What happened to Douglas Prasher? The Nobel Prize strictly limits shared awards to three people. In 2008, the Prize in chemistry was famously shared by Roger Tsien of the UC San Diego School of Medicine, Martin Chalfie at Columbia University, and the Marine Biological Laboratory’s Osama Shimomura for their work on the discovery and development of green fluorescent proteins (GFP). The fourth man out was Douglas Prasher, who had isolated and sequenced the gene for GFP, then generously provided the data to scientists like Tsien, Chalfie and Shimomura. When the 2008 prize was announced, though, Prasher was working as a courtesy shuttle driver for a Toyota dealership in Huntsville, Alabama. Prasher’s story – a tale of professional and personal misfortune – has been widely reported, but it appears to have a happy – or at least happier – ending. Prasher has returned to science and, specifically, to Tsien’s UC San Diego lab, where he is working as a staff research associate on new ways to screen cell mutations for optical properties. You can read his updated story here in The Scientist.
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What happened to Douglas Prasher?

The Nobel Prize strictly limits shared awards to three people.

In 2008, the Prize in chemistry was famously shared by Roger Tsien of the UC San Diego School of Medicine, Martin Chalfie at Columbia University, and the Marine Biological Laboratory’s Osama Shimomura for their work on the discovery and development of green fluorescent proteins (GFP).

The fourth man out was Douglas Prasher, who had isolated and sequenced the gene for GFP, then generously provided the data to scientists like Tsien, Chalfie and Shimomura. When the 2008 prize was announced, though, Prasher was working as a courtesy shuttle driver for a Toyota dealership in Huntsville, Alabama.

Prasher’s story – a tale of professional and personal misfortune – has been widely reported, but it appears to have a happy – or at least happier – ending. Prasher has returned to science and, specifically, to Tsien’s UC San Diego lab, where he is working as a staff research associate on new ways to screen cell mutations for optical properties. You can read his updated story here in The Scientist.

Digging on the Altman CTRI

Local leaders and luminaries gathered Thursday, Jan. 10, to officially break ground on the Altman Clinical and Translational Research Institute (CTRI), a new structure that will bring together laboratory and clinical researchers in a collaborative search for faster, better ways to treat and cure disease.

Though the morning was notably cold and windy, a series of speakers brightly celebrated “the great day,” among them: UC San Diego Chancellor Pradeep Khosla, vice chancellor for Health Science and dean of the School of Medicine David Brenner, MD, CTRI director Gary Firestein, MD, UC San Diego Health System chief executive officer Paul S. Viviano, Department of Pediatrics chair Gabriel Haddad, MD, and San Diego Mayor Bob Filner.

All extolled the passion and investment of Steve and Lisa Altman, long-time San Diego philanthropists who have pledged $10 million toward construction of the $269 million, 7-story building that will rise near the UC San Diego Thornton Hospital, Moores Cancer Center, Sulpizio Cardiovascular Center and Jacobs Medical Center, which is currently under construction.

“We know translational medicine is the future. This building will be a centerpiece of that vision,” said Khosla, observing that engineers, doctors, computer scientists, geneticists, microbiologists and others will all work together under one roof. “They won’t be able to avoid each other.”

Brenner said places capable of combining the resources, people and vision to create something like the Altman CTRI are rare. “This will be a place where people can access the leading-edge care that only an academic medical center can offer,” he said.

The Altman CTRI is slated to open in early 2016.

