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Dr Joel Mackay was interviewed in 2002 for the Interviews with Australian scientists series. By viewing the interviews in this series, or reading the transcripts and extracts, your students can begin to appreciate Australia's contribution to the growth of scientific knowledge.
The following summary of Mackay's career sets the context for the extract chosen for these teachers notes. The extract covers Mackay's description of the role of protein molecules in DNA transcription and his explanation of why it is important to determine the shape of those proteins. Use the focus questions that accompany the extract to promote discussion among your students.
Joel Mackay was born in 1968 in Auckland, New Zealand. He studied organic chemistry at the University of Auckland, receiving a BSc and an MSc. In 1990 he won a Commonwealth Scholarship to study at Cambridge University, where he looked at the mechanism of the action of antibiotics at the molecular level.
Having received his PhD from Cambridge in 1993, Mackay worked for a year as an experimental scientist at the CSIRO Food Research Laboratory. He began his present association with the University of Sydney in 1995, initially as a postdoctoral fellow, then as a research fellow, and now as a senior lecturer in the School of Molecular and Microbial Biosciences.
His work has focused on using physical methods to characterise biological processes. For example, he looks at the shapes of protein molecules and determines how these shapes affect their attachment to DNA and to other proteins. This kind of study can lead to the development of drugs that are designed specifically to target a protein with a particular shape, and thus block its negative effect.
Mackay won the Australian Society for Biophysics Young Investigator Award in 1997 and the Roche Molecular Biochemicals Medal from the Australian Society for Biochemistry and Molecular Biology in 2001. In 2002 he received the Australian and New Zealand Society for Magnetic Resonance Young Investigator Medal, and won the Science Minister's Prize for Achievement in the Life Sciences, an award for scientists under the age of 35. He has also been chosen by the Australian Research Council to assess grant applications, a position requiring a thorough understanding of the subject and of the research process.
Fundamentals: the role of protein molecules in DNA transcription
How would you describe your type of science?
The work we do is very much trying to understand processes that happen in the bodies of all organisms. We want to understand them right down at the most fundamental level, at the basic molecular level, to find out how individual protein molecules and individual pieces of DNA actually interact with each other and how their interactions allow all of the functions that go on inside us to be carried out.
We focus on one particular area, DNA transcription, trying to understand how that works. You can think of that as part of the process by which different cells in different parts of your body are able to carry out different functions. Every cell in our bodies contains exactly the same sequence of DNA, and the sequence of DNA that we have – our genome – is a blueprint that describes everything about us. And one of the fundamental questions in biology is how all these different types of cells can arise when they all contain the same information. A cell in your heart and a cell in your brain both contain exactly the same DNA, but clearly they have very different functions, they look very different from each other and a lot of the chemistry that they carry out is very different. So for some time now our interest has been in understanding how this differentiation can occur.
Can protein shapes be usefully modified?
What types of projects are you currently involved in? Maybe you could give us some examples of your lab’s work.
One of the things we focused on very early is how specific protein molecules can attach themselves to DNA and to other protein molecules, how these large complexes of proteins can be built up surrounding pieces of DNA, and how they can then control how certain genes are switched on and switched off. You can understand processes like that at all sorts of different levels; we are trying to understand at a very fundamental level how these individual molecules can interact with each other – how strong these interactions are, and how specific, and also, when these interactions take place, what effects they have on which genes are expressed and which are not.
One thing we have been interested in is the development of blood cells, because that is one of the best understood developmental processes within mammals. So we have focused a lot of our work on how specific proteins that are involved in blood cell development interact with each other and with DNA to control the development of blood cells.
That work then has led us on to looking at how some of these specific types of proteins are suitable for the processes that they carry out, such as for binding to DNA, or for interacting with other proteins. We know proteins all have different, very specific shapes that allow them to carry out their functions, so we have tried to understand why these specific structural motifs – these specific shapes – are suitable.
Some of these shapes seem to be very, very robust and able to tolerate lots of mutations (changes in their amino acid sequence). And so we have realised that these different structures may be actually very useful as a kind of designer drug system. That is, you can take a specific protein shape – a molecular scaffold, if you like – and introduce changes onto its surface so that the scaffold is then able to interact with a target such as some sort of protein or other molecule that has gone haywire and is giving rise to a disease condition, for example. Indeed, a lot of cancers are based around one or more proteins doing something they are not supposed to be doing, or doing far too much of whatever they normally do. So if we can make specific designer molecules to target those recalcitrant proteins, we might have a good chance of blocking their bad effects and the diseases they are causing.
Looking indirectly at protein shapes
How do you figure out the shape of a protein, of a molecule? They are too small for you to take a picture of them by microscope, aren’t they?
That’s right. They are about 10 times smaller than the scale that the most sophisticated microscopes – electron microscopes – can look at. There are basically two experimental methods that can be used to determine the shapes of proteins by ‘looking’ at them indirectly. One method is X-ray crystallography: essentially, X-rays are fired at a sample of your protein, which is in a crystalline form, and the way those X-rays are scattered can tell you the shape of the protein.
We have used another method, nuclear magnetic resonance spectroscopy (NMR) – for which Kurt Wütrich was awarded the Nobel Prize in Chemistry this year, in 2002 – because it has been the most suitable for the proteins we’ve been looking at. In a way it is more complex to understand, but it works by taking advantage of the fact that a protein molecule may contain thousands of hydrogen atoms. If we irradiate the protein with radiofrequency radiation – basically radio waves – the individual hydrogen atoms will respond and absorb some radiation. And then we are effectively able to measure that absorption.
The key feature is that we are able not only to measure the absorption of radiation by an individual hydrogen atom, but also to see correlations, or connections, between pairs of hydrogen atoms that are close to each other in the structure of the protein. Now, imagine that a protein has thousands or hundreds of thousands of hydrogen atoms all over its surface and all over its inside as well, and that you can create a map that tells you the distances between each pair of those atoms. Essentially, that allows you to describe the shape or the structure of the protein. And that’s the method that we use by choice.
An edited transcript of the full interview can be found at http://www.science.org.au/scientists/interviews/mackay.
Focus questions
Select activities that are most appropriate for your lesson plan or add your own. You can also encourage students to identify key issues in the preceding extract and devise their own questions or topics for discussion.
designer drugs
DNA transcription
genes
nuclear magnetic resonance spectroscopy
protein shapes
X-ray crystallography
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