The man with radioactive atoms flowing through his veins seems calm. He moves onto a gurney and lies still as it slides into a humming, doughnut-shaped scanner at Vancouver General Hospital. His foot hurts—a lot—and the machine takes sharp 3-D snapshots of bones and soft tissue within by imaging these atoms, their radiation shining brightest where there is increased blood flow to the injury.

This kind of bright beacon does not just illuminate feet. More than 30 million times a year, all over the world, scans that use these atoms track the irregular beat of damaged hearts, uncover deadly cancers and explore brains devastated by stroke. These pictures rely on an obscure isotope called technetium 99m, used in an imaging process called single-photon emission computed tomography. The injected technetium gives doctors an unmatched window into the body, allowing them to pinpoint damage or disease so they can save patients' lives. These images can show finer detail than other tests, and the radiation dose is extremely low and safe.

Now these precious pictures are endangered. The radioactive atoms coursing through this patient's foot got their start at an old nuclear reactor thousands of kilometers away in Chalk River, Ontario. On October 31, 2016, that reactor stopped making the source material for the isotope. At that moment North America was left with no domestic source of this vital medical tool, and 20 percent of global production disappeared. Chalk River will shut down completely in a few years. And the problem gets worse.

Very nearly all of the world supply comes from just six research reactors. Four of them are more than 50 years old and increasingly prone to breakdowns. Two reactors, in Belgium and the Netherlands, now account for half of global capacity and will be shuttered in the coming decade. New nuclear plants are planned but could take more than a decade to complete. Last September the U.S. National Academies of Sciences, Engineering, and Medicine rang a loud alarm with a report saying there was a “substantial” chance of shortages in the near future.

Doctors are worried. “It's something we need on a daily basis,” says Eric Turcotte, a nuclear medicine specialist at the University of Sherbrooke in Quebec. These tests are especially useful for detecting bone cancer or fractures—the foot patient's physicians were looking for small breaks—and for revealing blockages in a heart patient's arteries. They are often given to people with chest pain or other signs of blood vessel disease. Other techniques produce blurrier, less exact images or use higher doses of radiation that pose a greater danger of harm. Benjamin Chow, a cardiologist at the University of Ottawa Heart Institute, says that a shortage would force doctors to fall back on less accurate methods, increasing patient risks, or to skip the tests altogether.

Worse, cutting back to just a few production sites creates an easily broken supply chain. Almost all of the isotope decays in a day and cannot be stockpiled. Each short-lived dose for a patient has to be freshly milked from a container holding its source, a longer-lasting isotope called molybdenum 99. Supplies of that material need to be flown in every few days from the reactors that make it, halfway around the world. Bad weather and canceled flights could mean no scans. “If an airport is closed, just think how vulnerable we are,” frets François Bénard, a clinician-scientist at the BC Cancer Agency in British Columbia.

The isotope's production cycle raises another problem: nuclear terrorism. To create molybdenum 99, most reactors use weapons-grade highly enriched uranium (HEU). There is a global push to stop using HEU by 2020 because dangerous people and rogue states want to steal it. But converting reactors to use low-enriched uranium (LEU) means more downtime, and LEU reactors ultimately produce less molybdenum 99.

To avert this looming crisis, researchers in the U.S. and Canada have been racing to develop radically new technologies to produce molybdenum 99 and technetium 99m without nuclear reactors, instead using more nimble particle accelerators and other machines. Not only could these techniques avoid shortages, they could also be cheaper and produce much less radioactive waste. Now, with global capacity dropping sharply, the researchers are about to find out if their alternatives are up to the challenge.

Coming Up Short

Doctors already have bitter experience with what happens when molybdenum 99 runs out. Back in 2009 and 2010, both the Canadian and Dutch reactors were off-line for extended periods, causing a global shortage that left doctors scrambling to find alternative diagnostic tests. “The crisis in 2009 was a wake-up call for everyone,” says Sally Schwarz, president of the Society of Nuclear Medicine and Molecular Imaging. “Diagnostic tests couldn't be performed, and patients suffered. We don't want to be in that position again.”

One common fallback for a technetium 99m heart test, for instance, uses another radioisotope called thallium 201. But this isotope produces blurrier images and doubles the patient's radiation dose, says heart-imaging specialist Venkatesh L. Murthy of the University of Michigan. And other, nonradioactive methods, such as echocardiography, are not as precise. Technetium 99m hits a sweet spot between resolution, safety and cost, he says.

Sobered by the effects of the shortfall, the Canadian government soon afterward began the $45-million Isotope Technology Acceleration Program (ITAP) to develop alternative ways to make technetium 99m. Its leading project may be ready to go online by the end of this year.

Instead of an enormous reactor plant, the technology uses a small particle accelerator called a cyclotron, which can fit in the basement of a hospital. The cyclotron smashes protons into a target made of a different isotope, molybdenum 100, and the collision produces technetium 99m at the site. The isotope's short half-life means that a single cyclotron can serve only a limited area. But most of Canada's big cities already host similar machines, so it should be possible to roll out the solution across the whole country, says Paul Schaffer, an associate lab director and former head of the nuclear medicine division at Canada's flagship cyclotron center, TRIUMF, which developed the method. TRIUMF, located in Vancouver, ran pilot tests to demonstrate that it can make enough technetium 99m during a six-hour cyclotron run to meet the needs—about 500 scans a day—of the province of British Columbia, which has a population of nearly five million.

