Russ Knapp formulates a new pharmaceutical agentfor animal testing.
In a hospital in Kyoto, Japan, a middle-aged man lies on a hard table, a huge camera suspended over his chest. Something is not quite right with his heart—his doctor has told him that. But his symptoms are subtle, their cause uncertain so far: no clogged arteries, no decline in blood flow, no damage to his heart muscle.
What's wrong? What's wrong? he broods, as a needle pierces a vein in the crook of his arm. What's wrong with me?
From the needle flows a solution of fatty acids that have been "tagged" with radioactive iodine-123. His blood washes them into his heart as it flows through coronary arteries, nourishing the heart muscle with oxygen and nutrients. The heart muscle cells extract fatty acids for fuel, even the radioactive ones. All the while, the iodine-123 decays, emitting photons that the hovering gamma camera records, revealing—pinpoint by pinpoint, until a bright galaxy of photons has accumulated—the places in the heart where those fatty acids remain unmetabolized. Such places are regions of dying muscle tissue that are not often identified by the usual blood-flow markers such as thallium-201.
Something is indeed wrong—the man is in the early stages of heart disease; left untreated, eventually it could kill him. Instead, thanks to this early diagnosis, there will be treatment. Instead, there will be hope.
When atomic bombs destroyed Hiroshima and Nagasaki half a century ago, the Japanese people were linked forever to the nuclear researchers at a Manhattan Project outpost in Oak Ridge, Tennessee. Out of the secret installation in the rolling hills had come the uranium to fuel the first bomb as well as the proof that plutonium could be made in sufficient quantities to stoke the second.
| An ORNL-developed imaging agent helps diagnose heart disease in Japanese patients. |
But even a mushroom cloud can have a silver lining. Today, the same technology that begot the atomic bomb brings healing balm, uniting ORNL researchers with hundreds of thousands of Japanese who may be suffering from heart disease. Japan is the first country where this ORNL-developed, radioactive imaging agent called BMIPP—marketed there as Cardiodine®—has won full governmental approval for use in hospitals and clinics.
Russ Knapp formulates a new pharmaceutical agent
for animal testing.
Call it irony. Call it redemption. Russ Knapp, head of ORNL's Nuclear Medicine Group, calls it "incredible." "Imagine," he says, "more than 100,000 patients have been tested with this agent. It's not just a neat idea in some lab. It's actually useful."
ORNL's nuclear medicine man speaks with an almost parental pride, as well he might. From its birth on Knapp's bench to its introduction into Japanese clinics, Cardiodine® was nearly 20 years in the making. In fact, in the same space of time, Knapp's own children grew from babies to young adults. He hopes to see the agent approved in Europe, and then in the United States, by the end of the decade—but those approvals will take much time and even more money. The tortuous path from idea to actuality is a hard truth for researchers in nuclear medicine—harder, perhaps, than in any other medical specialty. After all, if you're playing with atomic fire, you don't want anyone to get burned. Radiopharmaceuticals must be tested—first in the lab, then in animals, finally in people with real diseases. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) seek to ensure that these substances can be used and disposed of safely.
But the fact that Cardiodine® has left home, as it were—passed beyond Knapp's guiding influence and into clinical life—offers hope that some of his group's many other promising ideas can follow the same path.
Imagine an isotope that could relieve the pain and swelling of rheumatoid arthritis or the agony of end-stage cancer... not the $1800-per-dose version currently used, but one generated right in the hospital for only $40 a dose. Imagine zooming in on a cancer untreatable by conventional radiation or chemotherapy, binding a tiny, well-aimed speck of isotope to the tumor, then burning it away, a millimeter at a time. Imagine lighting up the brain with a radioisotope that binds to receptors in nerve and brain cells—the group of receptors most likely to shut down in Alzheimer's disease—to confirm or rule out that diagnosis with certainty. Imagine.
