Argonne News

Researchers from the University of Chicago and Argonne have deciphered the three-dimensional structure of insulin-degrading enzyme, a promising target for new drugs because it breaks down not only insulin but also the amyloid-beta protein, which has been linked to the cognitive decline of Alzheimer's disease.

In the Oct. 19 issue of Nature (available online Oct. 11), the researchers describe the structures of insulin-degrading enzyme (IDE) in complex with four of the proteins it digests: insulin, amyloid-beta, amylin and glucagon. The structures are exciting because they suggest ways to develop drugs that could either speed up or slow down this ubiquitous enzyme's activity.

"The structure of insulin-degrading enzyme tells us a lot about how it works, which is somewhat unorthodox," said Wei-Jen Tang, associate professor in the Ben May Institute for Cancer Research at the University of Chicago and director of the study. “Understanding how it works gives us clues about how to design drugs either to inhibit or activate it.”

“By introducing small, targeted mutations, we have already been able to increase the enzyme's activity by as much as 40-fold,” he said. "That gives us a blueprint for the next step, trying to devise a drug that would produce a similar effect."

Ever since I. Arthur Mirsky discovered IDE in 1949, physicians have sought ways to manipulate it. Mirsky thought that by inhibiting the enzyme he could help diabetics by making their insulin remain active longer. More recently, as scientists realized that IDE was also involved in clearance of amyloid-beta, they have begun searching for ways to supercharge the enzyme to see if it could prevent the build-up of the amyloid plaques that are a hallmark of Alzheimer's disease.

Despite more than half a century of intensive research, however, insulin-degrading enzyme has remained "an especially elusive pharmacological target," biochemist Malcolm Leissring of the Scripps Research Institute and neurobiologist Dennis Selkoe of Harvard Medical School wrote in a commentary that accompanies the Nature article.

Using Argonne's Advanced Photon Source, Tang and colleagues were able to solve the structures of this enzyme in complex with insulin and with amyoid-beta, as well as amylin and glucagon. These "high-resolution crystal structures open the door to the rational design of pharmacological modulators of this important protease," wrote Leissring and Selkoe.

The enzyme, Tang's team reports, resembles the video-game character “Pac-Man,” with two bowl-shaped halves joined by a hinge at one end and held closed, most of the time, by a latch of hydrogen bonds on the other end. When the bowls come together, like a shut mouth, they enclose a chamber, shaped like a triangular prism, large enough to contain relatively small peptides, such as insulin or amyloid-beta, which have fewer than 50 amino acids.

Although it can cleave larger molecules, the proteins IDE degrades most readily fit neatly within this chamber. Negative electrical charges on their outer surfaces help to align them with the positive charges on one inner surface of the chamber. Once they are in place, the enzyme slices them multiple times into tiny pieces, which are then discarded.

Although the enzyme's structure is similar to Pac-Man, its behavior differs. Pac-Man keeps his mouth wide open to gobble up anything in his path. With IDE the mouth is usually closed. The hydrogen-bond latch that holds the jaws together protects its active, or catalytic site.

But in a series of experiments, Tang and colleagues were able to make small mutations of IDE that altered only the latch, disrupting the alignment of contacts that normally keep the enzyme closed. Three of these altered versions of wide-open IDE proved to be 30 to 40 times more active than the normal version of the enzyme.

"This suggests that the rate-limiting step may be the speed at which the enzyme can reopen and then clamp down on a new morsel rather than the time it takes to chew something up," said Tang. "This makes us think that if we can slightly alter its shape, we can substantially boost its activity."

The researchers are now searching for small molecules that can duplicate the effects of those mutations, shifting the balance toward the open rather than the closed state. “Such compounds,” the authors note, “might facilitate the clearance of amyloid-beta and other pathologically relevant IDE substrates.”

“By revealing IDE's active site in unprecedented detail,” notes the commentary, “the new structures provided by Tang and coworkers hold great promise for finally realizing Mirsky's dream.”

The National Institutes of Health, the University of Chicago Diabetes Research and Training Center and the American Heart Association funded the study. Additional authors include Yuequan Shen and Marsha Rosner of the Ben May Institute for Cancer Research at the University of Chicago, and Andrzej Joachimiak of the Midwest Center for Structural Genomics and Structural Biology Center at Argonne.

Argonne's laboratory-level goals have been established for fiscal year 2007 to provide guidance for the performance-appraisal process. The goals have been posted online.

Associate laboratory director and division goals are under discussion and will be available soon; updates will be posted in Argonne Today.

• Become recognized as the premier science and technology lab supporting the DOE mission.

