A simple technique for stamping patterns invisible to the human eye onto a special class of nanomaterials provides a new, cost-effective way to produce novel devices in areas ranging from drug delivery to solar cells.
The technique was developed by Vanderbilt University engineers and described in the cover article of the May issue of the journal Nano Letters.
The new method works with materials that are riddled with tiny voids that give them unique optical, electrical, chemical and mechanical properties. Imagine a stiff, sponge-like material filled with holes that are too small to see without a special microscope.
What I want: a very powerful miniature home medical test lab. Get your blood, and assorted secretions tested any time you want. Very early stage cancer testing in your own bathroom would be especially good. Catch and remove the cancer before it spreads. But very early stage means very small. The hard part will be to precisely locate it once it leaves some sort of signature in the blood.
Picture a drug based on RNA as a mini computer program aimed at running in our cells rather than in a silicon computer. Such a drug in theory could carry out much more complex behaviors than conventional simpler chemical compounds. Stanford researchers are working on RNA-based drugs that would only turn on in cancer cells.
Current treatments for diseases like cancer typically destroy nasty malignant cells, while also hammering the healthy ones. Using new advances in synthetic biology, researchers are designing molecules intelligent enough to recognize diseased cells, leaving the healthy cells alone.
"We basically design molecules that actually go into the cell and do an analysis of the cellular state before delivering the therapeutic punch," said Christina Smolke, assistant professor of bioengineering who joined Stanford University in January.
This is the sort of approach we need to wipe out cancer. The current chemo drugs are nowhere near specific enough in the cells they target. The whole body ends up getting damaged. Also, the rates of failure for chemo are very high for many types of cancer.
The trick is to activate only in the presence of biomarker materials that are characteristic of cancer cells. That's a tough job because human cancer cells are human cells. Coming up with suitable biomarkers and ways to make RNA react to them is not easy.
"When you look at a diseased cell (e.g. a cancer cell) and compare it to a normal cell, you can identify biomarkers—changes in the abundance of proteins or other biomolecule levels—in the diseased cell," Smolke said. Her research team has designed molecules that trigger cell death only in the presence of such markers. "A lot of the trick with developing effective therapeutics is the ability to target and localize the therapeutic effect, while minimizing nonspecific side effects," she said.
Smolke will present the latest applications of her lab's work at the American Association for the Advancement of Science (AAAS) meeting in Chicago on Friday, Feb. 13.
These designer molecules are created through RNA-based technologies that Smolke's lab developed at the California Institute of Technology. A recent example of these systems, developed with postdoctoral researcher Maung Nyan Win (who joined Smolke in her move to Stanford), was described in a paper published in the Oct. 17, 2008, issue of Science.
"We do our design on the computer and pick out sequences that are predicted to behave the way we like," Smolke said. When researchers generate these sequences inside the operating system of a cell, they reprogram the cell and change its function. "Building these molecules out of RNA gives us a very programmable and therefore powerful design substrate," she said.
The ability to selectively kill all cancer cells in the body would not only put an end to cancer as a killer but also open up the door to a lot more therapies for other diseases. Hormone replacement therapies that increase the risk of cancer would no longer pose that problem for their use. So we could jack up our aging metabolisms with hormones and pay less of a price for doing so.
Using a sort of hacking approach to drug activation to only turn toxic drugs on in cancer cells is an obvious idea and other groups are working on it. See my 2004 post DNA Nanomachine Computers Against Cancer.
We need technologies that will allow our bodies to be repaired as thoroughly as we repair our cars. Some UCSD researchers find that titanium nanotubes can cause stem cells to become osteoblasts that speed bone repair.
San Diego, CA, January 29, 2009 --Engineers at the University of California at San Diego have come up with a way to help accelerate bone growth through the use of nanotubes and stem cells. This new finding could lead to quicker and better recovery, for example, for patients who undergo orthopedic surgery.
Nanotube implants might some day become a routine part of orthopedic surgery.
“If you break your knee or leg from skiing, for example, an orthopedic surgeon will implant a titanium rod, and you will be on crutches for about three months,” said Sungho Jin, co-author of the PNAS paper and a materials science professor at the Jacobs School of Engineering. “But what we anticipate through our research is that if the surgeon uses titanium oxide nanotubes with stem cells, the bone healing could be accelerated and a patient may be able to walk in one month instead of being on crunches for three months.
“Our in-vitro and in-vivo data indicate that such advantages can occur by using the titanium oxide nanotube treated implants, which can reduce the loosening of bones, one of the major orthopedic problems that necessitate re-surgery operations for hip and other implants for patients,” Jin added. “Such a major re-surgery, especially for older people, is a health risk and significant inconvenience, and is also undesirable from the cost point of view.”
By controlling nanotube diameter the researchers can instruct stem cells to turn into bone-forming osteoblast cells.
This is the first study of its kind using stem cells attached to titanium oxide nanotube implants. Jin and his research team – which include Jacobs School bioengineering professors Shu Chien and Adam Engler, as well as post doctoral researcher Seunghan Oh and other graduate students and researchers –report that the precise change in nanotube diameter can be controlled to induce selective differentiation of stem cells into osteoblast (bone-forming) cells.
The biggest challenge with stem cells is instructing them to become the right kind of cell at the right place in the body. A material implanted where the repair is needed has the advantage of being very local in its effects. That can work for highly targeted repairs where a particular piece of tissue needs fixing.
