Nanomedicine's brave new world

In just a few years, doctors will know everyone's genetic identity. This knowledge will be a blessing -- and a curse.

Published November 28, 2005 12:14PM (EST)

It's the not-too-distant future, say 2016. You have been diagnosed with Stage III melanoma. Cancer has metastasized throughout your body. Just 10 years ago, in 2006, the choice of treatment would have been based on the type of primary cancer, the size and location of the metastasis, your age, your general health and your treatment history. Your prognosis would have been gloomy. But that was back in 2006, before we entered the era of nanomedicine.

In 2016, your doctor will be capable of scanning your entire genome in a few minutes. She will do this because every cell has a different gene expression pattern or profile. When a cell becomes cancerous, this profile changes. Your Stage III melanoma has a unique, schizoid genetic signature reflecting both a skin cell heritage and a newly acquired outlaw metabolism. Your doctor will explain that while your cancer has a great deal in common with other Stage III melanomas, it is not exactly like any other. Your doctor knows this because for the past few years DNA from virtually every melanoma patient in the U.S. healthcare system has been routinely extracted, scanned and deposited in a national database. This population of sequences, fully analyzed and with a user-friendly graphic interface, is available in real time. Searching this database for any specific cancer sequence will be about as difficult in 2016 as finding Madonna's birthday on Google is today.

The exam room of 2016 reflects a rainbow of nanomedicine paraphernalia. Diaphanous pink microtubes sit in bubble packs like sets of false nails. Red motorized pipettes hang in translucent blue plastic racks like designer tool kits from the Starship Enterprise. Shelves are filled with what appear to be airline-size single-serving cereal boxes with very slick, stunningly bright labeling. These boxes contain individually packaged, ready-to-use diagnostic kits with exciting brand names -- DNA Warrior, Mighty Clone or Gene Catcher. An invisibly small drop of your body's fluid is injected into the DNA Warrior, which is a cylindrical cassette the size of a pinhead. This cassette is slotted into the Sherlock Genomes molecular diagnostics system.

From the outside, this "system" appears considerably less complex than your current cellular telephone. Inside, a single melanoma cell is purified from your blood via solid-phase fluorescent immunoaffinity chromatography, a technique in which a single cancer cell is "hooked" from amid millions of its healthy companions using a synthetic antibody molecule and "reeled in" on the beam of light produced when the two unite. Twenty years ago this technique required a million-dollar instrument the size of a 767 cockpit and a dedicated operator. Now it is little more than routine blood work.

Once purified, the renegade cell is moved via electroosmotic microfluidic channels to a lab chip that, in another venue, could pass for a credit card. Electroosmosis uses the charged molecules on the surface of the channel itself to cause a solution to flow in a specific direction. This will only work when a tube or channel is extremely small. Microfluidics use pipes the size of a human hair to create plumbing systems that empty into reaction chambers much smaller than the head of a pin. This enormous volume is dictated by the dimensions of your humanity -- any smaller and a living cell wouldn't fit inside. On the lab chip, a purified cancer cell relinquishes its cache of chromosomes and within seconds your entire genome has been sequenced. That bears repeating. In a few years single-molecule DNA sequencing will be a reality. The 2.91 billion bits of biological data that bestow your unique genetic identity will be available virtually anytime for the cost of a routine blood test. Sound far-fetched? Two weeks ago J. Craig Venter, the genomics entrepreneur who paced the U.S. government to the completion of the Human Genome Project, announced that he hopes to offer $10 million as a prize (he originally pledged $500,000) for automated DNA sequencing technology that can decode a human genome for $1,000. At that same conference, a commercial instrument capable of sequencing 1 billion bases, or chemical groups, of DNA per day was unveiled.

A machine that "shreds" a billion bases of DNA a day could burn through the human genome in 72 hours. Yet we fully expect that this phenomenal accomplishment will be eclipsed within a few years by nanoengineering. Around the world, research teams are closing in on single-molecule DNA sequencing technology. One group has published a design for an instrument that could place a million single-molecule sequencers on a device the size of a postage stamp. To accomplish this, each sequencer will have an operating volume of one zeptoliter -- much less than one billionth of one billionth of a liter! There can be no doubt that within a few years, most individuals will have their genome sequenced and encoded as part of their medical record. And this is just the beginning.

