BOOK REV IEWS
Book Reviews
DECODING DARKNESS: THE SEARCH FOR THE
GENETIC CAUSES OF ALZHEIMER’S DISEASE
By Rudolph E. Tanzi and Ann B. Parson. 281 pp., illustrated.
Cambridge, Mass., Perseus, 2000. $26. ISBN 0-7382-0195-2.
T HE writing in medical journals is deliberately devoid
of emotion, which may explain why writers of books
about science are flourishing these days. They can add dra-
ma and elucidate complexities. A scientific autobiography
written with a journalist can be a winner, as illustrated by
Decoding Darkness, which could have been subtitled “Alz-
heimer’s Research Goes Molecular.” Rudolph Tanzi is direc-
tor of the Genetics and Aging Unit at Massachusetts Gen-
eral Hospital. Ann Parson is a professional writer.
As autobiography, Decoding Darkness commands atten-
tion. In 1980, after having graduated from the University
of Rochester, Tanzi was playing keyboard in a rock band
and writing best-selling songs. Fifteen years later, he had won
two prestigious awards for research on Alzheimer’s disease.
The transition was not direct.
When Tanzi returned to Boston in 1980, he answered a
bulletin-board advertisement and became a technician for
James Gusella — hunting for the Huntington’s disease gene.
Their success led to a lasting friendship, more than the typ-
ical relationship between mentor and student. Tanzi was
there from the beginning — from the setting up of the
laboratory through the historic mapping of the gene in
1983 that made Huntington’s disease the first disease to be
mapped without knowledge of the gene product. At Gusel-
la’s suggestion, Tanzi took on a side project — developing
markers for chromosome 21. That chromosome is home to
the gene for Down’s syndrome, and people with that con-
dition are at high risk for Alzheimer’s disease. Tanzi there-
fore began to work on the laboratory’s collection of DNA
from families with Alzheimer’s disease.
Gusella advised Tanzi to take graduate courses in neu-
robiology, not genetics. In 1985, Tanzi left the laboratory to
become a graduate student. He left his Alzheimer’s project
to Peter St. George-Hyslop, who was first Tanzi’s trainee and
then, simultaneously, a partner and competitor.
In addition to being an autobiography, the book is a
primer of molecular genetics. Tanzi thought the biologic vil-
lain in the Alzheimer’s story must be the accumulation of
insoluble amyloid in plaques throughout the brain. Before
long, he was joined by dozens of competitors who sought
mutations in the gene for the amyloid precursor protein
on chromosome 21. Tanzi describes the tedium and long
hours of fruitless searching as well as the joy when a link-
age was found. He explains the methods he and his col-
leagues used and provides simple figures to explain how the
mutant gene works.
There are no human villains among the investigators,
but there is drama aplenty. George Glenner first character-
ized the amyloid in the cerebral Alzheimer’s plaques; he him-
self died of amyloidotic heart disease. Charles Epstein, a lead-
er in recognizing the connection between Down’s syndrome
and Alzheimer’s disease, was seriously injured by the psy-
chotic Unabomber. Research partners split up over argu-
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ments about patent rights. Friends became mutually wary.
A German scientist publicly accused U.S. investigators of
practicing “murderous science” in their development of a
rapid autopsy program to provide brain tissue for research;
one Jewish leader took personal offense. Commercial com-
panies contributed transgenic mice that carry mutant amy-
loid genes and develop plaques like those in humans, but
these companies sometimes refused investigators access to
the mice and promoted competitive secrecy. Tanzi himself
is more than a consultant to one company; he has “an eq-
uity interest.”
Tanzi seems blessed with an amiable disposition. He re-
ceives bruises but makes no enemies and bears no long-
term grudges. He describes the anguish of knowing he is
in a race with other investigators without being aware of how
many or who they are — he names 47 investigators who
contributed to the progress in this field, but there are more.
Tanzi lost one race when he had almost reached the goal
himself, and his marriage was threatened when, racing, he
spent Christmas and New Year’s Day in the laboratory.
