August 2009 Archives

Joseph Lykken of Fermi National Accelerator Laboratory gave a great talk discussing the many ways we use accelerators today, and from there what we will expect the next generation of accelerators to do. For the non-physicists in the crowd it was a helpful overview and at such an interdisciplinary meeting it never hurts to explain the fundamentals.

The big news in accelerator physics these days is the restart of the Large Hadron Collider at CERN in Geneva (shown above with the underground tunnel illustrated above ground). With a price tag of $10 billion and a time line of 20 years to build, Lykken emphasized the empirical trouble with operating such a machine. As the largest piece of machinery in the world as well as one of the most complicated, the LHC holds twenty seven kilometers of wiring, magnets, cooling systems and advanced technologies. You're bound to run into a few bugs, like those that shut down the machine last September. But the LHC is on schedule to restart this fall when scientists will get to fullfill their ambitions of finding a particle that gives matter mass, uncovering the nature of dark matter, and recreating conditions during the big bang. The science it hopes to produce is truly tantalizing for scientists and science lovers everywhere.

The LHC is the largest and most powerful accelerator in the world, but the field also expands horizontally into smaller, yet equally important applications. There are, of course, medical applications such as proton therapy which treats on the order of 8,000 patients a year at 25 proton therapy centers in the US. There are even more biological applications at synchrotron light sources: accelerators that give off X-rays as they drive particles around a circle. These powerful X-rays are becoming a standard part of protein crystallography, and offer many other biological applications. Soon the first free electron laser will start up at SLAC National Accelerator Laboratory and offer scientists a chance to watch incredibly fast processes such as protein folding and molecular motion in real time.

Accelerators may even give aid to the energy crisis and reduce global warming. Accelerator scientists may totally revamp nuclear power by developing a type of accelerator that drives a thorium reactor (rather than uranium or plutonium which are limited resources as well as major safety issues). The waste from these reactors would have a half life of 30 years, instead of thousands. The device would require a linear proton accelerator with particle energies of 10 megawatts, which does not exist yet, but plans are stirring.  

Scientist all over the world are contributing to plans for a project called the International Linear Collider, or ILC, a 31 kilometer electron-positron collider that would compliment the LHC. No country has granted space or funding yet, but there are already over 2,000 collaborators from 300 countries working on preliminary plans.

Fermilab, Lykken's home institution, continues to reach for the cutting edge of accelerator science in the US. Fermilab hosts a premier proton therapy center, and is home to the country's most powerful proton-antiproton accelerator, the Tevatron, which will lead the hunt for the Higgs boson until the LHC comes back online. Fermilab has plans to continue leading the field by hosting at least one of two proposed next generation projects. The first, Project X, would be the first superconducting linear collider, the advantages of which are increased stability and lower wall-plug power consumption. There is also buzz for the first muon collider at Fermilab. The lifetime of a muon is less than a microsecond, so the challenge for building such a machine is trifold: create, collect and make a beam out of these particles in less than a microsecond. The collisions would provide new physics to study and save energy and reduce size.

Particle physicists certainly want to push the upper limit of accelerator power, but to go any bigger than the LHC would begin to cost in the hundreds of billions of dollars, which would require some major justification. So the next generation, if they hope to continue to push the energy limits, must eventually reduce in size. This would not only mean big accelerators with even more power, but also making small accelerators smaller; so that, for example, proton therapy devices could it inside an office rather than a football field.

The leader in such technology comes from plasma wakefield accelerators, where particles sit in a plasma (rather than a vacuum) and in one version are accelerated with lasers. One bunch of electrons actually catches a ride on the wake of a bunch in front of it - like a water skier behind a boat. These accelerators could move particles to the same speeds as current technologies, but at 1/1,000^th the distance.

 "The traditional R&D model for new accelerator technologies has been that the particle physicists...do this R&D and everybody else benefits from [it]," said Lykken. "This model has worked very well in the past; it's still working. But if we really want...to turn around the time from the basic accelerator technology development to something you can use in a hospital, we need to get closer connections between the people doing this kind of research and the people that know what they want to use it for."

It took scientists more than twenty years after the first DNA sequencing technology was discovered to sequence the entire human genome; yet our own cells complete this task every time our bodies produces a daughter cell.  So to achieve the goal of real time DNA sequencing, Pacific Biosciences had the idea to spy on Mother Nature as she goes to work copying DNA. Now, the company's commercial device planned to be on the market in 2010, promises to be 20,000 times faster than current second generation technology, with turn around time of about ten minutes rather than ten days. Chief Technology Officer Steve Turner says in four to five years, new technologies promise to rocket this technology forward even further, making it will possible to sequence an entire human genome in fifteen minutes, on a chip that costs less than 100 dollars.