No equation can represent the astonishing technological trajectory we are on. The trek from Olduvai Gorge to Mesopotamia -- from Homo habilis to the wheel -- took 1.5 million years. A mere 5,500 years took us from the wheel to the double helix. Then 50 years to the human genome. Nanotechnology, our ability to build molecular devices with atomic precision, is the transcendent culmination of our co-evolution with tools. With the advent of nanomedicine, we will turn these tools inward.

The National Cancer Institute's fact sheet on nanotechnology and cancer says, "Most animal cells are 10,000 to 20,000 nanometers in diameter. This means that nanoscale devices (having at least one dimension less than 100 nanometers) can enter cells  to interact with DNA and proteins. Tools developed through nanotechnology may be able to detect disease in a very small amount of cells or tissue. They may also be able to enter and monitor cells within a living body."

According to the National Institutes of Health, nanotechnology could create devices capable of reporting the onset of cancer at the exact moment of molecular metamorphosis, long before today's tests are effective. The key, as with DNA sequencing, is single-molecule sensitivity. One approach will use individual carbon nanotubes (molecular rods about half the diameter of the DNA molecule itself) to literally trace the physical shape of a single DNA molecule the way a phonograph needle traces a vinyl record. Another early-detection strategy will use the quantum dots (Q-dots) described in a previous article. Latex beads filled with these crystals will be designed to bind to specific DNA sequences. When the crystals are stimulated by a flash of light, they emit colors that light up the sequences of interest. By combining different-sized quantum dots in a single bead, scientists will create probes that release a spectral bar code specific for each type of cancer mutation.

Nanotechnology will also create tools to eradicate cancer cells without harming healthy cells. In therapy applications, as in detection, single-molecule recognition is the key. Each magic nanobullet will home in on a specific, targeted molecular structure. In fact, the goal is to treat cancer like an infectious disease. We will be vaccinated with nanoparticles that continuously circulate through the body. This cancer vaccine -- really a primitive cancer-killing nanobot -- will detect molecular changes, assist with imaging, release a therapeutic agent and then monitor the effectiveness of the intervention.

How close are we to cancer-killing nanobots? The NIH Web site talks about nanoshells -- minuscule beads coated with gold. By manipulating the thickness of the layers constituting the nanoshells, scientists will design them to absorb specific wavelengths of light. The most useful nanoshells are those that absorb near-infrared light, which can easily penetrate into the body. Absorption of light by the nanoshells generates a lethal dose of heat. Researchers can already link nanoshells to antibodies that recognize cancer cells. In a "magic bullet" scenario, nanoshells will seek out their cancerous targets. Once they have docked, they will be zapped with near-infrared light. In laboratory cultures, the heat produced by light-absorbing nanoshells killed tumor cells while leaving neighboring cells intact. Experts believe quantum dots, nanopores and other devices may be available for clinical use in five to 15 years. Therapeutic agents are expected to be available within a similar time frame. Devices that integrate detection and therapy could arrive in the clinic in about 15 to 20 years, which means a cure for your Stage III melanoma and other forms of cancer could arrive within your lifetime.

Things like quantum-dot bar codes and magic bullets made of gold nanoshells are in the lab right now. But these therapies are not pure nanotechnology. Rather, they are a hybrid of nanotech, biotech and conventional chemotherapy. For true believers, the real revolution will come when scientists start building molecular devices from their component atoms. The wildest dreams of nanomedicine are displayed in the Nanomedicine Art Gallery, where you can view illustrations and animations of futuristic phenomena including bronchial airbots, bacterium zappers, blood probes and microbivores. According to the artist, the microbivore is "a theoretical nanorobot" that will cruise our bodies in the relentless pursuit of bad actors. If we can program these bots to eat bacteria, we can program them to eat cancer cells: So microbivores will quickly morph into the sheriffs of the nano-West, clearing out evildoers and varmints of all stripes.

Not everyone believes that molecular assemblers will be viable. But with or without them, it's undeniable that revolutionary nanomedicine-based tools are on the way. And when they arrive, they'll turn our world upside down -- and not always in a good way.