Tanzi himself is no braggart, and he acknowledges that
the genetic discoveries seemed to come simultaneously in
reports from many laboratories. However, he was one of
the first to map the gene for the amyloid precursor protein
to chromosome 21. He ruled out mutations in that gene
among the families studied at the Massachusetts General
Hospital; he provided one of the first genetic maps of the
chromosome; and he came so close to identifying the gene
for presenilin 2 that he was included as an author in the
report that did so. After the book was published, Tanzi de-
scribed a locus on chromosome 10. Four other genes had
been implicated: the amyloid precursor protein, two pre-
senilins, and the susceptibility-factor allele APOE-4. Tanzi
and his associates were at the forefront of three of those
achievements.
Funding for research on Alzheimer’s disease increased
from $13 million in 1980 to more than $400 million per
year in the 1990s. Therapeutic trials based on the amyloid
theory are in progress, investigating a vaccine against amy-
loid, inhibitors of the proteases that produce the amy-
loidogenic peptides, and drugs that lower the levels of zinc
and copper in the brain. The story is unfinished.
By the time you finish the book, you will hope that Tan-
zi and the others will make further progress, because Alz-
heimer’s disease is the great white whale of age-related neu-
rodegenerative diseases. There are 4 million victims now
— a disaster for their loved ones and their caretakers, at an
annual cost of $100 billion for the nation. The situation is
destined to become worse as people live longer. The dom-
inant theory is that genetic susceptibility interacts with en-
vironmental factors to cause Alzheimer’s disease. Head in-
jury increases the risk, whereas the use of estrogens and
nonsteroidal antiinflammatory agents may be protective. By
the end of the book, you will also hope that we will see
more progress in therapy, so that Tanzi and Parson can
give us an upbeat second edition.
Research on Alzheimer’s disease did not begin with mo-
lecular genetics, and sporadic cases account for more than
95 percent of all cases. However, the genetic clues to amy-
loid formation apply to the sporadic disease as well as to
familial Alzheimer’s. Fifty years ago, not much was known
about Alzheimer’s disease; modern research began in the
1960s. For readers who are interested in the days before
molecular genetics, oral-history interviews have been re-
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
corded by Robert Katzman and Katherine Bick, themselves
pioneering investigators (Alzheimer Disease: The Changing
View. San Diego, Calif.: Academic Press, 2000). You do not
have to be a geneticist or a neurologist to enjoy Decoding
Darkness; Alzheimer’s disease is a commanding problem
for all of us. The story is invigorating, the progress is fan-
tastic, and the writing is lively.
LEWIS P. ROWLAND, M.D.
Columbia–Presbyterian Medical Center
New York, NY 10032
THE HIDDEN STRUCTURE: A SCIENTIFIC
BIOGRAPHY OF CAMILLO GOLGI
By Paolo Mazzarello. Translated and edited by Henry A. Buchtel
and Aldo Badiani. 407 pp., illustrated. New York, Oxford
University Press, 2000. $90. ISBN 0-19-852444-7.
G REAT conceptual advances in science are often based
on great technical advances. Either type of discovery
can bring scientific fame. In 1896 Riva-Rocci devised the
mercury sphygmomanometer for measuring blood pres-
sure, but it took several decades for hypertension as a cause
of disease to be unmasked. Conversely, Watson and Crick
in 1953 discovered the structure of DNA but not the
technique of x-ray crystallography that limited the number
of possibilities for their model. There are countless other
examples, but it is rare for a scientist to develop both a new
instrument and new ideas. Camillo Golgi (1843–1925) did
his utmost to be more than the inventor of a revolutionary
staining technique for nerve tissue. The “reazione nera,” or
black reaction, which he discovered in 1873 after system-
atic experiments, consisted of immersing specimens in sil-
ver nitrate after fixation with potassium dichromate. It al-
lowed visualization of nerve cells and their ramifications in
unprecedented detail. In The Hidden Structure, the excite-
ment of this discovery is conveyed to the reader mainly
through words, because the histologic illustrations are sparse.
Once Golgi’s technique was used in other countries (he
published almost exclusively in Italian), it stirred a flurry
of new hypotheses about the anatomical organization and
eventually the function of the nervous system.
