Researchers probe kidney damage, protection in lupus

From the FMS Global News Desk of Jeanne Hambleton (UK)

Courtesy utsouthwestern.edu

by Aline McKenzie – 214-648-3404 – aline.mckenzie@utsouthwestern.edu

DALLAS – April 21, 2009

UT Southwestern Medical Center researchers probe kidney damage, protection in lupus. Kidney damage associated with the autoimmune disease lupus is linked to a malfunction of immune cells that causes them to congregate in and attack the organs, researchers at UT Southwestern Medical Center have discovered in a mouse study.

In a separate study with an international team, the researchers also found that a certain set of genes appears to protect the kidneys from a different sort of immune attack in both mice and humans.

“These studies, taken together, uncover two important molecules that underlie the pathology of lupus, particularly kidney disease,” said Dr. Edward Wakeland, chairman of immunology at UT Southwestern and co-senior author of the studies.

“In addition, they highlight a certain molecule as a potential target for treating this disease,” he said.

In the first study, which appears in the April issue of The Journal of Immunology, the researchers examined several strains of mice that mimic human lupus. They found that immune cells in those mice overproduced a particular molecule called CXCR4. In fact, the mice had up to twice as much CXCR4 as their normal counterparts in several types of immune cells. The lupus-prone mice also had more immune-system cells in their kidneys, indicating that the inflammatory action of the immune cells might be causing the kidney damage.

The CXCR4 molecule was already known to play a role in creating various types of blood cells and also has been shown to be active in cancer and AIDS. Cells with CXCR4 on their surface are attracted to another molecule released by cells in various organs, so they migrate toward those organs, including the kidney.

When the researchers treated the lupus mice with a substance that blocks CXCR4, the symptoms of lupus significantly diminished; many symptoms of kidney failure were averted; and the mice lived longer. The increased lifespan was greater when treatment began at an early age.

“This study indicates that drugs acting against CXCR4 might become useful therapies,” said Dr. Chandra Mohan, professor of internal medicine and co-senior author of the studies.

In the second study, published in the April issue of The Journal of Clinical Investigation, the researchers found that some members of a family of genes called kallikreins offered a degree of protection in both mice and humans against a type of kidney damage caused by a different mechanism.

For this mouse study, the researchers administered antibodies that attack a part of the kidney called the glomerular basement membrane, the portion of the organ that performs its main function of filtering wastes from blood. They then looked for genes that turned on or off in response to the antibody assault.

Nine forms of the kallikrein, or klk, gene became more active, resulting in a two- to sixfold increase in the proteins encoded by the genes in normal mouse strains, compared with lupus-prone strains. When some mice were given substances that block the action of kallikrein proteins, they showed more severe symptoms of lupus, suggesting that kallikreins protect against renal disease.

The researchers also studied 340 German patients with systemic lupus, matched with 400 healthy control subjects. The patients with lupus and kidney damage had klk genes that were different from those in the healthy patients. Similar findings were noted in a larger, more varied group of patients from Europe, the United States and Korea.

“All humans have Klk genes, but our findings show that some of us have a particular version that increases our risk for systemic lupus,” Dr. Wakeland said.

Future research will examine the mechanisms by which CXCR4 and klk genes might be aberrantly regulated in lupus and how they could be therapeutically targeted in human lupus, the researchers said.

Other UT Southwestern researchers involved in the first study were lead author and graduate student Andrew Wang; Dr. Anna-Marie Fairhurst, assistant instructor of immunology; Dr. Katalin Tus, instructor of immunology; former graduate student Srividya Subramanian; Dr. Yang Liu, postdoctoral researcher in internal medicine; Dr. Fangming Li, assistant professor of pediatrics; Dr. Peter Igarashi, professor of internal medicine; and Dr. Xin Zhou, professor of pathology. Researchers from the Université Paris-Descartes and Chemokine Therapeutics, Canada, also participated.
The study was funded by the National Institutes of Health.

Other UT Southwestern researchers involved in the second study were lead co-authors Dr. Kui Liu, instructor of internal medicine, and Dr. Quan-Zhen Li, assistant professor of immunology; Li Li, research associate in internal medicine; Jinchun Zhou, research scientist in immunology; Mei Yan, research associate in internal medicine; Dr. Qiu Ye, former postdoctoral fellow in immunology; Shengxi Liu, senior research associate in immunology; Dr. Chun Xie, former instructor in internal medicine; and Drs. Zhou and Liu.

Researchers from Oklahoma Medical Research Foundation; University of California, San Franciso; Long Island Jewish Health System, Manhasset; Medical University of South Carolina; and University of Alabama at Birmingham also participated, as did researchers from institutes in Sweden, Spain, Argentina, Germany, South Korea, Italy and the United Kingdom.

