Professor Discusses Neuromuscular Disease Research

Baylor College of Medicine professor Thomas Cooper expressed his research lab’s interest in neuromuscular disease in the fifth lecture of the Natural Science and Mathematics Colloquium Series this semester, held on March 10.

In front of a large audience of students, professors, and community members in Schaefer Hall, Thomas Cooper, Professor of Pathology at Baylor, discussed developmental mechanisms that can lead to the symptoms of neuromuscular disease, including the more common myotonic dystrophy, in his presentation Developmentally-Regulated Alternative Splicing and Its Disruption in Neuromuscular Disease.
Cooper was not afraid to tell his audience how little is known about the mechanism of alternative splicing and myotonic dystrophy itself; rather, it serves as a major stimulus for his research.

“It’s exciting to find out how little we know,” he said.

Beginning with what is known about the genetics behind alternative splicing, Cooper discussed the central dogma of gene expression. DNA, a double-stranded sequence of nucleotides housed in the nucleus of a cell, undergoes a process known as transcription, where a single-stranded version of DNA (called mRNA) is created. This single-stranded sequenced undergoes processing in the nucleus before exiting into the cell’s cytoplasm as mature mRNA, which in turn undergoes a process known as translation to generate a functional protein.

While this sequence of events is generally followed, Cooper’s work focuses on the processing of pre-mRNA in the nucleus of the cell. RNA processing itself plays a major role in the expression of genes as proteins, simply due to the structure of the RNA itself. RNA is composed of, essentially, two types of gene sequences: introns, which do not code for a specified expressed gene, and exons, which do code for the expressed gene.

During pre-mRNA processing, the exon regions are precisely spliced, or cut, so that exons combine to make an exact coding sequence.
If splicing is not exact, and extra sequences appear in between the exons or if the exons are cut short, the resulting protein will usually be deformed in some way, as each building block of the final protein product (called an amino acid) is added based on sets of three nucleotides.

“If it misses a nucleotide or adds a nucleotide by mistake, it puts the sequence out of frame, and it’s not going to make a protein,” said Cooper.

Alternative splicing refers to the removal of certain introns and exons in various ways to make a different mRNA sequence, which in turn leads to a different protein. Given the extremely high number of possibilities of mRNA products, alternative splicing is regulated.

“A lot of proteome diversity changes not because of transcription,” said Cooper, “but what happens after the gene is transcribed.”
Cooper illustrated this point by describing the Dscam gene, a sequence found in chromosome 21 in humans that, with a certain mutation, can lead to Down Syndrome. The final mRNA product is composed of four main exons.

The first exon is chosen among 12 different exons, while the second is chosen among 48 different exons, the third among 33 different exons, and a fourth among two exons. Given the different combinations of these sequences, 38,000 possible mRNA sequences could be generated, up to 30,000 possible proteins due to alternative splicing alone.

This process can be regulated in multiple ways, including regulation of transcription. This would involve either increasing the activity (upregulating) or decreasing the activity (downregulating) of proteins involved in that process, or using positive and negative regulators to control which regions the spliceosomes (proteins and molecules that bind to splicing sites) bind.

Myotonic Dystrophy (DM) is the second most common form of muscular dystrophy, and is caused by a disruption in the alternative splicing mechanism. In this disease, the alternative splicing abnormality leads to the addition of nucleotide repeats.

Having more of these CTG repeats (named after the nucleotide bases that make up the mutation) causes a faster onset of the disease symptoms; while having 8-40 CTG repeats is normal, DM patients can have 80-2000 repeats.

Unlike other alternative splicing disorders, however, DM occurs in an intronic region, which does not even code for a portion of the final protein. Instead, the major problem occurs while the sequence is still in the pre-mRNA form.

The large repeat region is not able to leave the nucleus for further processing and translation, and instead serves as a toxic buildup in the nucleus. This buildup can be visualized using staining techniques, which show condensed matter (foci) in the nuclei of cells.
The CTG repeats, CUG repeats in pre-mRNA form, sequester (essentially, bind and deactivate) a splicing factor known as MBNL-1 (Muscleblind-like), which causes another splicing factor (CUGBP-1) to be induced (leading to the CUG sequence repeats and DM symptoms). CUGBP buildup can also be visualized, and correlates with MBNL buildup at the foci sites in the nuclei.