Leech neurons stained with voltage-sensitive dye. Top UCSD Health Sciences stories of 2012  The results are in from our first-ever faculty survey of the top UC San Diego Health Sciences stories for 2012. Faculty were asked to pick their top three stories from 15 choices culled from the dozens of news reports and releases produced last year by the UC San Diego Health Sciences Marketing & Communications office. The top spot went to Mark Tuszynski’s paper, published in the September 14 issue of Cell, in which he and colleagues were able to regenerate axonal growth at the site of severe spinal injury in rats using neural stem cells. The work has obvious implications for efforts to develop therapies to restore central nervous system and motor function. In second place was a PNAS paper out of Roger Tsien’s lab which reported creating a new generation of fast-acting fluorescent dyes that optically highlight electrical activity in neuronal membranes. The achievement will help scientists better decipher how brain cells function and interact. In third place was research by a multi-institution team, headed by Sharon Reed in the UC San Diego Departments of Pathology and Medicine and James McKerrow at the UC San Francisco Sandler Center for Drug Discovery, that identified an existing drug was also effective against Entamoeba histolytica. This parasite causes amebic dysentery and liver abscesses and results in the death of more than 70,000 people worldwide each year. The findings were published in the June issue of Nature Medicine. You can read more about all of the 2012 selections below. Fast-acting dyes highlight membrane activities of neurons (R. Tsien, E. Miller, et al.) Researchers induce functional Alzheimer’s neurons in vitro from pluripotent stem cells (L. Goldstein, et al.) Brain cancer patients treated with novel viral vector that leaves healthy cells untouched (S. Kesari, et al.) New weight loss surgery folds stomach into smaller size (S. Horgan, et al.) Drug found for parasite that causes amoebic dysentery, kills thousands worldwide (S. Reed, et al.) New surgical technique may reverse paralysis, restore use of hand (J. Brown, et al.) New technology pinpoints source of irregular heart rhythms, improves treatment (S. Narayan, et al.) Novel enzyme target identified for anti-malarial drug development (L. Bode, et al.) New method indentifies whether leukemia will be aggressive or slow-moving (T. Kipps, et al.) Patterns in adolescent brains could predict heavy alcohol use (S. Tapert, et al.) Potency of statins linked to muscle pain and weakness (B. Golomb, et al.) Neural stem cells regenerate axons in severe spinal cord injury (M. Tuszynski, et al.) New way of fighting high cholesterol upends assumptions (C. Glass, et al.) Blocking tumor-induced inflammation impacts cancer development (M. Karin, et al.) Study finds potential new drug therapy for Crohn’s disease (W. Sanborn, et al.)
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Leech neurons stained with voltage-sensitive dye.

Top UCSD Health Sciences stories of 2012 

The results are in from our first-ever faculty survey of the top UC San Diego Health Sciences stories for 2012.

Faculty were asked to pick their top three stories from 15 choices culled from the dozens of news reports and releases produced last year by the UC San Diego Health Sciences Marketing & Communications office.

The top spot went to Mark Tuszynski’s paper, published in the September 14 issue of Cell, in which he and colleagues were able to regenerate axonal growth at the site of severe spinal injury in rats using neural stem cells. The work has obvious implications for efforts to develop therapies to restore central nervous system and motor function.

In second place was a PNAS paper out of Roger Tsien’s lab which reported creating a new generation of fast-acting fluorescent dyes that optically highlight electrical activity in neuronal membranes. The achievement will help scientists better decipher how brain cells function and interact.

In third place was research by a multi-institution team, headed by Sharon Reed in the UC San Diego Departments of Pathology and Medicine and James McKerrow at the UC San Francisco Sandler Center for Drug Discovery, that identified an existing drug was also effective against Entamoeba histolytica. This parasite causes amebic dysentery and liver abscesses and results in the death of more than 70,000 people worldwide each year. The findings were published in the June issue of Nature Medicine.

You can read more about all of the 2012 selections below.

Fast-acting dyes highlight membrane activities of neurons (R. Tsien, E. Miller, et al.)

Researchers induce functional Alzheimer’s neurons in vitro from pluripotent stem cells (L. Goldstein, et al.)

Brain cancer patients treated with novel viral vector that leaves healthy cells untouched (S. Kesari, et al.)

New weight loss surgery folds stomach into smaller size (S. Horgan, et al.)

Drug found for parasite that causes amoebic dysentery, kills thousands worldwide (S. Reed, et al.)

New surgical technique may reverse paralysis, restore use of hand (J. Brown, et al.)

New technology pinpoints source of irregular heart rhythms, improves treatment (S. Narayan, et al.)

Novel enzyme target identified for anti-malarial drug development (L. Bode, et al.)

New method indentifies whether leukemia will be aggressive or slow-moving (T. Kipps, et al.)

Patterns in adolescent brains could predict heavy alcohol use (S. Tapert, et al.)

Potency of statins linked to muscle pain and weakness (B. Golomb, et al.)

Neural stem cells regenerate axons in severe spinal cord injury (M. Tuszynski, et al.)

