Prion Pioneer

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In a January 1995 Scientific American article, Stanley B. Prusiner wrote:

"Fifteen years ago I evoked a good deal of skepticism when I proposed that the infectious agents causing certain degenerative disorders of the central nervous system in animals and, more rarely, in humans might consist of protein and nothing else. At the time, the notion was heretical. Dogma held that the conveyers of transmissible diseases required genetic material, composed of nucleic acid (DNA or RNA), in order to establish an infection in a host."

Today Prusiner, a professor of neurology at the University of California at San Francisco is hardly a heretic. He has won the highest accolade in science for his discovery of prions, tiny protein molecules that seem to cause a variety of slow acting--and inevitably fatal--diseases in animals and humans; the name is an acronym for "proteinaceous infectious particles." The Nobel Assembly at the Karolinska Institute cited Prusiner for "his pioneering discovery of an entirely new genre of disease-causing agents and the elucidation of the underlying principles of their mode of action."

According to the Nobel panel, prions are now firmly established as a group of pathogens along with other well-known infectious agents, including bacteria, viruses, fungi and parasites. In animals, they are seen to be the causative agent of scrapie, a disease of sheep, and bovine spongiform encephalopathy (BSE), the well-publicized "mad cow disease." In humans, prions are believed to cause kuru, a much studied disease of the Fore people in New Guinea, and several hereditary forms of dementia, including Creutzfeldt-Jakob disease (CJD), which affects about one in a million people.

Of Prusiner's numerous discoveries, possibly the most startling--and controversial--was that prions can reproduce without genetic material because they are forms of ubiquitous proteins found in humans and animals. Yet when he and his colleagues identified the first prion pathogen as a protein they knew there must be a gene somewhere that carried the DNA coding for its production.

In 1984 gene probe experiments found the matching sequences not in a virus or bacterium but in the genome of all mammals. The normal prion protein was an ordinary component of white blood cells (lymphocytes) and was found in many other tissues as well. Normal prion proteins are particularly abundant on the surface of nerve cells in the brain.

Then how do prions cause disease? Subsequent research showed that the prion protein could sometimes fold into a different and very durable conformation. Infectious prions with this configuration would set off a chain reaction that would convert normal protein to the deadly form. In some diseases, such as CJD, the pathogenic proteins are created by a genetic mutation.

Prusiner believes that it is the buildup of this abnormal protein in the brain that causes the damage responsible for the characteristic dementia of prion diseases. Regions within diseased brains have a characteristic porous and spongy appearance (evidence of extensive nerve cell death) and affected individuals exhibit neurological symptoms, including impaired muscle control, loss of mental acuity, memory loss and insomnia.

Some researchers remain skeptical of Prusiner's findings. Even so, his work has opened the door to developing treatments for prion diseases. Investigators are already seeking ways to block the activity or formation of the abnormal proteins. It may also have contributed to the understanding of more common dementia illnesses, such as Alzheimer's disease.


THE PRION DISEASES Stanley B. Prusiner inScientific American, Vol. 272, No. 1; January 1995.

TEMPEST IN A T-BONE? Paul Wallich in Scientific American Explorations, August 1996

DEADLY ENIGMA, Tim Beardsley in Scientific American Science and the Citizen, December 1996


Freezing Atoms

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Because atoms in gases normally zip along at speeds of about 4,000 kilometers per hour, it's hard to take a close look at them. But in 1985 Steven Chu and his colleagues at AT&T Bell Laboratories in Holmdel, N.J., discovered a way to use laser light to cool atoms and slow their motion to the more stately speeds of less than a tenth of a kilometer per hour. They dubbed their creation "optical molasses" because the light beams behaved like a thick liquid.

Barely more than a decade later, laser cooling has become a powerful tool for investigating the behavior of atoms, resulting in theoretical insights in quantum mechanics. The technique is now on the verge of resulting in practical applications, such as far more precise atomic clocks and instruments.

The significance of this development has also won recognition in an equally rapid fashion. The Royal Swedish Academy of Sciences awarded the 1997 Nobel Prize in Physics to Chu, now at Stanford University, and two other key workers for advancing the technology of trapping atoms: Claude Cohen-Tannoudji of College de France and Ecole Normale Superieure in Paris, and William D. Phillips of the National Institute of Standards and Technology in Gaithersburg, Md.