Nanomedicine will be one of the greatest boons in human history. It could eventually allow doctors to save millions of lives and prevent entire populations from contracting various diseases. But it could also push the cruel divide in medical access that already exists to the absolute limit. Those with access to nanomedicine will face a different cruel divide, created by the inevitable time lag between the availability of diagnostic tools and efficacious cures. This gap, perhaps a decade or more, will raise its own set of unprecedented ethical questions -- ones that will get even thornier once those cures are available. In the near future this tsunami of nanomedical choices could literally drown our healthcare and insurance systems.

Some of these choices involve elective genetic selection. If we can find and reprogram cancer or diabetes genes, we can certainly find and reprogram genes for simple physical traits like height or eye color. Genetic engineering raised these questions, but nanomedicine ensures they are here to stay. The physiological genetics of more complex traits like personality, sexual orientation and antisocial behavior will not be far behind. Likewise, nanobots that circulate and release chemicals on cue need not be limited to medicinal applications. (Think of the fate of the liquor industry when ethanol-releasing bots are online.) The ethical and financial implications of these developments are obvious.

But long before we have cures, nanomedicine-based diagnostics will create its own vortex of urgent healthcare issues. In the less distant future, say 2012, single-molecule DNA sequencing will mean that your genome will become an integral part of your medical record along with all sorts of other biomolecular identifiers. Beyond DNA sequencing, the tools of nanobiotechnology will allow us to predict both the metabolic state and the ultimate fate of cells and tissues with increasing precision. As a result, medicine will enter a phase we might call "Cassandra and the bell curve" -- an uneasy situation in which we can predict the future, but only partially, with the result that we never get a truly specific prophesy to believe in.

On a long enough timeline, this means a new arsenal of weapons for, among other things, the war on cancer. It will be the promised golden age of biopharmaceuticals. But meanwhile the smart money is in diagnostics.

Lots of companies are eager to get in on the ground floor. In 2000 Celera Genomics made history as the private company that forced an international consortium of developed nations to share the glory of sequencing the human genome. Celera still markets the intellectual property created by this accomplishment, but the heavyweight champion of DNA sequencing is now vigorously pursuing a career in the ring of molecular diagnostics. Celera Diagnostics is focusing its discovery efforts on "identifying genetic variations associated with common, complex diseases." And it is "working to develop new diagnostic products and to improve human health through an approach we call Targeted Medicine."

In theory, targeted medicine (aka personalized medicine) sounds awesome, and whenever it's viable most of us will want it. But before it is perfected, it will leave all of us -- patients, doctors, governments, healthcare providers and insurance companies -- in a frustrating, confusing and sometimes tragic limbo. And even after it is viable, it will raise huge questions, ones for which there are no easy answers.

Consider recent progress in the molecular diagnostics of breast cancer. Breast cancer patients with the same stage of disease can have markedly different treatment responses. In practical terms this means that no woman with breast cancer, even from the same demographic, has exactly the same illness as any other. Each woman's cancer has its own unique genotype. Currently, conventional medical treatment with chemotherapy can reduce the risk of metastases by approximately one-third. However, clinical data also show that 70-80 percent of patients receiving chemotherapy do not, in fact, benefit from it. Put simply, at least seven out of every 10 women patients endure chemotherapy for nothing. The agonizing current dilemma for doctors and patients is that chemotherapy will prolong life for three of the 10 women, but we can't determine which three.

The plan is to use gene-scan data to predict which patients will benefit from chemo. In 2002, workers in the Netherlands used a DNA microarray to develop a gene expression profile that outperformed all currently used clinical parameters in predicting disease outcome. They suggested that their findings provided a strategy to select patients who would benefit from adjuvant therapy (i.e. chemotherapy and/or radiation). This information, originally published as basic research, reached the public in articles with encouraging titles like "New Study Could Cut Breast Cancer Overtreatment." In this article, a member of the research team was quoted as saying, "We have confirmed that we can predict with 90 percent certainty that a patient will remain free of breast cancer for at least five years." Since then things have improved, but only incrementally.

