Elemental Shortage

ELEMENTAL SHORTAGE The world is running out of cheap phosphorus, the element that lies at the heart of great agricultural advances and thorny environmental problems. Biologists are only now beginning to understand what it means for evolution and human health. James Elser at a study site in southern Norway Although a limnologist in Phoenix and a molecular biologist in Atlanta have never met before, a single element ties them together. James Elser works at Arizona State University and studies aquatic life in lakes and streams. He has developed a fascination for the evolution of life from its earliest beginnings and worries about the damage an overabundance of phosphorus has done to our ecosystems and how its looming depletion will affect our lives. Related Articles 1 Even if global supplies stretch for the next 300 to 400 years, as the phosphate industry contends, the most easily processed rocks are in ever-shorter supply, and the United States will have exhausted its reserves by 2050. When these reserves run out, the world will become more reliant on deposits that contain a lower concentration of phosphate and are laced with radioactive elements like uranium and thorium, or heavy metals like cadmium. “There is nothing on the market that can replace phosphate on the scale that we need it,” Cordell says. To conserve phosphate, researchers like Cordell caution that we should change our diets and increase the efficiency with which we use phosphate. In other words: do exactly what some scientists believe our cellular pathways and unbalanced ecosystems are telling us we should be doing. Even though Elser, 51, had been studying phosphorus for his entire career, Cordell’s paper was the wake-up call he needed. Twenty-five years ago, the limnologist first headed out with a white-bearded desert rat and ichthyologist named Wendell Minckley to see the aquatic wonderland of Cuatro Ciénegas, not too far south of the Texas-Mexico border. The “four swamps” in this desert basin represent one of the world’s most unique and isolated ecosystems, with strange fishes and even stranger microbes. The Río Mesquites and surrounding ponds are crowded with mineralized microbial mats known as stromatolites. These mats once covered the Earth and are now generally known from just a few supersalty pools around the world, such as those in Shark’s Bay, Western Australia. Stromatolites in Poza Azul, a pond at Cuatro Ciénegas © HENRY ROMERO/Reuters/Corbis Indeed, Cuatro Ciénegas has a venerable marine heritage—half its microorganisms trace their ancestry to an ancient ocean. But now it is freshwater, and this nutrient-deprived oasis is so starved for phosphorus that one bacterial species, Bacillus coahuilensis, has even opted for a sulfolipid membrane, rather than the ubiquitous phospholipid bilayer surrounding most other cells.2 In marine ecosystems, the ratio of carbon to phosphorus atoms in microbes is about 100:1. At Cuatro Ciénegas, it reaches as high as 5000:1. Elser believes that studying these ratios, which are part of what he calls “biological stoichiometry,” is key to tracing not only the history of life but the workings of organisms and ecosystems.3 Years ago, he became enthralled by the fact that if you dump a bunch of phosphate in some lakes, tiny Daphnia quickly overtake their slower-growing microscopic crustacean neighbors, called copepods. What accounted for this difference in growth rates? In the late 1990s, he sat down with a group of grad students and scribbled on a blackboard every biomolecule that contained phosphorus. He asked each member of the team to dig through the literature and find out which molecule commanded the most phosphorus in biological contexts. ATP is phosphorus-rich, but there is hardly any of it in the cell. Phospholipids are abundant, but not that high in phosphorus. DNA and RNA have the same amount of phosphorus per nucleotide, but there is between 2 and 20 times as much RNA in every cell. Growing organisms depend on a steady supply of RNA and, consequently, phosphorus. “We realized that there was enough extra RNA in Daphnia to explain all the extra phosphorus they have compared to copepods,” he says. That work provided an early connection between biogeochemistry and lake ecology. But it also made Elser think about the wider implications, and the extent to which phosphorus—unlike common but crucial elements like oxygen, carbon, hydrogen, and nitrogen—might be the limiting factor in the expansion of the human population. Do humans respond to excess phosphate more like Daphnia or copepods? A link to human health would not reveal itself until several years later. George Beck grew up in Wilmington, Delaware, a short