Why Neurome Now?
Neuroscience is perhaps the most promising field
for future application of bio-medical discoveries for the
treatment and prevention of the major unsolved human diseases.
This is because: 1) the brain is thought to express more genes
than any other organ in the body, and 2) the brain must monitor
and control all other aspects of bodily function, from heart
rate and blood pressure, to temperature, to salt and water
balance, to blood sugar and feeding, as well as all reproductive
actions, and in humans complex mental activities such as language,
mathematics, abstractions and long term strategies.
Until recently, the process of identifying genes expressed
in the brain has been slow, let alone determining what these
genes encode and where in the brain’s complex circuitry
are the neurons that express these genes.
However, as widely trumpeted in the press, two massive efforts
have now resulted in the nearly complete initial inventories
of the human genome, and that of the mouse is said to be well
along towards completion. The mouse genome is a critical next
step in harvesting the value of the information of the genome
pertinent to disease vulnerability and resistance, since the
mouse is the only mammal in which we can manipulate human
disease-related genes to be expressed in whole animal models
of human disease to determine what are the critical environmental
factors that interact to render an individual vulnerable or
resistant to a disease.
By understanding the genetic vulnerabilities that underlie
neurodegenerative illnesses, major opportunities for the development
of new treatments begin to present themselves. Neurome has
developed a suite of proprietary technologies that enable
insight into these genetic vulnerability factors, and the
company is positioned to employ these technologies in pursuit
of novel therapeutics to treat Alzheimer’s disease,
Parkinson’s disease, Huntington’s disease and
Amyotrophic Lateral Sclerosis.
Neurons Exhibit Selective Vulnerabilities
Before the era of modern medical genetics, neurodegenerative
diseases were understood mainly in terms of the neurological
problems that arise during the final stages of the patients'
lives, and the pathological findings revealed at autopsy by
microscopic examination of their brains and spinal cords.
The result of nearly a century of such studies has revealed
that neurodegenerative disorders do not destroy all neurons.
Rather, neurons show patterns of disease-specific selective
vulnerability: certain neuronal cell classes and associated
circuits fail during the progress of the disease whereas others
remain viable. The symptoms of the disease reflect the losses
of the vulnerable neurons and their circuits. As genetic clues
to the biochemical basis of these diseases have emerged from
human studies, powerful mouse models of these diseases have
been developed through manipulation of key disease-related
genes. Importantly, the brains of these genetically manipulated
animals reproduce critical elements of the disease in humans:
certain neuronal cell classes and their associated circuits
fail whereas others remain viable, and do so in highly analogous
Figure 1. Images showing dendritic
spine morphology in a mouse model of human Alzheimer’s
disease. The image on the left shows spines from a normal
animal, while the image on the right shows significant degenerative
loss of spines in an age-matched diseased animal, as indicated
by the arrows.
The key to each disease lies in these patterns of disease-specific
selective vulnerability. If we understand the unique attributes
that make a particular neuron vulnerable and how that neuron
differs from a resistant one, we should be able to protect
the vulnerable neuron from the disease process. Using tools
with the speed and precision of the Neurome Technologies,
these early reflections of pathology can be identified quantitatively
in the animal models, thereby defining the earliest neurons
vulnerable to the pathological process, as well as those shown
to be fully resistant to the disease process. This time line
of vulnerability and resistance creates a pathway for achieving
opportunities for novel therapeutic and preventive solutions.
ALS is a particularly compelling example of selective
vulnerability, particularly as manifested in the mouse
models of familial ALS that result from mutations in the enzyme
superoxide dismutase 1 (SOD1). However, while several clear
molecular mechanisms of neurodegeneration have been proposed
for ALS, they have not been carefully considered in the context
of selective vulnerability, and in fact, the molecular and
cellular determinants of selective vulnerability in ALS remain
How do we develop the cell and circuit-specific interventions
that are required to effectively treat disorders such as ALS?
