse strain with reduced ocular size and a
phenotype resembling ACG. Subsequently, we have identified the gene
responsible for this condition. Comparative genetics has led to
identification of mutations in the same gene in human families with
similar phenotypes. Doug Gould, Ph.D.
Assistant Professor of Ophthalmology and Anatomy
University of California San Francisco
Institute of Human Genetics
Dr. Gould obtained his B.Sc.
with Specialization in Genetics and his Ph.D. in Medical Genetics from
the University of Alberta in Edmonton, Canada. His Ph.D. thesis, in the
lab of Dr. Michael Walter, was to understand the molecular mechanisms
that underlie ocular developmental defects. These defects often
lead to glaucoma in human families. In 2001, Dr. Gould moved to Dr.
John’s Lab to undergo postdoctoral training.
Doug’s projects were primarily focused
on using mouse models to understand the mechanisms of glaucoma. In the
first of his two main projects, Doug sought to understand how mutations
in the myocilin gene (Myoc) lead to primary open angle glaucoma (POAG).
MYOC mutations are the most frequently identified genetic cause of POAG,
but the pathogenic mechanism(s) remained elusive. Doug tested two
contemporary hypotheses about MYOC pathogenesis by first characterizing a
mouse model that over-expressed the MYOC protein and secondly by
characterizing a mouse model that expressed a mutant Myoc allele that
was analogous to a common and aggressive human mutation. Doug’s data
indicate that abnormal protein molecules are necessary to induce disease
and show that accumulation of these molecules in ocular cells is not
sufficient to induce glaucoma. These data agree with a growing
literature from other groups and a recent report suggesting that the
abnormal mutant proteins have to be mis-targeted to the peroxisome to
Doug’s second major project was to
develop new mouse models of glaucoma. A novel mutant mouse line was
identified in a mutagenesis screen. Doug mapped the gene and identified a
mutation in the type IV collagen alpha 1 gene (Col4a1). He showed that
Col4a1 mutation can cause ocular dysgenesis in a genetic context
dependent manner. On a permissive background mutant mice have severe
anterior segment dysgenesis and optic nerve hypoplasia. On a resistant
background both phenotypes are profoundly modified and we have
identified a genetic modifier locus that is able to rescue anterior
While identifying the gene and
characterizing the ocular phenotypes, the John Lab discovered that Col4a1 mutant
mice also had cerebrovascular defects including large cerebral cavities
and multi-focal cerebral hemorrhages. This work led to the
identification of COL4A1 mutations as a major genetic cause of a rare
but severe human disease called porencephaly and the speculation that
alleles of COL4A1 may contribute more broadly to hemorrhagic stroke in
human patients. Importantly, Doug’s experiments show that Col4a1
mutations weaken blood vessels and predispose to trauma-induced
hemorrhage in mice. Important collaborations demonstrated that this is
also true in some human families. This work suggests that behavioral
modifications/interventions may substantially decrease the risk of
severe (even lethal) hemorrhage that can be induced by trauma in
individuals with these mutations at all stages of life.
Dr. Gould started his own laboratory in
2006 at UCSF School of Medicine in the Departments of Ophthalmology and
Anatomy and the Institute for Human Genetics where he is continuing to
study the mechanisms of Col4a1-related pathogenesis in the eye and other
organs. He rapidly obtained external funding, including NIH, and has been honored by awards. His email is email@example.com.
Michael Anderson, Ph.D.
Associate Professor of Physiology & Biology
University of Iowa
Dr. Anderson performed his
graduate work studying developmental neurobiology utilizing Drosophila.
During his postdoctoral studies with Dr. John his research focused on
the mechanisms causing glaucoma in DBA/2J mice. These mice develop a
pigment liberating iris disease and a form of glaucoma resembling human
pigmentary glaucoma. Using genetic approaches, two genes were identified
) that play early roles in this disease. Both of these
genes encode melanosomal proteins.