The study was funded in part by the Alliance for Lupus Research and the National Institutes of Health.
Visit http://www.utsouthwestern.org/rheumatology to learn more about clinical services in rheumatology at UT Southwestern. Visit http://www.utsouthwestern.org/dermatology to learn more about UT Southwestern’s clinical services in dermatology, including autoimmune diseases.

(http://www.utsouthwestern.edu/home/news/index.html)

FOR MORE STORIES ON HEALTH SEE http://jeannehambleton77.wordpress.com

ROBOT MAKES SCIENTIFIC DISCOVERY ALL BY ITSELF

From the FMS Global and UK News Desk of Jeanne Hambleton

Courtesy NewsGatorNews

By Lizzie (iamlizzieee@yahoo.com) – April 02, 2009
Categories: Artificial Intelligence, Robotics, Science Tools, Web/Tech

For the first time, a robotic system has made a novel scientific discovery with virtually no human intellectual input.

Scientists designed “Adam” to carry out the entire scientific process on its own: formulating hypotheses, designing and running experiments, analyzing data, and deciding which experiments to run next.

“It’s a major advance,” says David Waltz of the Center for Computational Learning Systems at Columbia University.

“Science is being done here in a way that incorporates artificial intelligence. It is automating a part of the scientific process that has not been automated in the past.”

The demonstration of autonomous science breaks major ground. Researchers have been automating portions of the scientific process for decades, using robotic laboratory instruments to screen for drugs and sequence genomes, but humans are usually responsible for forming the hypotheses and designing the experiments themselves. After the experiments are complete, the humans must exert themselves again to draw conclusions.

Meanwhile, some software programs can analyze data to generate hypotheses or conclusions, but they do not interact with the physical realm. Adam is the first automated system to complete the cycle from hypothesis, to experiment, to reformulated hypothesis without human intervention.

Adam’s British designers, led by Ross King at Aberystwyth University in Wales, acknowledge that the robot’s discoveries have been “of a modest kind” thus far.

Its proving ground as a scientist has been the genome of baker’s yeast, a popular laboratory species. Baker’s yeast is one of the best understood organisms, but 10 to 15 percent of its roughly 6,000 genes have unknown functions. The scientists hoped Adam could shed light on some of these mystery genes.

They armed Adam with a model of yeast metabolism and a database of genes and proteins involved in metabolism in other species. Then they set the mechanical beast loose, only intervening to remove waste or replace consumed solutions. The results appear Thursday in Science.

Adam sought out gaps in the metabolism model, specifically orphan enzymes, which scientists think exist, but which have not been linked to any parent genes. After selecting a desirable orphan, Adam scoured the database for similar enzymes in other organisms, along with the corresponding genes. Using this information, it hypothesized that similar genes in the yeast genome may code for the orphan enzyme.

The process might sound simple — and indeed, similar “scientific discovery” algorithms already exist — but Adam was only getting started. Still chugging along on its own, it designed experiments to test its hypotheses, and performed them using a fully automated array of centrifuges, incubators, pipettes, and growth analyzers.

After analyzing the data and running follow-up experiments — it can design and initiate over a thousand new experiments each day — Adam had uncovered three genes that together coded for an orphan enzyme. King’s group confirmed the novel findings by hand.

Waltz thinks Adam will inspire other scientists. “They will realize they can automate more of the process than they currently have. They can explore a wider range of possibilities without doing it all by hand.”

King is already expanding his Robot Scientist fleet by producing Eve, which will autonomously design and screen drugs against malaria and schistosomiasis.

“Most drug discovery is already automated,” says King, “but there is no intelligence — just brute force.” King says Eve will use artificial intelligence to select which compounds to run, rather than just following a list.

If robotic scientists made their way into other labs, their human counterparts would not be out of a job anytime soon. If anything, they may find their work more exciting.
“There may be teams of humans and machines,” says King.

“Robots will be doing more and more of actual experimental work and simple cycles of hypothesis generation. Humans would migrate to more strategic and creative positions. How can we waste trained post-docs by making them pipette things in labs? It’s crazy.”

But with advances in artificial intelligence, it is conceivable that the role of robots would, in the more distant future, creep deeper into the human realm, progressing from lab technician to lab head.

Robots may even be capable of performing supposed acts of genius, such as Einstein’s conception of special relativity.

“There is not any intrinsic reason why that would not happen,” says King. “I think there is a continuum between the really basic types of science that you would get from Adam, and the things I can do, and then Einstein-type science. A computer can make beautiful chess moves, but it is not doing anything special. It is just doing more of the same thing. In my view that is what is going to happen in science.”

King may already have a head start: Deep Blue could never have beaten Garry Kasparov without engineer Feng-Hsiung Hsu moving the pieces on its behalf.

(http://blog.wired.com/wiredscience/2009/04/robotscientist.html)