We also need ways to instruct stem cells to go to particular types of tissue that might be scattered all around the body. For example, bone marrow stem cells age along with the rest of the body. Well, we have about 206 bones per person (I say "about" because there is some variation - for example, some people have an extra rib). That's a lot of places to instruct stem cells to go to and replace aged stem cells. We will need additional techniques for more widespread stem cell delivery.
Scientists have developed nanometer-sized ‘cargo ships’ that can sail throughout the body via the bloodstream without immediate detection from the body’s immune radar system and ferry their cargo of anti-cancer drugs and markers into tumors that might otherwise go untreated or undetected.
This delivery system is in an early stage of development, so far tested only on mice.
In a forthcoming issue of the Germany-based chemistry journal Angewandte Chemie, scientists at UC San Diego, UC Santa Barbara and MIT report that their nano-cargo-ship system integrates therapeutic and diagnostic functions into a single device that avoids rapid removal by the body’s natural immune system. Their paper is now accessible in an early online version here.
“The idea involves encapsulating imaging agents and drugs into a protective ‘mother ship’ that evades the natural processes that normally would remove these payloads if they were unprotected,” said Michael Sailor, a professor of chemistry and biochemistry at UCSD who headed the team of chemists, biologists and engineers that turned the fanciful concept into reality. “These mother ships are only 50 nanometers in diameter, or 1,000 times smaller than the diameter of a human hair, and are equipped with an array of molecules on their surfaces that enable them to find and penetrate tumor cells in the body.”
Just because they can put molecules on the surface of these nanodevices does not mean they know which molecules to attach in order to maximize selective targeting of only cancer cells. That's a whole other problem which we really need excellent solutions for. But assuming a solution to that latter problem then these nanodevices could carry chemotherapy toxins into cancer cells to selectively kill only cancer cells.
These microscopic cargo ships could one day provide the means to more effectively deliver toxic anti-cancer drugs to tumors in high concentrations without negatively impacting other parts of the body.
They tested imaging enhancement payloads in mice. But this mechanism could also be used to deliver toxic chemotherapy to tumours.
The researchers loaded their ships with three payloads before injecting them in the mice. Two types of nanoparticles, superparamagnetic iron oxide and fluorescent quantum dots, were placed in the ship’s cargo hold, along with the anti-cancer drug doxorubicin. The iron oxide nanoparticles allow the ships to show up in a Magnetic Resonance Imaging, or MRI, scan, while the quantum dots can be seen with another type of imaging tool, a fluorescence scanner.
Their bigger problem is probably going to be how to get highly selective on just which cells these packages will enter.
The researchers are now working on developing ways to chemically treat the exteriors of the nano ships with specific chemical “zip codes,” that will allow them to be delivered to specific tumors, organs and other sites in the body.
Can this approach cure cancer? The question will depend in part on whether the surfaces of cancer cells look different enough from normal to provide highly selective delivery into cancer cells.
But this approach could be enhanced with smart payloads. Imagine a payload that includes a genetic sequence. It could get activated only in cells which internally look like cancer cells. So the package might make it into cancerous and non-cancerous cells but only do real damage in cancer cells. But that would probably be a bigger payload than a chemotherapy agent. So that makes packaging harder to do.
Once we can cure cancer and repair our internal organs with stem cells and replacement organs our big problem is going to be brain aging. Alzheimer's, Parkinson's, strokes, and other causes of dementia and brain decay will all need solutions. Alzheimer's might be solved even before cancer. But the other diseases of aging brains will be tougher problems to solve.
To develop treatments that will turn back the aging clock and make our bodies young again we need more powerful tools. Given the right tools aging is a curable disease. The development of nanotechnology is the most powerful trend underway that will bring aging reversal within our reach. With that thought in mind a new development in "nanoglassblowing" provides a new way to create more powerful devices for manipulating cells and biological molecules.
While the results may not rival the artistry of glassblowers in Europe and Latin America, researchers at the National Institute of Standards and Technology (NIST) and Cornell University have found beauty in a new fabrication technique called "nanoglassblowing" that creates nanoscale (billionth of a meter) fluidic devices used to isolate and study single molecules in solution—including individual DNA strands. The novel method is described in a paper posted online next week in the journal Nanotechnology.*
Traditionally, glass micro- and nanofluidic devices are fabricated by etching tiny channels into a glass wafer with the same lithographic procedures used to manufacture circuit patterns on semiconductor computer chips. The planar (flat-edged) rectangular canals are topped with a glass cover that is annealed (heated until it bonds permanently) into place. About a year ago, the authors of the Nanotechnology paper observed that in some cases, the heat of the annealing furnace caused air trapped in the channel to expand the glass cover into a curved shape, much like glassblowers use heated air to add roundness to their work. The researchers looked for ways to exploit this phenomenon and learned that they could easily control the amount of "blowing out" that occurred over several orders of magnitude.
Nanodevices might seem boring. Research on them does not produce immediately usable dietary advice, medical treatments, or even investment advice. But nanotechnology is going to become the great enabler for the development of medical treatments and methods of human enhancement. Nanotechnology for biology is following the same pattern that we've seen in the development of computer chips which keep getting smaller, cheaper, and more powerful.
To manipulate biological molecules with precision and control the devices that manipulate them must operate at the small scale of individual biological molecules. The size of these nanochannels comes close to the size of DNA.
As a result, the researchers were able to create devices with "funnels" many micrometers wide and about a micrometer deep that tapered down to nanochannels with depths as shallow as 7 nanometers—approximately 1,000 times smaller in diameter than a red blood cell. The nanoglassblown chambers soon showed distinct advantages over their planar predecessors.
To put that 7 nanometers in perspective, the DNA double helix is about 2.4 nanometers across. So a 7 nanometer channel is almost 3 times bigger than the DNA that would need to pass thru if this technology gets used to create DNA testing devices.