These abnormalities can lead to many issues, including problems in alternative splicing of other genes, faulty chloride channels in the muscle cells (which lead to the tensed muscles characteristic of DM), and insulin resistance (due to the inability to properly splice the adult form of the receptor).

Using a mouse model, Cooper’s lab studied the effects of altering the levels of CUGBP1 on the expression of DM-related symptoms. DM symptoms can be created in a mouse by injecting it with a chemical known as tamoxifen, which leads to the increased levels of CUGBP found in adult patients with DM.

By injecting the mice with BIS-IX, an inhibitor that slows production of CUGBP, the mice showed the same levels of mutated pre-mRNA, but not in a toxic buildup characteristic of DM; furthermore, the mortality of the mice was significantly reduced.

“PKC inhibitors [like BIS-IX] are being used as therapeutics for individuals with other diseases,” said Cooper.

Cooper concluded his presentation with a discussion of Baylor College itself, and the differences between being a researcher and a medical doctor. “The hardest part of research is all of the decisions you have to make,” he said. “You have to know how to make your best calls and know when to cut things off.”

“I thought Dr. Cooper did a good job at leading the audience into his area of expertise,” said Biochemistry professor Danielle Cass. “It seems that he tries to always keep in mind the patients with DM and how his research could benefit them.”
“I thought it was well-presented, but rather complicated,” said sophomore Steven Sheridan. “Considering the audience, I thought it was too advanced and fast-paced.”

Bernard Uncovers the Social Sciences’ ‘Secret Life’

Anthropologist and ethnographer Dr. H. Russell Bernard visited St. Mary’s College on Monday, February 15, 2010 to lecture on “The Secret Life of Social Science.” He is the former Editor-in-Chief of the American Anthropologist journal anda  recipient of the Franz Boas Award from the American Anthropological Association.

Bernard spoke of how the social sciences, from anthropology to psychology, have a hand in running (almost) everything, even though most people today would never consider humanities as having such an impact on certain aspects of the daily life. “The topic today,” stated Bernard at the start of his lecture, “is not about anthropology, but what I hope anthropologists will take heed of.”

Famous for his work on statistical analyses relating to human cultures and societies, he naturally started by talking on a survey that he conducted which asked randomly selected individuals what they considered social sciences had contributed since the start of the 21st century.

Most of the individuals polled had stated that psychology had contributed and changed to some extent, but almost one-fourth believed that social sciences had either made no contribution at all, or had even made things worse. “We don’t really think of social science as having an impact,” stated Bernard, “but it does.”

He continued on with a discussion of how the act of polling, when mixed with psychology, can greatly affect marketing. This in turn greatly affects the lives of billions of people each day since whenever an individual is polled, they leave a trail of information about themselves behind.

That, he explained, is how tobacco industries in the United States are able to target the youth of the country by placing images of adventure or romance within their ads. This is what they agree will most likely grab the eye of the targeted age group, without having to use any text.

Before Bernard even gave his lecture, though, he took the time to sit down with a couple of students in order to answer questions and discuss anthropology over lunch. “I had a great time getting personalized advice from an anthropology god,” said junior Julie Franck. “It isn’t very often that students get to talk directly to someone who wrote the textbook they are studying from.”

He even found the time in order to visit an anthropology course and talk to the students in the class. “He is extremely approachable and friendly,” said junior Chris Morihlatko, “and was willing to help me out with finding connections for some jobs. Anyone interested in anthropology or sociology should take the time to read his material.”

Bernard was also able to produce some laughs from the gathered students, professors, and St. Mary’s community members during his lecture when he discussed how Queen Elizabeth created, in 1566, what could be considered the first lottery in order to help pay for taxes. “Lotteries,” Bernard said. “A tax on people who were bad at math!”

Overall, most attendees who were able to meet with Bernard before or after the lecture enjoyed his enthusiasm about the field of anthropology and his eagerness to hear everyone else’s stories. “He gave me personalized advice,” said Franck, “listened to my plans and made me even more enthusiastic to accomplish anything nearly as influential as his work.”

Gitelman Breaks Eastern European Taboos on Holocaust

Gitelman spoke about the ways in which the sinister aspects of the Holocaust made their way into the USSR.Last week, a visiting professor, whose interests include politics and ethnicity in former Communist countries, came to campus to speak about the Holocaust in the Soviet Union.

