Free-electron laser feature
Exploring the interactions of light and matter
By David F. Salisbury
Oct. 9, 2001
The manifold interactions of light and matter play a critical role in the drama of life. They provide
the energy that makes life possible, as well as the vision required to appreciate its beauty. In the
last 200 years, scientists have learned a tremendous amount about the nature of light and of
matter. Yet there are still significant gaps in our understanding of this fundamental interplay which
the Free-Electron Laser (FEL) is helping to bridge.
The different colors of the rainbow and the spectrum of colors produced by a prism illustrate one
of light’s fundamental characteristics: It exists in a virtually infinite number of shades. Each color
is produced by an electromagnetic wave of a specific wavelength, frequency and energy. Visible
light spans only a tiny sliver of the entire electromagnetic spectrum. Bluer colors have shorter
wavelengths, higher frequencies and carry more energy. Redder colors have longer wavelengths,
lower frequencies and carry less energy. The lower end of the spectrum ranges from radio waves
that are hundreds of meters long, through millimeter-sized microwaves, to infrared radiation
associated with radiant heat. The upper end proceeds from the ultraviolet rays that cause
sunburn, through X-rays, up to gamma rays with wavelengths less than the diameter of an atom
and energies three trillion times greater than typical radio waves.
Each color, or wavelength, interacts with matter in a different way. Radio waves push around
free-flowing electrons, generating electrical signals in metal antennae. Microwaves cause the
water molecules to vibrate inside solid food, producing the heat that cooks it. Ultraviolet radiation
from the sun breaks down DNA. Different materials absorb and radiate light at different
wavelengths. The patterns of absorption and radiation form universal signatures that allow
scientists to identify the elemental composition of a material, whether it is in a laboratory on earth
or surrounding a star in a distant galaxy.
The FEL is an ideal instrument for charting the interactions of light and matter in many of the still
unexplored regions of the electromagnetic spectrum. Unlike most conventional lasers, the FEL
can be tuned over a broad range of the spectrum ranging from the infrared to the ultraviolet. In
addition, the FEL design allows for very high power levels.
The W.W. Keck Foundation Free-Electron Laser Center at Vanderbilt is one of four university FEL
centers in the United States and one of only nine such centers worldwide where scientific
research is conducted.1. It operates in the infrared portion of the spectrum. It can produce laser
light in wavelengths ranging from two to nine microns2 and has a peak power of more than 10
megawatts.
Vanderbilt has the only FEL in the world licensed to use this powerful beam for surgical
operations on human patients. The first human surgery using a free-electron laser beam was
performed successfully on December 17, 1999. The laser beam was used to destroy part of a
brain tumor. This feat was repeated the following September with a second patient. Two weeks
later the FEL was used for eye surgery. It was used to cut the sheath surrounding the optical
nerve of a patient whose eye was being removed. This and several subsequent surgeries
following the same protocol have shown that the laser is a superior instrument for such an
operation.
Another center development with significant medical potential comes from the X-ray portion of the
spectrum. Experiments with the FEL beam have shown that it is possible to produce
monochromatic X-rays by colliding the infrared beam head-on with a stream of electrons
1
For a complete list see http://sbfel3.ucsb.edu/www/vl_fel.html
A micron is one millionth of a meter or one 25-thousandth of an inch. Human hair: about 100 microns.
Particles smaller than 35 microns are invisible to the naked eye.
2
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accelerated to relativistic velocities 3. Essentially, the infrared photons bounce off the electrons
and pick-up enough energy to transform them into X-rays in the process. The monochromatic Xray beam is similar to a laser beam 4. Monochromatic X-rays are capable of producing sharper,
cleaner images than conventional X-ray machines, but, until now, the only sources for this kind of
radiation have been billion dollar synchrotron radiation laboratories associated with large particle
accelerators. A private company5 with Vanderbilt support has developed a prototype
monochromatic X-ray machine that it estimates should cost about $1 million to produce
commercially.
The FEL is also proving its worth in the emerging field of proteomics6. Now that the human
genome has been sequenced, researchers are beginning the task to characterize all of the
millions of proteins that build, power, regulate and protect living organisms. But to do so new
methods must be developed for rapidly identifying and characterizing these microscopic
machines. One method under development relies on the FEL beam. By tuning the beam to the
right frequency, researchers have shown that they can identify proteins that have been roughly
separated in an electrophoresis gel7 It works by selectively heating the gel molecules enough to
release the proteins without breaking them. Once the molecules are freed, an electric field
pushes them into a mass spectrometer, a conventional instrument that provides a precise
measurement of the protein’s mass, an important key to its identity.
Laser surgery, monochromatic X-rays, and protein characterization are three areas where
research at the Vanderbilt FEL is showing particularly promising results. There are a number of
other worthwhile research projects also being conducted there. The center currently receives
about $3 million in external support from the Department of Defense, the National Institutes of
Health and several foundations. Center management has identified four areas for growth:
materials science, particularly the use of the FEL in nanotechnology research; laser surgery;
proteomics, identification of the structure and function of proteins; and, in vivo imaging, using the
FEL and monochromatic X-ray beams to image individual molecules in living animals.
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Velocities approach the speed of light, where effects predicted by Einstein’s theory of relativity become
significant.
4 All but a few percent of the photons are the same wavelength, but they are not coherent.
5 The company is named MXISystems. Its website is http://www.mxisystems.com/#top.
6 The proteome is defined as all the proteins associated with a given genome and proteomics is the effort to
catalog and characterize all these proteins and to compare how they function in different conditions.
Chemical & Engineering News Online has published a good overview of the subject at
http://pubs.acs.org/cen/coverstory/7831/7831scit1.html.
7 Electrophoresis gels are widely used to separate proteins, nucleic acids and other bio-molecules. It relies
on the fact that when electrically charged molecules are added to a gel and an electrical charge is applied,
the molecules begin migrating through the gel. Lighter molecules with more electrical charges move more
rapidly than heavy molecules with fewer charges. So molecules of roughly the same size then to form bands
in a strip of gel.
3
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Free-electron laser feature
How the free-electron laser works
The free-electron laser (FEL) is an ideal instrument for charting the interactions of light and matter
in many of the still unexplored regions of the electromagnetic spectrum. As a laser 8, it produces
light in a single wavelength. Ordinary white light contains particles of light, or photons, with a
broad range of different colors. So, when white light strikes an object, it causes a multiplicity of
responses. By contrast laser light provokes a far more limited set of reactions. This allows
scientists to use it to measure the physical properties of materials with great precision.
Ordinary lasers, however, operate at a fixed frequency. That is, they produce light in only one
color. This has limited their usefulness. A number of different types of lasers have been created
that produce light at a number of different wavelengths ranging through much of the
electromagnetic spectrum. Also, researchers have found ways to alter their output frequencies by
using lenses made of special optical materials. Nevertheless, there are a number of regions of
the spectrum where few, if any lasers operate.