New way of fighting high cholesterol upends assumptions (C. Glass, et al.)

Blocking tumor-induced inflammation impacts cancer development (M. Karin, et al.)

Study finds potential new drug therapy for Crohn’s disease (W. Sanborn, et al.)

How the Nose Knows Whether we’re awake or asleep, and whether an odor is familiar or new, appears to determine our response to smells. Since we know that smells are highly evocative as well as serving to warn us of danger like smoke or spoiled foods, how the brain perceives odors is of interest to scientists. Researchers at the University of California, San Diego School of Medicine wondered how sensory representations, in this case the sense of smell, are shaped by the state of an animal and its history. They studied this question in the mouse olfactory bulb, the part of the brain involved in the perception of odors. Their major conclusion is that the way in which sensory information such as odor is represented isn’t fixed or static, but highly dynamic and flexible. It is modulated by brain state such as wakefulness, experience, even by simple sensory exposure to smells. According to the researchers, his could be the basis of why novel or unfamiliar odors are such noticeable stimuli for humans, compared to familiar odors. Using a powerful means for monitoring the activity of brain neurons in mammals – called two-photon calcium imaging – the UC San Diego team, headed by Takaki Komiyama, PhD, assistant professor in the UCSD Department of Neurosciences, recorded the activity of specific neuronal cell types in mice, following the activity of the same set of neurons over days, weeks and months. With this technique, the researchers explored how wakefulness and odor experience modulate the activity of two neuron types in the olfactory bulb, namely mitral cells – the principal neurons of the bulb – and granule cells, very small brain cells that account for nearly half of the neurons in the central nervous system. Granule cells are the major class of interneurons that inhibit mitral cells. The team imaged the activity of mitral and granule cell populations in awake mice, and subsequently anesthetized the mice to find out how odor representations differ between the awake and anesthetized state. They found that anesthesia increases odor responses of mitral cells. In contrast, granule cell activity is dramatically reduced with anesthesia. These results suggest that, in awake animals, mitral cell odor representations are made sparse by the action of local inhibitory circuits, and that studies in anaesthetized animals may have underestimated the actions of granule cells. Next, the researchers looked at how mitral cell odor representations in awake mice are shaped by experience. By monitoring the response of same sets of mitral cells to a panel of odors, they found that repeated odor experience causes a gradual lessening of mitral cell responses which accumulates across days. This change is odor-specific – the same mitral cells still respond strongly to other smells. The plasticity, or ability of the neuronal connection to change in strength, recovers gradually over months. “Intriguingly, this plasticity is not expressed when the mouse is tested under anesthesia, indicating that wakefulness plays a key role in the dynamic nature of mitral cell odor representations,” Komiyama said. “All available evidence from comparative genetics and neuroanatomy suggests that mouse and human olfactory systems function similarly,” he added. “We have many reasons to believe that what we found in this study in mice directly translates to the perception of odors in humans.”
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How the Nose Knows

Whether we’re awake or asleep, and whether an odor is familiar or new, appears to determine our response to smells. Since we know that smells are highly evocative as well as serving to warn us of danger like smoke or spoiled foods, how the brain perceives odors is of interest to scientists.

Researchers at the University of California, San Diego School of Medicine wondered how sensory representations, in this case the sense of smell, are shaped by the state of an animal and its history. They studied this question in the mouse olfactory bulb, the part of the brain involved in the perception of odors.

Their major conclusion is that the way in which sensory information such as odor is represented isn’t fixed or static, but highly dynamic and flexible. It is modulated by brain state such as wakefulness, experience, even by simple sensory exposure to smells. According to the researchers, his could be the basis of why novel or unfamiliar odors are such noticeable stimuli for humans, compared to familiar odors.

Using a powerful means for monitoring the activity of brain neurons in mammals – called two-photon calcium imaging – the UC San Diego team, headed by Takaki Komiyama, PhD, assistant professor in the UCSD Department of Neurosciences, recorded the activity of specific neuronal cell types in mice, following the activity of the same set of neurons over days, weeks and months.

With this technique, the researchers explored how wakefulness and odor experience modulate the activity of two neuron types in the olfactory bulb, namely mitral cells – the principal neurons of the bulb – and granule cells, very small brain cells that account for nearly half of the neurons in the central nervous system. Granule cells are the major class of interneurons that inhibit mitral cells.

