ASU Research E-Magazine: Shaking the Tree of Life

Sudhir Kumar and his colleagues are using novel approaches and tools to uproot the conventional scientific wisdom of biology. In the process, they are giving the tree of life a good shaking.

Click, click, clack. Click, click, clack. Click, click, clack.

The sound pours through the doorway. Click, click, clack.

Welcome to Sudhir Kumar’s laboratory. Step inside. Be prepared for a shock. The familiar sights and sounds of modern research—clanking test tubes, scurrying technicians clad in white lab coats, winking LED displays and expensive, beeping gadgets—are nowhere to be found.

Click, click, clack. The rhythmic tapping is the sound of scientists pounding away on arrays of fashionable onyx computer keyboards. A large bank of networked computers is the vital piece of technology that sustains Kumar and his team as they work to solve some of the greatest unanswered questions in biology.

How and when did life on Earth evolve?

How can scientists identify the genes involved in human scourges such as cancer?

How does an organism develop from a tiny, fertilized egg into an adult body made up of trillions of cells?

Kumar is director of the new Center for Evolutionary Functional Genomics (EFG) at Arizona State University. The EFG is just one part of the Biodesign Institute at Arizona State University. Kumar and his colleagues are using novel approaches and tools to uproot the conventional scientific wisdom of biology. In the process, they are giving the tree of life a good shaking.

Kumar is a multidisciplinary scientist trained in genetics, evolutionary biology, and electrical engineering. He uses a new branch of science called bioinformatics as a tool to find answers to big questions.

Kumar defines bioinformatics as “any type of information processing that relates to biology.” Using bioinformatics requires a deep understanding of biology, computer science, and statistics.

Bioinformatics is a totally new way of studying biology. Kumar brushes aside experimental approaches that involve live organisms (in vivo) or test tubes (in vitro). He does his work using only the silicon power of computer microprocessors. This type of worked has been dubbed science in silico.

“Investigators working in an experimental laboratory are constrained by a number of factors,” Kumar explains. “The work has its own infrastructure that requires equipment and supplies of many types. Of course, there is always the care and maintenance of the organisms being studied.”

Kumar’s group enjoys much more flexibility. They can simultaneously take on many different questions that involve different organisms.

He mines existing data banks for available data to address the questions that most interest his team. “That data usually exists in huge amounts. It almost always requires us to develop new analytical methods and tools,” he says.

“Data mining” mimics the pioneering spelunkers of yesteryear, only the steady sound of pick axes on rock has been replaced by the crunching of raw scientific data on computers. The valuable nuggets of information are buried within national database repositories such as GenBank.

GenBank contains more than 23 million DNA sequence records deposited over the years by scientists from around the world. The gemstones waiting to be found and understood are part of the immense streams of DNA sequence data.

Molecular Clocks
Kumar does not shy from the tough questions. He has worked to identify when exactly modern mammals originally burst onto the evolutionary scene. The fossil record places the emergence of mammals at about 65 million years ago. Scientists refer to this period as the K/T boundary.

K/T refers to the distinct iridium-rich mineral layer deposited and preserved in rock samples that occurred between the Cretaceous (K) and Tertiary (T) geologic periods. It was during this time when mass extinctions spelled doom for 75 percent of all life on Earth and brought an end to the Age of Dinosaurs. But the fossil record for early mammals was incomplete. To address the question of early mammal emergence, Kumar needed a new kind of watch, a new way to tell evolutionary time.

The ASU scientist built himself a “molecular clock” to study the problem. The molecules that make up Kumar’s molecular clock are DNA, the chemical blueprint for life found in every cell in every organism.

The complete DNA information contained in an organism is called a genome. By comparing the DNA sequences of genes found in the genomes of different organisms, Kumar devised a new way to tell time.

“Copies of the genome are being made continuously and passed on through each new generation. Over time, mutations, or errors, are always occurring within a genome,” he explains.

Think about it in terms of your office photocopier. The machine does not always work perfectly. In much the same way, the cellular machinery necessary to copy a genome can jam and breakdown. The result is a DNA mutation.

“There are going to be errors in any process that involves the mass copying of information. When studying genomes, mutations are the errors,” he continues. “But not all mutations affect the function of protein production or the genomes themselves. These mutations are known to accumulate more or less linearly with time. Essentially, this is where we get the concept of molecular clocks.”

Molecular clocks are not precisely accurate. “However, these clocks do provide a direct relationship between time and evolutionary distance,” Kumar says.

Kumar’s work in this area has received world recognition. Writing in the journal Nature, his group used molecular clocks to push back the emergence of mammals on Earth to between 90 million and 110 million years ago. That is almost 30 million years earlier than evidence from the fossil record indicates.

