Because NM Senator Pete Dominici has had the misfortune to be diagnosed with Pick’s Disease, specifically one of the pathological subtypes of frontotemporal lobar degeneration (FTLD), we thought our readers might be interested in knowing more. Arnold Pick MD (1851 – 1924) was a Czechoslovakian neurologist and psychiatrist. He is known for identifying the clinical syndrome of Pick’s Disease and the “Pick bodies” that are hallmark characteristic of the disorder. Pick bodies are spherical cytoplasmic inclusions found within neurons in affected portions of the brain. They cause neurons to swell, taking on a “ballooned” appearance. Pick bodies contain the protein Tau, and hence the disease is also referred to as a tauopathy (along with progressive supranuclear palsy, corticobasal degeneration, and others). Pick was the first to name reduplicative paramnesia, the delusional belief that a place or location has been duplicated. He was also the first to use the term dementia praecox (in 1891). Pick undertook extensive pathological studies of patients with neuropsychiatric diseases, and his work on the cortical localization of speech disturbances and other functions of the brain won him international acclaim. In addition to more than 350 publications, many of them on apraxia, of the ability to execute or carry out learned purposeful movements and agrammatism, the inability to speak in a grammatically correct fashion. Pick wrote a textbook on the pathology of the nervous system.

Pick’s Disease is a rare and fatal degenerative disease of the nervous system. It is characterized by signs of severe frontal or temporal lobe dysfunction, including loss of memory, disorientation, apathy, reduced initiative, lack of insight, and, in later stages, speech disorders, prominent grasp and sucking reflexes, and terminal decerebrate rigidity, dystonia (a movement disorder which causes involuntary contractions of muscles), and tremor. It usually occurs between the ages of 40 and 60, more often in women than in men. Course may take from a few months to 4 or 5 years to progress to complete loss of intellectual function. Death takes place 7-10 years after the onset of symptoms. It is due to atrophy of the frontal and temporal lobes. Clinically there are major overlaps with Alzheimer’s presenile dementia. Some experts consider these diseases as one entity, and the term Pick-Alzheimer disease has been used. These are, however, two separate entities. Arnold Pick described progressive mental deterioration in a 71-year-old man. On autopsy, his brain showed unusual shrinkage of the frontal cortex. Cortex shrinkage is different from the anatomical changes in the brain associated with Alzheimer’s disease. Compared with Alzheimer’s disease, which accounts for 50 to 60% of dementia cases, Pick’s disease accounts for about 5%. While average age of onset for Alzheimer’s disease is about 50 years, Pick’s disease may appear a decade earlier. Pick’s disease is apparently hereditary and autosomal dominant inheritance has been reported.

Researchers in Finland have just published results of a study showing that farmers can substitute human 1) ___ for conventional fertilizer and get a notable increase in cabbage yields. The research team at the University of Kuopio, grew cabbages using a conventional fertilizer, human urine that had been stored for 6 months, or no soil additive at all. In an upcoming issue of the Journal of Agricultural and Food Chemistry, the researchers report that the urine treatment yielded cabbages that were bigger and carried fewer 2) ___ than those grown by either other approach. Although the 3) ___ content of urine depends on what someone has eaten, analyses of the urine used in these experiments showed that its nitrogen, phosphorus, and potassium contents were comparable to those of 4) ___ fertilizer. Urine collected from one individual over the course of a year could fertilize a 90-square-meter plot, yielding more than 160 cabbages, the team calculates. The data indicate that a urine-treated plot would yield 64 kilograms more cabbage than one 5) ___ conventionally. Big cabbages appear to owe their superior growth to experimental fertilization with human urine. Earlier this year, the Kuopio scientists reported that cucumbers also benefit from the use of urine as fertilizer.

ANSWERS: 1) urine; 2) germs; 3) nutrient; 4) commercial; 5) fertilized

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GENETIC PIONEERS Three scientists won this year’s Nobel Prize in medicine for work on creating “knockout mice.” The larger one lacks a gene that limits muscle growth. From left, the Nobelists are Martin Evans of Cardiff University, Wales; Mario R. Capecchi of the University of Utah; and Oliver Smithies of the University of North Carolina at Chapel Hill.

by Lawrence K Altman

The New York Times, October 9, 2007

Two Americans and a Briton won the 2007 Nobel Prize in medicine yesterday for developing the immensely powerful “knockout” technology, which allows scientists to create animal models of human disease in mice.

The winners, who will share the $1.54 million prize, are Mario R. Capecchi, 70, of the University of Utah in Salt Lake City; Oliver Smithies, 82, of the University of North Carolina in Chapel Hill; and Sir Martin J. Evans, 66, of Cardiff University in Wales.

Other scientists are applying their technology, also known as gene targeting, in a variety of ways, from basic research to the development of new therapies, said the Nobel Committee from the Karolinska Institute in Stockholm that selected the winners.

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The knockout technique provided researchers with a superb new tool for finding out what any given gene does. It allows them to genetically engineer a strain of mice with the gene missing, or knocked out, then watch to see what the mice can no longer do.

After the first decoding of the mouse and human genomes in 2001 yielded thousands of new genes of unknown function, knockout mice became a prime source of information for making sense of these novel genes.