On a dreary Feb. 3 evening, students, professors, and local residents gathered in the Blackistone Room of Anne Arundel Hall to hear University of Michigan’s Professor of Political Science Zvi Gitelman. St. Mary’s Professor of Religious Studies, Professor Katharina Von Kellenbach introduced Gitelman as her esteemed colleague whom she first met in 2006 while completing a fellowship at the Holocaust Memorial Museum in Washington.

“The planned systemized murder of 6 million Jews is known as the Holocaust. This word does not exist in the Soviet Union,” said Gitelman.

Until 1991, no studies had been published on Jews in the Soviet Union– an incredulous fact to sophomore Lauren Bennett. She said, “I found it shocking that the USSR had not published any information about the destruction of the Jews until after the end of the U.S.S.R.” Gitelman unpacked the rationale behind this with an anecdote dating back to 1966, when he attended the 13th symphony in Leningrad, Russia.

The composer, Dmitri Shostakovich, chose to include the famous “Babi-Yar” poem which points blame at the Soviet government for ignoring the Nazis when they massacred over 100,000 Jews and left them in what is now recognized as a mass gravesite in Kiev, Ukraine. Gitelman was curious about the concert hall’s overcrowding and was told that ‘today is a Jewish holiday.’ He learned that the symphony was a tribute to three Russians who had the courage to raise issue of the Holocaust in public in such a demonstrative way.

Gitelman further expounded on the idea of the Holocaust as taboo in Eastern Europe, explaining that the war on the west front and war on the east front were viewed differently. Senior Alex Borman expressed his admiration for Gitelman’s decision to shed light on the subject, saying “the view from the Eastern Front [is] a topic that we only hear about rarely.” Yet the Soviet Union lost a substantial portion of its population during the war, roughly 12 percent. By war’s end, Soviet forces lost 9 million soldiers and another 19 million civilians.
Professor Walter Hill from St. Mary’s Political Science Department shared his opinion on the subject, saying “[Gitelman] reminded us of the scale of the event, and I am always shocked and saddened by the size of killings.”

At the time, the Soviet Union was composed of 120 to 130 different nationalities; Gitelman asked the audience why the focus centered on an unpopular one. The answer, according to Gitelman, resided in Joseph Stalin and his philosophy. Due to his large distrust of the Jewish people, Stalin was extremely adamant about not “giving the war to the Jews nor making it a Jewish issue.” Instead, he wanted to “give” the war to the Russians since they (in Stalin’s opinion) were the heroic ones. In addition, many Soviets were aware that focusing on the Holocaust would raise Jewish consciousness. Gitelman pointed out, “there was nothing to be gained and a great deal to be risked by dwelling on the Jewish holocaust.”

Despite the odds stacked against them, Jewish soldiers gladly and enthusiastically fought alongside their comrades. However, by 1942, Jews in the U.S.S.R. started to see a change. “It was okay to tell the public that Jews were being singled out,” said Gitelman. Then reports began excluding Jewish casualties altogether and comrade-hostility rose. Jews in the U.S.S.R. started to realize that the Holocaust was not just affecting the west; it had invaded Eastern Europe as well.

Wanting to illustrate the Holocaust’s impact on Jews today, Gitelman summarized for his audience a series of interviews he conducted with Jewish World War II veterans. To them, the Holocaust was a tragedy but not the focus. ‘Instead, [the focus must be] the bravery. This role has not been appreciated in the west or Israel,” said Gitelman. “Therefore, [Russian Jews] are attempting to write this chapter into history themselves. It is a point of personal pride.”

Controversy still exists today when it comes to distinguishing national loyalties. For example, Gitelman explained how Lithuanians, Estonians, and Ukrainians served as Nazi camp guards but only with the intention of stripping the Soviet government of its power. Nevertheless, the Soviets lost faith in their fellow people as a result of various groups becoming confused over loyalties and identity due to the U.S.S.R.’s demographic growth during wartime. This lends support to many Eastern European’s refusal to speak about the Holocaust; former members of the U.S.S.R. are concerned with having their reputations tarnished, proving that the Jews’ mission to ‘rewrite the national narrative’ is truly ambitious. Gitelman said, “[Jews view the Holocaust as] a story of untold bravery. There is a desire to uncover what is hidden.”

