guide to the sensor of a digital camera. The image detected by the digital camera may
be displayed on a monitor or computer. A scanning transmission electron microscope has achieved better than 50 pm resolution in annular dark-field imaging mode
and magnifications of up to about 10,000,000Â, whereas most light microscopes are
limited by diffraction to about 200 nm resolution and useful magnifications below
2000Â.
Molecular biologists have attempted to combine these techniques in order to
solve important problems and Klug used methods from X-ray diffraction, microscopy and structural modelling to develop crystallographic electron microscopy in
which a sequence of two-dimensional images of crystals taken from different angles
are combined to produce three-dimensional images of the target. He studied the
structure of transfer RNA and found what is known as zinc fingers as well as the
neurofibrils in Alzheimer’s disease. He received the 1975 Nobel Prize for his
research in this area. This approach has progressed in the subsequent decades, and
Joachim Frank, Jacques Dubochet and Richard Henderson were awarded the Nobel
Prize in 2017 for developing cryo-electron microscopy for the high-resolution
structure determination of biomolecules (Table 1).
Between 1975 and 1986, Joachim Frank developed an image processing method
in which the electron microscopes’ fuzzy two-dimensional images are analysed and
merged to reveal a sharp three-dimensional structure. Jacques Dubochet discovered
how water could be retained in the electron microscopy sample chamber. Liquid
water evaporates in the electron microscope’s vacuum, which makes the biomolecules collapse. In the early 1980s, Dubochet succeeded in vitrifying water – he
cooled water so rapidly that it solidified in its liquid form around a biological sample,
allowing the biomolecules to retain their natural shape even in a vacuum. In 1990
Richard Henderson succeeded in using an electron microscope to generate a threedimensional image of a protein at atomic resolution. This breakthrough proved the
technology’s potential. The desired atomic resolution was reached in 2013, and
researchers can now routinely produce three-dimensional structures of biomolecules.
In the past few years, scientific literature has been filled with images of everything
from proteins that cause antibiotic resistance to the surface of the Zika virus.
Biochemistry is now facing an explosive development and is all set for an exciting
future [117].
8 Summary
In this chapter, I have attempted to give a qualitative introduction to the early history
of X-ray crystallography and a summary of the related diffraction techniques which
have been developed subsequently. In this way, I hope that I have provided a suitable
introduction to the subsequent chapters which address the current state-of-the-art
issues in studying the structures of small molecules. For those who wish to delve
deeper into the mathematics and technical developments, I can strongly recommend
references [5–14]. References [19–27] provide more details concerning the early
36
D. M. P. Mingos
be displayed on a monitor or computer. A scanning transmission electron microscope has achieved better than 50 pm resolution in annular dark-field imaging mode
and magnifications of up to about 10,000,000Â, whereas most light microscopes are
limited by diffraction to about 200 nm resolution and useful magnifications below
2000Â.
Molecular biologists have attempted to combine these techniques in order to
solve important problems and Klug used methods from X-ray diffraction, microscopy and structural modelling to develop crystallographic electron microscopy in
which a sequence of two-dimensional images of crystals taken from different angles
are combined to produce three-dimensional images of the target. He studied the
structure of transfer RNA and found what is known as zinc fingers as well as the
neurofibrils in Alzheimer’s disease. He received the 1975 Nobel Prize for his
research in this area. This approach has progressed in the subsequent decades, and
Joachim Frank, Jacques Dubochet and Richard Henderson were awarded the Nobel
Prize in 2017 for developing cryo-electron microscopy for the high-resolution
structure determination of biomolecules (Table 1).
Between 1975 and 1986, Joachim Frank developed an image processing method
in which the electron microscopes’ fuzzy two-dimensional images are analysed and
merged to reveal a sharp three-dimensional structure. Jacques Dubochet discovered
how water could be retained in the electron microscopy sample chamber. Liquid
water evaporates in the electron microscope’s vacuum, which makes the biomolecules collapse. In the early 1980s, Dubochet succeeded in vitrifying water – he
cooled water so rapidly that it solidified in its liquid form around a biological sample,
allowing the biomolecules to retain their natural shape even in a vacuum. In 1990
Richard Henderson succeeded in using an electron microscope to generate a threedimensional image of a protein at atomic resolution. This breakthrough proved the
technology’s potential. The desired atomic resolution was reached in 2013, and
researchers can now routinely produce three-dimensional structures of biomolecules.
In the past few years, scientific literature has been filled with images of everything
from proteins that cause antibiotic resistance to the surface of the Zika virus.
Biochemistry is now facing an explosive development and is all set for an exciting
future [117].
8 Summary
In this chapter, I have attempted to give a qualitative introduction to the early history
of X-ray crystallography and a summary of the related diffraction techniques which
have been developed subsequently. In this way, I hope that I have provided a suitable
introduction to the subsequent chapters which address the current state-of-the-art
issues in studying the structures of small molecules. For those who wish to delve
deeper into the mathematics and technical developments, I can strongly recommend
references [5–14]. References [19–27] provide more details concerning the early
36
D. M. P. Mingos