The team imaged the activity of mitral and granule cell populations in awake mice, and subsequently anesthetized the mice to find out how odor representations differ between the awake and anesthetized state. They found that anesthesia increases odor responses of mitral cells. In contrast, granule cell activity is dramatically reduced with anesthesia. These results suggest that, in awake animals, mitral cell odor representations are made sparse by the action of local inhibitory circuits, and that studies in anaesthetized animals may have underestimated the actions of granule cells.

Next, the researchers looked at how mitral cell odor representations in awake mice are shaped by experience. By monitoring the response of same sets of mitral cells to a panel of odors, they found that repeated odor experience causes a gradual lessening of mitral cell responses which accumulates across days. This change is odor-specific – the same mitral cells still respond strongly to other smells. The plasticity, or ability of the neuronal connection to change in strength, recovers gradually over months.

“Intriguingly, this plasticity is not expressed when the mouse is tested under anesthesia, indicating that wakefulness plays a key role in the dynamic nature of mitral cell odor representations,” Komiyama said.

“All available evidence from comparative genetics and neuroanatomy suggests that mouse and human olfactory systems function similarly,” he added. “We have many reasons to believe that what we found in this study in mice directly translates to the perception of odors in humans.”

Card 10 in Hermann Rorschach’s original inkblot series. You can see the entire series and how Nazi leaders Adolph Eichmann, Hermann Goering and Albert Speer interpreted the images here, courtesy of Cabinet magazine Judgments after Nuremberg As a young professor of psychiatry in the 1970s, Joel E. Dimsdale studied concentration camp survivors – and their families – in the years after World War II. What were the psychological consequences of their suffering and trauma? What mechanisms did they use to cope? One day a man came to visit Dimsdale at his Boston office. He had heard the professor speak and believed Dimsdale should study another group as well: the Nazi perpetrators who had conceived and implemented the camps that resulted in the murder of millions. The man said he had met some of Nazi leaders. The man had killed some of them. “He was one of the executioners at the Nuremberg trials,” recalled Dimsdale, now a professor emeritus in the UC San Diego School of Medicine. The trials, of course, were a series of highly publicized, history-making military tribunals held by Allied victors to judge and punish the surviving remnants of Nazi German leadership after the war. Scores of political, military and public officials were tried, most notably 22 defendants in the Bavarian city of Nuremberg over several months in 1945 and 1946. These were some of Nazi Germany’s most notorious leaders: Field Marshall Hermann Goering, deputy Fuhrer Rudolf Hess, army head Wilhelm Keitel, SS leader Ernst Kaltenbrunner, and interior minister Wilhelm Frick, who had co-authored the Nazi’s anti-Semitic Race Laws introduced in 1935 in, ironically, Nuremberg. Though Dimsdale continued and expanded his psychiatric research, ultimately conducting hundreds of studies about stress, sleep and how patients cope with severe illness over a long and distinguished career, he took the advice of the Nuremberg executioner and eventually wrote a book about the trials and efforts to better understand the psychology of the accused. “One of the great questions of psychology is the anatomy of malice,” said Dimsdale, “and nowhere is that subject more compelling than in trying to explain the behavior of the accused war criminals at Nuremberg. Were they inherently depraved monsters or ordinary men corrupted by power and circumstances? Were they somewhere on a continuum of human behavior or distinctly different? How did they get that way?” [[MORE]] Dimsdale’s book – Survivors, Victims and Perpetrators: Essays on the Nazi Holocaust – was published in 1980. It’s now out-of-print, but Dimsdale has recently resumed his ruminations on the subject, speaking at public lectures and grand rounds. The story he tells is a psychological thriller. Sixty-six years after the trials ended, it remains a tale fraught with twists and unanswered mysteries. In 1945, two American military officers were tasked with profiling the Nazi prisoners at Nuremberg: Major Douglas M. Kelley and Lt. Gustave M. Gilbert. It was, according to Dimsdale, “the collaboration from hell.” Kelley and Gilbert developed a deep and enduring dislike of each other. In part, it may have been because they came from distinctly different backgrounds: Kelley was a native, upper class San Franciscan. He had a medical degree at UC San Francisco and doctorate in medical science from Columbia University. Gilbert was the New York-born son of Jewish-Austrian immigrants. He attended the School for Ethical Culture on a scholarship, then earned a psychology degree at Columbia. Not surprisingly, Kelley and Gilbert also came to very different conclusions about their Nazi subjects. Some of that difference derived from one of the tests they