• Maximize scientific impacts from Argonne user facilities through technological innovation.

• Implement Target-Zero goals in safety performance and environmental stewardship; integrate ESH&Q and security into all work.

• Enable the lab's science mission through excellence in operations by integrating science needs into operations more efficiently and effectively.

• Expand collaborations, partnerships, and IPA/detailee assignments that demonstrably leverage laboratory capabilities, enhance national security, increase the value of transferred technology and contribute to workforce development.

• Achieve B+ or above in all Performance Evaluation and Measurement Plan metrics.

The electronic system for the October Argonne Combined Appeal Renewal Drive is now available. It is accessible by logging into the Inside Argonne web page, selecting the "Personal Info" tab, clicking on "My Payroll" and then selecting the Argonne Combined Appeal link on the left hand side. More specific instructions are available at http://inside.anl.gov/community/aca/fall_2006.html. The renewal system will be available throughout the month of October.

If no action is taken, contributions will continue at the previously selected level until the next campaign in May, 2007.

With the change from an October to May Argonne Combined Appeal campaign month, employees should note they are entering a pledge for an interim time period of November 2006 until June 2007 when deductions from the next regular campaign drive in May 2007 will take effect. The schedule change was made to move the campaign away from the busy fiscal year transition.

Regular, non-union, full-time and part-time Argonne employees have been given data entry access to their own performance appraisals through Monday, Oct. 23. If you are asked by your supervisor, you may key in or copy and paste draft assessments of your FY06 performance and your individual FY07 draft goals directly into your own performance appraisal. Both you and your supervisor will be able to see whatever is being keyed into the performance appraisal during this time.

1. Go to Inside Argonne ( www.inside.anl.gov ) and enter your Argonne user name and password. Select the applications tab at the top, and click on the Performance Appraisal link on the All Employee menu bar on the left. Your employee view page will appear.

2. Choose the Data Entry tab on your employee data page. You will see your name on a listing. Select your name.

3. Choose Edit Performance Appraisal from the menu on the left to enter or copy/paste directly into your performance appraisal. (Click the Help tab to access complete instructions)

If you are off site, you must access the performance appraisal Web application via VPN Client software using your Argonne domain account.

University of Chicago President Robert Zimmer has chosen Thomas Rosenbaum as the next provost of the university. Rosenbaum has served as the university's vice president for research and for Argonne National Laboratory since July 2002. He will become the university's second-ranking officer effective Jan. 1, 2007.

"Tom's deep commitment to excellence across the university and his significant record of accomplishment on the faculty and administration make him an ideal choice for our next provost," Zimmer said. "His leadership was instrumental in the university's successful bid in an open competition to retain management of Argonne, one of the nation's largest and most important federally funded research centers.

"He brings to the provost's office expertise in addressing the most difficult problems through the combined strength and insight of multiple perspectives from across disciplines. As we look ahead to developing ambitious plans for the arts and humanities, social sciences, the physical and biological sciences, and the schools, Tom's appreciation for the broad array of academic environments, modes of inquiry, and needs throughout the divisions and schools will be especially important."

Rosenbaum succeeds Richard Saller, the Edward L. Ryerson distinguished service professor, who will return to the faculty after completing his current five-year term as provost in December.

Rosenbaum is the John T. Wilson distinguished service professor in physics at the university. He is an expert on the quantum mechanical nature of materials--the physics of electronic, magnetic and optical properties at the atomic level--that are best observed at temperatures hundreds of degrees below zero.

Rosenbaum currently chairs the multi-institutional Science Policy Council of Argonne.

As provost, Rosenbaum will be responsible for academic appointments, programs and budgetary priorities at the university, which has 2,160 faculty members and a student enrollment of 12,500. A search will soon begin for a new vice president for research and for Argonne National Laboratory.

Employees are invited to "Six Steps to a Secure Retirement," a workshop offered by Wachovia Securities (a Prudential representative). The workshop provides guidance on how to invest money for retirement and is intended for all ages. The workshop has been highly recommended by Argonne employees who have attended in the past.

The one-hour workshop will be held Wednesday, Oct. 18, at noon in the Building 213 Cafeteria private dining room. Seating is limited; for a reservation call Cheryl at (630) 285-8876. .

The Argonne Running Club will hold its annual Director's Run Wednesday, Oct. 25. The five-kilometer run and two-mile walk starts from New Brunswick Laboratory at noon. Employees and guests of any skill level are welcome. Refreshments will be served after the event.

