When I was eleven I watched a cancer patient die. Doctors thought that they could remove a tumor from his throat, but surgery revealed that the tumor had metastasized. After a few rounds of radiation and chemotherapy—just three months after I saw this man sipping a beer in his favorite chair—he was utterly defeated and hardly recognizable lying on his deathbed.

Soon after, one of this man’s sons—a heavy drinker like his father—was cited for drunken driving for the second time. His brother, fed up, pinned him against a wall and said, “You’re acting like a bum, and your boozing is gonna ruin your life!” It wasn’t pretty, and could’ve made things worse, but it worked. The drinking stopped. And it never started again.

Many families share similar or worse stories. And each family hopes for a cure, even though cancer and addiction have been entrenched in our society for centuries. Is this hope realistic? In 2050, when I might be sitting in my favorite chair, will we be rid of these scourges?

State of the union

In 2000, cancer killed more Americans than anything except heart disease, leaping past six other leading causes of death in less than one hundred years. And in 2005 it passed heart disease for the first time as the leading killer of Americans under eighty-five. Back in 1900 cancer accounted for less than 4 percent of all deaths. Today, it’s nearly 25 percent.

The percentage jumped in part because more cancers are accurately diagnosed today than in 1900. Our Western diet and new carcinogens in the environment account for some of the rise. Perhaps most importantly, treatments and prevention methods for other diseases improved, allowing people to live longer but succumb to cancer later. According to the American Cancer Society, mortality rates for other major killers plummeted between 1970 and 2002—stroke by 63 percent; heart disease by 52 percent; and accidents by 41 percent. During the same span, cancer mortality rates decreased by less than 3 percent.

Still, Shelton Earp, director of Carolina’s Lineberger Comprehensive Cancer Center, says two-thirds of the 1.5 million Americans annually diagnosed with cancer are cured, usually because the disease is caught early. But some cancers evolve quietly, without detection. They metastasize—break free of their capsules, as Earp says, and spread. “Those are the tumors we can’t treat very well.”

But things are changing, he says, because of better use of early detection and personalized medicines that supplement radiation, surgery, and existing chemotherapy drugs. Earp points to Herceptin, a drug now used to treat the 20 percent of breast cancer patients who over-express a molecule called HER2.

“This is one of the first examples where understanding the biology of a particular cancer subtype resulted in a targeted drug that has become the standard of care,” Earp says. Herceptin works best in concert with chemotherapy, and such combinations, he says, will become more common during the next two decades.

“The 2050 dream is dropping the chemo part and just treating tumors with targeted agents—maybe multiple ones—which would either cure the cancer or, more likely in some instances, suppress it,” Earp says. “It’s possible that we will turn some forms of cancer into chronic diseases, so that you might have cancer but it would be like having diabetes.”

One reason for such hope is genetic analysis. Geneticist Chuck Perou pinpointed five biologically distinct breast tumors that come from at least two cell types—basal-like and luminal epithelial cells. This knowledge—gained by using DNA microarrays that allow scientists to view thousands of genes simultaneously—could unveil more targets for drugs. It has already helped explain one reason why breast cancer kills more African American women than white women (see race and breast cancer).

Looking ahead, Perou says, “I think we’ll get ten standard treatments for a disease like breast cancer in the next ten years, whereas five or ten years ago we only had one or two.”

Making it personal

Earp says that by 2050 genetic analysis will help family doctors, not just geneticists, predict which people will inherit genetic mutations or predispositions to cancer. Someone with a predisposition might never get cancer unless a carcinogen triggers the disease. Genetic research, he says, might also show how individual patients will react to chemotherapy or medication so that doses can be better regulated.

This is one reason why Earp, Perou, and geneticist Jim Evans are excited about the Thousand Dollar Genome project, an NIH-funded effort to create technology so that sequencing a patient’s entire genome costs a thousand dollars instead of a million.

As a clinical geneticist, Evans helps determine if current cancer patients are at risk of recurrence due to inheritance, having an unusual cancer, or being diagnosed at a young age. He also consults with patients on prevention options, some of which—mastectomy and preventive drug therapy—will probably seem draconian in fifty years. But right now they are real options for people at high genetic risk. People with some other diseases, such as Alzheimer’s disease, have no preventive options.

Evans hopes that by 2050 treatments and prevention methods for Alzheimer’s and other diseases catch up with genetic testing. We might even develop different ways to cure genetic disorders.

Between hope and reality

Gene therapy could be one such way. In simplest terms, gene therapy is replacing bad genes with good ones to cure a disease. In the 1990s, scientists were excited, the media grasped the basic idea immediately, and people expected quick results. But some early clinical trials didn’t work. In 1999, a patient with liver disease died after receiving gene therapy. That triggered a backlash and stigmatized the procedure.

