Robots in the bloodstream: the promise of nanomedicine

February 26, 2002 by Robert A. Freitas Jr.

In just a few decades physicians could be sending tiny machines into our bodies to diagnose and cure disease. These nanodevices will be able to repair tissues, clean blood vessels and airways, transform our physiological capabilities, and even potentially counteract the aging process.

Originally published December 2001 in the Novartis Journal Pathways. Published on February 26, 2002.

It is the year 2031, and the age of advanced nanomedicine has arrived. A young man arrives at his physician’s office with a mild fever, nasal congestion, discomfort and a cough. The physician pulls from her pocket a lightweight, handheld device resembling a pocket calculator. She unsnaps from it a cordless, self-sterilizing, pencil-sized probe and inserts it into the patient’s mouth as if it were a tongue depressor. On the tip of the probe are billions of molecular assay receptors, mounted on hundreds of self-guiding retractile stalks. Each receptor is sensitive to the chemical signature of a specific kind of bacterium or virus. “Ahhh,” says the patient, and a few seconds later a three-dimensional, color-coded map of his throat appears on the display panel of the device. Beneath the map scroll columns of data, revealing the unique molecular signature of a known and unwelcome bacterial pathogen.

With the diagnosis complete, the infectious microorganism can be exterminated. No need for antihistamines, cough drops and a week-long course of antibiotics. The physician keeps several generic classes of nanorobots in her office for just such a circumstance. Using a desktop appliance in her office, she programs billions of nanorobots to find, recognize and destroy the particular microbial strain. The nanomachines are suspended in a carrier fluid that the patient inhales into his lungs, after which the mobile devices march down the patient’s throat, propelled on tiny legs. Following a search pattern, the nanorobots ingest and destroy the harmful bacteria they encounter using mechanical and chemical phagocytosis. The patient feels nothing: nanorobots are the size of bacteria, which constantly crawl on and inside the body without ever being noticed. After several minutes, the physician activates an acoustic homing beacon to guide the nanorobots back into the patient’s mouth, where she retrieves them through a collection port on the tip of the homing device. A further survey with the original diagnostic probe reveals no evidence of the pathogen.

This is a wonderful vision of medicine in the future, but how do we get there from here? Nanotechnology (“nano” from the Greek word for dwarf) involves engineering and manufacturing at the molecular, or nanometer, level. One nanometer is one billionth of a meter, about the width of six bonded carbon atoms. How does one build at this scale?

Scientists at New York University have adopted the self-assembly approach, and have succeeded in producing complementary strands of DNA that can zip themselves into complex structures. They have built cubes, octahedra and other solids made of just a few thousand nucleotides each, by the billions per batch. Meanwhile at Cornell University, researchers have genetically engineered a natural biomotor normally found in the enzyme ATPase to allow it to incorporate nonbiological parts such as a silicon nitride bar 100 nanometers in length, making the first artificial hybrid nanomotor (see ‘In Pictures’ side panel, 1). In a microscopic video presentation, dozens of bars attached to artificial molecular motors in a large precise array could be seen spinning at 200 revolutions per minute, like a field of tiny propellers.

Another way to build at the molecular level is by positional assembly – picking and placing molecular parts exactly where you want them. A device capable of positional assembly would work much like the robot arms that manufacture cars on automobile assembly lines, or like the ribosome that assembles amino acids one by one into proteins in our cells. The US engineering firm Zyvex Corp. [for whom the author works as a research scientist] is aiming to be the first to create an artificial molecular assembler using positional assembly to manufacture atomically precise structures.

Elsewhere, researchers at Harvard University have constructed the first general-purpose “nanotweezers,” using a pair of electrically controlled carbon nanotubes (side panel, 2). These have successfully grasped 300-nanometer clusters of polystyrene spheres and extracted a single semiconductor wire 20 nanometers wide from a mass of entangled wires. The scientists hope eventually to produce nanotweezers small enough to grab individual large molecules.

Such nanoresearch will eventually lead to applications affecting almost every aspect of modern life, including the home, transport, computers, energy and the environment. Some of the most important and life-changing applications, however, are likely to be seen in medicine. We may see the first nanomedical materials and devices in use within the next few years. Scientists at the University of Michigan’s Center for Biologic Nanotechnology are currently pursuing the use of dendrimers as a safer and more effective genetic therapy agent. Dendrimers (side panel, 3) are branching synthetic molecules that can be grown nanometer by nanometer to reach the desired size. They take on a spherical shape, and have sufficiently large openings and cavities to carry small molecules – dendrimers could therefore be used to sneak DNA into cells without triggering an immune response. At the same center, researchers have reported using dendrimer “nanodecoys” to trap and deactivate influenza virus particles.