This technology makes it easier to create funnels that can guide DNA and other biological molecules into the small channels.
"In the past, for example, it was difficult to get single strands of DNA into a nanofluidic device for study because DNA in solution balls up and tends to bounce off the sharp edges of planar channels with depths smaller than the ball," says Cornell's Elizabeth Strychalski. "The gradually dwindling size of the funnel-shaped entrance to our channel stretches the DNA out as it flows in with less resistance, making it easier to assess the properties of the DNA," adds NIST's Samuel Stavis.
The technology can be used to manipulate whole cells or individual molecules.
Future nanoglassblown devices, the researchers say, could be fabricated to help sort DNA strands of different sizes or as part of a device to identify the base-pair components of single strands. Other potential applications of the technique include the manufacture of optofluidic elements—lenses or waveguides that could change how light is moved around a microchip—and rounded chambers in which single cells could be confined and held for culturing.
A new nanotechnology that can examine single molecules in order to determine gene expression, paving the way for scientists to more accurately examine single cancer cells, has been developed by an interdisciplinary team of researchers at UCLA's California Nanosystems Institute (CNSI), New York University's Courant Institute of Mathematical Sciences, and Veeco Instruments, a nanotechnology company. Their work appears in the January issue of the journal Nanotechnology.
This ability to measure the expression of a single gene in a single cell is part of a larger (or smaller) trend: The development of tools that can measure and manipulate biological systems at the scale of their smallest individual components.
Cancer researchers and other biomedical researchers have spent decades trying and failing to cure many diseases because they lacked the tools needed to figure out the mechanisms of a large variety of diseases. What is going to make the next 20 years so different than what has come before is the development of tools for manipulation and detailed measurement of activities inside of cells.
Their use of the phrase "individual transcript molecules" sounds like they can measure the presence of individual molecules of messenger RNA.
Previously, researchers have been able to determine gene expression using microarray technology or DNA sequencing. However, such processes could not effectively measure single gene transcripts—the building blocks of gene expression. With their new approach, the researchers of the work reported in Nanotechnology were able to isolate and identify individual transcript molecules—a sensitivity not achieved with earlier methods.
"Gene expression profiling is used widely in basic biological research and drug discovery," said Jason Reed of UCLA's Department of Chemistry and Biochemistry and the study's lead author. "Scientists have been hampered in their efforts to unlock the secrets of gene transcription in individual cells by the minute amount of material that must be analyzed. Nanotechnology allows us to push down to the level of individual transcript molecules."
Biomedical science is going to be revolutionized by "GRIN" technology that will be much cheaper and more powerful.
"We are likely to see more of these kinds of highly multi-disciplinary research aimed at single molecule sequencing, genomics, epigenomic, and proteomic analysis in the future," added Bud Mishra, a professor of Computer Science, Mathematics, and Cell Biology from NYU's Courant Institute and School of Medicine. "The most exciting aspect of this approach is that as we understand how to intelligently combine various components of genomics, robotics, informatics, and nanotechnology—the so-called GRIN technology—the resulting systems will become simple, inexpensive, and commonplace."
Computers got cheaper because they kept getting smaller. Microfluidic devices and microsensors on chips are going to do the same thing to biological science and medicine. Small and mass produced devices driven by complex software will accelerate the rate of advance of biomedical research by an order of magnitude or more. We will develop cures for almost every disease and rejuvenation technologies as well.
The Johns Hopkins University is preparing to aim enormous research and educational resources at some exceedingly small targets.
Drawing on the expertise of more than 75 faculty members from such diverse disciplines as engineering, biology, medicine and public health, the university today officially launched its ambitious new Institute for NanoBioTechnology.
The institute will strive for major advances in medicine by developing new diagnostic tools and treatments based on interdisciplinary research conducted at the atomic or molecular level. The institute will encourage the movement of these campus breakthroughs into the private sector for further development and marketing. At the same time, institute members will train the next generation of scientists and engineers in this emerging field, offering both graduate-level instruction and a new undergraduate minor in nanobiotechnology.
The functional components of cells are molecules. To measure and manipulate small components requires the development of technology that operate on the same scale as the target systems. Nanotechnology for biological systems therefore is the right approach for the development of great diagnostics, disease treatments, and enhancements.
The Johns Hopkins institute will have 4 main emphases:
The interdisciplinary nature of the institute makes sense as well. Engineers, chemists, materials scientists, and people from other disciplines are needed in biology to do nanotech for biotech.
Advances in microfluidics will eventually drive the cost of biological science experiments by orders of magnitude. The rate of advance of biological science and biotechnology will greatly accelerate when advances in microfluidics enable the development of minature labs on a chip. Such devices will allow massive numbers of experiments and manipulations of cells and cellular components to be done in parallel at very low cost.
Neuroscientist Rudolfo Llinas and his colleagues envision an entire array of nanowires being connected to a catheter tube, which could then be guided through the circulatory system to the brain. Once there, the nanowires would spread into a kind of bouquet, branching out into tinier and tinier blood vessels until they reached specific locations. Each nanowire would then be used to record the electrical activity of a single nerve cells, or small groups of nerve cells.
The nanowires would be very small as compared to the thickness of capillaries.
Writing in the July 5, 2005, online issue of The Journal of Nanoparticle Research, the researchers explain it is becoming feasible to create nanowires far thinner than even the tiniest capillary vessels. That means nanowires could, in principle, be threaded through the circulatory system to any point in the body without blocking the normal flow of blood or interfering with the exchange of gasses and nutrients through the blood-vessel walls.
