UC San Diego bioengineering professor Kun Zhang has been awarded $14 million to build 3D digital maps of human organs, accurate to the single-cell level.

The money comes in two grants from the National Institutes of Health.

-- One grant for $8.7 million will fund work on a map of the entire human brain. The five-year-grant is from the NIH BRAIN Initiative.

-- The other grant, for $5.3 million, is for mapping the lungs, kidneys, bladder and ureters. That four-year grant is part of a larger initiative called the Human Cell Atlas, which aims to “map the adult human body at the level of individual cells.” It’s funded by the NIH’s Human BioMolecular Atlas Program.

Until recently, such projects would have been infeasible, because the imaging tools to detect the location of individual cells organized in large numbers as tissues or organs didn’t exist.

Zhang and colleagues will add their own methods to better analyze the nuclei of individual brain cells, and to integrate the single-cell data into larger maps.

The ultimate goal is to develop scalable maps that can zoom out to describe the functions of whole systems, and zoom in to the level of single cells and genomes, Zhang said in a statement.

“Just like what we’re doing with mapping the human brain, we can use this technology to understand what a normal lung, kidney and bladder should look like and how it should function down to the resolution of a single cell,” he said in the statement. “We can then begin to understand the basis of injury and repair of the body’s principal barriers.”

Tumor suppressor or tumor promoter: Context matters

According to a simplistic model, mutations drive cancer by interfering with tumor suppressor genes. So restoring normal function will control the tumor.

But in the case of an enzyme called AMPK, it isn’t simple. This protein complex can inhibit or drive tumor growth, depending on the state of the tumor.

How this happens was reported Nov. 8 in a study led by Salk Institute professor Reuben Shaw in the journal Cell Metabolism. His work was performed in mouse models of lung cancer and human samples of non-small cell lung cancer.

AMPK inhibits tumor growth by slowing down cellular metabolism when it senses a lack of fuel. Cancer cells generally run at a high metabolic rate by a different process than normal cells, allowing them to proliferate and invade other tissues.

So when AMPK is disabled, it helps incipient cancers to grow unchecked. But in larger, more advanced cancers, activity of AMPK seems to promote tumor growth.

Shaw and colleagues discovered that in larger tumors, where the inside cells have difficulty getting nutrients, AMPK sends a signal for the cells to scavenge nutrients from themselves. This cellular recycling or cannibalism — take your pick — helps the tumors to grow, Lillian Eichner, one of the paper’s co-authors, said in a statement.

“Previously we were focused on how we could activate AMPK,” said Eichner, a Salk research associate. “Now that we’ve identified this mechanism, we can shift to how to inhibit it in certain cancers.”

To find new ways to fight brain decline, Salk Institute gets $19.2 million grant

Salk Institute researchers have been awarded $19.2 million to study age-related cognitive decline caused by Alzheimer's disease and similar conditions that affect thinking and memory.

Rusty Gage, president of the Salk Institute, is leading the eight-year grant from the American Heart Association and Allen Institute, announced Friday.

The grant is part of a total $43 million pledged by the two entities to explore these diseases in addition to healthy brain aging. The balance of the funds is going to scientists at Stanford University and University Hospitals Cleveland Medical Center.

The Salk team is acting under the assumption that these brain disorders are caused by a combination of biological system failures associated with aging. Their goal is to understand how these systems keep brains healthy, and from there to understand how their failures result in cognitive decline.

Salk scientists are developing new methods to study old and diseased brain cells. These include rudimentary brain "organoids," cell cultures and models of aging. These will be studied with data techniques to identify the cells and pathways most involved in brain aging.

Numerous attempts to stop Alzheimer's have focused on relieving specific conditions, such as by reducing accumulation of toxic proteins called beta amyloid and tau. None of these has demonstrated more than a very modest effect -- too modest to cure the disease or even stop it from progressing.

While beta amyloid and tau appear involved in the disease, the researchers are acting on the belief that multiple failures tip the balance from health to damage of brain cells. These as yet unknown factors also need to be addressed to restore a healthy environment for the brain.

Alzheimer's is known to be associated with a number of factors, including some genetically linked. However, the most widespread and consistent association is with age itself.

Salk Institute’s O’Shea gets $1.5 million grant for DNA study

Clodagh O’Shea has been awarded a $1.5 million grant from The Paul G. Allen Frontiers Group, according to the Salk Institute.

The Salk Institute professor will get the money over three years to study how DNA and associated proteins are packed in the cell nucleus. This complex, called chromatin, maintains DNA stably and allows it to be read out as needed.

Knowing how chromatin works could help understanding of diseases when this structure goes awry. It’s also a fundamental part of cellular biology that’s not well understood.

DNA functions dynamically, with stretches of DNA being unwound from chromatin when needed and stored away when not needed.

Chromatin also organizes DNA in a three-dimensional state that helps determine its function. This role isn’t apparent when DNA is thought of in a linear context. Pieces of DNA that may appear distant by sequence could actually be bent close together in three-dimensional space.

O’Shea is developing methods to image chromatin’s structure and function in space and in time, as its configuration changes with cellular functions.

One of her innovations is the use of a light-activated dye that coats DNA with metal. This is combined with a form of electron microscopy developed by Mark Ellisman’s lab at UC San Diego to show chromatin’s shape as it works in living cells.

The grant is from the institute’s Allen Distinguished Investigator program, which funds research not likely to get traditional funding, but which could significantly advance understanding of biology.