conducted at Nuremberg: the Rorschach. Though eventually eclipsed by shorter, simpler and cheaper methods, the Rorschach test was a common personality assessment tool in the middle decades of the last century. Developed by Swiss psychiatrist Hermann Rorschach, it consists of a series of 10 abstract ink blots, some with color. Test-takers are asked to describe what they see in each image. Test-givers analyze these answers, looking for response patterns that reflect specific personality traits. The Rorschach test can be effective, said Dimsdale, but it requires carefully controlled testing conditions and expertise in accurately interpreting patient responses. “They have a deceptive air of simplicity, but they’re very complex to score.” Though quite famous in psychological circles, the Rorschach tests at Nuremberg were fundamentally flawed. “Kelley was an expert on Rorschach testing; Gilbert wasn’t,” said Dimsdale. “Gilbert spoke German; Kelley didn’t. He had to rely upon a translator. In both cases, there are real questions about the validity of the work.” After conducting their own independent tests, Kelley and Gilbert arrived at different assessments. “Kelley said the Nazis were no different from anyone else with power. They were on a continuum of evil,” said Dimsdale. “Gilbert thought they were vicious, depraved psychopaths who were distinctly evil.” Gilbert despised all of the Nazis without exception. Kelley got along with several of them, most notably Goering, who would eventually ask Kelley if he would adopt his daughter after Goering’s execution. Kelley declined and Goering, in fact, avoided execution by taking a fatal potassium cyanide pill the night before he was scheduled to be hanged. (Interestingly, the Nazis at Nuremberg seemed to welcome and enjoy the tests, according to Eric Zillmer, a professor of neuropsychology at Drexel University who wrote his own account in The Quest for the Nazi Personality in 1995. The Nazis, Zillmer said, believed the tests might affirm that they were a superior race. Plus, they were often bored in the weeks leading up to the actual trials. The tests became a sort of amusing competition among them.) Neither Kelley’s nor Gilbert’s Rorschach results were used in the trials. They never became part of the official court proceedings. Instead, the results became part of a different story. In 1947, a Rorschach expert named Molly Harrower asked 10 leading psychologists to interpret the test results. All 10 declined. The results remained largely ignored until 1975 when Harrower revisited the issue, provoking a fierce debate between those who thought the Rorschach tests revealed major psychopathology and those who weren’t so certain. Harrower asked a panel of Rorschach experts to review the Nuremberg test results, which were not identified and which were mixed with test results from contemporary psychiatric patients and Unitarian ministers. The experts found no single, uniform, abnormal personality that could serve to explain Nazi behavior. “That’s what people would have liked. It would be simpler and more comforting if we could just say the Nazis were different from the rest of us,” said Dimsdale. “But nothing proved that they were consistently, manifestly different. Rather, the results suggest that people will do evil under certain circumstances.” Kelley said much the same thing in his own 1947 book 22 Cells at Nuremberg. His Nuremberg test results, however, have never been made public. Today, they are stored in the archives of the Chicago Psychoanalytic Society. In later life, Gilbert continued to focus upon the nature of Nazi psychology. In 1950, he published a psychological profile of Adolf Hitler based upon deductions derived from his interviews at Nuremberg. In 1961, he testified at the Jerusalem trial of the Nazi fugitive Adolf Eichmann, describing again his interviews at Nuremberg that linked Eichmann to the Holocaust killings. The court did not include Gilbert’s psychological analyses as part of his testimony. Gilbert, who became a psychology professor at Long Island University in Brooklyn, NY, died in 1977 at the age of 66. Kelley died much earlier and far more mysteriously. After Nuremberg, Dimsdale said Kelley “seemed to get on with his life.” He returned to California and became a noted professor of psychiatry and criminology at UC Berkeley. But he also reportedly began drinking and occasionally flew into rages. On New Year’s Day in 1958, the 45-year-old Kelley appeared in front of his family at home with a cyanide pill between his teeth. He bit down and died. Kelley’s death was eerily similar to Goering’s suicide a dozen years earlier. The source of Kelley’s cyanide has never been determined.
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Card 10 in Hermann Rorschach’s original inkblot series. You can see the entire series and how Nazi leaders Adolph Eichmann, Hermann Goering and Albert Speer interpreted the images here, courtesy of Cabinet magazine

Judgments after Nuremberg

As a young professor of psychiatry in the 1970s, Joel E. Dimsdale studied concentration camp survivors – and their families – in the years after World War II. What were the psychological consequences of their suffering and trauma? What mechanisms did they use to cope?