Relatively simple nanodevices could soon offer cures for major conditions such as diabetes. Researchers at Ohio State University and the University of Illinois have managed to construct silicon-based microcapsules highly perforated with “nanopores,” each as small as 20 nanometers in diameter. These pores are large enough to allow small molecules such as oxygen, glucose and insulin to pass through, but are small enough to impede the passage of much larger immune system molecules such as immunoglobulins. Microcapsules containing islet cells could be implanted beneath the skin of some diabetes patients, temporarily restoring the body’s delicate glucose control feedback loop without the need for powerful immuno-suppressants that can leave the patient at serious risk for infection. The same method of encapsulation could be used to treat other enzyme- or hormone-deficiency diseases. Encapsulated neurons could also be implanted in the brain and then electrically stimulated to release neurotransmitters, possibly as part of a future treatment for Alzheimer’s or Parkinson’s disease.

Artificial “biobots” could be in our bodies within five to 10 years. Advances in genetic engineering are likely to allow us to construct an artificial microbe – a basic cellular chassis – to perform certain functions. These biobots could be designed to produce vitamins, hormones, enzymes or cytokines in which the host body was deficient, or they could be programmed to selectively absorb and break down poisons and toxins. A new company called engeneOS, Inc., founded in late 2000, has already announced plans to develop artificial Engineered Genomic Operating Systems using the techniques of molecular biology. These systems will comprise a library of component device modules and proprietary modular components. This will allow the engineering and construction of programmable biobots with novel form and function.

The greatest power of nanomedicine will emerge in the longer term, perhaps 10-20 years from now, when we learn how to design and construct complete artificial nanorobots using strong diamond-like materials, nanometer-scale parts, and onboard subsystems including sensors, motors, manipulators, power plants, and molecular computers.

One example is an artificial mechanical cell called a respirocyte, which could be used to keep a patient’s tissues safely oxygenated for up to about four hours (at maximum dosage) if their heart has stopped beating. These cells (side panel, 4) could also enable a healthy person to sprint at top speed for at least 15 minutes without breathing, or to sit underwater at the bottom of a swimming pool for hours. Still entirely theoretical, the respirocyte is a micron-wide spherical nanorobot made of 18 billion atoms precisely arranged in a diamondoid structure to form a tiny 1,000-atmosphere pressure tank. Several billion molecules of oxygen and carbon dioxide can be absorbed into, or released from, this tank using computer-controlled molecular pumps powered by serum glucose and oxygen. External gas concentration sensors would allow respirocytes to mimic the action of the natural hemoglobin-filled red blood cells, with oxygen released and carbon dioxide absorbed in the tissues, and vice versa in the lungs. Each respirocyte would be able to hold 200 times more gas per unit volume than a natural red cell, so a few cubic centimeters injected into the human bloodstream would exactly replace the gas carrying capacity of the patient’s entire 5.4 liters of blood.

Other proposed medical nanorobots offer equally astonishing performance improvements over nature. For instance, micron-size artificial mechanical platelets could allow complete hemostasis (control of bleeding by clot formation) in just one second, even for moderately large wounds, a response time 100-1,000 times faster than the natural system. This would be achieved by rapidly unfurling a compactly stowed onboard biodegradable mesh under the control of an onboard computer. These “clottocytes” would be about 10,000 times more effective as clotting agents than an equal volume of natural platelets.

Nanorobotic phagocytes called microbivores could patrol the bloodstream, seeking out and digesting unwanted pathogens including bacteria, viruses or fungi. Each nanorobot could completely destroy one pathogen in just 30 seconds – about 100 times faster than natural leukocytes or macrophages – releasing a harmless effluent of amino acids, mononucleotides, fatty acids and sugars. No matter that a bacterium has acquired multiple drug resistance to antibiotics or to any other traditional treatment. The microbivore will eat it anyway, achieving complete clearance of even the most severe septicemic infections in minutes to hours, as compared to weeks or even months for antibiotic-assisted natural phagocytic defenses, without increasing the risk of sepsis or septic shock. Related nanorobots could be programmed to recognize and digest cancer cells, or to clear circulatory obstructions within minutes in order to rescue stroke patients from ischemic damage.

More sophisticated medical nanorobots will be able to intervene at the cellular level, performing surgery within cells. Physician-controlled nanorobots could extract existing chromosomes from a diseased cell and insert newly manufactured ones in their place, a process called chromosome replacement therapy. This would allow a permanent cure of any pre-existing genetic disease, and permit cancerous cells to be reprogrammed to a healthy state.

In recent years, many gerontologists have begun to think of aging as a genetic disease that might be cured. New evidence from the Human Genome Project suggests that just a few hundred genes at most may be directly involved in aging. If we can completely understand these few genes and how they work, we may be able to alter them to eliminate this unwanted syndrome. Using cytosurgical nanorobots, corrected genes could be installed in every one of the 10 trillion tissue cells in our bodies. We would then no longer naturally age, and our bodies would again repair themselves as well as they did when we were children.

Although nanotechnology is in its infancy, researchers are steadily making major breakthroughs. If we can learn to harness and precisely control the ability to manipulate molecules, then many aspects of our lives will change forever. In particular, the ability to carry out medical procedures at the molecular level will revolutionize medical practice. The next few decades will be very interesting indeed.

Copyright 2001, Pathways, The Novartis Journal. Reprinted with permission.