A disease mechanism-based treatment development plan must
ultimately identify the cellular and molecular changes that
are the earliest maladaptations of the disease process. Such
an approach should be designed to reveal mechanistic targets
within vulnerable circuit-specific locations. Neurome’s
technologies as applied to mouse models of ALS are ideal for
both the discovery and evaluation of targets that can be associated
with the cell classes and circuits at the core of this devastating
disorder. Neurome is aggressively targeting ALS with such
The Neurome Technologies are capable of generating data ranging
from the level of whole brains down to the level of DNA and
protein sequence. All levels of resolution for a given gene
product may be probed, in a seamless, integrated 3-D display
that is quantitatively accurate. For example, if a particular
neurotransmitter receptor were the object of inquiry, the
data will reflect relative mRNA levels across brain regions,
distribution and number of neurons containing the related
protein within the brain areas of interest, high-resolution
data on intraneuronal distribution of the protein, and quantitative
ultrastructural data on the synaptic representation of the
receptor. The high-resolution data, in particular, will be
obtained and displayed within the context of identified cells
and circuits, not just brain regions.
Figure 2. Distribution of plaque
accumulation in a mouse model of human Alzheimer’s disease.
The region outlined in red shows plaque accumulation restricted
to a selective area (outer molecular layer) within the dentate
gyrus of the hippocampus. This plaque accumulation is associated
with damage to vulnerable neurons in this region.
Neurome's scientists have already demonstrated,
using this research approach, their ability to define at a
cellular and neuronal circuitry level those neurons that are
vulnerable and those neurons that are resistant (in AD), and
to establish when these neurons begin to show their divergence
in vitality. Neurome’s technology platform is uniquely
suited for both the discovery and evaluation of targets and
drug candidates that may be useful in addressing defects associated
with the cell classes and circuits that are at the core of
those human neurologic disorders.
The Neurome Technologies
While the tools for neurochemistry, neuroimaging, and neuronal
gene discovery are advancing rapidly, the same cannot be said
for current methods of gene expression mapping in the brain
– a critical next step in determining the molecular
basis for the diseases that can confer vulnerability or resistance
to brain related diseases. Neurome’s technology platform
is comprised of a suite of proprietary, patent-protected software,
hardware, instrumentation, reagents and methods that in combination
allow high-throughput, rigorous and standardized quantitative
measurement of brain morphology and quantify gene expression
patterns and the resultant morphological details of brain
structures with an unprecedented level of sensitivity, specificity,
and resolution. The technologies include:
TOGA® (TOtal Gene expression Analysis)
is a patented method of identifying and determining the
concentration of nearly all of the genes active in a sample
cell or tissue. TOGA® will reveal new molecular targets
for intervention strategies, and Neurome’s microscopy-based
technologies can be used to identify and characterize the
cells that express these molecular targets to account for
the pathologies in animal models of neurodegenerative diseases.
MiceSlice™ provides ultra-high resolution
digital brain sections from the standardized preparation
of brain section tissues. Microscope image tiles are seamlessly
reassembled into one brain section and rotated to perfect
alignment. MiceSlice™ provides the foundation material
for the development of standardized experimental protocols.
NeuroZoom™ is a computerized microscopy
system that supports the precise extraction, analysis, and
display of quantitative data from the MiceSlice™ microscope
images of the brain, including morphometrics, stereology
and image processing. NeuroZoom™ automation supports
high throughput analysis of ultra-high resolution images
and promotes standardization of data analysis using the
brain database models in BrainArchive™.
BrainArchive™ is a comprehensive
database of neuroinformation and serves as an electronic
brain "atlas", for archiving, integrating and
comparing brain structure and circuitry data from NeuroZoom™.
Reference brains from several transgenic mouse models have
been imaged and aligned with high precision and ultra-high
resolution using NeuroZoom™. BrainArchive™ presents
virtual sections from its electronic brain atlas, digitally
displaying both qualitative and quantitative gene expression
data required from the mouse brain.
BrainPrint™ supports digital profiles
for comparison of quantitative, spatial and volumetric data
from different transgenic mouse models. BrainPrint™
analyzes all of the experimental data originating from NeuroZoom™
stored in BrainArchive™ and identifies those characteristics
useful for developing profile information corresponding
to certain traits under various phenotypes. Once a brain
dataset has been properly described, different genetic conditions
may be quickly compared and displayed.
Neurome’s strategy hinges on the ability to obtain
a new generation of brain information: standardized, quantitative
datasets that for the first time adequately and accurately
depict the molecular, cellular and circuitry patterns of brain
activity that determine both normal and variant functions
of the brain, region by region and circuit by circuit –
a new generation of data offering answers to new questions.
These are the types of datasets the Neurome Technologies were
designed to collect, organize and analyze, and it places Neurome
on the leading edge of CNS drug discovery and development.