The FEL is ideal for exploring the unknown regions in the spectrum because it is tunable over a
broad range of the spectrum. That enables researchers to study how different materials respond
as the wavelength of light impinging on them changes. In addition, the FEL is capable of
producing very high power levels. The power level is important in applications like surgery where
the beam needs enough energy to vaporize soft tissue and bone.
Both the FEL’s tunability and power are the result of its unusual design. In most other lasers, the
lasing process occurs within a liquid, solid or gas. So the wavelengths are limited by those
permitted by the electrical structure of the material. Similarly, the power of the beam is limited by
the amount of energy that the material can withstand before breaking down.
The FEL, however, is not subject to this limitation because it produces laser light by sending
bunches of electrons through a series of magnets in a vacuum. These electrons are first
accelerated to nearly the speed of light9 and then they are sent through a device called a
“wiggler” or “undulator.”
The wiggler consists of a series of magnets with alternating north and south poles. As a bunch of
electrons travels through this alternating field, it causes them to wiggle back and forth in a fashion
that causes them to emit some photons of a specific color. These photons are directed onto a
mirror that allows 15 percent of them through and reflects 85 percent back along the beam line.
At the end of the beam line is another mirror that reflects the photons back up the beam line. The
distance between these two mirrors is set with extreme precision so that each bundle of photons
meets a new bunch of electrons starting through the wiggler. These photons stimulate the
electrons to produce even more photons. After thousands of iterations the power of the laser
beam builds up until it reaches a steady state.
The color of the laser beam can be varied in two ways: putting more power into the electron beam
and changing the spacing between the magnets in the wiggler. The Vanderbilt FEL is designed to
operate at infrared frequencies and can be tuned from two to nine microns.
Because the production of laser light occurs in a vacuum, an FEL can be designed to operate at
extremely high power levels. The Vanderbilt FEL is designed to produce a beam with a peak
power of more than 10 Megawatts and an average power of 10 Watts.
8
LASER is an acronym for light amplification by stimulated emission of radiation. It is a device that creates
an intense beam of light of a single frequency in which all the waves are in step with each other (a condition
called coherency). It does so by triggering an atomic-level cascade that causes large numbers of atoms to
release photons of the same color at nearly the same time. For more information about laser light, laser
characteristics and laser applications go to Encyclopedia.com at
http://www.encyclopedia.com/articles/07237.html.
9 At velocities approaching the speed of light effects predicted by Einstein’s theory of relativity become
significant.
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Lasers come in two basic types: continuous and pulsed. One produces a continuous beam of
light and other produces light in pulses. The Vanderbilt FEL is a pulsed laser. Its beam consists of
a series of extremely short pulses, each lasting less than a billionth of a second.
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Electromagnetic spectrum
The electromagnetic spectrum consists of the entire range of radiation that is made of oscillating
electrical and magnetic fields. The visible rainbow produced by a prism is just a sliver of the entire
spectrum. It extends from radio waves, which can be thousands of feet long, to gamma rays with
wavelengths shorter than the diameter of the nucleus of an atom 10. You can think of light as pure
energy. It doesn’t have any mass and it travels through space as an electromagnetic wave train.
Each color, or wavelength, is associated with a specific frequency and amount of energy. The
longer the wavelength, the slower the frequency and the less energy a wave carries. In many
cases electromagnetic radiation acts like a classical wave, such as spreading out after passing
through a pinhole. However, light in its various forms is also made up of discrete particles, called
photons and in many circumstances acts like a stream of particles.
10
The spectrum spans 19 orders of magnitude. It would take 10,000,000,000,000,000,000 of the shortest
gamma-ray wavelengths lined up end-to-end to stretch the same length as the longest radio wave.
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Radio waves are what AM/FM
radio, wireless telephones, and television stations use to send you popular songs, carry your
conversations and allow you to watch your favorite sitcom. Radio waves are produced by causing
electrons to vibrate back and forth in a metal antenna. They are the longest waves in the
electromagnetic spectrum and can vary from more than 100,000 feet down to an inch.
Microwave radiation is used for radar, transmitting large amounts of information across the
country and warming food and popping popcorn. Microwaves range from an inch to 1/25 th of an
inch in length.
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Free-electron laser feature
Infrared radiation is associated with heat, although even objects like ice, that we consider cold,
emit IR waves. Radiant heaters use infrared light to directly warm objects without heating the air
around them. IR sensors are also used in home security systems to detect intruders. Vanderbilt’s
free-electron laser operates in this region of the spectrum. Infrared waves range from 1/25 th of an
inch down to a few millionths of an inch. The standard unit of measurement in this region is the
micron, which is one millionth of a meter, or 1/25,000th of an inch.
Visible light matters most to people because it is what our eyes can see. But it is a tiny sliver of
the entire electromagnetic spectrum. We can only see wavelengths ranging between 0.4 to 0.7
microns. If you were building a scale model of the spectrum and set the width of visible light equal
to the width of a human hair, then the entire spectrum would stretch about a light year, one
quarter the distance to the nearest star!
Ultraviolet or UV radiation is produced by the Sun along with visible light. With wavelengths
between a tenth to a thousandth of a micron, UV carries a greater punch than visible light. That is
the reason it causes sunburn and skin cancer. Fortunately, the atmosphere, including the ozone
layer, filters out much of the ultraviolet radiation before it reaches the surface.
X-rays range from a thousandth to a 100 thousandth of a micron or, in smaller units, from a
nanometer to a hundredth of a nanometer. The smallest X-ray wavelengths are comparable to
the size of an atom. X-rays. The first medical X-ray in America was taken at Dartmouth College in
1896. The monochromatic X-ray developed at Vanderbilt holds promise for significantly improving
the quality and safety of medical X-rays.
Gamma-rays are even more energetic than X-rays. The only natural sources of gamma rays on
Earth are radioactive materials. However, they are created artificially by high-energy particle
accelerators and nuclear power plants. Gamma-ray wavelengths vary from a hundredth of a
nanometer down to a few hundred thousandths of a nanometer—lengths comparable to those
found in the nucleus of an atom. Gamma-rays are produced by the some of the most energetic
events in the Universe, such as stellar explosions and matter falling into massive black holes.
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Free-electron laser feature
Replacing the scalpel with a beam of purest light
Star Trek’s doctor, Leonard McCoy, would approve. In the popular science fiction series McCoy
routinely used lasers for surgery and would shudder at the thought of using something as crude
and unhygienic as a scalpel. So the good doctor would no doubt applaud the fact that
researchers and surgeons at Vanderbilt’s Keck Free-Electron Laser Center are laying the
groundwork for eventually replacing the scalpel with laser light in both brain and eye surgery.
Of course, not just any laser light will do. Conventional lasers are finding growing applications in
medical practice. Researchers have tried to use them for brain surgery in the past, but they
largely abandoned the effort because the amount of collateral damage to surrounding tissue is
too great and in neurosurgery a fraction of a millimeter can spell the difference between success
and failure. At the same time, the extreme delicacy of the eye has kept it one of the least
accessible areas of the body.