Even some successful trials drew criticism, says Jude Samulski, director of the UNC Gene Therapy Center. Gene therapy cured nine of eleven patients with severe combined immunodeficiency disease—or bubble boy disease—but two patients got leukemia because the therapy somehow turned on the cancer-causing gene LMO2. Chemotherapy helped those two patients, who are now in remission. (In another study, twenty-four immunodeficiency disease patients were cured, so far without side effects.)

Conversely, other drug trials have far worse results but are often deemed successful. Gene therapy has a stigma, Samulski says, in part because people think scientists are messing with our basic building blocks. We expected too much too soon, he says.

“When the human genome was sequenced, everybody thought it would be like a recipe book. But like most things, there’s more mystery to it.”

Image: Jude Samulski.

Viruses deliver genes to cells. Image: Jude Samulski.

Click to read photo caption. Image: Jude Samulski.

Gene therapy, he says, requires sophisticated understanding of several things, including molecular biology, gene regulation, and virology—Samulski’s specialty. He takes a virus, strips out the infectious parts, and builds the virus back up so it can act like a shuttle delivering cargo—normal genes.

In one trial, he injected a shuttle virus into a mouse with muscular dystrophy, and now the mouse can run on a treadmill. After many steps, scientists are currently making sure that the treatment is safe for humans. If that checks out, then the therapy will be tested as a cure.

So will gene therapy cure some forms of cancer by 2050?

“Absolutely,” Samulski says. “No doubt about it. We’re not even in the infancy of this, we’re in the womb, but that’s an exciting and important place to be.”

It’s exciting, but complex and time-consuming, and few scientists understand this better than pathologist Oliver Smithies. For fifty years, he’s been unveiling genetic mysteries in lab animals. His technique, gene targeting, allows scientists to replace normal genes with mutated ones in the embryonic stem cells of female mice. The mutated stem cells are returned to female mice, whose offspring then develop a particular disease. The technique led to the creation of thousands of varieties of genetically engineered mouse models, each with a particular disease biology that scientists can study and use to test potential cures. This method is quickening research at UNC and around the world.

Smithies says that by 2050 some diseases that originate from a single inherited defect will likely be cured. “But these single-defect diseases are uncommon,” he says. “The common inherited problems, like high blood pressure, are very complex and we don’t know all the factors. There are many little things in different combinations that make it difficult to sort out.”

It will take years—a lifetime in some cases—to get a handle on such genetic problems. Huge breakthroughs are possible, Smithies says, but most of the time progress comes incrementally.

Carolina researchers are getting close to creating cancer mouse-models that mimic human tumors, Earp says, and these will dramatically speed the testing of new targeted therapies and novel means of early detection.

“This will be very important, for example, in lung cancer, where we don’t have curative therapy, and we desperately need better means of early detection,” he says.

Nanotechnology, Earp points out, also offers hope for new treatments and detection methods. Carolina researchers are exploring several options. For instance, chemist Joseph DeSimone is using techniques from the electronics industry to develop nanoparticles that carry conventional cancer-killing agents. The surfaces of these particles are laced with peptides or nucleic acid aptamers designed to seek out only tumor blood vessels and tumor cell receptors. This way, normal cells won’t be harmed as they are with chemotherapy.

Also, chemist Wenbin Lin is developing magnetized nanoparticles that enhance brain MRIs so doctors can see a patient’s brain tumor more definitively, and also determine more quickly whether therapy is working. And since the nanoparticles are magnetic, it might be possible to use a magnetic field outside the body to direct anti-cancer nanoparticles into tumors. For this, Lin is working with physicist Richard Superfine, who created the magnetic field technology, and is using one of Terry Van Dyke’s engineered mice that develop brain cancer.

The unknowns

New and better treatments will come, scientists say, but Earp points out that “there’s always the law of unintended consequences.” Sometimes anti-cancer drugs cause other serious problems.

Evans says that there are intricate interactions among environment, genes, behavior, medicine, and chance that we don’t understand at all.

“Genetics is very important,” he says, “but it’s not the whole ball game.”

For instance, American women—who are more susceptible to breast cancer than women from any other nation—are ten times more likely to develop breast cancer than Japanese women. But as soon as Japanese women come to the United States, their risk increases substantially, and the next generation of Japanese American women face almost the same risk as American women. Is it diet, pesticides, food additives, pollution? All of the above? Earp says, “I think it’s the food. There’s a change in human physiology that results from our Western lifestyle and diet. It’s unlikely to be growth hormone in milk or pesticides. Every time we’ve looked at that, the link to cancer just hasn’t been found.”

It’s tough to keep track of the many epidemiological studies about one food causing this or helping that, especially when various foods affect people differently. (See Endeavors, Spring 2005, “Ten Simple Rules.”) Some health behavior specialists suggest that researchers should come up with better ways to study diet. In a perfect world, researchers could make sure that participants in epidemiological studies maintain their eating habits for much longer periods of time so that the effects of food, vitamins, or minerals can be better understood. Also, nutrition might play a critical role during certain times of life. What if our diets and environment—years before we have kids—are the underlying sources of problems that affect our children way down the line?