Argonne is working with Lenovo and IBM Corporation to replace recalled lithium-ion batteries for Argonne-owned ThinkPad laptops.

Lenovo and IBM Corporation, in cooperation with the U.S. Consumer Product Safety Commission and other regulatory agencies, have announced the voluntary recall of about 526,000 lithium-ion batteries manufactured by Sony Corporation. These batteries were manufactured for use with specific ThinkPad notebook computers shipped from February 2005 to September 2006. Lenovo will offer customers free-of-charge replacement batteries for all recalled batteries.

In cooperation with Procurement and EQO, CIS is coordinating an exchange of eligible batteries with Lenovo. Employees with Thinkpad R-Series (R51e, R52, R60, R60e), T Series (T43, T43p, T60) or X Series (X60, X60s) laptops should go to www.lenovo.com/batteryprogram to determine if the battery is one eligible for exchange under the recall. If you have a recalled battery, please remove the battery from the laptop and contact the CIS Help Desk at 2-9999, option 2 or help@anl.gov with the serial number of the laptop and the barcode number from the battery. While it is preferred that the batteries be exchanged through CIS, please contact the help desk for tracking reasons even if you have already initiated an exchange directly with Lenovo.

Lenovo has posted a battery recall FAQ online that covers safety and exchange related details. Lenovo says that the exchange of batteries could take up to four weeks.

Questions regarding the recall can be directed to Jim Dust (CIS) at ext. 2-8540. Safety-related questions regarding lithium-ion batteries should be directed to Bob Arthurs (EQO) at ext. 2-8227.

Under the University of Chicago/Argonne Scholarship Plan, children of full-time, regular Argonne employees are eligible to compete for full-tuition scholarships. To be awarded a scholarship, the student must be accepted for freshman-level admission to The University of Chicago and must be among the most qualified applicants from Argonne families, as judged by The University of Chicago.

Application and verification forms are available in the Division of Educational Programs (DEP), Division Office, Building 223, Room M-125 or by calling Carol Reynolds at ext. 2-4114. Students may also fill out the Basic Information Form and the application online at uncommonapplication.uchicago.edu. Students who wish to compete for a scholarship are required to complete the verification form that must be validated by DEP to be accepted by the university and should be received no later than Dec. 1.

This University of Chicago/Argonne Scholarship Plan will provide full tuition payment. The university will continue to provide one-half tuition remission to dependent children of full-time, regular Argonne employees who are admitted for study in the college or the laboratory schools of the university. For information on the tuition remission program, call Performance Development in Human Resources at ext. 2-3410. For information about University of Chicago admissions, call 773-702-8654.

Rosario Andino will perform at Argonne's Building 402 Conference Center Saturday, Oct. 21, at 8 p.m.

Andino is a world class piano virtuoso. She will present a showcase program that includes familiar classical piano pieces by Beethoven, Schumann, Chopin and List, as well as seldom-heard Cuban dances by composers from the last two centuries.

The concert is open to the public. Visitors who are U.S. citizens need photo identification to enter the site, and should call to register before the concert. Non-U.S. citizens must register before the event by calling (630) 252-3751 during business hours.

Admission is $25. To order tickets, call ext. 2-3751 or mail a request using the online ticket request form. Remaining tickets will be available the week of Oct. 16 in the Building 213 Cafeteria between noon and 1 p.m.

Arts at Argonne will hold four more concerts in the 2006 – 2007 Chamber Music series:

Employees urged to take the 'Change a Light' pledge

A new U.S. Department of Energy program is encouraging the use of compact fluorescent light bulbs (CFLs) in the home.

CFLs provide high-quality light while requiring less energy while lasting longer than typical incandescent bulbs. Energy Star qualified CFLs use 66 percent less energy than a standard incandescent bulb and last up to 10 times longer. Replacing a 100-watt incandescent with a 32-watt CFL can save at least $30 in energy costs over the life of the bulb.

If every household in the United States replaced one light bulb with an Energy Star qualified compact fluorescent light bulb (CFL), it would prevent enough pollution to equal removing one million cars from the road.

"Since the Department of Energy is a partner in this project, it is extremely important that we set a good example," said Energy Secretary Samuel Bodman. "Every agency in our government has been asked to participate, and I truly hope that the DOE will lead the way with the highest level of participation. Your participation level will speak volumes about the importance of using Energy Star bulbs, since you are respected as our nation's energy experts."

From Oct. 4-31, individuals can pledge to "Change One Lamp" at DOE's Energy Star Web site. Argonne will receive credit from DOE for every participant who enters the laboratory's name and an "anl.gov" e-mail address.