Today, the existence of a radically new kind of laser, called a free-electron laser (FEL), promises
to transform both brain and eye surgery. Unlike conventional lasers that produce light at set
wavelengths, the FEL beam can be tuned through a wide spectrum of colors. That has allowed
researchers to find the optimal wavelength for cutting cleanly through living tissue. In addition, the
FEL is extremely powerful. Although some conventional lasers produce light in the 1 to 10
micron11 range, as does the Vanderbilt FEL, they do not produce light intense enough for surgery.
In addition, the FEL produces laser light in a series of billionth-of-a-second pulses. In the case of
surgery, these pulses act something like the teeth on a saw to cut through tissue particularly
cleanly and effectively.
In the past seven years Vanderbilt researchers have discovered that an FEL beam with a precise
wavelength of 6.45 microns can slice through soft tissue with less collateral damage than the
sharpest steel scalpel. The scientists still don’t know exactly why infrared light of this specific
wavelength works so well, but its effectiveness has been well documented in a series of
experiments with animal and human tissue that culminated in the free-electron laser’s first use in
a human surgery in December 1999.
Vaporizing brain tumors with a beam of light
Michael Copeland—a former Vanderbilt neurosurgeon now in private practice in Kansas City,
Missouri—was the first doctor to use the FEL beam on a patient, Virginia Whitaker, 78, who is
also from Kansas City. The operation was conducted according to a protocol12 designed to be the
safest possible test of the FEL beam’s capabilities. Whitaker had a tumor of a type that can be
removed using traditional methods with a high success rate. Copeland 13 opened the skull using
traditional techniques. He only used the laser to remove14 a sugar-cube-sized amount of tissue
from the center of the tumor mass. The rest of the golf-ball-sized tumor was removed using
conventional methods. Examination of the tumor showed that the laser beam removed tissue with
only one to three cell layers of collateral damage.
Initial efforts to use the FEL beam as a surgical scalpel centered on a shorter wavelength near 3
microns, but they failed. The researchers picked 3 microns because it was one that is absorbed
readily by water molecules, but they discovered that it worked too well, creating microscopic
steam explosions and excessive heat that damaged surrounding tissue.
11
A micron is one millionth of a meter or one 25-thousandth of an inch. Human hair: about 100 microns in
diameter. The smallest dust particle visible with the naked eye is about 35 microns in diameter.
12 All human surgeries performed with the free-electron laser are conducted according to a protocol that has
been approved by a panel of experts, called the Institutional Review Board, who are charged with ensuring
that any extra risk that may be involved is justified by the potential benefits.
13 Copeland was assisted by Peter E. Konrad, assistant professor of Neurological Surgery, and Dr. Kevin P.
Clarkson, assistant professor of Anesthesiology
14 The laser beam does not cut like a knife. Instead, it acts more like a hot poker placed on the surface of a
block of ice. The tissue that it touches ablates, breaks apart and dissipates into the air.
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In 1993 Vanderbilt biophysicist Glenn Edwards 15 got the idea of trying wavelengths around 6.4
microns, a wavelength absorbed both by water and many protein molecules. A number of his
colleagues didn’t think the idea had much merit, but Edwards persisted. "It seemed more relevant
to focus on the absorption of laser light by the proteins in soft tissue rather than water," he said.
After making some basic measurements and doing some back-of-the-envelope calculations,
Edwards and Vanderbilt ophthalmologist Regan Logan tried the beam on some corneal tissue. It
drilled a perfect hole. “We looked at it in disbelief. I had never before had an experiment work the
first time," he said.
Edwards and Logan invited a number of other scientists to test the technique, including Michael
Copeland. They conducted a number of experiments on a variety of tissues and found that
wavelengths near 6.45 microns were optimal for cutting all soft tissues. 16 Since then other
researchers have found two wavelengths—7.5 and 7.7 microns—that cut through bone
particularly cleanly.
Copeland led a research effort that confirmed that 6.45 microns worked just as well with brain
tissue as it does with other kinds of soft tissue. His goal is to use the laser beam to vaporize brain
tumors completely while minimizing the damage to healthy brain tissue. In the operation on Mrs.
Whitaker and two follow-up operations over the following year and a half, he found that the laser
beam worked “beautifully, just the way that we expected.”
In the future, neurosurgeons working with the laser hope to use it with a computer-assisted
guidance system that will allow them to safely remove small brain tumors near vital nerves and
arteries that are too risky to cut out with conventional techniques.
Probing the hidden area behind the eye
Shortly after the second brain surgery, another team of surgeons began testing the FEL beam’s
usefulness for eye surgery. Here the issues are slightly different. The extreme delicacy of the eye
makes the area behind it one of the most difficult parts of the body to treat. “It is one place we
haven’t visited yet,” says Denis O’Day17, who was involved in early studies that applied the FEL to
ophthalmology, “and this approach has the potential to take us there.”
Because of the experimental nature of the procedure, the initial eye surgery on a human was
performed on a patient18 with end-stage traumatic glaucoma who was having the eye removed.
The operation was performed by Assistant Professors of Ophthalmology Karen Joos and Louise
Mawn. First, the surgeons rotated the eye in the socket to expose the optic nerve using the wellestablished procedure of detaching a muscle on one side of the eye. 19 Second, they cut a tiny
flap in the optic nerve sheath using the laser beam. Finally, they removed the entire eye.
Normally, cutting the optic nerve sheath is used to treat a condition called pseudotumor cerebri, a
relatively common neurological illness among young, obese women. A build-up of cerebral-spinal
fluid in the optic nerve causes blurred vision, headaches and even loss of vision. Because
pseudotumor cerebri occurs eight times more frequently in young women than in young men,
scientists suspect that hormones play a role, but little is known about its cause. Surgery is called
for when the condition does not respond to dietetic and medical treatment. Cutting a small
opening in the sheath surrounding the optic nerve relieves the pressure build-up, preventing
further vision loss and, in some cases, even restoring lost vision.
“I’m a traditional surgeon, so I was very skeptical when I was first confronted with the idea of
using a laser for this kind of an operation,” admits Mawn. “After trying it out several times on
animals, however, I became convinced that this is a better, safer and more efficient approach.”
He left Vanderbilt to become the director of Duke’s FEL program.
The research was published in the journal Nature [Vol. 371; 29Sept1994].
17 The George Weeks Hale Professor and chair of ophthalmology.
18 The patient preferred to remain anonymous.
19 Currently, the only alternative is to cut an opening in the facial bones surrounding the eye, which causes
permanent scarring or disfigurement.
15
16
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Mawn is particularly impressed by the fact that the laser beam can be focused to a much smaller
size than a scalpel or scissors, allowing it to be handled more precisely. In the case of the
operation on the optic nerve sheath, the FEL has an additional advantage: a microscopic layer of
fluid between the nerve and sheath dissipates the heat of the laser and so provides an extra layer
of protection for the delicate nerve fibers.