DNA polymerase is a natural enzyme that constantly makes copies of DNA. DNA is a double stranded chain, and when the two strands are separated, it's possible to recreate one based on the other. That's because DNA consists of only four building blocks, or nucleotides. Each nucleotide only pairs up with one other: adenine (A) pairs with thymine (T), and guanine (G) pairs with cytosine (C). Thus, if one side of the chain reads AATTGGCC, the other side reads TTAACCGG. Polymerase unzips a DNA chain and as long as there are nucleotides to be had, it grabs them and makes a copy of the chain.

Second generation DNA sequencing techniques use polymerase as a reagent, throwing it away after reading only a few nucleotides in the sequence. Turner says one of his company's main objectives was to achieve what they call Single Molecule Real Time DNA Sequencing (SMRT DNA sequencing) in which they keep the polymerase around longer. One the main problems with watching the polymerase is knowing how to see the nucleotides. Second generation techniques attach a different color fluorophore molecule to each type of nucleotide, lighting them up like Christmas lights. But a whole chain of these lights creates too much background noise to see the individuals and their order on the chain.

Pacific Biosciences overcame this first challenge by attaching the fluorophores to a part of the nucleotide that is naturally cleaved off by the DNA polymerase. It diffuses away with 100% efficiency in a totally natural process, and keeps the background noise to a low minimum.

To illuminate the individual nucleotides as they are attached to the chain, the company has developed a SMRT chip- a strip of metal with thousands of small wells in it (see image). At the bottom of each well is a polymerase, resting on a glass bottom, and latched onto a strand of DNA which it will unzip and begin to copy. Base pairs fly around the surface of the chip, but only a few at a time dip down into the well. This immediately minimizes the background noise from those unattached nucleotides. Engineers shine a laser through the glass bottom, but the light does not come up through the well. This uses the same concept found in your microwave oven. You don't want those microwaves flying around the kitchen, but you want to see what's cooking. So the door of the oven has small holes cut in it, which are large enough to let visible light escape, but too small for microwaves to pass through. Similarly, the wavelength of the laser light is too large to pass up through into the wells. But there is an evanescent penetration volume of only a few zeptoliters (10^-21). This illuminates the polymerase, but not the space around it where the nucleotides are floating. And when a nucleotide is bound to the DNA cahin, it releases a burst of light.

The Pacific Biosciences technique uses no reagent, unlike second generation sequencing methods which use a tremendous amount of reagent (it would take two semitrailers full to sequence an entire human genome). It's 20,000 times faster and only takes ten minute to turn around from the time the sequencing finishes. In addition, the Pacific Biosciences it has three times the read time - or the length of a DNA strand that is read sequentially before the process stops. Normally this is shortened by an overwhelming background noise.

Considering that the technique utilizes a lense and a single-photon CCD array to collect the light, Turner says he hopes DNA sequencing will come to be considered a type of medical imaging in the next ten years.

Pancreatic cancer strikes less than 2% of the population, yet this brutal disease has one of the highest mortality rates among patients, with a mean survival time of only four to six months after diagnosis. Scientists hope that early detection will be the key to increasing patient survival rates, and Dr. Kimberly Kelly from the University of Virginia has dedicated her research to learning more this deadly cancer. Within the year her team hopes to go to clinical trials with new biomarkers to target early indicators of the cancer, as well as stem cells left over after removal.

Kelly's strategy begins with bacteriophages: viruses that bind to bacteria and cause them to create millions of copies of the virus phage. In a technique developed some years ago, scientists attach a random amino acid sequence to the bacteriophage which causes the host bacteria to also generate millions of random peptides. Kelly and her team take this zoo of peptides and throw them up against pancreatic cancerous cells and see what sticks. Peptides that "stick" to the cancer cells are chemically bound to proteins on the cell surface and become new biomarkers for those cells. This technique can be used for any cancer or disease and requires very few lab resources, as the peptides can all compete for the cancer cells at the same time so they don't need individual handling or individual tissue samples. It's also very fast. The trade off, says Kelly, is that it may not find all of the cell surface proteins, but it will find the high expressers. They've identified about thirty where there could be tens of thousands on the cell surface.

After finding a group of desired peptides and producing them synthetically, the team worked to attach marker molecules to the peptides. Thus, they can inject the patient with the peptide, which will bond to the cancer cells, and the marker will appear in a scan of the patient. An iron oxide molecule will appear in an MR scan, and an indium molecule will appear in a SPECT scan. The team is looking for cancer cells as well as cancer stem cells and pre-cancer lesions. The lesions may help in early detection, while stem cells left behind after tumor removal are often what cause recurrence. This targeting of specific cells could provide information about what type of treatment doctors should pursue in individual patients or eventually assist in targeted drug delivery.

Their progress is approaching a critical phase as they hope to have the first human trials ready within a year. They are in the process of completing preclinical trials and toxicology tests. The first steps will be small; simply making sure the biomarkers work in humans, and then identifying pre-cancer lesions. Ultimately, she says, early detection and treatment is the goal.