Such boundaries can be found in every branch of medicine—cardiology, oncology, neuropsychiatry, gastroenterology. Working with Knapp at their edges is a small but varied team of scientists—organic chemists, a microbiologist, radiochemists, and always some visiting researchers, who come from every corner of the world to his lab ("There are very few places to get formal training in this kind of research," he explains). In turn, the Nuclear Medicine Group reaches back out to the wide world for collaborators. Researchers are testing ORNL's new nuclear medicine technologies in clinics not only in the United States but also in hospitals in Australia, China, Germany, Italy, Japan, and Uruguay.
Gamma camera images show uptake of a rhenium agent
in skeletal tissue for the treatment of cancer-induced bone
pain caused by metastases in a 66-year-old patient suffering
from prostate cancer. The rhenium agent (Re-188-HEDP) was
prepared using Re-188 obtained from ORNL's
tungsten-188/rhenium-188 generator. The agent is being tested in patients in
Germany. Courtesy of H. Palmedo, M.D., S. Guhlke, and H.-J. Biersack,
M.D., Clinic for Nuclear Medicine, University of Bonn,
Germany.
"One of my major responsibilities is to establish and manage collaborative programs," Knapp says. "I spend almost one-quarter of my time planning and coordinating joint research projects and writing joint grant applications and papers. This work guides decisions on future nuclear medicine research projects."
However, if the world is Knapp's proving ground, it is not exactly his oyster: in an era of shrinking federal budgets and dwindling research dollars, advancing the frontiers of nuclear medicine has become more difficult. Where ORNL once had four research reactors plus an accelerator to produce radioisotopes, the High Flux Isotope Reactor (HFIR) is now the only source remaining. And a local clinical partner, Oak Ridge Associated Universities, lost its nuclear-medicine funding a decade ago.
Tough times and a tough planning climate have served both to focus and to expand the research of the Nuclear Medicine Group, which is primarily supported by DOE's Office of Health and Environmental Research. "When you're trying to decide what research to do, a key thing is what facilities you have," he notes. "We have a reactor, so we do a lot with reactor-produced isotopes. But we've found that it may actually be an advantage not to have a clinical component—if we had clinical colleagues here, they would most probably focus on one area, and it would be hard to be as broad as we are. The fact that we can interact with medical specialists in many areas gives us much more flexibility." In short, where resources are limited, Knapp substitutes resourcefulness. So when Knapp begins to transform ideas and imaginings into doctors' tools, he has to be practical right from the start.
Pain is what you get when you're dying of cancer, including breast or prostate cancer. Quick to metastasize, the primary tumors release cells that often home in on the skeleton and begin boring into bone. These metastases squeeze the nerves and send out chemical by-products that nettle the body's pain receptors. Inflammation brings more pressure. Pressure brings more pain.
At this stage, forget cures. It's all the doctors and nurses can do just to ease the torment.
"These people are often near the terminal stage of the disease, and until the end, their quality of life can be horrible," Knapp says. "They're in great pain, and they can also suffer terrible side effects from the steroids and narcotics they're given for relief."
In Europe, a rhenium radioisotope—rhenium-186—is used to help alleviate bone pain. "But you have to make every dose in a reactor," Knapp notes. "Because it has only a 90-hour half-life, you have to ship it overnight to the hospitals over and over again. These requirements make it very expensive—about $1800 for a single patient dose. Treatment with strontium-89, an FDA-approved agent made from an enrichment product from ORNL calutrons, costs about the same."
| As a pain reliever for people with cancer-induced bone pain, rhenium-188 is effective and less expensive than other treatments. |
Knapp and his colleagues propose a slightly different isotoperhenium-188, the same isotope that shows such promise for treating primary tumors. As a pain reliever, it could prove just as effective as rhenium-186 and at a cost of only $40 a dose, based on daily use of a generator for several months.
Arnold Beets (left) measures the alpha-particle radioactivity emitted by a radioisotope sample held
by Saed Mirzadeh. Photograph by Tom Cerniglio.