The operation was performed with a special, curved probe that was designed by research
assistant professor Jin H. Shen. The procedure was based on several years of basic scientific
research. As part of this effort, Joos worked closely with Vivien Casagrande, professor of cell
biology, psychology and ophthalmology. They compared the cutting characteristics of the FEL
beam with those of conventional surgical methods on a number of different animal species. The
studies included a detailed analysis of the biological response of the nerve cells to these injuries
and their effects on visual function. This preliminary research has now been confirmed by six
operations following the same basic protocol.
The process of rotating the eye in the socket is technically difficult and carries a high degree of
risk. The eye surgeons think that they can avoid these complications by combining the FEL probe
with an endoscope, a slender optical instrument that allows the user to see parts of the body that
are ordinarily hidden from view. According to Joos, they have developed such a combined probe,
which is only 1.5 millimeters20 thick, and have been using it in animals to evaluate its
effectiveness for treating conditions like congenital glaucoma. In a paper published in the Journal
of Glaucoma, for example, they report using this method to treat congenital glaucoma. The
combination endoscope/laser allowed them to locate and cut open the eye’s natural drainage
areas located around the outside rim of the iris even when they were hidden beneath an opaque
cornea.
An effort to develop an orbital endoscope was made in the 1970s, but was abandoned because
there was no way to control bleeding if it started behind the eye, the researchers say. Combining
the instrument with an FEL beam, however, could overcome this obstacle. For one thing, the
laser beam does not appear to cause as much bleeding as mechanical cutting. Also, its smaller
size and precise handling allows surgeons to avoid disrupting even very small blood vessels.
“The surprising thing about these operations,” summarizes center director David Piston 21, “is that
there have been absolutely no surprises. The laser beam has performed exactly as predicted.”
Because of their size, cost and complexity, no one expects free-electron lasers to begin showing
up in hospitals in the foreseeable future. But once researchers have identified the specific
characteristics that make the FEL so effective at cutting tissue and bone, it should be possible to
design special purpose lasers that replicate these characteristics. These devices would be much
smaller, simpler and less expensive and so could ultimately replace the steel scalpel with beams
of pure light.
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20
One twentieth of an inch.
Associate professor of molecular physiology and biophysics; associate professor of physics, investigator
and fellow of the John F. Kennedy Center
21
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Free-electron laser feature
News conference following first human surgery
with a free-electron laser beam
A news conference was held on Monday, December 20th, 1999 on the Vanderbilt
campus three days after the first human surgery using a free-electron laser.
Following are excerpts from the comments of Virginia Whitaker, the patient who
had a tumor removed from her brain, and Michael Copeland, the neurosurgeon
who performed the operation.
Mrs. Whitaker:
I feel fine, I feel good, and I love these people. I have so much confidence in them. I
knew, about 30 minutes after I talked to this man that I would do this. And I just hope it does help
other people and other doctors.
Well, it feels like I am looking outside on someone else. I have never been anybody
important, you know, and for me to be sitting here talking to you people, it doesn’t seem like it is
me. I am watching someone else do this, but I am glad it is me.
I was never scared, before God, I wasn’t. I was apprehensive, because I had a brother
who had to have brain surgery twice, but it was from an injury in the Navy, but no I really wasn’t
afraid. I knew [Dr. Copeland] would save my life. He wasn’t going to let me die, was he?
Do you want to see my head? I look like a real goon.
There is only one bad thing about [the successful operation]: I can’t blame every mistake
I make on the tumor any more!
Michael Copeland:
The unique thing about the FEL here, is that unlike conventional surgical lasers which
typically only have one static wavelength of light that they produce, the FEL has essentially an
infinite number of wavelengths of light that it can output. So really it was the only laser that could
be used for this operation. However, the trick was figuring out, out of that infinite number of
wavelengths which one do you choose as the right wavelength. So the hard part was figuring out
that 6.45 micron radiation minimizes collateral terminal injury, in other words, the tissue right next
to your incision has the least amount of injury to it….
We feel this is a breakthrough, in that we can vaporize tissue and have almost no ill
effects on the tissue immediately next to it. So the advantage of this laser, when it is fully utilized
and fully exploited, is that we can make incisions in normal brain infrastructures or remove
structures such as tumors … without injuring the adjacent brain. In some parts of the brain a
millimeter is like a mile and can make the difference between doing well as a patient or having a
devastating injury. It may seem like just a millimeter, but in the brain stemwire and speech
cortex, that is a mile.
The scalpel has a lot of mechanical problems. The brain is a lot like jello really and if you
have ever tried to cut jello with a knife, you just can’t do it without tearing it up. The other tool that
we have at our disposal is bipolar forceps, which create an electrical charge between the tips of
the forceps and create heat. That’s four millimeters of thermal injury to the brain. We have
conventional lasers, which also produce collateral thermal injury, so there is either mechanical
injury or heat injury with all the incision tools that we have now. So [the FEL] adds another
weapon to our armamentarium.
That doesn’t mean that everyone will need to have an FEL. What we are trying to
establish is what wavelength has properties that minimize collateral thermal injury. Once we have
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established that, then the industry can create, hopefully, a tabletop laser that cranks out 6.45
micron radiation and that can be an inexpensive way for everyone to take advantage of it.
We couldn’t have had a nicer person to start with. We are trained in medical school to
keep an arm’s distance from your patients because sometimes you make an unpopular decision
and you don’t want to get clouded….This was such a delightful woman that it has been real easy.
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Creating a new kind of X-ray machine
According to the old saying, necessity is the mother of invention. But in the case of the
monochromatic X-ray project, which holds the promise for significantly improving both the quality
and the safety of medical X-rays, it was not necessity but frustration that provided the impetus.
For many years, Frank E. Carroll, chest radiologist and breast cancer researcher at the Vanderbilt
University Medical Center Department of Radiology, has been frustrated with the poor quality of
mammograms. “I’ve been reading mammograms for decades and, when I do, I still feel like I’m
standing in quicksand! We find a lot of things, but miss a lot of them, too,” he says.
So in 1987 Carroll and several colleagues 22 studied the problem systematically and identified the
quality of the X-ray beam as the major factor standing in the way of improving mammography.
The standard X-ray tube used in hospitals produces a beam that contains a broad spectrum of
frequencies23. It generates “soft” X-rays that barely penetrate the skin at the low end of the
spectrum. At the high end, it produces “hard” X-rays that ricochet off bone and tissue, creating a
fog that obscures subtle features in X-ray images.
“Existing X-ray machines do not do a very good job of mammography,” Carroll says flatly. “The
radiation dose is high. The accuracy is very poor. The beam that we use is simply not well suited
to what we are doing.”
When a group of Vanderbilt scientists banded together to submit a proposal to the Department of
Defense to create a free-electron laser center on campus, Carroll joined in because he thought
there might be a way to use the unusual laser to produce better X-rays. When the Strategic
Defense Initiative Organization approved funding for the Vanderbilt center, however, they did not
support Carroll’s proposal because they thought it was too far out.