One day a man came to visit Dimsdale at his Boston office. He had heard the professor speak and believed Dimsdale should study another group as well: the Nazi perpetrators who had conceived and implemented the camps that resulted in the murder of millions.

The man said he had met some of Nazi leaders.

The man had killed some of them.

“He was one of the executioners at the Nuremberg trials,” recalled Dimsdale, now a professor emeritus in the UC San Diego School of Medicine.

The trials, of course, were a series of highly publicized, history-making military tribunals held by Allied victors to judge and punish the surviving remnants of Nazi German leadership after the war. Scores of political, military and public officials were tried, most notably 22 defendants in the Bavarian city of Nuremberg over several months in 1945 and 1946.

These were some of Nazi Germany’s most notorious leaders: Field Marshall Hermann Goering, deputy Fuhrer Rudolf Hess, army head Wilhelm Keitel, SS leader Ernst Kaltenbrunner, and interior minister Wilhelm Frick, who had co-authored the Nazi’s anti-Semitic Race Laws introduced in 1935 in, ironically, Nuremberg.

Though Dimsdale continued and expanded his psychiatric research, ultimately conducting hundreds of studies about stress, sleep and how patients cope with severe illness over a long and distinguished career, he took the advice of the Nuremberg executioner and eventually wrote a book about the trials and efforts to better understand the psychology of the accused.

“One of the great questions of psychology is the anatomy of malice,” said Dimsdale, “and nowhere is that subject more compelling than in trying to explain the behavior of the accused war criminals at Nuremberg. Were they inherently depraved monsters or ordinary men corrupted by power and circumstances? Were they somewhere on a continuum of human behavior or distinctly different? How did they get that way?”

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A cluster of malignant breast cancer cells (stained brown) metastasized to the liver. Image courtesy of the National Cancer Institute. Study Helps Resolve Debate About How Tumors SpreadA team of scientists, led by researchers at the University of California, San Diego School of Medicine, has shown for the first time how cancer cells control the ON/OFF switch of a program used by developing embryos to effectively metastasize in vivo, breaking free and spreading to other parts of the body, where they can proliferate and grow into secondary tumors. The findings are published in the December 11 issue of the journal Cancer Cell.In 90 percent of cancer deaths, it is the spreading of cancer, known as metastasis, which ultimately kills the patient by impacting ever-more tissues and functions until the body fails. Ten years ago, a French cancer researcher named Jean Paul Thiery hypothesized that tumor cells metastasized by exploiting a developmental process known as epithelial-to-mesenchymal transition or EMT. EMT is seen in developing embryos whose cells transform from stationary epithelial cells into more mobile mesenchymal cells, the latter able to migrate to new locations and create new types of tissue and organs. Thiery proposed that cancer cells also switch “ON” EMT, temporarily changing attributes so that they can detach from primary tumors, enter the bloodstream and seed new tumors elsewhere. After arriving at a new location, the cancer cells then turn “OFF” the EMT program and grow into carcinoma metastases or tumors.Thiery’s hypothesis was controversial because researchers haven’t been able to find supporting evidential proof in vivo. “Although this model was proposed in 2002, there have been no experiments done to attest to it in a spontaneous tumor model,” said Jing Yang, PhD, associate professor of pharmacology and pediatrics and senior author of the Cancer Cell paper. “Our new study provides an in vivo demonstration of the reversible EMT in metastasis and helps to resolve the controversy on this leading theory in metastasis.”Using a mouse squamous cell carcinoma model, Jeff Tsai, PhD, a postdoctoral fellow in Yang’s lab and first author of the study, with help from collaborators at the Whitehead Institute for Biomedical Research in Cambridge, MA and The Sanford-Burnham Medical Research Institute in La Jolla, showed that activation of an EMT-inducing gene called Twist1 is sufficient to turn “ON” the EMT switch and promote carcinoma cells to disseminate into blood circulation.  Equally importantly, the researchers found that turning “OFF” the EMT switch at distant sites is essential for disseminated tumor cells to proliferate and form metastases.  Their findings indicate that reversible EMT likely represents a key driving force in human carcinoma metastasis.  “There are many similarities between developmental EMT and EMT in metastasis,” Yang said.  “Both processes seem to use the same cellular machineries and signaling pathways to activate the EMT program. During embryogenesis, the EMT program tends to be more permanent and epithelial cells commit to a mesenchymal fate.  Our study shows that carcinoma cells need a reversible EMT to achieve efficient metastasis. It suggests that EMT reversion could be a critical step to wake up tumor cells from dormancy, a phenomenon in which cancer patients develop metastasis years after the initial primary tumor diagnosis and removal.”It’s not entirely known how Twist1 becomes active in primary tumors, though previous studies have pointed to factors like hypoxia and inflammation in the tumor microenvironment. Researchers do not know exactly how Twist1 is “turned off at distant organs.” Yang said these are subjects of current experiments. More broadly, the published findings suggest that more research is needed to determine how to target EMT to combat cancer metastasis. Several pharmaceuticals and research institutes are already pursuing EMT inhibitors as possible cancer treatments.  “Since reversion of EMT promotes colonization and growth of metastases, this study actually cautions that therapies inhibiting EMT could be counterproductive in preventing distant metastases when patients already present circulating tumor cells. Instead, blocking EMT reversion may prevent dormant tumor cells from establishing metastases.”
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A cluster of malignant breast cancer cells (stained brown) metastasized to the liver. Image courtesy of the National Cancer Institute.