“Our results showed for the first time that early mammals may have lived along with dinosaurs long before the extinctions that occurred at the K/T boundary,” Kumar says. “These early mammals were probably tiny creatures, perhaps no bigger than a mouse.”

Using the new timeline, Kumar and colleagues were also able to compare the early history of mammals with the geological history of the Earth. Our planet was a particularly violent and cataclysmic place around 100 million years ago.

“The continents were breaking apart 100 million years ago, just about the same time that mammal groups were being established,” Kumar says.

His group proposed an idea to fit the time and events. The “Continental Breakup Hypothesis” is to the point. Simply stated, it says that when individual animals or large groups of mammals are stranded on an inland or land mass that is split from the main population; over a long period of time those creatures will evolve into new species. In recent years, the predictions from this hypothesis have been validated by other scientists.

“In addition to studying the fossil record, the molecular clock technique is now commonly used by scientists,” Kumar says.

Solving Disease Riddles
Evolution is just one area of study. Kumar’s group is also using their tools and expertise to unravel the biological riddles of cancer, cystic fibrosis, and other catastrophic diseases. To find answers, Kumar stewards a large DNA farm, using gene sequences from a virtual DNA zoo of animals.

One of those animals is the puffer fish. Japanese sushi chefs use the puffer fish to prepare a delicacy known as fugue. However, prepared incorrectly, the chef can kill his clientele. One puffer fish contains enough deadly toxin to poison all the guests in the restaurant.

When Kumar started using the DNA of puffer fish and other organisms in an effort to cook up new ways to identify genetic mutations, he caught the attention of Jeffrey Trent and other medical scientists. Trent is the director of the Translational Genomics Research Institute (TGen), recently established in downtown Phoenix.

“Sudhir Kumar is a world recognized scientist,” Trent says. “Many of the tools developed by his group were used at the National Human Genome Research Institute.”

Much of Kumar’s work was key to the successful completion of the Human Genome Project, the massive international effort to sequence the three billion chemical letters of DNA that make up our human chromosomes. The sequencing work was finished in April, 2003, exactly 50 years after scientists James Watson and Francis Crick solved the elegant spiral structure of the DNA molecule.

Scientists at TGen use genome science as a tool to solve the medical riddles of cancer. They want to transform the idea of cancer as an acute life-threatening disease into one that is more a manageable, chronic disease.

“Cancer is really 212 different diseases,” Trent says. “We are giving Kumar specific intervals within the human genome where we think there are likely to be genes for certain key diseases. His group will then use their tools to help us identify those genes. Then we can test the genes at TGen,” he explains.

The ASU scientists take these genome intervals and compare them with similar intervals stored in databases related to other animals such as puffer fish, chickens, mice, and cows. By studying the same gene across different species over evolutionary time, Kumar can precisely pinpoint the sequences within the gene that are the most conserved, the sequences that do not change.

To date, Kumar has found that the most conserved DNA letters within a protein over evolutionary time are the most vital towards that gene functioning properly. Why? Because mutations that cause disease are found most often in these positions.

Throughout the course of evolution, nature holds onto the most vital DNA information and discards the rest. By identifying the changes in the letters, Kumar’s group can now assist the scientists at TGen to choose new directions in which to focus their experimental work.

Serious Number Crunching
Kumar’s work requires heavy duty computer power. ASU’s new IBM supercomputing facility will fill the need.

Researchers use the supercomputer to analyze massive amounts of data quickly. They want to learn how individual genes are acting against one another.

Jeff Touchman is director of the TGen DNA Sequencing Center and also an ASU assistant professor of biology. He says that scientists need the supercomputer to help tease apart incredibly complicated genetic pathways. The device can manage the 27 billion calculations sometimes required for this type of analyses. In 14 minutes, the supercomputer can do the calculations that would take a typical desktop computer 14 years to solve.

“The hope is that the mechanisms of certain diseases will fall out of such analysis,” Touchman says. “Understanding the mechanism of disease is the first step toward better diagnosis and eventually effective treatment.”

These types of collaborative projects are the reason why ASU established the Biodesign Institute. “The mission of the Biodsign Institute is to design devices, methods, and tools that are going to help human health and better the human condition,” Kumar says.

Kumar directs the Center for Evolutionary Functional Genomics (EFG), one of seven core groups of researchers at the Biodesign Institute.

“The EFG is completely informatics oriented. We use bioinformatics and evolutionary principles to further biological knowledge,” he says.

In the future, Kumar and his colleagues plan to remain nimble and flexible enough to continue making discoveries in such seemingly disparate areas as cancer research, biological evolution, developmental biology, and software development.

“In every sense, development and evolution are intertwined. I think of it as all one project,” he explains. “I’ve always liked evolution because so much remains unknown and it is so challenging to infer history. I want to immerse myself in many different areas and learn to see the interconnections.”—Joe Caspermeyer