The research program encourages scientists to pursue creative and innovative ideas about biomedical and behavioral research with the aim of addressing today’s major challenges in these fields. Total funding for the awards is about $123 million and comes from the National Institutes of Health Common Fund, and a number of institutes and centers.

The 2013 91̽»¨recipients:

, assistant professor of microbiology, studies how head-on collisions between DNA-code reading machineries accelerate evolution. Her work on harmless bacteria shows that they appear to speed up their evolution by positioning genes along the route of expected traffic jams in DNA-encoding. This tactic might also be imitated by harmful bacteria to adjust to conditions in the body, thereby strengthening their virulence or causing persistent infections. Similar methods for speeding up evolution during environmental stress are likely to occur in other living creatures as well. With her New Innovator Award, Merrikh will look at the clashes that take place when a DNA strand is being read to create a new set of genes during cell reproduction or to produce a protein. The work will explain natural mechanisms of gene repair and mutation, and provide insights into evolution and adaptation.

, associate professor of genome sciences, and his lab have created rapid, cost-effective methods to study subtle differences in DNA codes among people. His group is interested in how these genetic variations might affect susceptibility or resistance to disease, or response to treatment. Testing for such genetic variations is increasingly helping to guide and personalize health care. However, patients often carry difficult-to-interpret variants in clinically relevant genes such as those linked to breast and ovarian cancer. Shendure’s Pioneer Award will support the search for new approaches to estimate the consequences of all possible variants of clinically relevant genes. He hopes this will improve the interpretation of human genome sequences in diverse clinical and research settings.

, assistant professor of bioengineering, works on creating new organ-specific microenvironments for both regenerative medicine and therapeutic development. Zheng and her group are developing 3-D systems in vitro that display the complex architecture of bone marrow and function to generate blood cells. These systems could allow for the preclinical testing for therapies to increase blood cell counts in diseases where they are low. This system also has the potential to be scaled up to generate enough blood cells for transfusions. Zheng’s research project is called “A microfluidic bone marrow niche for the study of hematopoiesis.”

Bacteria appear to speed up their evolution by positioning specific genes along the route of expected traffic jams in DNA encoding. Certain genes are in prime collision paths for the moving molecular machineries that read the DNA code, as 91̽»¨ scientists explain in this week’s edition of Nature. Read the .

The spatial-organization tactics their model organism, Bacillus subtilis, takes to evolve and adapt might be imitated in other related Gram-positive bacteria, including harmful, ever-changing germs like staph, strep, and listeria, to strengthen their virulence or cause persistent infections. The researchers think that these mechanisms for accelerating evolution may be found in other living creatures as well.

Replication – the duplicating of the genetic code to create a new set of genes– and transcription – the copying of DNA code to produce a protein – are not separated by time or space in bacteria. Therefore, clashes between these machineries are inevitable. Replication traveling rapidly along a DNA strand can be stalled by a head-on encounter or same-direction brush with slower-moving transcription.

The senior authors of the study, , 91̽»¨assistant professor of microbiology, and , 91̽»¨professor of microbiology, and their research teams are collaborating to understand the evolutionary consequences of these conflicts. The major focus of Merrikh and her research team is on understanding mechanistic and physiological aspects of conflicts in living cells – including why and how these collisions lead to mutations.

Impediments to replication, they noted, can cause instability within the genome, such as chromosome deletions or rearrangements, or incomplete separation of genetic material during cell division. When dangerous collisions take place, bacteria sometimes employ methods to repair, and then restart, the paused DNA replication, Merrikh discovered in her earlier work at the Massachusetts Institute of Technology.

To avoid unwanted encounters, bacteria orient most of their genes along what is called the leading strand of DNA, rather than the lagging. The terms refer to the direction the encoding activities travel on different forks of the unwinding DNA. Head-on collisions between replication and transcription happen on the lagging strand.

Despite the heightened risk of gene-altering clashes, the study bacteria B. subtilis still orients 25 percent of all its genes, and 6 percent of its essential genes, on the lagging strand.

The scientist observed that genes under the greatest natural selection pressure for amino-acid mutations, a sign of their adaptive significance, were on the lagging strand. Amino acids are the building blocks for proteins. Based on their analysis of mutations on the leading and the lagging strands, the researchers found that the rate of accumulation of mutations was faster in the genes oriented to be subject to head-on replication-transcription conflicts, in contrast to co-directional conflicts.

According to the researchers, together the mutational analyses of the genomes and the experimental findings indicate that head-on conflicts were more likely than same-direction conflicts to cause mutations. They also found that longer genes provided more opportunities for replication-transcription conflicts to occur. Lengthy genes were more prone to mutate.

The researchers noted that head-on replication-transcription encounters, and the subsequent mutations, could significantly increase structural variations in the proteins coded by the affected genes. Some of these chance variations might give the bacteria new options for adapting to changes or stresses in their environment. Like savvy investors, the bacteria appear to protect most of their genetic assets, but offer a few up to the high-roll stakes of mutation.

The researchers pointed out, “A simple switch in gene orientation …could facilitate evolution in specific genes in a targeted way. Investigating the main targets of conflict-mediated formation of mutations is likely to show far-reaching insights into adaptation and evolution of organisms.”

The research project was supported with start-up funds from the 91̽»¨Department of Microbiology and with grants from the National Institutes of Health (RC4AI092828 and RO1 GM084318.)

Scientists on this project, in addition to Merrikh and Sokurenko, were Sandip Paul, Samuel Million-Weaver, and Sujay Chattopadhyay, all of the 91̽»¨Department of Microbiology.