Fortunately, the researcher was able to convince The Eastman Kodak Company that his ideas
had merit. Kodak funded his efforts for the first three years. That allowed Carroll and his
colleagues—Charles Brau, professor of physics; Marcus Mendenhall, a research associate
professor; Robert Traeger, senior research assistant; Glenn Edwards, former FEL center director
now at Duke University; and research physicist James W. Waters—to create a preliminary design
for the monochromatic X-ray beam line that they wanted to add to the Vanderbilt FEL.
They tried several different approaches and finally hit on one that looked as if it would work. The
basic idea is very simple. Generate a beam of electrons and accelerate them to nearly the speed
of light. At the same time, create a high-powered beam of infrared laser light. Direct the two
beams so that they collide head-on. When you do that successfully, the infrared photons should
bounce off the electrons and gain the energy required to transform them into X-rays in a process
called the Inverse Compton Effect. Making it work was another matter altogether.
What interested Carroll about such a system is that it should produce monochromatic X-rays—Xrays of a single wavelength. This is very similar to an X-ray laser. Unlike laser light, however, it is
not coherent. That is, the light waves are not all aligned. Despite this lack, Carroll realized that a
monochromatic beam would have many advantages for medical imaging compared to current
“polychromatic” X-ray sources.
A great deal was already known about the characteristics of monochromatic X-rays because they
are a byproduct of the massive particle accelerators that have been developed by high energy
physicists to study the basic structure of subatomic matter. Originally, this “synchrotron radiation”
22
Ronald Price, professor of radiology and radiological sciences; David R. Pickens III, associate professor of
radiology and radiological sciences; James W. Waters research associate professor of physics; Charles A.
Brau, professor of physics; and former doctoral student WeiWei Dong.
23 The wavelengths of X-rays are traditionally expressed in terms of the amount of energy that they carry.
The units of these measurements are thousands of electron volts or KeV. An electron volt is the amount of
energy that it takes to push an electron across an electrical potential of one volt. This is a very small unit of
energy: One KeV is less than a quadrillionth of the energy required to power a 100-watt light bulb for an
hour.
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was considered a problem because it siphoned energy from the beam lines that were central to
the physics experiments being run. Then scientists realized that these X-rays were themselves a
valuable resource. They found a way to control their production and have set up special
laboratories, called synchrotron laboratories, specifically to give scientists access to these X-rays.
Nevertheless, Department of Defense officials continued to dismiss the idea until John Madey,
the inventor of the free-electron laser, stood up in a meeting and stated publicly that this was a
good idea and advised them to fund it.
Government support allowed Carroll to modify the Vanderbilt FEL to test the idea. The changes
were made in 1998 and proved the naysayers wrong. At the same time, the experiment showed
that a free-electron laser was not the ideal instrument for the purpose. For one thing, the FEL
produces so much radiation that it must be operated in a heavily shielded room. Also, the
strength of the X-ray beam that it generated was so low that extremely long exposure times were
required to produce X-ray images.
“So we thought about it and decided to get rid off all the bad things about the FEL beam and keep
all of the good things: to make a new kind of machine that we had never seen before,” Carroll
says. The key to the new design was a conventional type of infrared laser, a machine that can
produce a beam with about 1,000 times the power of the FEL called a tabletop terawatt laser
developed by Positive Light [http://www.poslight.com/index.html] in Los Gatos, CA. The
researchers combined this powerful laser with a similarly sized linear accelerator for producing
relativistic electrons. They estimate that this instrument could be built small enough to fit in a
standard-sized X-ray room and should cost about $1 million dollars apiece when mass produced.
That compares to the billion dollar price tag for building new synchrotron radiation centers.
Carroll and his colleagues went to officials at the Office of Naval Research (ONR), which had
taken over management of the free-electron laser program, and asked for an additional $10
million in order to begin producing these monochromatic X-ray machines commercially. ONR
agreed to back the project if the university was willing to invest the matching funds required to set
up a commercial company for this purpose. Vanderbilt had recently set up the Office of
Enterprise Development to help support the commercialization of technology based on university
research. So the university agreed to use this fund to meet ONR’s conditions and set up a new
company—MXISystems, Inc. [http://www.mxisystems.com/#top]—to develop these new
machines.
The university received the grant in July 1999 and the company began building a prototype in one
of the laboratories at the FEL center. On April 10, 2001 they turned on the new machine and
made X-rays for the first time. They are currently in the process of improving the machine’s
performance and making it easier to produce full X-ray images.
“So now we have a beam no one has ever had before. It is basically one frequency, although it is
not truly monochromatic. And it is tunable. Now we have to convince people that we can use this
to make better images,” says Carroll.
Their initial effort is to use the new beam to produce conventional X-ray images. Because the
beam can be tuned to produce X-rays ranging from 15 to 50 KeV, operators can pick the
frequency that does the best job of imaging the part of the body of interest. MXISystems and
Vanderbilt scientists believe that they can produce images with greater detail than conventional
X-ray machines using half the dosage. Also, the device produces X-rays in extremely short
pulses24. As a result, it can take sharp pictures of subjects even if they are moving rapidly. 25
In this mode, the monochromatic X-ray machine should also go a substantial way toward meeting
Carroll’s initial objective. Tumors should stand out much more clearly. He estimates that tumor
24
Two to 10 picoseconds. A picosecond is a trillionth of a second. It is such a brief period that light only
travels one hundredth of an inch in a picosecond.
25 In fact, one possible non-medical application that the researchers have identified is X-raying turbine
blades in jet engines while they are running!
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Free-electron laser feature
tissue should be 11 percent lighter than normal tissue using monochromatic X-rays compared to
the half a percent difference with conventional X-ray beams.
But this is only the beginning. There are several other ways to use monochromatic X-rays that
have even greater medical potential.
One such approach is called “time-of-flight imaging.” In normal imaging, all the photons that make
it through the body contribute to the final image. This includes photons that have bounced around
in the body before emerging and so blur the image. With the extremely short pulses generated by
the new X-ray source, the scientists can install electronic detectors that only measure the photons
that pass through the body directly. This has the potential for reducing dosages by another factor
of ten.
Photons in conventional absorption X-ray imaging actually deliver very little information. Photons
that pass through the body strike the X-ray plate, while those that are absorbed don’t. Physicists
know that photons contain hundreds to thousands of times more information than that. As the Xray photons travel through tissue they undergo subtle changes in phase. With a monochromatic
light source, scientists can tap into this information through a process called phase contrast
imaging. Research done with synchrotron radiation has shown that this approach can provide
valuable information about changes in tissue density, and edges between different organs and
body parts show up clearly. For example, phase contrast images can show individual muscles,
which are completely invisible to conventional X-rays.
The monochromatic X-ray machine will also foster another technique, called K-edge imaging, that
Carroll predicts will become a “whole new field of radiology.”