The team describes a proof-of-principle experiment in which they first guided platinum nanowires into the vascular system of tissue samples, and then successfully used the wires to detect the activity of individual neurons lying adjacent to the blood vessels.
Rodolfo R. Llinás of the New York University School of Medicine led the team, which included Kerry D. Walton, also of the NYU medical school; Masayuki Nakao of the University of Tokyo; and Ian Hunter and Patrick A. Anquetil of the Massachusetts Institute of Technology.
Nanowires that can receive electrical signals can also be set up to send signals.
"In this case, we see the first-ever application of nanotechnology to understanding the brain at the neuron-to-neuron interaction level with a non-intrusive, biocompatible and biodegradable nano-probe," said Roco. "With careful attention to ethical issues, it promises entirely new areas of study, and ultimately could lead to new therapies and new ways of treating diseases. This illustrates the new generations of nanoscale active devices and complex nanosystems."
Likewise, the nanowire technique could greatly improve doctors' ability to pinpoint damage from injury and stroke, localize the cause of seizures, and detect the presence of tumors and other brain abnormalities. Better still, Llinás and his coauthors point out, the nanowires could deliver electrical impulses as well as receive them. So the technique has potential as a treatment for Parkinson's and similar diseases.
Picture an embedded nanotech computer wired up to feed the mind information as images, sounds, or simply thoughts that suddenly happen. At the extreme the nanowires could be used to take over a person and control them. Picture a "Manchurian Candidate" controlled by a foreign power. Or picture criminals whose nanocomputers monitor their thoughts and send inhibiting messages that prevent violent acts and other forbidden behavior.
Using embedded nanowire sensors to make sense of complex thoughts in brains will remain hard to do for years to come. But I predict that identification of some basic emotions or urges will be easier to accomplish. Once reactive loops to suppress emotions such as hostility or sexual desire reach technical feasibility consider the issues we'll face. Should rapists or pedophiles up for parole be required to submit to nanowire circuitry implants that suppress their sexual desires? One can even imagine a home surveillance system where the parolee can get their sexual desires unlocked only if they present a willing adult to a video camera hooked up to a police station. A parolee's sexual desires could even get automatically deactivated using a GPS monitoring device that activates as they leave home. Or a home transmitter that unblocks their sexual desire circuits could have a reach of only, say, 50 feet around their house and as they move away they lose the signal that allows their sexual desires to work.
Repressive regimes could use embedded nanowire circuits to ensure obedience or as interrogation tools to activate a person's memories and force them to talk. On the bright side embedded nanowires could enable viewing of movies or listening without any external device to carry along. One could have an embedded internet link to allow one to think search requests. I'm reminded of the movie The President's Analyst where "The Phone Company" kidnaps James Coburn's character to try to convince him to advise the President of the United States to support embedding electronic phone circuits in everyones' brains. I'm also reminded of the Stargate SG-1 Goauld that take over the brains of humans that they enter into.
Ramez Naam's book More Than Human has a treatment of Llinas's proposal as well. He covers the wider issue of brain-computer interfaces in his chapter The Wired Brain. Some of what he writes about neurobiology research was news to me when I read it. Another good book to read at the same time is Joel Garreau's book Radical Evolution.
Some scientists at a few Calfornia research centers have received funding to develop nanotech therapies against atherosclerotic plaques in arteries. Note that this an announcement of the beginning of their research efforts. But the announcement is notable because these scientists are attempting to develop nanodevices to hook onto and modify arterial plaque.
The Burnham Institute has been selected as a "Program of Excellence in Nanotechnology" ("PEN") by the National Heart, Lung, and Blood Institute ("NHLBI") of the National Institutes of Health ("NIH"). A partnership of 25 scientists from The Burnham Institute, University of California Santa Barbara, and The Scripps Research Institute will use the $13 million award to design nanotechnologies to detect, monitor, treat, and eliminate "vulnerable" plaque, the probable cause of death in sudden cardiac arrest.
Led by Jeffrey Smith, Ph.D., of the Burnham Institute and the principal investigator of the program, the scientific team is comprised of biochemists, vascular biologists, chemical engineers and physicists. "This is a novel approach to bring experts from all these fields together," said Dr. Smith. "And it's very exciting. These groups do not normally work together. But in this instance, I think it's going to produce some real scientific progress."
Recent studies have shown that plaque exists in two modes: non-vulnerable and vulnerable. Blood passing through an artery exerts a shearing force and can cause vulnerable plaque to rupture, which often leads to occlusion and myocardial infarction. This is a significant health issue: of the nearly one million people who die each year from cardiac disease, 60 percent perish without showing any symptoms. As many as 60 - 80 percent of sudden cardiac deaths can be attributed to the physical rupture of vulnerable plaque.
"We intend to exploit this new understanding of atherosclerotic plaque," said Dr. Smith. "By focusing on devising nano-devices, which can be described as machines at the molecular level, we will specifically target vulnerable plaque. That cannot be accomplished today. My colleagues and I hope that our work will lead to real diagnostic and therapeutic strategies for those suffering from this form of cardiac disease."
The project team will work on three innovative solutions to combat vulnerable plaque; 1) building delivery vehicles that can be used to transport drugs and nanodevices to sites of vulnerable plaque; 2) designing a series of self-assembling polymers that can be used as molecular nano-stents to physically stabilize vulnerable plaque, 3) creating nano-machines comprised of human proteins linked to synthetic nano-devices for the purpose of sensing and responding to vulnerable plaque.