drive from the Chesapeake Bay. Even at a young age, he knew about the huge algal blooms—fueled by runoff containing phosphate from fertilizers and detergents—that were smothering the copepods, crabs, and sea grass beneath them. “Phosphate really is a fuel for growth,” he says of the phenomenon he’s observed time and time again at a molecular level. Phosphate sparked Beck’s scientific interest about 10 years ago, when he realized that the compound is more than just a molecular building block—it’s also an important signaling molecule. He was trying to figure out the molecular details of bone building. Surprisingly, the key turned out to be phosphate: An increase in free phosphate in the extracellular matrix around the bone-building osteoblast cells could directly change gene expression inside those cells, upregulating some pathways and downregulating others.4 James Elser at Cuatro Ciénegas Beck knew that phosphate-stimulated signaling pathways were not limited to osteoblasts. And when he began working at the National Cancer Institute in Bethesda, Maryland in 2000, he discovered that phosphate signaling triggered tumor growth in some in vitro experiments.5 If such a finding held up in a mouse model—a big if—it would suggest that excess phosphate consumption could lead to cancer. And that’s what Beck has spent the last 10 years trying to figure out. In 2005, when Beck arrived at his new position on Emory’s Atlanta campus, he immediately began preparations for his first phosphate experiments with live mice, using a knockout strain that had been developed as a model for studying skin cancer. At 8 weeks of age, female mice were randomly assigned a diet of either 0.2 percent phosphate or 1.2 percent phosphate. In humans, the USDA recommends a daily phosphate intake of 1250 mg, although most Americans exceed that by about 100 mg. Beck’s mice were consuming the equivalent of either 500 mg or 1800 mg per day. Beck then dosed the mice with a carcinogen from cigarette smoke called dimethylbenzanthracene, together with another chemical to stimulate cell growth, and examined them once a week for squamous cell carcinomas. It took just 12 weeks for 80 percent of the mice on the high-phosphate diet to exhibit skin papillomas, the initial stage of cancer. Mice on the low-phosphate diet didn’t cross the 80 percent threshold until 15 weeks later. More importantly, after 19 weeks, mice on the low-phosphate diet developed an average of six skin papillomas compared to 10 in the high-phosphate mice.6 Although the 43-year-old scientist is not ready to tell the world to change its eating habits, he and his wife already have. “I’ve been doing this work for a while, and we don’t eat a lot of processed foods anymore—certainly not as much as the average American.” Considered in a wider context, Beck’s finding was hardly an outlier. Phosphate has long been known to cause calcification of the kidneys, which is why patients with kidney disease are placed on low-phosphate diets. More recently, Mohammed Razzaque, a cell biologist at the Harvard School of Dental Medicine, has found that a high-phosphate diet in mice led to premature signs of aging, such as infertility, emphysema, and muscle wasting. Soft body tissues, including the lungs and aorta, became calcified, and cell death increased in the kidneys, lungs, and muscles.7 Although clinicians have often chosen to use the word “hyperphosphatemia” to refer to high levels of phosphate in the diet, Razzaque went with a more direct term in his paper: “phosphate toxicity.” “I believe that high phosphate can be physically toxic to the cells themselves, and it will have a cumulative effect on the body’s organs,” he says. After being scraped from the ground, phosphate rock is processed from a chalky mineral into laundry detergents, Monsanto’s RoundUp weed killer, or fertilizer—its primary commercial form. The United States obtains most of its phosphate rock from domestic mines in Florida, North Carolina, and Idaho, but as those mines move toward exhaustion in the next 50 years, the country is increasingly dependent on Morocco, which sits atop the world’s largest phosphate reserves. Last year, ecologist Peter Vitousek of Stanford University and colleagues wrote a commentary in Science pointing out the world’s great “nutrient imbalance.” Corn growers in western Kenya, for instance, apply just 8 kg of phosphate fertilizer per hectare per year. Compare that to China, where farmers are using more than 10 times that amount: 92 kg of phosphate per hectare per year—way more than what the plants can actually use.8 Phosphate pebbles (right) fresh off the grading screens at the Mosaic Company’s South Fort Meade Mine in Florida, shown here © Nathan Benn/CORBIS © SCOTT AUDETTE/Reuters/Corbis To solve this nutrient imbalance, some scientists have begun taking a closer look at how plants actually absorb phosphate through their roots. Roberto Gaxiola, a plant physiologist at Arizona State University, says that the key to boosting a crop’s phosphate-uptake efficiency is to enhance the transport of glucose produced by photosynthesizing leaves. “The roots are like you and me,” he says; “they don’t photosynthesize so they need the combustible carbon” from glucose. He’s found that upregulating an enzyme called proton pyrophosphatase in roots helps plants acidify the soil, absorb phosphate, and can ultimately double the biomass of rice, tomatoes, and Arabidopsis growing in phosphate-poor soil.9 As physiologists like Gaxiola work to improve current crops through genetic engineering, and environmental engineers hunt for ways to recover phosphate from sewage and runoff in waterways, Elser and Beck believe breakthroughs could also come from a better understanding of the natural history of the phosphorus cycle. How does phosphorus move from organism to organism in ecosystems and what exactly does it do inside your cells? What mechanisms do organisms have to conserve it? Elser likes to compare phosphorus to gold. “We have a closed gold cycle,” he says; “after we mine it, we melt it down and recycle it because it is valuable. Phosphorus is on a one-way trip through our ecosystem.” According to Cordell’s analysis, just 20 percent of the phosphate rock used in food production makes it into our bodies. The rest is lost due to inefficiencies in fertilizer production and application, and crop harvesting, processing, and distribution. At Cuatro Ciénegas, however, phosphorus is as precious as gold. “The creatures in Cuatro Ciénegas have been saving phosphorus for a long time,” says microbial ecologist Valeria Souza of the National Autonomous University of Mexico. “They grow slowly, they recycle a lot, and nothing goes to waste.” Souza has shown that there is practically no free phosphorus in the water: it is all sequestered away inside living organisms that fight mightily for it. “There is tremendous warfare to snatch the phosphorus from the dead,” Souza says. In fact, the dearth of phosphorus means that organisms in Cuatro Ciénegas have tiny genomes and are reluctant to swap genes through horizontal gene transfer—an isolating process that has ultimately led to their diversification.10 A pool 10 meters away will have a completely different biota, as Souza discovered by examining 16S rRNA genes from 350 cultivated strains of bacteria and archaea. Soon after Beck began to recognize the importance of phosphate to osteoblasts in the early 2000s, Elser and his colleagues decided to find out what would happen if they added phosphate to streams at Cuatro Ciénegas. Immediately, the microbes coating the stromatolites in the streams took up the added phosphate and increased their rate of photosynthesis as well as their deposition of calcium carbonate. The snails that grazed on the microbial biofilms, in turn, grew faster and made more RNA, but only up to a point. As phosphate levels increased further, snail growth and survival declined. As may be the case in humans, excessive phosphate intake can be detrimental to snails.11 In some sense, Elser’s study mimics an experiment that occurred on a global scale 520 million years ago during the Cambrian explosion, which resulted in a dramatic expansion in the diversity of life. Prior to the Cambrian, life on Earth looked a lot like Cuatro Ciénegas: dominated by stromatolites growing in shallow waters. Around 600 million years ago, fungi and algae began to colonize land and started to weather the geological formations where phosphate had been locked up since Earth’s formation. Indeed, around that time deposits of phosphorite, the geological term for phosphorous-rich rocks, begin to appear in the marine geologic record as organic material and weathered rock trickled into shallow seas. If the influx of phosphate could have triggered the Cambrian explosion—when life diversified into many of the phyla we still see today—then its depletion could well reverse it. Just as cancer biologists have begun to apply principles of evolution and ecology to understanding the dynamics of multiplying cell populations, Elser has begun to think about the stoichiometry of the human body. Because tumors require lots of RNA in order to maintain their high growth rate, Elser suspected that tumor cells were relatively higher in phosphorus. In collaboration with John Nagy, a mathematical biologist at Scottsdale Community College, and other researchers, Elser analyzed the phosphorus content of