The addiction dilemma

There’s still much that we don’t know about cancer, even though it’s been classified as a disease for millennia. On the other hand, there is still disagreement in the general public about whether the age-old problem of drug addiction is a disease or a personal weakness. And although addiction is a huge public health problem, few treatments have broken the cycle of drug use, abstinence, and repeated relapse. People battling drug dependency still face a stigma, says psychologist Linda Dykstra, even though research has clearly revealed that addiction is a disease of the brain, involving specific brain regions and neurotransmitter systems.

Thanks to these findings, researchers are developing new treatments for drug dependence, especially for opiate dependence—the most recent one being buprenorphine. Dykstra’s lab was one of the first to reveal that buprenorphine has many of the same pharmacological properties as drugs such as heroin, and therefore can suppress heroin withdrawal in a similar way to methadone. Buprenorphine, though, doesn’t produce as many unwanted effects as methadone. And a doctor can prescribe it, so patients can avoid the stigma of visiting a methadone clinic. Scientists are now trying to develop a sustained-release form of buprenorphine that would require only a single injection once a month; this is a good example of an important incremental improvement for addiction treatment. A catch-all cure for addiction is unlikely, Dykstra says, even as genetic research unfolds swiftly.

“It’s not clear how new knowledge about genetics or individual susceptibility to drug addiction will advance the treatment of drug dependence,” Dykstra says. “But I don’t think addiction will go away. Simply popping a pill to cure addiction flies in the face of all we know about this disease right now. In time, we’ll certainly have better treatments, and it’s likely that many of these will lead to better compliance. Medications will have fewer side effects; they will be delivered in more convenient forms, perhaps even automatically released into the body in response to implanted devices that monitor brain circuits. Treatments will be less likely to disrupt work patterns and treatment regimens will be easier to follow.”

Dykstra says that behavioral support systems will likely always be a necessary component of treatment. “Addiction research is a relatively young field. It’s likely that recent advances in biomedical and behavioral sciences will provide knowledge needed to curtail the devastating cycle of relapse that so many drug-dependent people face. It’s also likely that we will more readily view drug dependence as a treatable disease.

“Current treatments for diabetes or even heart disease focus on managing the problem, not necessarily curing the disease,” she says. “Perhaps the same criteria should be applied to drug dependence.”

Society has already altered the way it views some forms of addiction. When Dykstra taught a course on drugs and human behavior, students watched scenes from old movies in which most characters had a drink in one hand and a cigarette in the other.

“The students were struck by that,” she says. “We’ve changed the way we view smoking in our culture.”

Alcohol’s grip on the brain

Fulton Crews, director of Carolina’s Bowles Center for Alcohol Studies, says that a similar change could happen with alcohol, to which 7 to 15 percent of Americans will be addicted sometime in their lives. “There’s a huge industry dedicated to teaching people that they are more attractive and interesting when holding an alcoholic beverage.”

That’s how the cigarette industry operated until health organizations attacked tobacco companies for basically selling nicotine addiction and hiding evidence that proved it. Most drinkers, though, are not alcoholics. So there’s not a direct parallel.

But Crews says that kids in their early teens who start drinking regularly have a 50 percent chance of becoming alcoholics, compared to 7 percent if they start at twenty-one. The developing adolescent brain of a regular drinker is learning to depend on alcohol, he says.

The alcohol industry won’t block efforts to curb underage drinking, Crews says, and parents will have to stop thinking of drinking as a right of passage. His center developed an educational kit to help science teachers show students the effects of alcohol on the brain.

Beyond prevention—and treatment programs such as Alcoholics Anonymous and cognitive behavior therapy—Crews says that there will be more drug therapies for addiction by 2050.

“There’s a hypothesis that those who respond well to one alcoholism medication called naltrexone actually have a genetic factor that makes them responsive,” Crews says. “If that’s true, then we’ll be able to genotype people and determine who should get it, and we’ll then have a robustly responsive group.” More people will use the drug, and pharmaceutical companies will produce more and better drugs, which is what happened with anti-depressants.

“If we can block that early progression of alcoholism in teens and improve therapy, we’ll have a huge impact by 2050.”

Maybe there won’t be catch-all cures for cancer and addiction by 2050, but what seems most likely is that fewer eleven-year-olds will watch seventy-year-olds succumb to cancer in three months, and there will be more ways to treat both diseases.

The man who quit drinking back in 1982 is thankful for the progress that science has already made. He took care of his widowed mother for twenty-two years until the very day she died. Then he got prostate cancer. Doctors found it early, and today he’s fine. He enjoys life, especially when he gets to bicker with his brother on just about every topic, except drinking.