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"The new methods of investigation that the Nobel Laureates have developed have contributed greatly to increasing our knowledge of the interplay between radiation and matter," says the Nobel citation. "In particular, they have opened the way to a deeper understanding of the quantum-physical behavior of gases at low temperatures."

To create the first "optical molasses," Chu's group aimed six intersecting laser beams at a cloud of sodium atoms in a vacuum chamber. Whichever direction the sodium atoms tried to move, photons of light pushed them back into the area where the beams crossed. About a million of the chilled atoms formed a glowing cloud the size of a pea.

The intense light acts like a liquid, slowing the atoms much as molasses will slow the motion of a falling marble. As the atoms slow, their temperature drops, and they cool to within a few millionths to a few billionths of a degree above absolute zero.

The trouble with optical molasses was that the atoms soon sank out of the trap because of gravity. It took more than laser light to trap an atom. By combining lasers with magnetic fields, the first magneto-optical trap (MOT) was created in 1987. It used six laser beams but had in addition two magnetic coils that gave a slightly varying magnetic field with a minimum in the area where the beams intersect.

Phillips, who was developing techniques for trapping atoms in magnetic fields, quickly adopted the MOT and attained in 1988 a temperature of 40 microkelvins (that's 40 millionths of a Celsius degree above absolute zero). That temperature was surprisingly low--theoretical calculations had suggested that they would not be able to get below 240 microkelvins. Cohen-Tannoudji and his colleagues later demonstrated that the accepted calculation was incorrect and proved it by cooling cesium atoms to two microkelvins.


In addition to atomic traps for holding chilled atoms in place, scientists have created "atomic fountains" in which laser-cooled atoms spray upward from an atomic trap like a jet of water. At the very top of the trajectory, the atoms are almost motionless for an instant.

Both Phillips and the Paris group have showed that with certain laser settings it is possible to trap the atoms so that they group at regular intervals, forming an "optical lattice." Researchers have also created a bizarre new state of matter, whose existence was originally postulated by Albert Einstein 70 years ago.

Called a Bose-Einstein condensate, a group of atoms is chilled to such a low temperature that the atoms' motion nearly stops and they begin acting like a single entity, a kind of super atom. First achieved by a group at NIST and University of Colorado researchers in 1995, the condensate formed at a temperature of about 20 billionths of a degree above absolute zero, a temperature lower than had ever been achieved previously. Since then, other laboratories have reported similar results.

Several research groups are now using the new tools to improve the precision of measurement. One goal is better atomic clocks, which are the standards of international timekeeping and calibrate the Global Positioning System, a satellite-based system used for navigation of ships and aircraft. Clocks with a precision 1,000 times that of the best now available seem possible.

The technique may also provide the key to packing more and more devices onto computer chips. Researchers at NIST's Atomic Physics Division are experimenting with lenses created from light to focus beams of atoms; such atomic beams could be used to etch circuit lines on semiconductors. Those lines would be far finer than those now made using glass lenses to focus light beams because atoms can be focused more accurately. "We are inverting matter and light," says Steven Rolston, a NIST physicist. The group is also working on instruments that may provide ultra-precise measurements of gravitational forces.

In a 1992 article in Scientific American, Chu summed up the excitement of the research: "Optical traps, to paraphrase a popular advertising slogan, have enabled us to 'reach out and touch' particles in powerful new ways.... It has been a personal joy to see how esoteric conjectures in atomic physics have blossomed: the techniques and applications of laser cooling and trapping have gone well beyond our dreams during those early days. We now have important new tools for physics, chemistry and biology."

The people who pick the winners at the Royal Swedish Academy of Sciences apparently agree.


COOLING AND TRAPPING ATOMS. W.D. Phillips and H.J. Metcalf in Scientific American Vol. 256, No. 3; March 1987.

NEW MECHANISMS FOR LASER COOLING C. N. Cohen-Tannoudji and W. D. Phillips in Physics Today Vol. 43, No. 10, October 1990.

LASER TRAPPING OF NEUTRAL PARTICLES Steven Chu in Scientific American Vol. 266, No. 2; February 1992.