Most human genes can also be studied in this way through their counterpart genes in the mouse. Mice have been likened to pocket-size humans, because they have the same organs and their genes are about 95 percent identical in sequence. Scientists have developed more than 500 mouse models of human ailments, including those affecting the heart and central nervous system, as well as diabetes, cancer and cystic fibrosis.

Scientists can now use the technology to create genetic mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal, the Nobel citation said.

Gene-targeting technology can knock out single genes to study development of the embryo, aging and normal physiology. So far, more than 10,000 mouse genes, or about half of those in the mammalian genome, have been knocked out, the committee said.

Researchers can also make conditional knockouts, mice in which a gene of interest can be inactivated in a specific tissue or part of the brain, at any stage in life. Another important variation is to tag a normal gene with a so-called reporter gene that causes a visible color change in all cells where the normal gene is switched on.

Knockout mice are so important in medical research that thousands of strains are kept available in institutions like the Jackson Laboratory in Bar Harbor, Me.

“The technique is revolutionary and has completely changed the way we use the mouse to study the function of genes,” said Dr. Richard P. Woychik, the lab’s director. “When people come across a novel human gene, one of the first things they think about is knocking it out in a mouse.”

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Keith Weller/Associated Press
Knockout Mice.

The three laureates, who are friends but work independently, also shared a Lasker Award in 2001. They began their work in the 1980s, and the first reports that the technology could generate gene-targeted mice were published in 1989. The reports involved a rare inherited human disease, the Lesch-Nyhan syndrome, in which lack of an enzyme causes fits of self-mutilation.

The prize was particularly rewarding for Dr. Capecchi, who said he lived as a street urchin in Italy during World War II and later had to prove his scientific peers wrong after they rejected his initial grant to the National Institutes of Health in 1980, saying his project was not feasible.

Dr. Capecchi’s mother, the daughter of an American, had lived in a luxurious villa in Florence and had become a Bohemian poet, writing against Fascism and Nazism. She refused to marry his father, an Italian Air Force officer with whom she had had a love affair.

When young Mario was not yet 4, the Gestapo came to their home in Tyrol, in the Italian Alps, to take his mother to the Dachau concentration camp — an event he said he remembered vividly.

Because she knew her time of freedom was limited, she had sold all her possessions and given the proceeds to an Italian farming family, with whom Mario lived for about a year. When the money ran out, the family sent him on his way. He said he wandered south, moving from town to town as his cover was exposed. He wandered, usually alone, but sometimes in small gangs, begging and stealing, sleeping in the streets, occasionally in an orphanage.

At the war’s end, the malnourished boy was put in a hospital for a year. During that time his mother, who had survived Dachau, searched hospitals and orphanages for him. A week after she found him — on his birthday — they were on a boat to join her brother in the home of a Quaker family in Pennsylvania.

The family put Mario in the third grade, where as a means of communication his teachers told him to draw murals. As he did, he slowly learned English. Because of the street smarts he developed in Italy, he became a class leader and the boy who beat up the bullies.

He went on to study political science at Antioch College, alternating periods of work and studies. Then he went to the Massachusetts Institute of Technology and Harvard, where he worked in the laboratory of James Watson, the Nobel Prize-winning co-discoverer of the structure of DNA.

When he decided to leave the Harvard faculty in 1973 because members of the department did not get along, he said, and did not recruit sufficient younger scientists, Dr. Capecchi went to Utah. Colleagues told him, he said, that he was “nuts” to leave Harvard’s Ivy League splendor. But Dr. Capecchi said Dr. Watson told him he could do good science anywhere.

Dr. Capecchi said the main advantage was that he could work on long-term projects more easily in Utah than at Harvard, where there was a push to get results quickly.

Dr. Capecchi said that when he reapplied to the N.I.H. in 1984 for the grant it had rejected in 1980, he was told, “We are glad you didn’t follow our advice.”

After learning he had become a Nobel Prize winner, Dr. Smithies told Agence France-Presse that “it’s actually a rather peaceful feeling of culmination of a life of science.”

Dr. Smithies has credited his interest in science to his boyhood love for radios and telescopes, and for a comic-strip inventor whom he wanted to emulate. He earned a scholarship to Oxford, then dropped out of medical school to study chemistry before moving to the University of Wisconsin. Because of a visa problem, Dr. Smithies worked in Toronto for about seven years before returning to Wisconsin. He became a geneticist and moved to the University of North Carolina 19 years ago.

Dr. Smithies is a licensed airplane pilot and is fond of gliding.

Dr. Evans had planned to have an “ordinary day” off work cleaning his daughter’s home in Cambridge, England, where he was visiting when he learned he won the prize. It was “a boyhood dream come true,” Dr. Evans told Agence France-Presse.

Like Dr. Capecchi, Dr. Evans said his scientific career was an upward struggle. In an interview with the Lasker Foundation, Dr. Evans said recognition was important to him because he often was a lone scientist who cried out against the consensus. In applying for grants, he said he was told many of his ideas were premature and could not be done.

“Then five years later,” he said, “I find everyone is doing the same thing.”

Nicholas Wade contributed reporting.