The energetic electrons emitted as rhenium decays don't just burn through tumors; they also reduce inflammation caused by the tiny metastases on the bones. Unlike narcotics, which merely deaden the nerves that feel the pain, rhenium relieves the inflammation that causes the pain.
Knapp and his team have devised a small rhenium generator—about the size of a thick paperback novel—that can produce hundreds of doses of rhenium-188 over several months, right in a hospital. It's a simple thing: a cylinder with rubber tubing at each end, shielded in a small lead box. At the top of the tube, tungsten-188—produced in the HFIR—binds tightly to aluminum oxide powder that has been saturated with acidic saline. As it decays, the tungsten turns to rhenium-188, which lets go of the powder. Wash more saline through the top, and out the bottom comes a solution of rhenium-188. It can then be chemically incorporated into a wide variety of therapeutic agents in forms such as a phosphorus compound (phosphonate) or a dimercaptosuccinic acid compound.
Prototype of ORNL's tungsten-188/rhenium-188 generator.
Photograph by Curtis Boles.
"And all the while, the tungsten's still decaying. You could use this for six months in a hospital—we've used one here for more than a year," Knapp says. "This is in itself a production system, so the costs are much, much less. That's one of our selling points."
"And someday," he continues, "we hope to take the technology a step further—to find ways to administer higher rhenium-188 doses that kill tumors without destroying the immune system's bone marrow."
| Rhenium-188 could also relieve inflammation and pain in joints from rheumatoid arthritis. And it costs much less than other therapeutic radioisotopes. |
This same isotope could also relieve inflammation and pain in joints swollen by rheumatoid arthritis. "People who can't even walk because of the pain could start walking again," Knapp predicts. "In the United States alone, there are a hundred thousand people each year who could benefit from this treatment. Their insurance companies should be able to afford it."
Fortunately, rhenium-188 has proved ideal for this sort of application, because it decays quickly and energetically, emitting beta particles that can reduce inflammation. Rhenium-188 was a choice isotope also because it costs much less than other therapeutic radioisotopes. "The price of rhenium-188 for this treatment," Knapp says, "is expected to be just a few percent the price of radioisotope treatments using rhenium-186 or strontium-89, greatly reducing health-care costs."
Others find hope in this isotope. "In 1995 I was invited by Professor L.Troncone, the head of nuclear medicine at Catholic University Hospital in Rome, to give a lecture in Rome as part of our collaboration," Knapp says. "When he had heard about this generator, he came to me and said, 'We have a great financial crisis in our country. I can't afford to pay $1800 a dose to relieve someone's pain. This isotope looks great. Can you help us?" The same need has been expressed in other countries, including Germany, Greece, and Uruguay.
Another of the Nuclear Medicine Group's promising new projects and examples of collaboration is a "magic bullet" designed to lock on to a tumor and burn it away. First came an idea from RhoMed, Inc., in Albuquerque, New Mexico: to use radioisotopes to make a nonradioactive, partially effective cancer treatment more potent. In the original treatment, a patient is injected with a chemical agent called octreotide—a small peptide, or amino acid cluster, synthesized from eight amino acids. In theory, the octreotide binds quickly to a tumor cell and turns off the growth hormones the renegade cell needs to thrive. "Unfortunately, it's only partially useful," Knapp says, "and only in certain situations."
Knapp had found a boundary and wanted to step beyond it by collaborating with RhoMed researchers. "We knew if the right radioisotope could be attached to that binding substance, we'd have a way to deliver radioactivity to that tumor." In fact, that approach had already been used to create a commercially available diagnostic tool that lets a doctor see where the tumor is, how many metastases there are, and how effective radiation or chemotherapy is proving. But researchers wanted to use radioactivity to treat, not just diagnose. And the isotope whose radioactivity they wanted to tap was rhenium-188.