The key concept here is "a patient" -- i.e. you or you but not her. This is the world of personalized medicine, made possible by gene-scan-powered molecular diagnostics. In a perfect future, these gene scans will tell us which seven women can decline chemotherapy. But in the immediate future, these scans will only tell us the probability that a woman can safely decline treatment. This probability will get better every year, but when will molecular diagnostics be reliable enough to base life-and-death decisions on?

This work on breast cancer is, literally, just the tip of the iceberg. Long before single-molecule DNA sequencing (or $1,000 genomes) hits the marketplace, thousands of labs around the world will be using standard biotechnology instrumentation such as DNA microarrays to create molecular profiles of people and populations. These profiles will be used to develop diagnostics for every major disease and disorder. Like reproductive cloning, this technology takes us to the very essence of what it means to be an individual. Unlike cloning, the field of molecular diagnostics is receiving almost universal acclaim as a worthy goal for the future of medicine.

"A little knowledge is a dangerous thing. So is a lot." Once again, Einstein provides the appropriate homily. Like the manifestation of Moore's law in computing, improvements in molecular diagnostics and nanomedicine are astonishing but still leave us far short of where we need to be. Unlike for the next generation of semiconductor chips, the time to market for each new product in targeted medicine will be measured in human lives. Before we have the set of genetic profiles or the tools to treat all breast cancers, we will know enough to modify the treatment regimes of a few breast cancers, then enough to help some breast cancers, then enough to help many. At what point will this knowledge be allowed to enter the healthcare system? Will everyone have access to it? Who will pay for it? And who will make all these decisions?

Theoretical microbivores notwithstanding, no one seriously questions the transformative power of nanotechnology for human health. But it is equally true that no one understands how this revolution in personal medicine will impact a healthcare delivery system that, for many, is already hopelessly complex and frustrating.

New pharmaceuticals now reach the marketplace by showing efficacy in clinical trials based on the average response of a patient population. But nanotech-based diagnostics will open the option of personalized medicine, which, by definition, means that there is no longer an "average" response to therapy. Each patient's treatment regime should be unique. But there's no way we can do that with our existing healthcare system.

The reality is that we will have a world of molecular diagnostics long before we have a world of molecular cures. In the immediate future, gene scans will guide the use of conventional or biopharmaceutical therapies. In this world, women diagnosed with breast cancer will be advised that postoperative chemotherapy will not extend their survival. But this advice will come with a statistical caveat. More correctly, each patient will get her own prognosis with her own statistical caveat. The woman, her doctor, her insurance company and the government will all receive a statistically weighted prediction about her future. How are society, the government, private industry and the individual going to deal with this situation? The first act of the drama called personalized medicine will still be written by nature, the second by biotechnology, the third by nanotechnology. But who or what will be the author of the finale?

Within a generation, nanotechnology will completely invert our concept of medication. Today vaccines come with literature warning of a low probability that "some people" are subject to side effects or complications. In the age of nanotechnology-driven personalized medicine there will be no such thing as "some people." Theoretically, you should be able to know if you are that one in 10,000. But will you want to know? Will you be allowed to know? What will it cost to know, and who will pay? What if you could have known but didn't ask ... or weren't told? And perhaps most disturbing of all: What if it turns out to be too expensive for society to pay for universal diagnosis, let alone treatment? Could we enter a world in which the rich live on and on, while the poor are denied even the knowledge of the disease that is inexorably killing them and whose prevention is at hand?

Our already faltering system was never designed for, nor can it handle, the flood of molecular diagnostic data that will reach biblical proportions within a decade. Just when we thought the web of healthcare delivery couldn't get any more tangled, patients, doctors and HMOs are about to meet the world of personal genome sequencing. Then will come gold nanoshells and, perhaps a bit later, microbivores.

And by the way, the proliferation of unique molecular identifiers will make medical privacy an impossibility because, ultimately, these types of data cannot be encrypted. The medium is the message. Millions of people have your fasting-blood-sugar value, but no one else on earth has your gene sequence. Get the idea? Any single-molecule-based nanomedical procedure could identify you beyond a shadow of a doubt. Yet a fundamental principle of nanomedicine is that billions of single-molecule fingerprints from DNA, RNA and proteins will be routinely available for diagnostic and therapeutic strategies. Which is the same as saying farewell forever to anonymity for your health records.

O brave new world, that has such genes in it!

By Alan H. Goldstein

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