primary tumors from the livers, kidneys, colons, and lungs of 121 patients. As predicted, lung and colon tumors had two to three times the phosphorus content of normal tissue, along with higher levels of RNA. However, the data for kidney and liver tumors did not support the theory, which led the team to posit that tumors in those tissues caused problems by having a lower cell-mortality rate, rather than a high cell-division rate, which would require more phosphate.12 Told about Elser’s study, Beck perks up a bit. He was unaware of the theory, but says that it makes a lot of sense. “That’s my thinking,” he says. “Cells need more phosphate to proliferate.” In terms of early-stage cancer, the evidence is beginning to stack up. Along with Korean collaborators, Beck has found that a high-phosphate diet can double the risk of lung cancer in some mice.13 But the link between phosphate and cancer is far from clear. In a separate study by the Korean group, phosphate can also suppress lung cancer.14 Meanwhile, a French group, led by Laurent Beck of the Université Paris Descartes, has recently found that knocking out a sodium-phosphate transporter in cultured cells can decrease cell proliferation and tumor growth.15 As research presses on, the political battle over phosphorus is just starting to heat up. The International Food Additive Council and the British Soft Drinks Association have challenged the recent work on dietary phosphate by Beck, Razzaque, and others, while the phosphate industry hopes to counter a decline in laundry detergent sales with an uptick in the use of phosphate in lithium-ion batteries for electric vehicles. Dana Cordell complains that the international community has yet to establish agreements to study the issue, as they have with topics such as carbon-dioxide emissions or nitrogen pollution from fertilizer. Last year, Elser founded the Sustainable P Initiative at Arizona State University to raise the profile of the problem in the United States, and is leading a symposium at the American Geophysical Union in San Francisco this December. “It’s all coming full circle,” he says. The phosphorus, however, keeps trickling away. References: 1. D. Cordell et al., “The story of phosphorus: global food security and food for thought,” Glob Env Change, 19:292-305, 2009. 2. L.D. Alcaraz et al., “The genome of Bacillus coahuilensis reveals adaptations essential for survival in the relic of an ancient marine environment,” PNAS, 105:5803-08, 2008. 3. J.J. Elser, A. Hamilton, “Stoichiometry and the new biology: the future is now,” PLoS Biology, 5:1403-05, 2007. 4. G.R. Beck et al., “Phosphate is a specific signal for induction of osteopontin gene expression,” PNAS, 97:8352-57, 2000. 5. K.A. Conrads et al., “A combined proteome and microarray investigation of inorganic phosphate-induced pre-osteoblast cells,” Mol Cell Proteomics, 4:1284-96, 2005. 6. C.E. Camalier et al., “Elevated phosphate activates N-ras and promotes cell transformation and skin tumorigenesis,” Cancer Prev Res, 3:359-70, 2010. 7. M. Ohnishi, M.S. Razzaque, “Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging,” FASEB J, 24:3562-71, 2010. 8. P.M. Vitousek et al., “Nutrient imbalances in agricultural development,” Science, 324:1519-20, 2009. 9. H. Yang et al., “Enhanced phosphorus nutrition in monocots and dicots over-expressing a phosphorus-responsive type I H+-pyrophosphatase,” Plant Biotech J, 5:735-45, 2007. 10. V. Souza et al., “Microbial endemism: does phosphorus limitation enhance speciation?” Nat Rev Microbiol, 6:559-64, 2008. 11. J.J. Elser et al., “Early Cambrian food webs on a trophic knife-edge? A hypothesis and preliminary data from a modern stromatolite-based ecosystem,” Ecology Letters, 9:292-300, 2006. 12. J.J. Elser et al., “Biological stoichiometry in human cancer,” PLoS ONE, 2:e1028, 2007. 13. M.H. Cho et al., “High dietary inorganic phosphate increases lung tumorigenesis and alters Akt signaling,” Am J Respir Crit Care Med, 179:59-68, 2009. 14. C.X. Xu et al., “Low dietary inorganic phosphate stimulates lung tumorigenesis through altering protein translation and cell cycle in K-ras Mice,” Nutr Cancer, 62:525-32, 2010. 15. L. Beck et al., “Identification of a novel function of PiT1 critical for cell proliferation and independent from its phosphate transport activity,” J Biol Chem, 284:e99959, 2009. http://bit.ly/PiT1func

Elemental Shortage

ELEMENTAL SHORTAGE

The world is running out of cheap phosphorus, the element that lies at the heart of great agricultural advances and thorny environmental problems. Biologists are only now beginning
to understand what it means for evolution and human health.

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