In the Economy of the Cell, Metal Is Money
Changes in the availability and cost of commodity metals such as copper, zinc and iron are fundamental indexes in the U.S. economy and are just as fundamental to the economy of the cells in our body. Without these metals, none of our cells can live or replicate, said Dr. Thomas O’Halloran at this year’s DeWitt Stetten Jr. Lecture on Oct. 19.
Since the late 1980s, O’Halloran, a professor of inorganic chemistry at Northwestern University, has been among the few life scientists exploring substances that are not, technically, alive.
“Because the definition of inorganic means ‘not living,’ we have a bias to relegate inorganic molecules to subordinate roles in biology,” he said. But inorganic chemistry is poised to make major new contributions to our understanding of human health and disease, said O’Halloran, especially in the areas of developmental biology and what leads to senescence or apoptosis in cells.
“The periodic table of the elements is a type of ‘Rosetta stone’ for understanding the building blocks of the universe; approximately a quarter of the known elements are essential for life,” said O’Halloran. “Cells cannot create or destroy elements, so the supplies and allocations of those that are essential must be diligently managed by the cellular machinery.
“These essential metals must be accrued to high levels in a cell before it can divide,” O’Halloran has found. “These are hardly trace substances at all.”
Sophisticated new technology permits researchers to count how many metals there are in small compartments of a cell. “It still floors me today,” said O’Halloran, how dependent all kinds of living cells are—from bacteria to comparatively large mammalian egg cells—on iron and zinc alone.
Scientists can now tell when a cell is ready to divide by measuring changes in subcellular metal composition, said O’Halloran. “This ‘inorganic fingerprint’ is a kind of signature for cell function.”
When he first entered the field, O’Halloran studied cells that are able to sense the presence of mercury. “Cells don’t like it, and bacteria evolved early warning systems to detect it,” he said. He discovered the family of proteins that act as metal sensors capable of turning off and on the expression of genes that eliminated the threat.
Further, he and his collaborators discovered another family of proteins—the metallochaperones—whose role is to bring metal to the proper address inside cells. “Ideas are still erupting” in the field of metal trafficking within cells, he said. In Wilson’s disease, for example, the excess buildup of copper that is a hallmark of the disease can be addressed with sulfur compounds that block copper’s negative effects.
Metals’ most dramatic role within cells involves fertility, said O’Halloran. Exhibiting the active function of the Irish wit gene, he recounted a walk on the beach with his wife, Prof. Teresa Woodruff, a reproductive biologist who studies mammalian egg development. He tried to explain the sudden buildup of zinc that occurs when a sperm cell—“one of the smallest cells in the body”—encounters the comparatively massive egg cell, the body’s largest.
“I don’t care about sperm, but if you tell me that zinc is doing something special in the egg, we can talk!” she said.
Together, O’Halloran and Woodruff have found that, during the 20-hour window when an egg cell is ready to be fertilized or perish, the number of zinc atoms increases by 20 billion, a 50 percent bump up. Then once the sperm cell meets oocyte, zinc is released in a so-called “zinc spark” that might rightly be regarded as the spark of life. The number of zinc ions then goes back down. Both the zinc uptick and the subsequent downbeat are critical steps at this time in development.
Together, the team created a new kind of electron microscope capable of detecting zinc sparks and has proven their existence. Such basic biological investigation may one day help answer the question “What makes a good egg?” he said.
“We can improve in vitro fertilization if we have the ability to quantitatively define what it means to be a good egg,” said O’Halloran. “The intensity of the zinc spark is a positive sign. It is a hallmark of human egg maturation and the intensity correlates with successful progression to the blastocyte stage.
“This is a really exciting time,” he concluded. “Metal fluxes are emerging not only as key events in developmental biology but also in the battleground between host and pathogen in many diseases.”