Life's Currency

ATP, or adenosine triphospate, is a chemical that sits at the very foundation of life. As the universal carrier of chemical energy in the cell, ATP is the medium through which food is converted to useful energy for the body's every function, from thinking to breathing to moving. It is not surprising then, that since ATP was discovered by the German chemist Karl Lohmann in 1929, researchers seeking to understand this amazing molecular machine have won a long string of Nobel Prizes.


The 1997 Nobel Prize in Chemistry adds another chapter to the ATP epic. This year's medals are being awarded to three researchers who have continued to probe the chemical system of ATP and its mechanisms of cellular energy transport. Half of the $1-million award is to be split between Paul D. Boyer of the University of California at Los Angeles and John E. Walker of the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. The second half of the prize recognizes the related work of Jens C. Skou of Aarhus University in Denmark.

ATP has been called the "cell's energy currency" because it captures energy released by the combustion of nutrients and transfers it to reactions that require energy, such as the assembly of cell components, muscle contraction, transmission of nerve messages and many other functions. It serves this function in all living organisms, from bacteria and fungi to plants and animals, including humans.

The ATP molecule consists of the nucleoside adenosine linked to three phosphate groups. When the outermost phosphate group is removed, energy is released and adenosine diphosphate (ADP) is formed. With added energy, ADP is converted back to ATP. Adult humans at rest convert about one half body-weight daily; during hard work the quantity can rise to almost a ton. "This is the machine that makes the money that the rest of the body spends," Boyer says. "Without it there would be no life at all."

The chemical that drives this back-and-forth conversion is an enzyme called ATP synthase. The contribution of Boyer and his colleagues was proposing a mechanism for how ATP is formed from adenosine diphosphate (ADP) and inorganic phosphate. Boyer, 79, began his studies of ATP formation in the early 1950s and is still highly active as a scientist.


Over several decades Boyer developed a model of how the various subunits of the ATP enzyme work together like gears, levers and ratchets to generate cellular energy. According to the Nobel committee, "his work has been crowned with unusual success in the past few years. ATP synthase has a mode of function that is unusual for enzymes, and this required much time and extensive studies to establish."

Walker and his co-workers determined the structure of the enzyme and confirmed Boyer's model. Walker made his first studies of ATP synthase at the beginning of the 1980s, determining the amino acid sequences in the constituent protein units and then collaborating with crystallographers to clarify the three-dimensional structure of the enzyme. "Walker's work complements Boyer's in a remarkable manner, and further studies based on this structure demonstrate the correctness of the mechanism proposed by Boyer," says the announcement from the Royal Swedish Academy of Sciences.


Skou, meanwhile, discovered a related enzyme in the ATP cycle: sodium, potassium-stimulated adenosine triphosphatase (Na+, K+-ATPase). This enzyme--the first molecular pump to be identified--maintains the balance of sodium and potassium ions in the living cell. Both ATP synthase and Na+, K+-ATPase are bound to membranes in the cell and linked with the transport of ions through them--but for different reasons.

Since the 1920s, it has been known that within the cells the sodium concentration is lower and the potassium concentration higher than in the liquid outside. Skou found the enzyme responsible and became the first scientist to describe an enzyme that can promote directed transport of substances through a cell membrane, a fundamental property of all living cells. Numerous enzymes have since been demonstrated to have essentially similar functions.

"The three laureates have performed pioneering work on enzymes that participate in the conversion of the 'high-energy' compound adenosine triphosphate (ATP)," the Nobel judges noted


THE Na+, K+-ATPase. J. C. Skou and M. Esmann in Journal of Bioenergetics and Biomembranes, Vol. 24, No. 3; 1992

THE BINDING CHANGE MECHANISM FOR ATP SYNTHASE: SOME PROBABILITIES AND POSSIBILITIES. Paul D. Boyer and John E. Walker in Biochimica et Biophysica Acta, Vol. 1140, No. 3, pages 215-250; January 1993

DIRECT OBSERVATION OF THE ROTATION OF THE F1-ATPase Hiroyuki Noji, Ryohei Yasuda, Masasuke Yoshida and Kazuhiko Kinoshita Jr., in Nature Vol. 386, pages 299-307; 1997