Graphic by Amanda Montañez; Source: Natural Resources Canada. Presented to House of Commons Standing Committee on Natural Resources, June 2, 2009

Currently the two-meter-wide cyclotron sits in a vault behind a thick steel door at the Vancouver facility of the BC Cancer Agency. Two thin metal tubes jut from the machine, carrying beams of protons traveling at about one-fifth the speed of light. At the other end lies the target: a thin, flat plate about 10 centimeters long, with a coating of molybdenum 100, housed in an aluminum cylinder. The plate is bombarded for six hours to transform some of the molybdenum 100 into technetium 99m. Then it is shot through an air-pressure tube into a lead-lined work chamber called a hot cell in another room, where operators separate and purify the technetium 99m. The result is a small vial of clear liquid containing enough of the isotope for hundreds of tests.

Vancouver General Hospital and the cancer agency are just wrapping up a clinical trial using this technetium in real tests on patients. The generation process generally starts in the early hours of the morning, and patients can be booked for injections starting at 1 P.M. The trial results so far indicate that the cyclotron technetium is just as safe and effective as the isotopes made with the molybdenum 99 containers.

TRIUMF and other ITAP partners launched a company last year to supply the technology to other cyclotrons. Already about 500 medical cyclotrons worldwide have sufficiently powerful beams to make technetium 99m in this way, in addition to their current tasks such as producing isotopes for positron-emission tomography scans. That existing base is a big advantage, Schaffer says: a new medical cyclotron might have a $5-million price tag, but it costs a tenth of that figure to retrofit an existing machine. In 2014 the British Nuclear Medicine Society recommended this approach as the most suitable way to supply technetium 99m, and Schaffer reckons that between 12 and 24 cyclotrons could meet Canada's entire needs.

Generating Advances

South of the Canadian border, in the U.S., however, cyclotrons are not generating as much enthusiasm—or technetium. The trouble is that the nation's hospitals were among the very first to build medical cyclotrons, and these older models cannot reach the higher beam energy that is now needed, Schaffer says.

Instead the U.S. Department of Energy's National Nuclear Security Administration is backing companies with different machines. One firm, NorthStar Medical Radioisotopes in Madison, Wis., hopes to use an electron linear accelerator (LINAC) to generate high-energy x-rays. These can knock a neutron out of molybdenum 100, transforming it into molybdenum 99, which will decay into technetium. LINACs are easier to license than nuclear reactors, cost less than cyclotrons and can essentially be bought “off the shelf,” says Carl Ross, a retired physicist who worked on linear accelerators at Canada's National Research Council. (Canadian Isotope Innovations, spun out of research funded under ITAP, is taking a similar approach but is not as far along.)

Yet for all their advantages, standard linear accelerators produce lower concentrations of molybdenum 99 than reactors do. So NorthStar has developed a completely new system to separate technetium 99m from the mixture of molybdenum isotopes that comes out of its LINACs. Dubbed “RadioGenix,” it pumps the mixture through a column of resin that absorbs only technetium. The molybdenum isotopes can then be recycled for another production run, and the pure technetium can be stripped from the column with a saline wash. The company hopes the system will be approved for clinical use this year.

Another solution, perhaps the most radical approach, comes from SHINE Medical Technologies in Monona, Wis., which wants to make molybdenum 99 by bombarding a liquid brew of LEU with neutrons. Those come from a LINAC that smashes deuterium into tritium. Both are heavy isotopes of hydrogen, and they fuse to form another element, helium. This merger releases a neutron. Those neutrons can then trigger fission reactions in the LEU target, forming molybdenum 99. The company says that the process produces concentrations of molybdenum 99 that are compatible with existing systems for transporting the isotope and separating, or milking, technetium 99m from it. (Because of the milking process, these canisters are whimsically dubbed “moly cows.”) In February 2016 SHINE got approval from the U.S. Nuclear Regulatory Commission to build its production facility, and it hopes to begin supplying by 2020.

Price Points

But smart technology is no guarantee of success. Costs will play a major role. “You need to make the product at a competitive price for it to be accepted by hospitals,” Bénard says.

Using current methods, technetium 99m costs about $20 to $25 per dose in North America. That is much lower than the true cost of production, in part because governments paid a large share for nuclear reactor fuel, waste handling and the original price of building the reactors themselves. “We became addicted to the fact that governments were subsidizing their operation,” Schaffer says. “That model is unsustainable.”

With the new technology and more private, domestic control over the supply chain, producers and governments plan to price technetium 99m to cover the expenses of maintaining the entire chain. Hospitals in British Columbia are bracing for a 40 percent price rise in the next few years, Schaffer says.

Pricing based on full-cost recovery could help the start-ups get off the ground and stay there. But they also face conflicting market forecasts. On one hand, aging populations in developed countries should increase demand for the heart tests that technetium 99m excels at, and the Chinese market is growing rapidly.

On the other hand, in recent years demand for technetium 99m has actually declined in many countries, according to the Organisation for Economic Co-operation and Development (OECD). The reason? The shortages of 2009–2010 spurred hospitals to reduce the amount of technetium in each dose. Image quality remained high because of smarter imaging software. As a result, the OECD projects that if new reactors and new methods come online there could be a glut and lower prices by 2021.

But many in the field remain unconvinced that replacement reactor capacity will arrive on schedule. “If we just rely on reactors, we'll end up in trouble again,” says the BC Cancer Agency's Bénard. To keep the images coming, he believes, new technologies must come into the picture.