A great deal of anatomical imaging, like angiography, 26 is done by injecting special compounds
into the body that show up clearly with X-rays. One commonly used contrast agent is iodine. But it
that has a greater degree of toxicity than radiologists would like, over and above the basic
damage done by the X-ray beam itself.K-edge imaging provides a way to reduce both contrast
agent toxicity and beam damage.
Tuning the energy of the beam to a value equal to the binding energy of the electrons in the inner
(K) shell of the contrast agent creates absorption effects that can greatly increase the
effectiveness of such compounds. That means that they can be used at much lower dosages.
Being able to tune the X-ray beam also means that researchers can choose among many more
compounds.
At higher energy levels, the body becomes increasingly transparent to X-rays. That means a
higher percentage of the X-ray photons pass through the body without doing any damage. So, by
identifying contrast agents of lower toxicity that work at higher energy levels, the adverse sideeffects of this type of radiology can be substantially reduced, Carroll says.
At the same time, it should be possible to use K-edge imaging to view a new level of detail within
the body. For example, an experiment performed by two of Carroll’s graduate students 27 has
shown that this approach can see microcirculation channels in blood vessels that are invisible in
conventional angiography while reducing both the radiation dose and the concentration of the
contrast materials given to the patient.
In addition to its radiological applications, the monochromatic X-ray may have an important role in
the basic research efforts made possible by the mapping of the human genome. Many of the
scientists involved say that the next step is “proteomics” – that is mapping and determining the
functions of the millions of proteins that act as the basic molecular machinery of living organisms.
One of the key techniques for determining the structure of complex molecules like proteins is Xray crystallography.
These characterization efforts are currently done primarily at the big synchrotron laboratories
because monochromatic X-ray beams are far superior to polychromatic beams for this purpose.
26
27
Examination of blood vessels using X-rays.
For an abstract go to http://www.mc.vanderbilt.edu/medschool/html/Mellon_Baughman.htm
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Demand for time on these beam lines is far greater than the time available, however. So
researchers must prepare lengthy proposals and wait long periods of time before they can
analyze their samples.
“Just imagine! With this technology we will be able to put 100,000 monochromatic X-ray sources
in 100,000 universities around the world for the cost of building just one centralized synchrotron
lab,” says FEL center director, David Piston.
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A better way to identify proteins in a cell
Following the mapping of the human genome, the next “big thing” in biomedical science is likely
to be proteomics: a newly coined term for identifying the structure and the role of the millions of
proteins that act as the basic molecular machinery of living systems.28 Many experts predict that
proteomics will be the source of many of the major advances in medical treatment in coming
decades.
Practitioners of this new field face a number of major challenges. One of the first is coming up
with fast, effective and relatively inexpensive ways of identifying these molecular movers and
shakers, which are too small to see in the most powerful optical microscope.
It just so happens that the free-electron laser may provide the key to just such a system. Recent
studies have shown that an FEL beam coupled with an instrument called a time-of-flight mass
spectrometer29 can directly measure the mass of proteins—a key step in identification—with
unprecedented ease and sensitivity.
One of the leading methods that biological scientists use to separate and identify different
proteins t is gel electrophoresis30. A solution of electrically charged proteins is loaded onto one
end of a long strip of special gel. When a voltage is applied between the ends of the gel, the
molecules begin migrating through the gel. Lighter molecules with greater electrical charge move
more rapidly than heavy molecules with fewer charges. So the molecules sort themselves into
bands that contain proteins of about the same size. This approach is good for many applications,
but proteomics demands more precise identifications.
For the last four years Physics Professor Richard Haglund and his students and research
associates have been looking at the interactions between the FEL beam and the different ways
that atoms within solid materials vibrate. In the course of these experiments, they have
discovered that the tunability and short pulse length of the FEL beam can be used to selectively
excite a special kind of vibration called an “anharmonic” vibration.
Solid materials vibrate in two different ways. Harmonic or lattice vibrations are like the vibrations
in a slightly stretched spring: they spread rapidly throughout a material and are manifested as
heat. Anharmonic vibrations, on the other hand, are strongly localized in specific atomic or
molecular structures. These vibrations can be extremely energetic and last for as long as 10 to 20
trillionths of a second before transforming into harmonic vibrations.
Having found that they can stimulate anharmonic vibrations, Haglund began looking for ways to
put this capability to use. Then, while reading an interview of J. Craig Venter 31, he learned that
the most promising technology for rapidly isolating and identifying proteins uses conventional
ultraviolet lasers to extract proteins from electrophoresis gels and identifies them by mass
spectrometry. As he read a description of the technique, the physicist realized that the tunable
beam of the FEL could do this job more easily and directly by inducing anharmonic vibrations in
the gel material itself.
28 DNA contains the recipes for generating or “expressing” the proteins that carry out the work of living cells.
29
An instrument used for measuring the mass of atoms and molecules with extreme precision. A sample is
ionized in a high vacuum and the ions are accelerated by strong electric fields into a field-free tube where
they drift toward a detector that produces a spike of electron current when the struck by the molecules.
Since more massive molecules drift at slower speeds than lighter molecules, the time at which the electron
signal occurs can be related very precisely to the molecular mass ..
30 Bergen County Technical Schools has a good overview of gel electrophoresis at
http://www.bergen.org/AAST/Projects/Gel/
31
President of Celera Genomics and leader of the private effort to map the human genome.
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The major complication with using conventional lasers for protein identification is that they heat
the gel/protein mixture so violently that the proteins break apart. Researchers have come up with
a work-around for this problem called matrix-assisted laser desorption-ionization32 (MALDI) mass
spectrometry (MS). They do so by adding another material, called a matrix, to the protein-gel
mixture. The matrix absorbs much of the energy in the laser beam and so moderates the heating
rate so that enough intact proteins are released and ionized to be identified. The addition of the
matrix material is the most complicated and time-consuming step in the entire process. Also,
many matrix materials are acidic and induce chemical changes in the proteins or alter their
delicate conformation.
Michelle Baltz-Knorr, one of Haglund’s graduate students, was interested in exploring how the
FEL beam interacts with the gel/protein system. She obtained samples of electrophoresis gel
from colleagues in molecular biology and began studying what happened when she irradiated it
with different wavelengths of infrared laser light. At a wavelength of 5.9 microns, she hit pay dirt.
She discovered that the gel molecules began loosening up and ejecting intact protein ions. Using
a mass spectrometer on the FEL beam line, she and Haglund demonstrated that they can identify
proteins in electrophoresis gels without going through the time-consuming sample-preparation
stage in conventional MALDI-MS. They have named the new process RIR-MALDI, for Resonant
Infrared MALDI.
The University has applied for a patent on the process and discussions are underway about
developing a special-purpose, solid-state laser that would cost about much less than the freeelectron laser, but duplicate the special features of the FEL beam required for this purpose.
The scientists believe that they can take this process even further. Baltz-Knorr has run additional
experiments that show it is possible to identify proteins encased in ice, rather than gel. The next
challenge will be to demonstrate that this method can identify a protein in extremely low
concentrations, as small as 100 to 1000 proteins in a trillionth of a liter of water. This would open
up the possibility of identifying proteins directly within individual cells.