In 1995, a cooperative research and development agreement was signed between ORNL and RhoMed. Researchers with varied backgrounds from both organizations were able to tackle an assortment of basic questions: What is the chemistry of the octreotide? Where can we hang an isotope? Which isotope should we use? Saed Mirzadeh, a radiochemist in the Nuclear Medicine Group, helped probe these particular questions; other team members explored similar questions in their own specialties in collaboration with RhoMed researchers, in particular with B. Rhodes, president of RhoMed, and P. O. Zamora, a cell biologist working at RhoMed on this project. Mirzadeh and Arnold Beets, also of the Nuclear Medicine Group, have worked closely with Knapp on problems related to the HFIR production and processing of the tungsten-188 parent radioisotope.
"The RhoMed researchers have been able to attach rhenium-188 to this octreotide, and they found evidence that this Re-188-RC-160 compound binds to tumors," Knapp reports. "They've done some animal studies—implanting small-cell lung carcinoma cells into mice. When the tumors had grown, they've injected the compound and demonstrated that it shrinks the tumors."
For human patients with soft-tissue cancers—cancer of the breast, the prostate, the uterus—this patented agent could offer a new avenue of hope. It has intrigued Knapp's European collaborators, such as Dr. Hans J. Biersack in Bonn, Germany. Biersack, chief of the Clinic for Nuclear Medicine at the University of Bonn, where Knapp worked in 19851986 and 19911992, expects to begin patient studies soon with the rhenium peptide agent to treat patients suffering from inoperable metastases of breast cancer and with the rhenium-188labeled phosphorus compound to relieve cancer-induced bone pain.
"Using this binding phenomenon looks like it might be an interesting way to deliver a therapeutic isotope," Knapp says. "It could be an alternative to traditional radiation therapy. We think it has a promising future, and that's pretty neat."
Dan McPherson injects a sample into a high-performance liquid chromatography
device, which
is used to purify compounds being developed to diagnose diseases of the heart and brain.
There is no cure for Alzheimer's disease. There isn't even a real diagnostic test for it; only a pathologist can truly confirm it, and only by examining the brain in an autopsy. Knapp and his team can offer no cure, but under the guidance of organic chemist Dan McPherson, they think they're onto a diagnosis. The secret is to know how the brain talks to itself—and where the lines of communication seem most vulnerable to Alzheimer's.
"When you think, when you move, when you experience pain, hunger, or lust, there are many networks of neurons firing in your brain," McPherson explains. "All the time, awake or asleep, the nerve cells in these networks have to communicate in some way. So a little chemical message is produced in this cell, and it travels over and excites the next cell. That's how the nerve impulse is propagated."
A neuron's message-sending equipment is called its neurotransmitter; incoming messages are picked up by the neuroreceptor. It's possible to synthesize a compound that will bind to active receptors; by tagging the compound with an isotope, it's fairly simple to make it visible to a gamma camera. That lets researchers see where receptors are turned on and taking messages.
In practice, of course, it's not quite that simple. Alzheimer's seems to damage one specific kind of receptors, called muscarinic-cholinergic receptors, which make up only 20% of all neuroreceptors. The challenge for McPherson and other members of Knapp's group has been to devise a molecule that binds only to those particular receptors, highlighting changes just in parts of the brain affected by the disease.
"It's a real challenge, chemically," McPherson says. Then he smiles. "But we think we have a molecule that will work."
The molecule, dubbed IQNP, was tagged with radioactive iodine-123 (the same isotope used in Cardiodine®). In its first tests, it successfully imaged a normal rat brain: it set the receptor-rich areas aglow, tracing a heart-shaped halo around the cerebrum.
However, it's a long, long road from rats to people, making collaboration crucial. Dr. Joachim Kropp, an associate professor at the Technical University in Dresden and board-certified nuclear medicine physician, was once a visiting researcher with Knapp at ORNL. Kropp hopes to do the first human studies in Dresden once the preliminary work and in vitro studies are done.
