Measuring our bodies’ machines

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[img_inline align=”right” src=”http://padnws01.mcmaster.ca/images/McGibbon_Graham.jpg” caption=”Graham McGibbon in his lab with a new capillary HPLC-MALDI spotter recently purchased with NSERC funding. Photo credit: Graham Jansz”]Curious youths claim the lives of countless radios and toasters every year, all for sake of understanding how they work. For many people, one of the inevitable steps in growing up involves taking things apart. Whether a gizmo, gadget, engine or perhaps our little brother's sand castle, we've all dismantled something.

McMaster University's Graham McGibbon dismantles proteins and he does so in an effort to understand how they work – an understanding that offers crucial insights into the functioning of our bodies and the treatment of disease. For McGibbon, an assistant professor jointly appointed to the Department of Biochemistry & Biomedical Sciences and the Department of Chemistry, the tools of the trade are much more advanced than the screwdrivers and pliers of the toaster dissection. McGibbon uses innovative scientific techniques and advanced equipment to answer the problems before him.

Proteins are the machines that complete nearly all the tasks that cells carry out. Such tasks are diverse and range from obtaining nutrients and disposing of wastes to growing and dividing into new cells. The functions of proteins are affected by changes or additions to their structure and by interactions with other proteins. Countless human diseases are the result of proteins that are not functioning properly, and many of the drugs used to treat diseases and illness interact with proteins in some way. McGibbon notes, “Our understanding of complex biochemistry gives us insights into how we might improve the quality of life and health.”

To break apart and study proteins, McGibbon explores and expands the applications of a tool called a mass spectrometer. A mass spectrometer works by giving a molecule an electric charge. Once the particles are charged, they can be manipulated in a way that allows the machine to determine their mass. Often, the molecule is broken up in the process, and the result is several charged particles. In either case, the machine is then able to count how many particles of each mass were generated from the initial sample.

The data generated by the mass spectrometer is fittingly called a mass spectrum. In the hands of a scientist like McGibbon, signals in the mass spectrum are like puzzle pieces that can be assembled to reveal the structure of the original sample.

Mass spectrometers are useful for studying proteins. Proteins are made up of building blocks called amino acids that are linked together. Conveniently, charged protein particles tend to break up where the individual amino acids are linked. This helps researchers determine the specific sequence of building blocks that makes up the protein – valuable information given this sequence dictates all the properties of the protein.

McGibbon's use of mass spectrometry gives him the ability to draw conclusions about structures, modifications, and interactions of proteins – the major factors affecting their function. This has profound medical implications: “I think that we can find protein modifications which relate to important disease states. If we have cells from a cancerous cell line, and we can identify a modification on that protein that is present in that cell but not a healthy cell, then we have a good start towards understanding how the modification plays a role.”

Prior to being able to use a mass spectrometer, McGibbon and his group must isolate the protein they wish to study. To do this, they use a technique called chromatography. Chromatography involves separating compounds that have different physical and chemical properties. Since any given cell contains thousands of different types of proteins, picking out a specific one can be like finding a needle in a haystack; it also means that a very small amount of the pure protein will be recovered.

Typically, the set-up of chromatography and mass spectrometry systems has meant that sacrifices have to be made to the accuracy of one or the other in order for them to be able to work together. However, under the auspices of the Natural Sciences and Engineering Research Council (NSERC), McGibbon has been able to advance his research through the use of a new tool that allows the chromatography and mass spectrometry aspects of his research to be optimized. This new tool, called a capillary HPLC-MALDI spotter, is also designed to work with tiny amounts of substances, such as the samples isolated for protein studies.

With this help from NSERC, McGibbon can work on refining and developing this complex technology to the point where it can be applied to countless practical applications.

As McGibbon continues to expand the technology of mass spectrometry he is opening the doors to better understanding, and eventually management, of many diseases. McGibbon himself demonstrates the applications of the technology he is exploring through his studies of glycosolated proteins.

Glycosolation involves the addition of a sugar-like molecule to a protein. This process can have a significant impact on the function of the protein. McGibbon observes, “[glycosylation] can occur on a wide variety of cellular proteins, some of which are known to be involved in neurological diseases and potentially cancer.” His work involves studying which parts of proteins are susceptible to glycoslyation and how the protein's functions and interactions change when it is glycosylated.

Not only is McGibbon committed to developing and applying technologies that have the potential to facilitate major strides in healthcare, but to his students and enjoys contributing to the development of researchers so they are capable of taking such strides themselves. He says, “Two first-rate undergraduate students that performed research projects in the lab this year are en route to graduate schools this fall.”

McGibbon recognizes the contributions that students can make towards a strong research group. He says, “I think that the internal talent pool, the students at McMaster, offers researchers at the University a great opportunity in terms of summer research . . . I've been impressed with the students' enthusiasm.” As they develop their specific research projects, the student researchers offer great talent and their own knowledge to the lab group.

McGibbon and his students are investing their time and skills into developing a fundamental understanding of proteins – the machines that run our body. Proteins are crucial and when they are broken, myriad health problems result. As with any machine, to fix it you have to know how it works; to know how it works you need to know how it's built; and to know how it's built you just might have to take it apart.

(The Natural Sciences and Engineering Research Council SPARK (Students Promoting Awareness of Research Knowledge) program was launched in 1999 at 10 universities across Canada. Through SPARK, students with an aptitude for communications are recruited, trained and paid to write stories based on the NSERC supported research at participating universities.)