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32
Desorption is the process of removing atoms and molecules that are sticking on a surface. Ionization is
the process of producing electrically charged atoms or molecules.
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Students play vital role in laser research
By Julie Neumann
Oct. 9, 2001
On projects ranging from bone surgery to protein identification, students play a vital role in the life
of Vanderbilt’s Free-Electron Laser Center. Undergraduates like Arman Hakimian get an
invaluable introduction to the world of research, while doctoral students like Michelle Baltz-Knorr
hone their research skills and painstakingly construct the intellectual groundwork upon which their
future scientific careers will be based.
The Undergraduate Student
Eyebrow ring, spiky hair, trendy clothes…not exactly your typical nerd attire. Then again twentyyear-old Arman Hakimian is not your typical science geek. He is getting the sort of hands-on
research experience about which most nerds can only dream.
Last summer Hakimian worked on bone ablation with physics research associate Borislav Ivanov.
The research focuses on using the free-electron laser (FEL) to break apart bone by
disassociating its bonds. Not only does the FEL allow a surgeon to cut with extreme precision, but
it also is ideal for the work because it can be tuned to frequencies where most of its energy is
absorbed by the water molecules or proteins that are present in abundance within living bones.
As a result, bone ablation done with the FEL requires less energy than saws or other lasers,
greatly reducing the damage it does to surrounding tissue. [FEL SURGERY]
The opportunity to work at the FEL was a lucky break for Hakimian, who was not expecting to
have such a fascinating summer job. “I wanted to do something different for a change over the
summer,” explained Hakimian. “Every single summer that I was a waiter I told myself that it would
be the last summer. Then the next summer would come and it’d be the easiest thing to make the
most money.” But this spring he took the initiative to ask his physics professor and major advisor
if they knew of any summer positions for undergraduates. “Three days before school was out I
got an e-mail from Professor Haglund33 saying that, if I was still interested, there was a job at the
FEL. I was absolutely ecstatic. I was about to give up, to just be a waiter again.”
When Hakimian showed up for work, it quickly became apparent that the bone ablation research
would be a perfect fit. “I am more interested in something that could be surgically applied since I
hope to be a surgeon one day,” noted the premed physics major. “This is more applicable to what
I enjoy.”
Instead of being put to work as the lab peon, Hakimian got to work on every aspect of the
research. “Borislav and I are the only two that work on this. We are the ones that are hands on
and do everything. We both set up the optics and cut specimens; I personally got the computer
up and running.”
Such responsibility was not always easy. He remembers his first experiences in the lab were like
“pushing me out of a plane with no parachute.” But he is quick to remark “sometimes that is the
best way to learn. You are either interested or not. If you’re not you’ll quit, but if you are you’ll
learn.”
Learning became a daily occurrence for Hakimian. The bone ablation research has required him
to work in areas of physics that were new to him. Though he has never taken an optics class, for
example, he estimates that he has acquired a working knowledge of the subject equivalent to
having completed a semester-long course.
He has also discovered the nature of real-world research. “The first experiments we did were so
rough. I was controlling the read-out on the monitor, pausing it and printing it because we didn’t
have it hooked up to a computer yet. Borislav was manually working the laser shutter, flipping the
33
Richard F. Haglund, Jr., Professor of Physics and Chair of the Department of Physics and Astronomy
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thing on and off,” Hakimian recalls, shaking his head with disbelief. “I was very shocked because I
saw so many problems. Everyone told me to calm down; they said ‘This is how it works.’ You take
all the problems and keep going.”
The end result is that Hakimian has come to love the work. “You can take it as a stressful job, but
I think of it as more of a challenge. As long as you are doing all that you can, you’ll come out on
top in the end.”
He hopes to be kept on throughout the remainder of the project. Having been involved since
nearly the beginning, he has watched the research evolve from scratch. He intends to squeeze in
lab time between classes so that he can continue his involvement.
The Doctoral Student
Across the hall from Hakimian, Michelle Baltz-Knorr is in her third year of research at the FEL.
The two labs appear to be mirror images of each other, the standard thick blue pipes of the laser
rising distinctly from a mess of wires and metal. Despite the nearly identical environment,
however, Baltz-Knorr’s work is dramatically different. She devotes her time to running
experiments designed to determine how best to utilize laser light to identify proteins, the
molecular machinery essential to life.
Currently, one of the leading methods for identifying proteins is a technique called matrix-assisted
laser desorption ionization (MALDI)34. It is a form of mass spectrometry35 that utilizes a laser
beam to separate proteins from a matrix and then ionize them so their mass can be measured
with a high level of precision. Mixing proteins with matrix material is a complicated and timeconsuming process. Also, a number of matrix materials are organic acids that can chemically
attack protein molecules; drying the matrix into tiny crystallites also changes the delicate
conformation of the proteins. But the matrix material is necessary because irradiating pure protein
samples with high-power lasers breaks up most of the proteins rather than desorbing them. So
researchers must add specific matrix materials to make the method work with the fixed-frequency
lasers that they have available. This creates something of a Catch 22: The scientists want to
identify a given protein, but to do so they must add agents that can alter the very molecules they
are attempting to identify.
Baltz-Knorr hopes to change all that with the help of the FEL. The fact that the FEL beam can be
tuned anywhere from 2 to 10 microns in wavelength greatly expands the universe of possible
matrix materials beyond those that work with conventional lasers. This has allowed the doctoral
student and her colleagues to explore novel matrix materials such as electrophoresis gel and,
most notably, biologically relevant compounds including water. [FEL MALDI]
“If you think about your body and you think about your cells, how much organic acid do you have
in there?” Baltz-Knorr asks wryly. “Hopefully not a lot.” With human cells being made up of nearly
80% water, the ability to perform mass spectrometry directly from water samples should have
dramatic implications for genetics and medical research. “The end product,” she explains, “is to
study proteins directly from cells.”
In addition to water, Baltz-Knorr has also worked with polyacrylamide gel, which is widely used in
gel electrophoresis. By demonstrating that the gel itself can be used as the matrix, she has laid
the groundwork for a faster and more cost-effective method for identifying proteins than those
currently in use.
“Having the FEL has allowed us to take more biologically relevant matrices such as
polyacrylamide or water and ask, ‘What wavelength would work? What can we do to not alter the
34
Desorption is the process of removing atoms and molecules that are sticking on a surface. Ionization is
the process of producing electrically charged atoms or molecules.
35 Mass spectrometry is a method for measuring the mass of atoms and molecules with extreme precision. A
sample, usually gaseous, is ionized in a high vacuum and the ions are accelerated into a region containing
strong electromagnetic fields. The fields deflect and focus the ions onto a detector in different locations
depending on the ratio of charge to mass that each carries.
