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the
A meticulously
constructed
atlas of the
Mind
human brain
reveals the
molecular roots
of mental By Allan R. Jones and Caroline C. Overly
illness and of
everyday behavior
56 s c i e n t i f i c a m e r i c a n m i n d S e p te m b e r/O c to b e r 2010
w w w. S c i e nti f i c A m e r i c an .c o m/M in d s c i e n t i f i c am e r i c a n m i n d 57
Human Mouse
Weight Three pounds 0.01 ounce
Volume 1,400 cubic 1.5 cubic
centimeters centimeters
(small (jelly bean)
cantaloupe)
Number of 100 billion 75 million
neurons
levels in different regions of the brain and the ways to get a molecular handle on those diseases. Indeed,
they change under certain circumstances. They do researchers have now connected more than 500
not disclose the biological underpinnings of these genes to Parkinsons disease, more than 600 to mul-
alterations in brain activity. To truly understand tiple sclerosis and more than 900 to schizophrenia.
how autism unfolds, say, or how best to treat de- The ever expanding list of gene candidates is both
pression, scientists want to know what is happen- a blessing and a curse. Although somewhere in this
ing inside the cells that control brain activity. genetic stockpile lies the key to understanding these
Genes, of course, provide the instructions for disorders, as the gene lists grow scientists have to
the molecular machinery inside a cell. Thus, biolo- laboriously sift through an increasing number of
gists have long been engaged in a complementary candidates and their interactions.
effort to connect certain genes to defined disorders Now our team at the Allen Institute for Brain
Science has developed a high-tech bridge between
brain anatomy and genetics: an online interactive
FAST FACTS atlas of the human brain showing the activity of the
Atlas of Thought more than 20,000 human genes. Preceded by a sim-
ilar atlas of the mouse brain, the Allen Human
predict a drugs benefits and side effects. by a new drug. Such information may help predict
a new medications therapeutic effects, as well as its
58 s c i e n t i f i c a m e r i c a n m i n d S e p te m b e r/O c to b e r 2010
w w w. S c i e nti f i c A m e r i c an .c o m/M in d s c i e n t i f i c am e r i c a n m i n d 59
60 s c i e n t i f i c a m e r i c a n m i n d S e p te m b e r/O c to b e r 2010
the key to solving problems such as obesity and an- trying to remember a list of words after five minutes
orexia. These circuits, which must integrate inter- and then again after 24 hours. The variants were
nal signals such as hunger and thirst with environ- also associated with differences in brain activity in
mental cues, also provide clues to the function of
analogous brain networks.
(The Authors)
In the past, scientists explained food and drink
consumption by focusing on single gene products, ALLAN R. JONES is chief executive officer of the Allen Institute for Brain
such as the hunger-stimulating hormone ghrelin, Science in Seattle. He received his Ph.D. in genetics and developmental
or single brain centers implicated in hunger, satiety biology from the Washington University School of Medicine in St. Louis.
or thirst. But in a study published in 2008 obesity CAROLINE C. OVERLY, who holds a doctorate in neuroscience from Har-
specialist Pawel K. Olszewski and his colleagues at vard University, is associate director of communications at the Allen Insti-
the University of Minnesota revealed a more com- tute. The authors thank Michael McCarthy for his help in the development
plex reality after they used the Allen Mouse Brain of this article.
w w w. S c i e nti f i c A m e r i c an .c o m/M in d s c i e n t i f i c am e r i c a n m i n d 61
A
G
G DNA
A bases
C
G
Microarray T
(chip) Section Spot containing copies of Part of one
of a chip a single DNA molecule DNA strand
In this image, a DNA ed by tissue samples ranging from the size of a pea
chip that has been (for larger, more uniform brain areas) to that of a
exposed to a sample
of brain tissue pinhead (for smaller, more intricate structures).
reveals the activity Developed in the mid-1990s, a DNA microarray
of thousands of is dotted with numerous microscopic DNA seg-
genes in one part of
ments, called probes, each of which binds the mRNA
the hippocampus.
Each spot denotes for a specifically matched gene and lights up to re-
activity from one veal both the presence and level of that genes expres-
gene. The brighter sion [see box above]. Some gene chips contain tens of
the spot, the more
thousands of probes, enough to test for the presence
J A R E D S C H N E I D M A N D E S I G N (t o p) ; C O U R T E S Y O F T H E A L L E N I N S T I T U T E F O R B R A I N S C I E N C E (b o t t o m)
active the gene.
of all human genes in a single experiment. Although
it cannot provide the same fine, cellular-level detail
the hippocampus while subjects performed these as the mouse brain atlas, the microarray strategy is
tasks. By looking up the gene in the mouse brain at- fast and yields numerical data as opposed to imag-
las, the researchers found that the gene is expressed es of slices of mouse brain that are much easier to
in the hippocampus sewing up the case that the analyze, enabling scientists to draw correlations be-
gene plays a direct role in short-term memory. tween different patterns of gene activity that might
elude the human eye.
From Mouse to Man In March 2009, after nearly two years of plan-
Given the stream of findings emerging from the ning, we were ready to begin making our human
mouse brain map, we hoped that a similar atlas of brain map. One hurdle remained: we needed a brain.
the human brain would yield even more fruitful in- The brain had to be free of disease or other abnor-
sights into diseases and behaviors that may differ be- malities. It had to be whole and fresh and obtained
tween humans and mice. Such discoveries may en- and quickly frozen within 24 hours of death or the
able better predictions about, say, which new medi- mRNA we were looking for would degrade and we
cines tested in animals will really work in people. To could not detect gene expression. Such brains are
build this bigger map, however, we needed a differ- rare, and when they are available other organs must
ent approach. Given the size of the human brain, an- be collected fi rst for people in need of an organ
alyzing gene expression in brain sections one gene at transplant. Only if our 24-hour window had not
a time would take decades. Our streamlined meth- closed by then and surviving family members gave
od involved the use of specialized gene chips, also their consent could we have the brain.
called DNA microarrays, to measure the activity of Nevertheless, we received the fi rst of several
all genes simultaneously in each of about 1,000 dis- brains needed for the atlas in July 2009, kicking off
tinct brain areas. These regions would be represent- the 10-month process required to complete data
w w w. S c i e nti f i c A m e r i c an .c o m/M in d s c i e n t i f i c am e r i c a n m i n d 63