I like the idea of "self-assembling polymers" for "molecular nano-stents" to stablize plaque. The idea is to anchor it down so it can't break free and cause a heart attack or stroke.
I feel so out of it since I didn't already know what "BioNEMS" means. They will develop bio-nanoelectromechanical systems (BioNEMS).
The multi-organizational team will build "delivery vehicles" that can be used to transport drugs, imaging agents and nano-devices directly to locations where there is vulnerable plaque; design molecular nano-stents to physically stabilize vulnerable plaque and replace its fibrous cap with an anti-adhesive, anti-inflammatory surface; devise molecular switches that can sense and respond to the pathophysiology of atheroma (fatty deposits on arterial walls); and develop bio-nanoelectromechanical systems (called BioNEMS) that can sense and respond to vulnerable plaque, ultimately providing diagnostic and therapeutic capability.
This is another example of development of a treatment that falls within the typology of 7 Strategies for Engineered Negligible Senescence (SENS) to halting and rejuvenate bodies by the removal of accumulated extracellular junk. They are not saying they are attempting to remove the plaque. But once they can target nanomachines to hook on to plaque they might find it just as easy to break it down to remove it as to stabilize it.
Widespread acceptance of SENS for rejuvenation is not necessary for the development of many SENS treatments. My guess is that for at least the next decade most treatments which will accomplish objectives which support SENS will be justified under the old paradigm of development of treatments against specific diseases. Efforts such as this one develop tools that will be useful for rejuvenation. So we are making progress toward the goal of engineered negligible senescence or perpetual youth.
Most discussions of biotech center around medical uses. Though agricultural uses also attract considerable attention and, especially in Europe, considerable opposition. However, there are plenty of potential industrial applications. A major category of applications is the use of enzymes to catalyze complex reactions for which there are no conventional catalysts. One major reason that this category of biotechnology hasn't taken off more rapidly is that enzymes break down fairly easily. However, some recent research results from the Department of Energy's Pacific Northwest National Laboratory brighten the prospects for industrial applications of enzymes as these scientists have developed a method of using nanotech particles to stabilize enzymes to last for months.
RICHLAND, Wash. — Enzymes, the workhorses of chemical reactions in cells, lead short and brutal lives. They cleave and assemble proteins and metabolize compounds for a few hours, and then they are spent.
This sad fact of nature has limited the possibilities of harnessing enzymes as catalytic tools outside the cell, in uses that range from biosensing to toxic waste cleanup.
To increase the enzyme's longevity and versatility, a team at the Department of Energy's Pacific Northwest National Laboratory in Richland, Wash., has caged single enzymes to create a new class of catalysts called SENs, or single enzyme nanoparticles. The nanostructure protects the catalyst, allowing it to remain active for five months instead of hours.
"The principal concept can be used with many water-soluble enzymes," said Jungbae Kim, PNNL senior scientist who described the feat here today at the national meeting of the American Chemical Society.
"Converting free enzymes into these novel enzyme-containing nanoparticles can result in significantly more stable catalytic activity," added Jay Grate, PNNL laboratory fellow and SENs co-inventor.
Nanotech particle stabilized enzymes could be used to for cleaning up toxic waste sites or for breaking down toxins that are continually produced by industrial processes. They could also be used to keep a wide variety of surfaces (including places within human bodies) from accumulating an assortment of types of crud and undesirable material.
Among the uses Kim noted for SENs is the breakdown toxic waste-a single treatment could last months. Stabilized enzymes are also a prerequisite for many types of biosensors. And they may be of interest for coating surfaces, with application ranging from medicine (protecting implants from protein plaques) to shipping (keeping barnacles off hulls). PNNL is investigating several other applications in the environmental and life sciences.
A way to stablize enzymes increases the value of discovering enzymes which have different forms of activity. So this advance is likely to spur searches through all manner of species to find enzymes for a variety of specific industrial and medical purposes.
A tiny nanowire sensor — smaller than the width of a human hair, 1,000 times more sensitive than conventional DNA tests, and capable of producing results in minutes rather than days or weeks — could pave the way for faster, more accurate medical diagnostic tests for countless conditions and may ultimately save lives by allowing earlier disease detection and intervention, Harvard scientists say.
In preliminary laboratory studies demonstrating the capability of the new sensor, the researchers showed that it has the potential to detect the gene for cystic fibrosis more efficiently than conventional tests for the disease. CF is the most common fatal genetic disease among people of European origin.
One of a growing number of promising diagnostic tools that are based on nanotechnology, the silicon sensor represents the first example of direct electrical detection of DNA using nanotechnology, according to the researchers. The sensor and the detection of the CF gene will be described in the Jan. 14 issue of the journal Nano Letters, a peer-reviewed publication of the American Chemical Society, the world's largest scientific society.
"This tiny sensor could represent a new future for medical diagnostics," says study leader Charles M. Lieber, Ph.D., a professor of chemistry at Harvard and one of the leading researchers in nanotechnology.
"What one could imagine," says Lieber, "is to go into your doctor's office, give a drop of blood from a pin prick on your finger, and within minutes, find out whether you have a particular virus, a genetic disease, or your risk for different diseases or drug interactions."
With its high sensitivity, the sensor could detect diseases never before possible with conventional tests, he says. And if all goes well in future studies, Lieber predicts that an array of sensors can ultimately be configured to a handheld PDA-type device or small computer, allowing almost instant test results during a doctor's visit or possibly even at home by a patient. It could potentially be used to screen for disease markers in any bodily fluid, including tears, urine and saliva, he says.
The sensor also shows promise for early detection of bioterrorism threats such as viruses, the researcher says.