Russ Knapp and Kathy Ambrose check
metabolism cages for studies of the distribution and
elimination of radiopharmaceuticals from rats.
But what preliminaries! First, there must be autoradiography studies, tests with normal and Alzheimer's-damaged brain tissue taken from autopsies (the samples have been frozen, so the neuroreceptors will still work). "Our collaborators in Stockholm, Sweden, put IQNP in solution, dip the pieces of tissue in there for awhile, then take them into the darkroom and put them on a piece of X-ray film," Knapp explains. "If the IQNP specifically binds in these regions, the radiation from the iodine exposes the film, producing dark images on a clear background, in the same way that visible light exposes photographic film to make a picture." Barry Zeeberg, at George Washington University Medical School, and R. E. Reba, at the University of Chicago, are collaborating on these studies.
These studies must be coordinated with more animal studies—in this case, on monkeys. Christer Halldin, a radiochemist at the Karolinska Institute in Stockholm, will pick up the task at this stage.
| Before it can be tried in humans, IQNP must pass toxicity tests. |
Finally, before it can be tried in humans, IQNP must pass toxicity tests. Two different species of rats and mice must be injected with the agent, blood and urine tests run, autopsies done, and everything formulated and written in a report acceptable to the FDA. Toxicity tests are "very expensive," Knapp frets. Fortunately, he has a friend—a very good friend—Jukka Hiltunen, who is managing director of a radiopharmaceutical company in Finland. If the autoradiography looks good and if the primate studies pan out, Hiltunen is expected to conduct the toxicity studies free of charge.
| ORNL researchers think the agent might help diagnose Alzheimer's disease. |
Huimin Luo, organic chemist and Hollaender postdoctoral fellow, synthesized a
fluorine-18labeled compound that may be useful for imaging memory loss using positron emission tomography of
the brain.
More recently, Huimin Luo, a Hollaender postdoctoral fellow working with Knapp and McPherson has successfully synthesized a new fluorine-18labeled analog, called FQNP, which may be useful for the same application using positron emission tomography. The result could be tools that may not only give a diagnosis but also show how severe the disease has become and how it's progressing. If the diagnosis is not the inexorable Alzheimer's, treatment may be possible because memory loss can have a number of causes.
| We think it could possibly be used to monitor the progression of Alzheimer's disease and the effects of therapy. |
Knapp is characteristically hopeful about the technique's future. "I hate to say that this technique could diagnose Alzheimer's disease," he cautions. "But we're really excited about its potential. We think it could possibly be used to monitor the progression of the disease and the effects of therapy."
Meanwhile, because the same receptors affected by Alzheimer's
are found in the heart's natural pacemaker, the researchers are also adapting
this same tool to unlock more cardiac secrets. It may not happen in matters
of romance, but when it comes to
neurotransmitters, at least, the
head and the heart may prove to have a lot in common.
The ancient Greeks used the myth of Pandora to explain the presence of pain and suffering in the world. In the story, the gods gave Pandora a box but forbade her to open it. Naturally, she could not overcome her curiosity. When she opened it—just for a peek—she unwittingly released all the miseries of the human condition contained inside. Bereft, alone, she stared at the empty box.
But then she noticed that it was not entirely empty. At the bottom remained a tiny but persistent spirit: Hope.
We are no different from the ancients. We, too, suffer the torments of sickness and death; we, too, take heart when we find hope.
Hope is a spirit that infuses Russ Knapp's research. Not just the general hope of every scientist—that all this work will advance human knowledge in some way—but a deeper, more specific longing: that all this work will relieve human suffering.
For people with Alzheimer's disease, terminal cancer, and rheumatoid arthritis, hope can seem elusive. But for some, the work of Knapp and his group will bring it within reach once more.
In Japan, tens of thousands of cardiac patients have already grasped it. Already taken it to heart.
Kit Carlson is a freelance writer who lives in Silver Spring, Maryland.
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