Golgi was less successful in staking his claims with re-
gard to these wider implications. His theory that nerve-cell
processes formed a giant anastomotic network was initially
attractive, because it fit with the emerging notions about
electricity in the nervous system. But with the ascendancy
of the cell theory in the second half of the 19th century,
fewer and fewer scientists were prepared to make an excep-
tion for the nervous system. The doctrine of separate nerve
cells, first proposed by His (in 1886) and Forel (in 1887),
was anathema to Golgi until the end of his life. The ultimate
insults were the term “neuron” (coined by Waldeyer in 1891)
and the successful campaigning for the individual nerve
cell by Ramon y Cajal. The Spaniard made a rather sudden
appearance on the international stage (he too published
only in his own language) and swiftly convinced the scien-
tific community with his superb preparations, made with
modified Golgi stains. He later added the concept of “dy-
namic polarization” (i.e., one-way traffic in nerve cells). Ca-
jal and Golgi would never get on well together. Irony dic-
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tated that in 1906 they were to share the Nobel Prize for
Medicine. Sadly enough, Golgi chose to use his official lec-
ture for another desperate attack on the neuron doctrine.
Though in his main theme of research Golgi’s work ex-
emplified a mixture of success and error, he was undoubt-
edly a great scientist in many other respects. That Mazzarel-
lo’s book makes this abundantly clear is its greatest merit.
The book follows Golgi from the cradle to the grave, in
24 chronologically arranged chapters. It describes his life-
long attachment to the University of Pavia, which was in-
terrupted only by a stint as the director of a psychiatric hos-
pital in the country. It was there, in his spare time and in
the kitchen of his private apartment, that he discovered the
black reaction. His name is also linked with the discovery of
several microscopic cellular structures (tendon organ, mus-
cle spindle) and subcellular structures (the Golgi apparatus).
What will be new to most readers outside Italy are his con-
tributions to general medicine with regard to intestinal-
worm infections, Bright’s disease of the kidney, and espe-
cially malaria. Golgi and his pupils not only accepted and
defended Laveran’s theory of a parasitic origin for malaria,
but they also provided many new pieces of evidence and
wholeheartedly threw their weight into a prolonged and
complicated battle with proponents of a “bacillus malariae.”
The book has some weak points, in addition to the elab-
oration of histologic details without corresponding illustra-
tions. The style does not always run smoothly, and in plac-
es it is too encyclopedic. Also, Golgi does not really come to
life as a human being, apart from his stubborn defense of
“reticularism”; however, he was probably reserved in his pri-
vate life, leaving few emotional traces for his biographers.
Where the book does succeed is in depicting a man who,
until his last moments, was totally dedicated to medicine
and to his university, at which he served as rector for a long
period late in his life. Inevitably, the reader is given many a
glimpse of the intricacies of Italian politics. Only one year
before his death, when he was 80 years old and had received
all imaginable honors, Golgi had to endure the transfer of
Pavia’s medical school to Milan, an event he had tried to
avoid for decades. All in all, the book is a good read, es-
pecially for aficionados of histology and neuroscience.
J. VAN GIJN, M.D.
University Medical Center Utrecht
3584 CX Utrecht, the Netherlands
DEAR MR. DARWIN: LETTERS ON THE EVOLUTION
OF LIFE AND HUMAN NATURE
By Gabriel Dover. 268 pp., illustrated. Berkeley,
University of California Press, 2000. $27.50.
ISBN 0-520-22790-5.
W HAT would happen if a modern biologist could get
in touch with Charles Darwin and enter into a lively
and stimulating discussion about recent developments in
evolutionary theory? Here, we have the answer. Molecular
biologist Gabriel Dover uses imaginary correspondence as
a literary device for explaining how our ideas about evolu-
tion have evolved since Darwin’s day.
Dover argues that evolution involves more than just nat-
ural selection and cites such phenomena of sampling error
 NOTIC ES
as genetic drift. The basic idea behind sampling error is eas-
ily recalled. Gene frequencies inevitably fluctuate at random.
Some alleles within a population may happen not to be
present in any of the zygotes that ultimately become the next
generation of adult organisms. This is more apt to happen
when the alleles are rare and in small populations. So pure
accident may result in the elimination or fixation of an al-
lele. The result is change in gene frequencies, but not ad-
aptation.