These findings suggested that a key
aspect of pigmentary glaucoma in DBA/2J mice involves aberrant
melanosomal processes affecting the toxic intermediates of melanin
production. In the course of studying modifiers of the DBA/2J form of
glaucoma, Dr. Anderson's research also found that immune reactions
contribute to the anterior chamber disease of DBA/2J mice and with other
lab members showed that bone marrow transfers confer a striking
neuroprotection against this form of glaucoma.
Dr. Anderson is currently a member of
the Departments of Molecular Physiology & Biophysics and
Ophthalmology & Visual Sciences at the University of Iowa. His
ongoing work continues to capitalize on the basic genetic skills of his
past training, utilizing mouse genetics to provide and test unique
hypotheses of ocular disease and now supplemented by clinical and human
genetic resources at The University of Iowa. His program is well established with several NIH grants and he recently became tenured. His email is firstname.lastname@example.org.
Richard Libby, Ph.D.
Department of Ophthalmology
University of Rochester Eye Institute
Dr. Libby did his doctoral
work in Dr. William Brunken’s laboratory (Boston College), where he
focused on the role of extracellular matrix in retinal development.
After completion of his doctorate, he joined Dr. Karen Steel’s group at
the Medical Research Council’s Institute for Hearing Research. There he
studied the pathogenesis of Usher Syndrome.
The majority of work that Dr. Libby
performed in the John Laboratory focused on the DBA/2J mouse glaucoma
model. The DBA/2J mouse glaucoma model mimics many human glaucomas in
that it is age-related and the pressure elevation is spontaneous and
variable. There is now extensive knowledge of the disease profile of
DBA/2J mice and the John Lab has been successfully exploiting this model to gain
fundamental insight into glaucomatous neurodegeneration. Dr. Libby's role was to identify the key molecules and pathways that are activated in response to elevated intraocular pressure, and which lead to vision loss. Furthermore, he was interested in identifying susceptibility factors underlying galucomatous neurodegeneration.
Using DBA/2J mice deficient in the
pro-apoptotic molecule BAX (a molecule that when active, triggers a cell
to kill itself), he found that Bax deficiency completely protected
retinal ganglion cells (RGCs; the cell bodies or soma) from apoptosis.
BAX was the first molecule shown to be necessary for glaucomatous RGC
death. However, BAX was not found to be required for RGC axon
degeneration. (In addition to a cell body, RGCs have a long process
known as an axon that connects them to the brain.) This is important
because it is the first data indicating that there are distinct somal
and axonal degeneration pathways in glaucoma. Furthermore, since axons
degenerated even though the soma did not, these results indicate that
somal death is not a prerequisite for axon degeneration in glaucoma.
While Bax deficiency did not protect RGC
axons from degeneration, it did delay axon degeneration, implicating
BAX as a potential glaucoma susceptibility gene.
These data suggest that a patient’s
susceptibility to glaucomatous vision loss could be directly linked to
Bax expression levels and that manipulating the BAX pathway could be a
powerful mechanism for slowing or preventing vision loss in glaucoma. In
collaboration with Dr. Robert Nickell's (University of Wisconsin) group,
we were also able to use the genetic resource of DBA/2J mice deficient
in Bax to evaluate two prominent glaucoma hypotheses. Genetically
controlled experiments were performed where RGC cells were insulted by
either mechanical axon injury or by an excitotoxin. The findings from
these induced cell death models were compared to the findings obtained
in the actual DBA/2J glaucoma. As in the actual glaucoma, Bax deficiency
protected somas after optic nerve crush, but it did not protect RGC
somas from excitotoxic injury. Together, these results support optic
nerve injury as a primary cause of RGC death in glaucoma but do not
support an excitotoxic mechanism.
During his time in the John Lab, Dr.
