David Galbraith: Reshaping bioscience, one genome at a time

For years, biomedical science has been turning individual genes on and off as way to treat gene-based maladies, and as a research tool. Now, a new challenge involves finding ways to bring the entire genetic blueprint of humans, animals and plants into play.

For that, a University of Arizona (UA) research team is seeking crucial innovations that may lead to advances in diagnosing and treating diseases, the war on cancer, increased productivity in agriculture to feed the ever-increasing world population, and more efficient production of biofuels.

The team is led by David Galbraith, PhD, professor of plant sciences in the College of Agriculture and Life Sciences and director of BIO5's Chemical Genomics and Translational Research Center. Together with his industry partner, High Throughput Genomics, a Tucson-based company, he is conducting a project in chemical genomics with a two-year $2.17 million grant for strategic research from Science Foundation Arizona.

A central goal is developing new technologies to study gene signatures, the complex patterns exhibited by the 20,000 or so genes in the human genome. That will be vital to cancer treatment since different cancers show different gene signatures.

'We think these different signatures explain why some patients respond to different treatments,' Galbraith said. 'And why others do not. If we could figure out the link between signatures, treatments and survival, we should be able to improve survival.'

Hospitals keep archives of the tissues removed in cancer surgery together with records of treatments given and survivorship. As new techniques emerge, labs can examine these archives to learn at a molecular level why the cancer appeared and how it might best be treated. Such screening creates what can be called personalized molecular therapy.

We believe each patient has a gene signature that will predict an outcome,' Galbraith said. 'We were in the dark about this up to now.'

One tool, or platform, that Galbraith employs allows a lab to measure the fragile RNA in the archived tissue. It is called the quantitative Nuclease Protection Assay, or qNPA. So far, the qNPA examines 16 genes at a time, providing a 16-gene signature. Galbraith is aiming to expand its capability to a 500-gene signature. The big step, the signature of all 20,000 or so human genes, is further down the road, but one day will help clinical oncologists quickly decide on the best treatment.

The qNPA platform is also ideally suited for drug discovery. With this platform, Galbraith says, a lab can take an entire chemical library from a company, as many as 100,000 chemicals, and look for possible benefits linked to each one. The trick is to find the gene signature that you want to tweak, to put it on the platform, and then look for chemicals that tweak it appropriately.

In the past, screening techniques have been too expensive or lack accuracy, Galbraith said. 'This limits our ability to characterize important diseases and to discover drugs that might be used to treat them.'

In agriculture, Galbraith says the new generation of technology will identify small chemicals that affect plants in precise ways. Research might find a molecule for a spray, say, that would make the plant temporarily resistant to drought or to insect attack.

An underlying theme of BIO5 is that of interdisciplinary collaboration. Galbraith says he believes that one important path leading to collaboration is the development of new technologies that can be used by scientists around the world.

With a long history of such work, Galbraith says he feels like a natural BIO5 member. One of the early technologies he pioneered was the use of flow cytometry and cell sorting for plants. One application, used by agricultural researchers worldwide, gauges the size of a plant's genome by measuring the amount of DNA present in a nucleus.

This can be done cheaply and rapidly, and therefore is now routinely used for seed certification, monitoring the development of transgenic crops, identification and classification of new and endangered species, and applications in plant breeding including rapid improvement of new cultivated varieties of seedless melons and kiwifruit.

A second application allows production of new interspecies hybrids that cannot be easily achieved through conventional plant breeding, using the ability of the cell sorter to identify and collect rare hybrid cells produced in the laboratory. In this way, improved varieties of canola were produced.

Galbraith is still developing flow cytometry, now working on using the cell sorter to identify and isolate different cell types in plants. This allows scientists to break up complex plant tissues and organs, which contain many different cells, into their component cells, and to separately examine the functions of these cells.

'Understanding how plants grow and develop at the level of single cells will greatly facilitate improvement of plants for agricultural and biomedical purposes,' he says.

In the first phase of his grant from Science Foundation Arizona, Galbraith is building bridges to the private sector and recruiting scientists to improve the needed technology. These scientists will be working to increase the throughput, sensitivity and accuracy of the measurement platforms, to define the genes and signatures that will be analyzed, and to reduce costs. Then the search for new chemicals can unfold.

Beyond the work on genomic science, he believes the Chemical Genomics and Translational Research Center's work will promote the growth of the UA region's biotechnology, creating a critical mass of research in Southern Arizona. 'We'd like to be the next San Diego,' he said.

Meanwhile, Galbraith's lab is laying a foundation for breakthroughs in chemical genomics with one goal, as he puts it, 'the direct discovery of drugs that do predictable things.'

Accomplishments

David Galbraith is known as "the father of plant flow cytometry." His early work, published in Science, Nature, Biotechnology, the Proceedings of the National Academy of Sciences, and Cytometry in the period of 1980-1990, defined equipment design and experimental conditions and methods for analysis and sorting of individual plant cells and organelles. These are now employed worldwide and form the basis for many advances in basic and applied plant biology and agriculture. His more recent work has provided refined techniques for exploring the regulation of gene expression within complex plant and animal cells.