Dr. Molecool

Quantum Iconoclast Randell Mills's Grand Visions of Microscopic Medicine

Randell Mills is a doctor better known for stirring up trouble in quantum physics than for giving flu shots. But now he's injecting new vigor into medical projects he claims will spur breakthroughs in fighting cancer and AIDS, as well as scanning the human body in three dimensions, in real time.

"You'll go in to see your doctor and he'll check you out with my scanner," Mills predicts. "If he finds cancer, you'll be treated for it as an outpatient with my therapy. If he finds something else—hypertension, an infection, arthritis—almost any medicine that he'll use will be more efficacious when he uses my drug-delivery molecule."

Mills is the founder of BlackLight Power Inc., based near Princeton, New Jersey. The company promises limitless clean energy and fantastic compounds, based on a "grand unified theory" that is hotly derided by luminaries in theoretical physics (see "Quantum Leap," Voice, December 28). Meanwhile, in a smaller laboratory down the hallway from those activities, Mills is quietly exploring medical innovations that no one seems to be calling nutty.

Illustration by Tom White

Mills says he plans to fold his medical ventures into BlackLight Power after that company has its initial public offering of stock, anticipated this year. Profits would then be plowed into his medical pursuits, he adds. "To me it's all the same; it's all engineering," says Mills.

Mills conceived many of his ideas while a student at Harvard Medical School or shortly after he graduated in 1986. Now 42, he acknowledges that it might seem odd that he backburnered early successes in medicine. He says he wanted to milk his brain while it was young and most nimble without the distractions of business or university politics. Today, he's ready to implement his designs.

In December 1988, Mills proposed in the peer-reviewed journal Nature how cancer might be destroyed with such little radiation that it could be treated on an outpatient basis. He says he was moved to improve cancer treatment when, as a student, he witnessed the private hopelessness of doctors caring for an otherwise healthy woman who was being slowly ravaged by tumors.

Currently, patients are carpet bombed with radiation in the hope that normal cells adjacent to cancer cells will be able to recover and reproduce, while malfunctioning cancer cells won't. Patients suffer terribly and injuries from repeated radiation can accumulate to a point where the cure itself threatens to become a killer. What Mills tested in mice were essentially the world's smallest smart bombs.

Dr. Greg Gagnon, assistant professor of radiation medicine at Georgetown University Medical Center, has investigated Mills's radiation technique, called Mossbauer Isotopic Resonant Absorption of Gamma Emission, or MIRAGE. Gagnon says Mills found a molecule to carry iron into a cell and plant it flush against DNA, the control center. Then comes the detonation.

The patient is given a tiny dose of gamma radiation, far less than a standard X ray. The gamma ray photons and iron atoms are tuned to react with each other in something called the Mossbauer isotope. When an iron nucleus absorbs a photon, it becomes unstable and releases a small burst of energy that knocks an electron out of its proper orbit, which then bumps outer electrons astray. What follows is an Auger cascade, a kind of microscopically localized electron explosion, Gagnon explains. "The electrons are shooting off, breaking things all over the place, and then the iron becomes attached to the DNA fragments. There's no way a cell can repair so much damage."

Healthy cells tear apart the transport molecule and the iron drifts safely off.

"It's just an amazingly clever idea. Randy is probably the most intelligent person I've met," remarks Gagnon.

Dr. John Humm, a medical physicist now at Memorial Sloan-Kettering Cancer Center who critiqued MIRAGE in Nature, argues that because such mild gamma rays wouldn't likely penetrate deep into tissue, "there would be severe limitations on clinical use. But having said that, this is nothing to sneeze at. The elegance of the idea is impressive. I know of no other way of so selectively inactivating sections of DNA." Scientists might instead embrace MIRAGE as a laboratory-setting microscopic cellular probe, Humm says.

Mills counters that while MIRAGE may not work for every cancer, in the years since the Nature article, he's found other Mossbauer isotopes that can work at deeper levels. In addition, he says, the radiation used in his original tests was so negligible that he could increase it by a factor of 1000 without any resulting discomfort to the patient.

Back then, Mills took a stab at bringingMIRAGE to hospitals, but researchers at would-be partner Bristol-Myers Squibb reported that test results weren't clear enough to pursue, according to M. Dianne DeFuria, senior director of business development.

DeFuria doesn't remember details, but adds that another factor could have been that the radiation therapy "may have involved equipment beyond the scope of a pharmaceutical company, meaning that we couldn't take it further alone."

Mills says he's since sharpened his technique to use ultrasound or magnetic scanners to take aim at malignant growths, and then destroy them with gamma rays pixel by pixel on a computer screen. Beyond that, he adds, "you should really think of this as a microscopic scalpel" good for cleaning out arteries and reducing swollen prostates, among other applications.

"If Randy is now meeting with good success, I hope he will come back," DeFuria says. "His mind was certainly appreciated here."

