An essential part of all living organisms, proteins perform many functions in living cells, serving as structural components and performing vital chemical reactions. And yet, the structures and functions of many proteins are still unknown. Some of the limitations in this field include problems in obtaining proteins to observe and the lack of specialized equipment necessary for experiments. Dr. Rachel Martin, Associate Professor in the department of Molecular Biology and Biochemistry at University of California, Irvine, couples a unique combination of instrument and technique development with biomedical research to closely study proteins, notably in the solubility and aggregation of proteins that make up the eye lens.

Dr. Martin and her interdisciplinary team of chemistry, molecular biology, and physics students develop new instrumentation and experimental methodology to observe how proteins work, what they look like, and what roles they play in biological systems. They particularly study the way proteins interact with water—some proteins are soluble, and others are not—because solubility is very important for a protein’s biological function. Studying eye lens proteins from humans and other animals to understand how they work, Dr. Martin and her team have made important breakthroughs in understanding how inheriting a single point mutation can cause people get cataracts at age six. The Martin group builds the necessary instrumentation to solve large biological problems and applies their new techniques to biomedically relevant proteins.

Current Research Includes:

• Investigating Proteins in the Human Eye Lens - Most proteins in our bodies are being degraded and recycled all the time, a process that usually takes anywhere from a few hours to about three weeks. This is not the case for the proteins in the eye lens, where new proteins are stop being produced early in life. The eye lens proteins you are born with must be soluble and stable enough to last for your entire life. This is particularly remarkable because proteins are packed into the lens at a very high concentration, providing the lenses their focusing power. In humans, the lens is about 50% protein and 50% water, the same as a typical protein crystal. In some fish, the lenses are more like 70% protein, the same water density as bone! When this system fails and the proteins precipitate, it results in a cataract. Dr. Martin and her team want to understand how protein solubility works on a molecular level, with the goal of preventing or reversing cataract formation. Their objective is to understand the molecular basis of eye lens function, including how the lens proteins interact with each other and why they are so extraordinarily soluble. This work will potentially lead to the development of improved biological materials, such as artificial lenses made of inexpensive biomimetic materials. This type of problem is not only relevant to cataract (their chosen model system). Other diseases, such as Alzheimer's, Parkinson's, and type-II diabetes have a similar basis in protein aggregation. Much of this work is done in collaboration with Prof. D. Tobias—a computational chemist who performs detailed molecular-scale simulations of their proteins, making predictions that help guide future experiments. Her team is currently trying to obtain a new light scattering instrument to measure the optical properties of the eye lens proteins. By measuring the light scattering properties in the eye and how it refracts and scatters light, her team is able to directly look at and understand its function. They hope to measure the light scattering properties within six months and to understand how eye lens proteins get modified by UV light within two years.
• Developing and Designing New Methodology and Instrumentation - Dr. Martin and her team develop state-of-the-art instrumentation to solve problems of real biological significance. The primary technique they use to understand proteins is or nuclear magnetic resonance (NMR), the technology magnetic resonance imaging (MRI) is based on. Instead of obtaining images of human tissue, they apply this method to observe molecules. NMR spectroscopy requires large amounts of highly pure protein, often labeled with particular stable isotopes, making isolation from human tissue impractical. Instead, Dr. Martin and her team insert a gene sequence coding for the desired protein into bacteria—usually E.coli—which then acts as a micro-factory, producing a large amount of the sample they wish to study. This technique enables her team to make essentially any protein of interest by getting the bacteria to grow it for them. They then investigate the proteins’ molecular properties, measuring how robust they are to disruption by heat and chemical treatments, solving their structures by NMR, and—in the case of eye lens proteins—their light scattering properties. Using this process, they have learned about the molecular basis for a genetic disease in which a single amino acid change in the gene of an eye lens protein results in young children developing cataracts. They were able to make both the healthy ‘wild type’ protein and the disease-related variant, perform the necessary experiments and compare at their differences. The team is now moving on to variants that mimic the protein damage that results in age-related cataracts. Performing this research requires new developments in NMR technology to perform challenging experiments that are not currently possible.
• Discovering New Proteins Using Genomics - In her previous work, Dr. Martin has had to depend on the many proteins that other researchers already discovered. However, the ability to read the sequence of an organism’s deoxyribonucleic acid (DNA) and discover new proteins opens many doors in protein research. With her husband and research collaborator, Dr. Carter Butts,Dr. Martin recently sequenced the genome of a carnivorous plant in order to discover new proteases (enzymes that break down proteins). In this collaboration, she performs the wet-lab biochemistry portion and he carries out the computational part of the genome sequencing. After extracting the genomic DNA from the plant cells, they use an instrument to read the genetic code containing instructions for producing the organism, including all of its proteins. The sequence comes out in tiny pieces, so it must be put together like a jigsaw puzzle, with a genome as the end product. As a result, they are able to search through the genome and find predicted genes. In particular, they are looking for novel protein functionality, discovering new types of proteases by finding genes that resemble (but not too closely!) known proteases. These gene sequences can then be used to produce the proteins of interest for molecular characterization.  By studying digestive enzymes that break down proteins in the plant’s prey, Dr. Martin and her team may be able to discover new enzymes, different from those of animals, that are capable of dissolving stubborn protein aggregates. Such enzymes could be used in many applications, such as breaking up protein aggregates in disease states, sterilizing medical equipment that has been exposed to protein aggregates, and preventing biofouling (buildup of harmful microorganisms) in medical devices that cannot withstand harsh chemical treatments.