A company called Nanosys is commercializing this nanotech sensor tecnology. Nanosys is pursuing a number of other applications of nanotech sensors.
Ultimately, the goal at Nanosys is to revolutionize sensors, nanoelectronics and optoelectronics by building products literally from the bottom up through molecular self-assembly that is cheaper, better and faster; uses less power; and basically delivers a lot more bang for the buck than today's most advanced devices. The technology that makes this possible is based on groundbreaking work in nanoelectronics by Dr. Charles Lieber, the Mark Hyman Professor of Chemistry at Harvard University.
Exactly how this process works is a closely guarded secret, but Lieber and his team have basically developed a way to make nanowires any way they want. They can control the size and shape of the wires, as well as the amount of impurities, or dopens, attached to the wires, thereby controlling the wires' conductive and photo-reactive characteristics, which, at the end of the day, dictate their usefulness.
"That was the real 'ah-ha' Charles Lieber came up with," Bock said. "That means that he can make devices much more quickly because he doesn't have to go look for the materials he wants each time, he just makes them."
Toto, pretty soon we are not going to be in Kansas any more.
The modified nanotubes have so far only been used to ferry a small peptide into the nuclei of fibroblast cells. But the researchers are hopeful that the technique may one day form the basis for new anti-cancer treatments, gene therapies and vaccines.
Cornell University Professor of Engineering, Applied and Engineering Physics Walt W. Webb and his group have shown (click thru to the page to see cool pictures).
ITHACA, N.Y. -- Tiny blood vessels, viewed beneath a mouse's skin with a newly developed application of multiphoton microscopy, appear so bright and vivid in high-resolution images that researchers can see the vessel walls ripple with each heartbeat -- 640 times a minute.
The capillaries are illuminated in unprecedented detail using fluorescence imaging labels, which are molecule-size nanocrystals called quantum dots circulating through the bloodstream. Quantum dots are microscopic metal or semiconductor boxes (in this case cadmium selenide-zinc sulfide) that hold a certain number of electrons and, thus, have a wide number of potential applications in electronics and photonics.
Writing in the latest issue of the journal Science (May 30, 2003), researchers at Cornell University and a nanocrystal manufacturer, Quantum Dot Corp., report that the nanocrystals are particularly useful for producing high-resolution, three-dimensional images inside living tissue.
"We have demonstrated a new approach to using quantum dots for biological studies of living animals," says Watt W. Webb, Cornell's S.B. Eckert Professor of Engineering and professor of applied physics, co-inventor of multiphoton microscopy (with Winfried Denk) and leader of the experimental imaging team at Cornell.
"Of course, there are easier ways to take a mouse's pulse," says Webb's Cornell collaborator, senior research associate Warren R. Zipfel, "but this kind of resolution and high signal-to-noise illustrates how useful multiphoton microscopy with quantum dots can become, in a biological research context, for tracking cells and visualizing tissue structures deep inside living animals."
Zipfel cited the study of vascular changes in cancer tumors as one possible application, cautioning that the Cornell researchers are not ready to recommend human-medicine clinical applications for quantum dot imaging, in part because some of the best fluorescing nanocrystals have unknown toxicity. However, mice used in the Cornell study are still alive and apparently healthy, months later, and are being monitored for long-term effects of their treatments.The Cornell researchers used quantum dots for fluorescence imaging microscopy because when excited by light, they emit bright fluorescence in different colors, according to their size, reports biophysics graduate student Daniel Larson. The quantum dots were 6 to 10 nanometers in diameter. (A nanometer is one one-billionth of a meter. By comparison, a red blood cell, at 7 millionths of a meter, is a thousand times bigger). "Even with their water-soluble coating, which is something like being encased in a soap bubble, the quantum dots are only about 24 nanometers in diameter," Larson notes.
Webb explains that the laser scanning microscope used in multiphoton microscopy is particularly adept at producing high-resolution, three-dimensional images inside living tissue because it combines the energies of two photons, striking a molecule at the same time, with an additive effect. Under the conditions used, this only occurs at the focus of the laser, so only at that point is the molecule excited to a state that results in fluorescence emission. This excitation is the same as if it arose from the absorption of a single photon of higher energy, but it is three-dimensionally localized since it is only occurring at the beam focus. The scanning microscope moves the laser beam across the area being imaged at a precise depth. When repeated scans at different planes of focus are "stacked," the result is a brightly lit and vividly detailed three-dimensional image -- and video that takes a viewer inside a living organism..
Because of the special properties of the nanoparticles, multiphoton microscopy with quantum-dot imaging can be 1,000 times brighter in tissue than conventional organic fluorophores (the chemical labels that are temporarily added to samples), says Webb. "We looked to quantum dots for even brighter images at better resolution, and that's what we found."
Results presented in the Science report show highly detailed images of capillaries beneath the skin of a living mouse after quantum dots were injected through a vein in its tail, as well as capillaries through the adipose (fat) layer around the mouse's ovaries. The researchers were particularly surprised at the saw-toothed ripples in the walls of one capillary image -- until they made a calculation. Noting the time it took to scan that part of the tiny blood vessel and the animal's heart rate during the experiment, they determined that each ripple represented the undulation of the capillary wall from one heartbeat.
Besides demonstrating the feasibility of microscopic angiography with quantum-dot labeling through skin and adipose tissue -- two of the most challenging tissue types -- the researchers said they had resolved several fundamental questions, including the fact that sometimes as many as half the dots in a preparation are not fluorescent.