Libby also participated in other projects ranging from studies designed
to identify susceptibility factors for developing glaucoma (blood
pressure, problems with eye development) to studies focused on
developing neuroprotective therapies (radiation with bone marrow
Dr. Libby started his own research
program at the University of Rochester Medical Center in 2006. He is
Assistant Professor in the Department of Ophthalmology where he continues to study the molecular pathways of glaucomatous
neurodegeneration and the genetic factors that underlie genetic
susceptibility. He rapidly obtained external funding, including NIH, and serves on various grant review bodies. His email is email@example.com
Xianjun Zhu, Ph.D.
for Human Molecular Biology & Genetics , Sichuan Academy of Medical Science & Sichuan
Provincial People's Hospital Chengdue, Sichuan, China
Dr. Zhu received his B.Sc. degree in Plant Molecular and Developmental Biology
from Peking University, Beijing. He went on to study in the Institute of
Microbiology, at the Chinese Academy of Sciences, Beijing and received his
master degree in Biochemistry and Molecular Biology. In 2000, Dr. Zhu entered
the program of Cell and Molecular Biology of the University of Texas, Austin and worked in Dr. David Stein's lab for his Ph.D. dissertation. A
major component of the project was to determine the molecular mechanism
that controls Drosophila dorsal-ventral polarity formation, specifically investigating the role of
glycosaminoglycans in Drosophila pipe-mediated dorsal-ventral
Dr. Zhu received his Ph.D. degree in Cell and Molecular Biology in 2006. He then joined the John Lab to pursue his postdoctoral
training using mammalian genetics and neurobiologic methods to study neurodegenerative disease. He gained expertise in experiments to test mechanisms of disease using mouse models of human disease, and in ocular, brain and spinal cord anatomy and pathology. His major project studied neurodegeneration in wabbler lethal (wl) mice. He determined that these mice develop a severe axonopathy affecting various nerves, the retina and parts of the brain. Interestingly, although their axons degenerate, the neuronal cell bodies survive in most affected tissues. Dr. Zhu characterized the mutant gene which affects cell membranes. Dr. Zhu also investigated the possible role
of glial cells in the initiation and/or propagation of glaucoma. Dr. Zhu is currently a Professor/Investigator at The
for Human Molecular Biology & Genetics, Sichuan Academy of Medical Science & Sichuan
Provincial People's Hospital Chengdu, Sichuan,
Ileana Soto, Ph.D.
Associate Research Scientist
Jackson Laboratory, Bar Harbor, Maine
Bio from time in John Lab
I graduated with a B.A. in Life Sciences from the University of Puerto
Rico. As an undergraduate student I worked in the laboratory of Dr. Rosa
Blanco at the Institute of Neurobiology. The research experience was
so great that I decided to apply for graduate school and continue doing
research in her laboratory. My thesis project in Dr. Blanco’s
laboratory consisted of determining the effects of basic fibroblast
growth factor (bFGF) in the survival and axonal regeneration of frog
retinal ganglion cells (RGCs) after optic nerve axotomy. In 2005, I
received my Ph.D. from the Biology Intercampus Program at University of
Puerto Rico. My studies in the frog visual system encouraged me to
continue further studies of the retina but with a more biomedical
During my first postdoctoral training experience at Johns Hopkins
University, I had the opportunity to work in the DBA/2J mouse glaucoma
model and to study molecular changes that occur in RGCs and glial cells
during the progression of glaucoma. However, a deeper interest for the
role of astrocytes in glaucoma, and the use of mouse genetics to
identify pathways and experimentally test mechanisms motivated me to
join Dr. Simon John’s laboratory for a second postdoctoral training. My
major projects are assessing the interactions between glaucoma and
diabetes and the impact of dietary components on disease outcome. I
plan to address whether cellular pathways activated in astrocytes
contribute positively or negatively to disease onset and progression. I
am also interested in possible therapeutic treatments that prevent or
delay the progression of the disease in mouse glaucoma models.
is to identify certain mechanisms involved in the pathophysiology of
glaucoma that can then be targeted for the treatment of the human
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