Study Helps Resolve Debate About How Tumors Spread

A team of scientists, led by researchers at the University of California, San Diego School of Medicine, has shown for the first time how cancer cells control the ON/OFF switch of a program used by developing embryos to effectively metastasize in vivo, breaking free and spreading to other parts of the body, where they can proliferate and grow into secondary tumors.

The findings are published in the December 11 issue of the journal Cancer Cell.

In 90 percent of cancer deaths, it is the spreading of cancer, known as metastasis, which ultimately kills the patient by impacting ever-more tissues and functions until the body fails. Ten years ago, a French cancer researcher named Jean Paul Thiery hypothesized that tumor cells metastasized by exploiting a developmental process known as epithelial-to-mesenchymal transition or EMT.

EMT is seen in developing embryos whose cells transform from stationary epithelial cells into more mobile mesenchymal cells, the latter able to migrate to new locations and create new types of tissue and organs. Thiery proposed that cancer cells also switch “ON” EMT, temporarily changing attributes so that they can detach from primary tumors, enter the bloodstream and seed new tumors elsewhere. After arriving at a new location, the cancer cells then turn “OFF” the EMT program and grow into carcinoma metastases or tumors.

Thiery’s hypothesis was controversial because researchers haven’t been able to find supporting evidential proof in vivo. “Although this model was proposed in 2002, there have been no experiments done to attest to it in a spontaneous tumor model,” said Jing Yang, PhD, associate professor of pharmacology and pediatrics and senior author of the Cancer Cell paper. “Our new study provides an in vivo demonstration of the reversible EMT in metastasis and helps to resolve the controversy on this leading theory in metastasis.”

Using a mouse squamous cell carcinoma model, Jeff Tsai, PhD, a postdoctoral fellow in Yang’s lab and first author of the study, with help from collaborators at the Whitehead Institute for Biomedical Research in Cambridge, MA and The Sanford-Burnham Medical Research Institute in La Jolla, showed that activation of an EMT-inducing gene called Twist1 is sufficient to turn “ON” the EMT switch and promote carcinoma cells to disseminate into blood circulation.  Equally importantly, the researchers found that turning “OFF” the EMT switch at distant sites is essential for disseminated tumor cells to proliferate and form metastases.  Their findings indicate that reversible EMT likely represents a key driving force in human carcinoma metastasis. 