Other authors of the Science article are Marcel P. Bruchez, principal scientist at Quantum Dots; Rebecca M. Williams, a research associate with the National Institutes of Health (NIH)-funded Bioimaging Resource at Cornell; Frank Wise, professor of applied and engineering physics; and Stephen W. Clark, a graduate student in Wise's laboratory. Funding came from NIH, the Defense Advanced Research Projects Agency and the National Science Foundation.
Note that as part of their quantum dot compound they used cadmium which is a toxic metal. For human imaging the development of quantum dots that have less potential for toxicity is desireable. Another problem with this approach is that since it uses light it would require the use of endoscopes to image internal organs. Still, the increased level of detail would be valuable in many circumstances.
The ability to image capillaries is of particular interest because capillary growth is a crucial element of cancer tumor growth. The ability to study this process with quantum dots (e,g, to test anti-angiogenensis compounds) will be useful for cancer research.
It is possible that quantum dots could be used in tricky ways to detect where new capillaries are growing and hence where a tumor is growing. If quantum dots could be developed that would mark existing capillaries in a way that persisted for weeks then this could ability be used in such a way that new capillary growth and hence new tumor growth could be detected. It is possible to make different types of quantum dots that emit at different frequencies. What could be done is to mark existing capillaries with quantum dots that emit light at once frequency and then a few days, weeks, or months later come back and inject quantum dots that emitted at a different frequency. Then imaging of an organ in a way that looked for each frequency of light could be done to detect capillaries that have capillaries that only emit at the frequency that the quantum dots from the second injection emit. Those capillaries that emitted at only one frequecy would be new growth capillaries and probably an indication of new growth tumor cells.
The using of quantum dots, rather than conventional dyes, resulted in a thousand-fold increase in resolution, says Webb. Additional studies found that the technique works well in fat tissue as well as through skin. "And they both scatter light like mad," he notes.
Another possible use of quantum dot imaging would be as a more sensitive method for detecting circulatory problems.
Researchers at Oak Ridge National Laboratory and the University of Tennessee have developed a micro-injection technique to deliver DNA into a cell's nucleus using nanofibers.
ORNL researchers expect big things from nanostructures
OAK RIDGE, Tenn., May 19, 2003 -- Arrays of nanofibers able to deliver genetic material to cells quickly and efficiently have researchers at Oak Ridge National Laboratory excited about potential applications for drug delivery, gene therapy, crop engineering and environmental monitoring.
Tim McKnight of ORNL's Engineering Science and Technology Division and researchers from several other laboratory divisions and the University of Tennessee are working to advance the science of micro-injection. The work builds upon the group's success with fabricating carbon nanofibers, which are tiny needles that provide a new approach to genetic manipulation of cells and biological organisms.
"By using an array of millions of carbon nanofibers that can be grown on various platforms -- or substrates -- we can streamline a proven technique for altering the DNA content of a cell," McKnight said.
That proven technique, micro-injection, involves introducing genetic material, DNA, directly into a cell's nucleus. This allows researchers to genetically alter the attributes of a cell and to exploit the cell to perform desired functions such as to produce a pharmaceutically active compound to grow under adverse conditions or to detect environmental hazards.
The group's technique, which has grown from a project funded by ORNL seed money in the spring of 2002, allows for highly controlled rapid delivery of genetic material into large numbers of cells.
"While we have focused predominantly on mammalian cells, the parallel micro-injection-based technique should be quite transferable to a wide variety of cell types, including those with rugged cell walls such as plants and bacteria," McKnight said.
Of particular interest is the fact that the new method allows researchers to attach DNA to the nanofibers. When they insert these nanofibers into cells, the DNA can be used to program the cell to produce new proteins, but it is not free to move around within the cell. As such, it has a less likely chance of inserting into the cell's chromosomes or being segregated to daughter cells when the cell divides. Mike Simpson of the group has somewhat paradoxically called this a "non-inheritable genetic modification."
This non-inheritable tethered DNA method has exciting potential, McKnight said. For instance, it may address some of the concerns related to genetically modified organisms. Already, scientists are using these organisms for a variety of agricultural and environmental applications. A well-known example is golden rice, engineered for improved nutritional value to help feed the world's expanding population. Locally, the group's collaborators at the University of Tennessee's Center for Environmental Biotechnology use genetically engineered bacteria immobilized to a sensing platform to provide highly sensitive warning systems against environmental toxins.
In the areas of agricultural and environmental applications, some people are concerned about the potential of uncontrolled release of genetically modified organisms to the environment. However, the tethered DNA approach might significantly reduce the risk of such release. While the organisms might escape from the system, the nanofibers hold the modifying DNA captive.
"So when or if the organisms become detached from the nanofibers, they would no longer have access to the modifying DNA and therefore should revert to their normal genetic makeup," McKnight said.
In addition to investigating nanofiber platforms for DNA delivery, the group is involved in a $1.7 million three-year effort to apply nanofiber devices for high-resolution molecular imaging of cells and tissue. The sponsor, the National Institutes of Health, is specifically interested in molecular imaging because such information can provide insight into disease.
ORNL also is beginning a collaboration with the Institute of Paper Science and Technology. The project is aimed at using these techniques for genetic manipulation of loblolly pine, the most important wood pulp species in the United States. In addition, ORNL is pursuing the technique for transdermal drug or gene delivery, whereby a small nanofiber-based chip could be attached to the skin and would inject the drug or genes into the body.
The groups' research on nanostructures was published recently in the Institute of Physics Publishing's Nanotechnology (April 9). Co-authors are Anatoli Melechko of the University of Tennessee and Guy Griffin, Michael Guillorn, Vladimir Merkulov, Francisco Serna, Dale Hensley, Mitch Doktycz, Doug Lowndes and Mike Simpson of ORNL.
