The Oxford Science Lecture Series

Professor Pamela J Bjorkman

California Institute of Technology

"Your mother's antibodies: How you get them and how we might improve them to combat HIV"

 Dorothy Hodgkin Memorial Lecture 2009

University Museum, Oxford, 11th March 2009

Dr. Bjorkman is the Max Delbrück Professor of Biology at the California Institute of Technology in Pasadena, California. She received a B.A. in Chemistry from the University of Oregon and a Ph.D. in Biochemistry from Harvard University. Whilst studying for her PhD she attended a lecture by Dorothy Hodgkin which inspired her to pursue a career in crystallography. She explained that Dorothy had once said that “you could understand something if you could see its molecular structure” and X-ray crystallography provides the ideal tool for that task.

Dr Bjorkman’s research studies the structure of antibodies, particularly those found in mother’s milk. Antibodies have a clover-leaf structure with one leaf (FC) which has a relatively constant composition and is used to move the antibody through cells, and two leaves (FAB) which are used to recognize the invading object. A typical mammal can produce up to 1016 different antibodies and so is able to recognize almost anything that threatens the system. In a newborn, the only source of antibodies is the mother, either through the placenta during gestation or from the mother’s milk. These antibodies have to pass from the milk through the gut wall and in to the circulation and it is this process which forms one of the areas of Dr Bjorkman’s research. She has found that FC receptors bind to the FC portion of the antibody at the acid pH found in the gut. The receptors pass the antibody through the gut into the blood, which is at a more alkaline pH, and at that pH the receptor releases the antibody into the bloodstream. Using X-ray crystallography, this process of binding and release can be investigated. As Dorothy had implied – once you have established the structure of the receptor you can understand why it binds antibodies at one pH but not at the other.

Within a cell there are many vesicles or containers, some of which are used to transport the antibodies across the cells of the gut, but which ones? This question cannot be addressed using X-ray crystallography because the scale of the vesicle is too large. Here Dr Bjorkman has turned to electron microscopy which enables her to visualize intracellular structures. Whereas electron microscopy used to be restricted to 2D images, the field has now progressed to provide 3D tomography and Dr Bjorkman has made a novel use of high school students, asking them to trace individual structures through sequential 2D slices and colour code them to provide a 3D map of the cell. In order to detect the antibodies within these structures, she labeled them with gold tags. She found that the majority of the antibodies were attached to microtubules, although some were found within large vesicles previously thought to be involved in transporting unwanted material out of cells. In fact most vesicles were capable of transporting the antibodies and she found no specific pathway for the transport process. She used the analogy of a passenger trying to get across a very busy freeway, there are multiple routes across and people will take the most convenient route at the time.

For the final part of her lecture, Dr Bjorkman went on to discuss the reasons why the body does not make efficient antibodies against the HIV. She described how HIV mutates rapidly and hides the active regions deep inside the structure, surrounded by sugar molecules. She said that approximately 10 antibodies capable of neutralizing HIV have now been identified after many years of research but that techniques to deliver these antibodies to the body have yet to be developed. Potentially stem cells could be engineered to generate these antibodies, and, as stem cells have the capability to renew themselves indefinitely, this would provide an endless source of the antibody.

In this lecture, Dr Bjorkman provided a fascinating insight into the transport of antibodies and how the two techniques of X-ray crystallography and electron microscopy can be used to investigate processes deep within the cell so that we can understand it. It is to be hoped that a PhD student in this audience was similarly inspired to pursue research using the fascinating technique of X-ray crystallography.

  Dr Carolyn Carr, Cardiac Metabolism Research Group, University of Oxford.