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Free-electron laser feature
sample?’” Explains Baltz-Knorr, “Most people have to say, ‘This is the laser I have: What sample
can I use to make it work? What processes do I need to go through?’ With the free-electron laser,
we can ask ‘How should we adjust the laser wavelength and pulse duration to get the optimum
yield of the proteins we are looking for?’ The results are very exciting.”
Three years of research have led to this point. Baltz-Knorr has spent five years at Vanderbilt as a
doctoral student, two of those years under a molecular biophysics training grant funded by the
National Institutes of Health. “I came in as undecided physics but was interested in biological
physics. My advisor, Richard Haglund, encouraged me to apply for the grant, which pulls students
from all disciplines…,” she pauses. “But I had no bio background except for biology and anatomy
in high school.”
So Baltz-Knorr had to start from scratch in biochemistry, spending the summers catching up and
relying on the sympathy of helpful professors. After the first year she was hooked, having
developed a passionate interest in understanding the workings of the body at the molecular level.
Soon after, she was brought into the IR-MALDI group at the FEL in hopes that she could apply
her newfound knowledge.
Immediately the selection and treatment of matrix material caught Baltz-Knorr’s interest. “I started
saying to Richard, ‘Why not look at different matrices, these acids aren’t in your cells, it’s not
natural.’” The team started on glycerol but quickly moved on to explore more biologically relevant
matrices. The FEL’s variable wavelength pushed them in the direction of polyacrylamide and
water.
After several long months of working out kinks in the equipment, Baltz-Knorr was finally able to
put her ideas to the test. “The first time I saw a signal from polyacrylamide gel I just about did
cartwheels around the room. It’s just this feeling of, ‘Oh it worked! Thank God.’”
“[When] you can produce signals that no one else has ever produced before, it’s an incredible
feeling. Especially when you look at it and know that this could have huge applications in the real
world, that people could actually use this in the medical field.”
She has remained passionate ever since. The work has certainly been challenging, but for BaltzKnorr that is part of the fun. “Sometimes what we see is a puzzle… we have to work backwards
and try to find the mechanisms and processes behind what’s happening. Even when you don’t
necessarily understand what you are seeing and why you are seeing it, it’s important. You know it
will help you down the road.”
The mass spectrometry research has been a slow but focused process, much like Baltz-Knorr’s
own growth as a physicist. “When you are starting out, you aren’t sure if this is way you want to
go and you are just trying to find your way, which can be a little daunting. I was very lucky that I
had a great advisor that encouraged me to think up my own project and find something I wanted
to do.”
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Looking to the future
Biophotonics—the application of light to illuminate and manipulate the hidden worlds of living
organisms—is the future direction that Vanderbilt’s free-electron laser center is taking.
“We envision ourselves as taking a leading role in exploring and applying new knowledge about
the interactions of photons and biomaterials,” says center director David Piston.
Building on existing programs, including the FEL surgery, development of the monochromatic Xray and use of the FEL for protein identification, this represents an ambitious expansion of the
range of the center’s activities.
Until recently the center has been a one-horse operation, almost entirely centered on the freeelectron laser. But the successful development of the monochromatic X-ray machine will soon
add a second novel light source to its research repertoire. In the future, Piston would like to add
at least two more new light sources.
The FEL was originally designed and constructed with funding from the Department of Defense
as part of the Strategic Defense Initiative and the DOD has continued to provide the lion’s share
of funding. In fiscal year 2001/2002, for example, it is providing $2.5 million out of the total $3
million in the center’s external funding. The National Cancer Institute is contributing $400,000 and
the remainder comes from three additional research grants from the National Institutes of Health.
“Our support from the Department of Defense is solid, and will continue to play a major role in the
center’s operation,” says Piston, “but we have set a high priority on diversifying our funding base.”
The center is concentrating on four major research areas:

Materials science. Center researchers have considerable expertise in thin films, organic
materials, nanocrystals, magnetic materials and glasses. One of their current projects is
the development of a new kind of microscope that uses the infrared light from the freeelectron laser. Developed in collaboration with researchers from the University of Rome
and the Naval Research Laboratory in Washington, DC, the scanning near-field optical
microscope (NSOM) can achieve a spatial resolution of a few hundred nanometers with
wavelengths in the one to seven micron range. This capability could have a major impact
on materials and biophotonics research. The scientists have begun applying this
technique to applications ranging from mapping the electronic structure of
semiconductors near surfaces and interfaces to the examination of chemical components
in biological cells.

Laser surgery. For ten years, center scientists have built up an extensive base of
knowledge of the way that the unique FEL beam interacts with human tissue and have
identified the specific wavelengths that can cut soft tissue and bone with a minimum
amount of damage to adjacent areas. In the last two years, this knowledge has been
applied to a series of surgeries with human patients that have been completely
successful. In fact, the biggest surprise has been that the operations went exactly as
expected. So far, operations have been done exclusively by Vanderbilt surgeons. In the
future, medical researchers from Duke and Stanford will also be participating. The center
is also supporting research to develop smaller and less expensive solid-state lasers that
can duplicate the characteristics that make the FEL beam such an effective light scalpel.

Proteomics36. Determining the functions of the myriad of proteins that play essential roles
in living systems is vital to applying the knowledge gained from the mapping of the
36
The proteome is defined as all the proteins associated with a given genome and proteomics is the effort to
catalog and characterize all these proteins and to compare how they function in different conditions.
Chemical & Engineering News Online has published a good overview of the subject at
http://pubs.acs.org/cen/coverstory/7831/7831scit1.html.
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Free-electron laser feature
human genome to finding new ways to treat and prevent disease. Using the FEL beam to
simplify and speed up the method currently being used to identify proteins appears likely
to play an important role in this rapidly emerging field. This technique, called IR-MALDI,
has the potential for identifying proteins in very small samples, and might even allow the
analysis of the proteins in single cells. In addition, the monochromatic X-ray has the
capability for drastically reducing the time and the difficulty involved in determining
protein structures through X-ray crystallography. This is the premier method for
determining the structures of complex biomolecules, but can only be done at a handful of
synchrotron laboratories associated with major particle accelerators. The center plans to
construct a second monochromatic X-ray device for this purpose.

In Vivo Imaging. Imagine being able to watch the movement of a single molecule inside
the body of a living animal! The center is using a number of novel techniques, to achieve
this goal. One approach is to use mice that have been genetically engineered to produce
special proteins that fluoresce when illuminated with laser light and then to insert optical
fibers into the mouse’s body to excite these molecules and trace their motion. Another is
to use the monochromatic X-ray to produce three-dimensional images of internal organs
with an unprecedented level of detail. Such a capability should shed important new
information about diseases such as cancer and diabetes.
In the 1960’s, lasers were characterized as a technology in search of an application. Today, they
are everywhere. Their remarkable success demonstrates just how important new light sources
can be, both as a research tools and as components in new technologies. Both the FEL and the
monochromatic X-ray have unique characteristics that virtually guarantee that they will be the
source of valuable new information about living systems and will provide the basis for important
new technologies in years to come.
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