ORNL is a DOE multiprogram research facility managed by UT-Battelle.
The development of nanotechnological tools that operate on the scale of cells and biological macro-molecules is going to provide a level of control over cellular and organismal processes that will enable a much greater ability to fix and change cells. This, in turn, will lead to medical treatments that make the current methods of treating disease seem absolutely primitive. Advances in nanotechnology will help provide the means to eventually reverse the aging process and make old bodies young again.
Microfluidics devices will be enhanced by embedded carbon nanotube sensors.
San Jose, Calif.--February 3, 2003--Cutting edge research is setting the stage for the practical deployment of carbon nanotubes as flow sensors. Studies drawing on both electrokinetic phenomena and slip boundary conditions are offering in-depth understanding of microfluid flow in restricted microchannels.
Complex experiments have now demonstrated that the Coulombic effect, involving direct scattering of free charge carriers from fluctuating Coulombic fields of ions or polar molecules in the flowing liquid, is stronger than the phonon drag effect in generating electric current/voltage.
The outcome has been the emergence of a model for a practical flow sensor, capable of being downsized to small dimensions as short as the nanotubes.
A new avenue has thereby been created to gauge flow in tiny liquid volumes, with high sensitivity at low velocities and exceptionally rapid response times.
Microfluidics will accelerate the rate of advance of biological science and technology. Microfluidic devices will certainly need a variety of built-in sensors. One application for microfluidic devices will be automated mini test labs to allow blood tests to be done right in a doctor's office or even at home.
Of course all technologies have their downsides and we need to learn to look at every technology and ask how it might (or, rather, will) be abused. In the face of microfluidics one method of abuse would be to use it to make biowarfare agents. A really complex microfluidic device ought to be able to synthesis a viral pathogen. This could even be used to carry out assassinations. Make a pathogen and put it on the surface of something the target is about to touch.
One big challenge in trying to develop nanotechnology is to find ways to control the arrangement of matter at the atomic level. Biological structures such as crystallized protein may provide a way to organize the formation of nanotech structures.
Crystallized proteins also hold great promise as nanostructure templates, said Vicki Colvin, director of Rice University's Center for Biological and Environmental Nanotechnology in Houston. At least 1,000 protein patterns are already known, more than what's available with polymers or other methods, she told the conference.
Many of the crystal structures have high percentages of water in them, an ideal setup for nanotech materials chemistry, Colvin said. Some of them are fragile, however, and would need a chemical "two by four" to do the job, she said.
A new nanotechnology method for delivering a toxic compound only to cancer cells is reported here:
Researchers believe the remarkably versatile "nanoclinic" has the potential to be adapted for treating numerous cancers and other diseases, as well as drug-delivery and diagnostic applications, and for nonmedical applications, such as use in cosmetic and skin-care products.
The magnetic nanoclinic is a thin silica bubble, the surface of which can be customized using a peptide carrier group to selectively target cancer cells. Inside the bubble are ferromagnetic nanoparticles that exhibit a strong inclination to align in the direction of a magnetic field.
The researchers foresee patients receiving the nanoclinics—which would be taken up by cancer cells but not normal cells and tissue—intravenously or by injection at the tumor site. They then would undergo an MRI procedure that would "switch on" the destructive capability of the particles, causing the membranes of cancer cells to rupture.
In a scientific paper in press with Biomedical Microdevices, the UB and Nanobiotix scientists describe how magnetic nanoclinics, less than 70 nanometers in diameter, can selectively destroy human breast and ovarian cancer cells in vitro when a magnetic field is applied. Studies are under way in animals aimed at demonstrating the selective uptake of nanoclinics by tumor cells.
What isn't clear from this is just how exactly are they getting the magnetic nanoclinic to be taken up only by the cancer cells. Have they solved that problem in a way that will work across a large assortment of different types of cancers? Do they need to get a sample from each tumor of each cancer sufferer and then look for a unique surface protein to build a binding peptide to match it? That strikes me as the hardest part of the problem.
Different nanoparticles with affinities to different proteins can be placed into the same cell. Then using different frequency lasers the locations and movements of different proteins can be tracked in the cell. Among the many potential applications for this technology would be more rapid and accurate tissue biopsy and drug delivery:
Because quantum dots are so small, their electrons are compacted, causing them to emit light or to act as a fluorescent tag. Quantum dots can bond chemically to biological molecules, enabling them to trace specific proteins within cells. Nie calls them "bioconjugated nanoparticles" – small particles that are chemically linked to biological materials.
Nanoparticle probes can be used as contrast markers in magnetic resonance imaging (MRI), in positron emission tomography (PET) for in-vivo molecular imaging, or they can be used as fluorescent tracers in optical microscopy. These tags can trace specific proteins in cells for cancer diagnosis or monitor the effectiveness of drug therapy. Because the dots glow with bright, fluorescent colors, scientists hope they will improve the sensitivity of diagnostic tests for molecules that are difficult to detect, such as those in cancer cells, or even the AIDS virus, Nie said.
Update: See this previous article on quantum dots as well.
"The technology could considerably accelerate and reduce the costs of developing and evaluating drug candidates," he said. "On the clinical side, molecular diagnostics are growing in popularity. It's an industry driven by costs and speed. This technology creates new forms of assaying biomedical indications for a lot less money in a lot less time."
Nie, meanwhile, said the technology ultimately may be so effective that it will be used in individualized medicine, or studying, for example, how drugs work in individuals.