"Argonne has reduced its building energy use by 30 percent since 1985, in part by switching to energy-efficient fluorescent lighting," said Gwendolyn Morrison, Argonne Energy Manager. "Lab employees can help extend this effort to their homes, one light bulb at a time."

Choral group seeks new voices

The Argonne Choral Group is looking for new voices. This group has existed for 25 years and performs music of easy to moderate difficulty for special events at the laboratory a few times per year, such as Veterans' Day and the holidays.

Rehearsals are typically during lunch time in the few weeks prior to the event. For additional information, contact Patrick Garner (NE), ext. 2-4872 or plgarner@anl.gov.

New theory on particle spin brings science closer to quantum computing

Physicists at Argonne have devised a potentially groundbreaking theory demonstrating how to control the spin of particles without using superconducting magnets — a development that could advance the field of spintronics and bring scientists a step closer to quantum computing.

Spintronics, also known as spin electronics, is an emerging technology that looks to develop devices that exploit the quirky world of quantum physics, or physics at the incredibly small atomic level, particularly the up-or-down spin property of electrons. Conventional electronics use the charge of the electron. Spintronic devices would use both the spin and charge, achieving new functionality.

Scientists across the globe are racing to develop the spintronics field. It could revolutionize the computing industry with chips that are more versatile and exponentially more powerful than today's most cutting-edge technology.

Physicists Dimitrie Culcer and Roland Winkler (XSD), along with Christian Lechner of Regensburg University, Germany, published their theoretical findings in the Sept. 8 issue of Physical Review Letters . Culcer and Winkler are at Northern Illinois University, in addition to their affiliation with the Advanced Photon Source at Argonne.

“Our research illuminates a new pathway for generating and manipulating the spin in semiconductors,” Winkler said. “This is important, because the use of bulky superconducting magnets would be impractical in most devices.”

The physicists theorize that spin can be induced and manipulated by running a current through gallium arsenide, a common semiconductor, in what is known as spin-3/2 hole systems, which previously have been little studied. Hole systems are “missing electrons,” while the fraction 3/2 refers to the magnitude of the spin. Spin-3/2 hole systems are created in semiconductors by “doping” — introducing impurities that have one less electron compared to the host material.

Geometry also must play a crucial role in spin manipulation, according to the researchers. They propose development of a nano-sized and L-shaped device that allows for the exploitation of the newly discovered effects in spin-3/2 hole systems.

“Spin polarization is achieved as the current flows around the corner,” Winkler said.

“We believe we've discovered a much simpler way for inducing spin polarization,” he added. “We don't need a big magnet. The only requirement in our case is an electrical current in the sample, which is much easier to achieve than putting the sample in a magnetic coil. For an electrical current, you only need two contacts.”

Culcer said the researchers hope the publication will raise awareness of new and exciting physics that can be accomplished in spin-3/2 hole systems.

“We do basic research and do not work directly on information technology,” Culcer said. “But researchers working on quantum computing are primarily interested in spin systems. For the past 50 years, scientists have intensely studied what's known as spin-1/2 systems.

“One of our primary goals with this paper was to demonstrate what could be accomplished with spin-3/2 systems,” he said. “We hope to point scientists in a direction that offers the possibility of new applications and hopefully ways of manipulating information in the future.”

Conversational English classes held at new time

Free conversational English as a Second Language (ESL) classes will now be held from 9:30 to 11:30 each Thursday in Building 223, Room L119.

The Newcomers Assistance Office of the Department of Educational Programs has found a team of four energetic ESL teachers who volunteer their time to lead the class each week. Depending on the skill levels and the number attending, the class will be divided into groups.

All interested visiting researchers and those accompanying them are welcome to attend the classes, improve their English skills and make new friends in the Argonne community. For more information contact the Newcomers Assistance Office at ext. 2-8647 or newcomers@anl.gov.

Downers South class starts work on environmental report

Each year, a biology class at Downers Grove South High School creates a Summary Site Environmental Report for Argonne. The students start with the full report — more than 200 pages of text, tables and statistics — and create a 16-page illustrated magazine suitable for the general public.

"The students learn about environmental concepts, regulations and monitoring and protection, and Argonne gets a beautiful, very readable magazine to hand out to interested members of the public," said Norbert Golchert (EQO), who leads the program each year in collaboration with Downers South teacher Kathleen Luczynski.

The students work on summarizing the full environmental report through the school year; their work is then edited and turned into a magazine by members of Argonne's Communications and Public Affairs Division. It is distributed at the Visitors Reception Center and on request.

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