According to Darwin’s theory of natural selection, ad-
aptation results when one organism has properties that al-
low it to out-reproduce another of the same species. Dover
does not mention another of Darwin’s mechanisms — cor-
related variability, or pleiotropy. Variation sometimes in-
volves traits that always go together, so that they both in-
crease in frequency even if only one of them is selectively
advantageous. Dover’s additional mechanisms are something
different. Because of the way in which chromosomes be-
have in the course of reproduction, the genome is constant-
ly being reorganized. Sexual reproduction generates change,
and Dover sees in it a cause of evolution (a “molecular
drive”) that interacts with selection and sampling error.
Although Dover explains all this very well, his real goal
is to rebut the metaphysics of Richard Dawkins, an Oxford
behaviorist who studied chickens before branching out and
writing popular books. Dover laments the influence of
Dawkins’s reasoning on persons who are not equipped to
see through it, especially textbook writers and social sci-
entists. Let me clarify what Dover is complaining about.
Dawkins decided to call genes, and other things of which
copies are made, “replicators.” The problem with that term
is that in ordinary English, the suffix “-or” refers to the
doer of the action. Thus, a replicator should be that which
does the replication, not that which is replicated. (Likewise,
a photocopier is not the copy that is produced by the ma-
chine.) Dawkins’s term is apt to dupe the unwary into think-
ing that a passive participant is an active agent. This is what
Dover has to grapple with: the metaphysics of agency. He
makes it abundantly clear that genes are not replicators, in
the sense of things that carry out replication. Rather, they
are replicated by the cells that contain them. More impor-
tant, he argues that organisms are active agents in evolution
by virtue of their roles in restructuring the genome in pro-
ducing compatibility among genes, chromosomes, and oth-
er components of organisms and species.
This suggests an important role for sex. Dover maintains
that molecular drive produces compatibility within repro-
ductive populations. The compatibility within species, to-
gether with the lack of it between them, is fundamental to
the modern “biological species concept.” The point that
species are not just abstractions but, rather, higher-level
units that play an important part in evolution is very much
in line with Dover’s antireductionist metaphysics. Howev-
er true it may be that species and other populations are
not likely to have adaptations over and above those of their
component organisms, there is no legitimate reason to ex-
trapolate and treat species and organisms as mere epiphe-
nomena of molecules.
Species are important because they are historical units
— things that evolve and give rise to the branches of the
phylogenetic tree. Dover is off the mark when he suggests
that biology is history, pure and simple, and that we seek
in vain for its laws of nature. Rather, biologists have been
seeking laws of nature in the wrong place. Although it is
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true that there are no laws of nature for organisms and
species, this is because organisms and species are concrete,
particular things, or “individuals” in the broad, metaphys-
ical sense. All laws of nature are about kinds, or things in
general, and not about instances of such kinds. In evolution-
ary biology, laws apply to kinds of populations, such as large
populations and small populations. For example, as the ef-
fective population size goes down, the frequency with which
alleles are fixed by sampling error goes up. This is a perfectly
legitimate law of nature: it is necessarily true of everything
to which it applies, irrespective of time and place. Howev-
er, it is a statistical law, since it does not predict which par-
ticular version of a gene will be eliminated from the pop-
ulation. The fact that so much of the lawfulness (such as
it is) of biology must be conceptualized in such statistical
terms gives scant comfort to those who would have us treat
human behavior in Laplacian, deterministic style.
One might wonder whether debunking the metaphysi-
cal pretensions of one’s colleagues is perhaps beneath the
dignity of a good scientist like Dover. Isn’t it enough to
joke about selfish chromosomal deletions and then get on
with one’s research? The trouble is that selfish genes are
becoming part of popular culture. The medical communi-
ty should brace itself for an onslaught of belief systems, al-
ternative therapies, and nostrums — all justified on the ba-
sis of what purports to be legitimate science.
MICHAEL T. GHISELIN, PH.D.
California Academy of Sciences
San Francisco, CA 94118
Book Reviews Copyright © 2001 Massachusetts Medical Society.
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Contact Harvard Medical School, CME, P.O. Box 825, Boston, MA
02117-0825; or call (617) 432-1525; or fax (617) 432-1562; or e-mail
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