Professor Predicts the Future, Discusses Error

For the first NS&M lecture of the semester, A. Bowdoin Van Riper, a professor at Southern Polytechnic State University, discussed why the future frequently turns out differently from the way we would expect. (Photo by Brendan Larrabee)
For the first NS&M lecture of the semester, A. Bowdoin Van Riper, a professor at Southern Polytechnic State University, discussed why the future frequently turns out differently from the way we would expect. (Photo by Brendan Larrabee)

For the first Natural Science and Mathematics Colloquium of the semester, Southern Polytechnic State University professor A. Bowdoin Van Riper presented on how views of the future have changed over the decades, and why they never seem to be accurate.

“Ladies and Gentlemen, behold the Future!  At least, behold the future as people invisioned it in the 1920s,” began Professor Van Riper, in a presenter’s voice that seemed to capture the audience of College students, faculty, and community members in Schaefer Hall’s lecture room on Jan 28.  “Really big skyscrapers…heliports outside your door for your own personal auto gyro…robot servants…and jumpsuits.”

As the decades have passed, ideas of how the future would be have evolved from food pills and flying cars to space stations and supersonic airliners, but these ideas never seem to define those futures, Van Riper explained.  “What’s missing in these past visions of the future?  Why are our visions of the technological future so often off the mark?”

Van Riper went on to explain one major reason for the flawed predictions: people believe that big technology will define the future.  While the atomic bomb and ballistic missile were both incredible innovations in the mid-20th century, no one expected the best invention out of World War II to be penicillin, the beginnings of a new wave of antibiotic drugs.  Big technology is certainly impressive, but not always era-defining, and certainly not always easy to predict.

Another fallacy people seem to follow is the idea that technological advances will happen without any way of controlling it.  Van Riper disagreed, stating that consumers have the power to endorse or reject any great technology simply by saying yes or no.  From the large kitchen computer with built-in recipes, to food pills that take away the social experience of dining, to the Boeing 7207 that flies at supersonic speed but costs a fortune to fly, Van Riper suggested one answer that anyone can give:  “Thanks, but no thanks.”

Van Riper presented a third possible reason for this trend, that people believe in linear growth in technology; that is, tomorrow’s technology will be bigger and better than that of today.  In reality, the growth is not so simple, following a more branching or even “hockey-stick curve” pattern due to the unpredictability of success of certain inventions over others.  But, with this curve comes another problem: with new inventions entering the market at a faster rate, the usefulness of previous inventions diminishes, decreasing the value of consumer products over time.

Some technological “masterpieces” truly are magnificent, but have too many negative aspects that make the benefits seem less helpful.

A nuclear-powered car may be more energy-efficient, even faster, but the damage due to a “fender bender” could be enormous.  Flying cars would certainly save airspace, but asking people who have difficulty enough with forward, backward, left, and right to also drive up and down would lead to catastrophic disasters, not to mention how dangerous an empty gas tank could be.

The lecture concluded with Van Riper discussing his own predictions for the future of our generation: wearable computers, smart houses, electric cars, designer genes, nanobots, and (Van Riper said with a smile) “jumpsuits.”

“I really enjoyed it,” said Dr. Charles Adler, an associate professor of physics at the College.  “I’m a long-time science fiction reader, and when you read science fiction from the 1950s, there are all of these predictions about the world in the future: by the year 2000, we’ll have bases on the Moon, settlements by Mars, and have had a nuclear war with the Soviets.  It’s always interesting to think why didn’t we get those things, although I’m glad we didn’t get the war, and I think that Dr. Van Riper’s talk showed why not, or at least some of the reasons why not:  the future isn’t a simple extrapolation of what went on in the past.”

“I thought he was very enthusiastic about his subject, which made me become involved in his presentation,” said Jesse Burke, a sophomore who also attended the lecture.  “I felt that he was correct to say that we always try to predict future technologies, but always expect way too much.”

The next lecture of the Natural Science and Mathematics Colloquia, Waging Chemical Warfare and Hazardous Waste: Green Chemistry at St. Mary’s College of Maryland, will be on Wednesday, Feb 10, presented by College chemistry professor Leah Eller.