In multiple wavelength anomalous diffraction changes are induced in the atomic scattering factor of
a heavy atom bound to the protein by measuring diffraction data at a number of different X-ray energies
where the anomalous scattering factors of the heavy atom are significantly different from one another.
The largest changes in the anomalous scattering factors of atoms occur around characteristic absorption
edges since their values are directly related to the atoms atomic absorption coefficient. This is convenient
since the majority of heavy atoms which bind to proteins have absorption edges which lie in the energy range
typically used for protein diffraction work, 
.
The earliest reported multiple wavelength experiment was performed in the early 70's by Hoppe
and Jakubowski [57] where a
sealed tube X-ray generator was used with Ni 
and Co 
characteristic radiation to determine
phases of the protein erythrocruorin containing Fe as its anomalous scatterer. The experiment showed that the small
changes in the Fe scattering power induced by a change of wavelength could indeed be used to calculate the unknown
phases. The use of characteristic X-ray energies restricted the method somewhat but not long afterwards in the
late 70's synchrotron radiation became available to the biological community. A continuously tunable source
of X-rays meant that X-ray energies could be selected which matched the scattering properties of the heavy
atoms present in the sample protein crystal. In 1978 Phillips [94] demonstrated that large anomalous
scattering effects at the 
edges of heavy atoms could be taken advantage of in MAD experiment by
optimally selecting the X-ray energies to maximise the differences in the heavy atom anomalous scattering around
the absorption edge.
It was also shown that phasing could be performed in essentially the same way as in the MIR method.
In 1980 Karle [64] suggested an algebraic approach to the solution of the phase problem which was specifically directed at the MAD method. This approach was thereafter adopted by Hendrickson [54] in the MADSYS data analysis package and has been used in the ab initio determination of a number of protein structures [120] [72] [115] [52] [42]. The classical MIR approach to MAD phasing has also been successfully used [62].