64 THE SCIENTIST | the-scientist.com
M
ention the word DNA, and virtually
everyone nods in understanding.
They know or think they know
what DNA does. It is the molecule that
carries our genes and defines who we are.
But mention the word ribosome, and even
most scientists will give you a blank stare.
Yet life needs the ribosome. The ribosome
is the machine that translates the DNA
code into the proteins that are essential
for life. Virtually every molecule made in
every living cell was made either by the
ribosome or by enzymes that were them-
selves made by the ribosome.
In my book, Gene Machine, I describe
not only the quest to understand the
ribosome, but also the human side of sci-
ence: the competition and rivalry, the
often quirky personalities, as well as the
blunders and dead ends along the road
to success. The result is a frank look at
what scientists are like and how science
actually progresses. It is also the story of
how a relative outsider like me suddenly
found himself in a high-stakes race for
the structure of the ribosome.
After the mid–20th century identi-
fication of DNA’s structure, many labs
worldwide established that the genetic
information of DNA is copied into an
intermediate molecule, messenger RNA
(mRNA). Other adapter RNA molecules,
the tRNAs, recognize a unit of three
bases on mRNA called codons, and bring
along the appropriate amino acids to be
joined together to make a protein.
Cell biologists showed that protein
synthesis in cells takes place in blobs
on the surface of an organelle called the
endoplasmic reticulum. When research-
ers isolated these blobs, now called ribo-
somes, the resulting particles were found
to be about two-thirds RNA, with the
remaining one-third comprising about50 proteins (ribosomes from higher
organisms are more complex and about
1.5–2 times larger). All ribosomes consist
of two subunits. The small subunit binds
mRNA, and contains the site where the
tRNAs recognize the codon on mRNA.
The large subunit contains the site of
peptidyl transfer, where a bond is formed
to attach the new amino acid to the
growing protein chain.
All this was known by the 1970s, but
the details remained murky. At the time,
the only technique available to deter-
mine the structures of large molecules
was X-ray crystallography. However, it
was unclear whether an object as large as
the ribosome could crystallize, and even
if it could, whether its structure could
be solved by crystallographic methods,
given that the entire ribosome consisted
of about 1 million atoms.
In 1980, Ada Yonath and Heinz
Günter Wittmann made an important
breakthrough when they produced the
first three-dimensional crystals of the
large subunit of the ribosome. A few
years later, a group in Russia headed by
Maria Garber produced crystals of both
the small subunit and the entire ribo-
some. Nevertheless, 15 years after the
first crystals, there was still no structure
of either subunit of the ribosome. Sev-
eral groups then entered the fray in the
mid- to late 1990s with new ideas and
approaches. These included Peter Moore
and Tom Steitz working on the 50S sub-
unit; Ada Yonath and I independently
working on the 30S subunit; and Harry
Noller, Marat and Gulnara Yusupov(a),
and Jamie Cate, working on the entire
70S ribosome. The intense competition
resulted in low-resolution structures in
1999 and atomic structures of both sub-
units in 2000. A low-resolution struc-ture of the entire ribosome in 2001 was
followed by high-resolution structures in
2005 and 2006. The work culminated
in the 2009 Nobel Prize for Chemistry
awarded to Yonath, Steitz, and me.
Solving the ribosome took many dispa-
rate technical advances. Among these were
the development of intense X-ray beams
from synchrotrons; cryocrystallography to
minimize radiation damage; electronic
detectors for X-rays; and very fast com-
puting and computer graphics to solve
and visualize structures. None of these
were developed with the ribosome in
mind. It shows that progress in science
does not occur in a vacuum. Rather,
when science and technology reach a
certain stage, a few people realize that
the next leap is possible.gVenki Ramakrishnan is a senior scientist
at the Medical Research Council’s Labora-
tory of Molecular Biology in Cambridge,
UK. He shared the 2009 Nobel Prize in
Chemistry for his work on solving the ribo-
some’s structure. Read an excerpt of Gene
Machine: The Race to Decipher the Secrets
of the Ribosome at http://www.the-scientist.com.Basic Books, November 2018READING FRAMESThe race to solve the ribosome’s structure reveals the nature of life
and the scientific enterprise.BY VENKI RAMAKRISHNANLife’s Ancient Machine