Mills has also demonstrated what might be a better way to use existing drugs to attack AIDS, herpes, and hepatitis. One of the problems doctors have in fighting these diseases is that the drugs best able to halt viruses and bacteria from reproducing often have trouble getting past cell membranes. They can be modified for that purpose, but that usually means dumbing down the medicinal value or causing side effects. Also, toxic concentrations of drugs must sometimes be used in hope that enough will get through.

Mills has designed a type of nontoxic molecule to ferry unadulterated drugs into cells, says Dr. Jim A. Turpin, who manages a retrovirology lab at Serquest, a Southern Research Institute company.

In Mills's approach, a drug enters the body as part of a molecule with three segments. Once past the membrane, the molecule will more likely encounter oxygen-free radicals, created during respiration, which exist inside cells in far greater numbers than outside.

The radical excites the first section of the three-part molecule in a chemical reaction that should release a photon of light. But that light is instead channeled as bond-shattering disruptive energy running along the molecular carrier, which then falls away like the spent stage of a rocket. The drug is left alone to do its work, and the carrier is excreted as waste.

Mills calls his system the Luminide method, because the carrier "is a light-powered drug-release molecule based on a reaction analogous to that used by fireflies to glow," and "it just sounds cool."

Turpin tested the technique on HIV-infected white blood cells using the AIDS drug Foscarnet. With the Luminide carrier, "we measured a minimum ninefold enhancement of antiviral activity in tissue culture," Turpin says.

Mills says he and Turpin will submit apaper on their findings to The Journal of Medicinal Chemistry in February. Tests in mice with Dupont Corporation have been successful, Mills claims, and he plans further studies in animals and humans. He adds that the method could be used for a host of applications, from antidepressants to plant pesticides, but purifying the compounds is difficult.

The National Institutes of Health may be interested in getting behind that effort with its own manpower and resources. When presented with Luminide overview materials for an opinion, Dr. Nava Sarver, chief of NIH's targeted intervention branch in the Division of AIDS, was "a little more impressed than I thought I would be. There seems to be some real potential there."

Sarver explains that her program helps scientists develop cutting-edge technologies without taking any profits or making patent claims. Luminide molecules appear to be suitable for oral administration, Sarver says, and "anything that increases potency and decreases toxicity is a go."

Sarver cautions that many promising ideas stumble in the final steps of clinical testing.

For Luminide to be closer to an ideal approach to treating AIDS, Sarver says she'd like to "tweak" it with Mills to target only infected cells or systems. "Specificity is the missing link here."

Immunologist Dr. Gillian Woollett of Pharmaceutical Research and Manufacturers of America agrees that targeting will be important. "It's a neat idea and there will be a lot of companies keen to talk with him. But he has some hurdles ahead of him."

If clinical trials for one drug are positive, Woollett says, "Maybe the floodgates will open. And AIDS is not a bad place to start. This system seems especially good for use in blood, and oxygen-free radicals are used most by the immune system."

But AIDS and other infections aren't the most likely killers lurking in peoples' bodies, Mills points out.

"Let me tell you how you're going to die," he casually offers. "I'll say you're going to die of heart disease, cancer, or a stroke, and I'll be right 95 percent of the time."

That's why Mills has another project in the works at Harvard that he says could revolutionize diagnostic medical imaging.

"The guy is amazing," remarks Dr. Samuel Patz, an assistant professor at Harvard Medical School, with an appointment in the Department of Radiology at the university's Brigham and Women's Hospital in Boston.

"I've worked with him on his medical inventions and he's contributed some nontrivial creative ideas about a new imaging technique. It's very exciting and has some real possibilities," Patz says.

Today's scanners work best by giving doctors two-dimensional snapshots of the human body. Mills claims he's designing a scanner that may, for example, allow a surgeon to take a live-image virtual reality walking tour through a patient's beating heart (it could also be used to scan industrial materials).

Mills expounds. "The machine would work by distinguishing differences made in the magnetic field at a location by the material itself, like bone versus lung." Data would stream into a computer through parallel channels from up to a million points, providing far sharper relief than anything currently available.

And if a strongly magnetic substance like iron were added to the bloodstream, through an injection of Geritol for example, "the vascular system would light up." That would allow a doctor and patient to see blood vessels growing to feed a tumor, or clots and cholesterol, without any invasion.

"After seeing this, you wouldn't eat that cheesecake if I told you not to," Mills quips.

The calculations involved are Herculean, says Patz, but "Randy has worked out the mathematics. I'm convinced of that."

Because the scanner would largely rely on existing hardware, "if someone like a General Electric were to get behind this, we could have a prototype in six months," Mills says.

Despite Mills's grand ambitions, he admits to being vexed by complexities in a genetic sequencer he envisions, and he dismisses dreams of immortality.

"Life is probably limited by arterial flow in the brain. Those vessels wear out. Maybe someone will find a way of drilling out and retubing them, but then they'll find something else. There's always a weak link."

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