“There are many similarities between developmental EMT and EMT in metastasis,” Yang said.  “Both processes seem to use the same cellular machineries and signaling pathways to activate the EMT program. During embryogenesis, the EMT program tends to be more permanent and epithelial cells commit to a mesenchymal fate.  Our study shows that carcinoma cells need a reversible EMT to achieve efficient metastasis. It suggests that EMT reversion could be a critical step to wake up tumor cells from dormancy, a phenomenon in which cancer patients develop metastasis years after the initial primary tumor diagnosis and removal.”

It’s not entirely known how Twist1 becomes active in primary tumors, though previous studies have pointed to factors like hypoxia and inflammation in the tumor microenvironment. Researchers do not know exactly how Twist1 is “turned off at distant organs.” Yang said these are subjects of current experiments.

More broadly, the published findings suggest that more research is needed to determine how to target EMT to combat cancer metastasis. Several pharmaceuticals and research institutes are already pursuing EMT inhibitors as possible cancer treatments. 

“Since reversion of EMT promotes colonization and growth of metastases, this study actually cautions that therapies inhibiting EMT could be counterproductive in preventing distant metastases when patients already present circulating tumor cells. Instead, blocking EMT reversion may prevent dormant tumor cells from establishing metastases.”

Meat your makerWhen you sit down on Thursday and give thanks, start perhaps with the fact you’re not eating the (Petri) dish above. At least not yet. What you’re looking at is not “synthetic” meat, but in vitro or cultured. Apparently, there’s a difference. Synthetic meat typically refers to imitation edible animal tissue made from a vegetable source, often soy or gluten. In vitro meat (which has other monikers, including the less-than-appetizing “shmeat”) is grown from scratch using muscle cells. “This is real meat because it is made of the same cells that meat is composed of,” said Gabor Forgacs, one of the men behind Modern Meadow, a company with plans to use three-dimensional bioprinting to eventually produce in vitro edible meat products. (The company will start first with simple leather products because it’s easier to create and grow skin cells than muscle.)While there’s no obvious demand for in vitro meat at the moment, its proponents say there is a need. Natural meat – the kind that originates from actual animals – is increasingly expensive, ecologically speaking. Using conventional methods, it takes 6.7 pounds of cattle feed, 52.8 gallons of water, 74.5 square feet of land and 1,036 BTUs of fossil fuel energy (enough energy to power a microwave oven for 18 minutes) to produce a quarter-pound of hamburger, according to the Journal of Animal Science. In vitro meat production requires only a fraction of those resources.However, don’t go looking for a lab-grown steak anytime soon. Technological advances have made bioprinting – a process in which biological elements like cells in a liquid form can be laid down upon each other in complex, three-dimensional formulations – more feasible, but nobody’s making anything yet that resembles a turkey breast or pork chop. Indeed, Modern Meadows short-term goal is to print edible slivers of meat two centimeters by one centimeter, less than half a millimeter thick.Sounds tasty.
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Meat your maker

When you sit down on Thursday and give thanks, start perhaps with the fact you’re not eating the (Petri) dish above. At least not yet.

What you’re looking at is not “synthetic” meat, but in vitro or cultured. Apparently, there’s a difference. Synthetic meat typically refers to imitation edible animal tissue made from a vegetable source, often soy or gluten. In vitro meat (which has other monikers, including the less-than-appetizing “shmeat”) is grown from scratch using muscle cells.

“This is real meat because it is made of the same cells that meat is composed of,” said Gabor Forgacs, one of the men behind Modern Meadow, a company with plans to use three-dimensional bioprinting to eventually produce in vitro edible meat products. (The company will start first with simple leather products because it’s easier to create and grow skin cells than muscle.)

While there’s no obvious demand for in vitro meat at the moment, its proponents say there is a need. Natural meat – the kind that originates from actual animals – is increasingly expensive, ecologically speaking. Using conventional methods, it takes 6.7 pounds of cattle feed, 52.8 gallons of water, 74.5 square feet of land and 1,036 BTUs of fossil fuel energy (enough energy to power a microwave oven for 18 minutes) to produce a quarter-pound of hamburger, according to the Journal of Animal Science.

In vitro meat production requires only a fraction of those resources.

However, don’t go looking for a lab-grown steak anytime soon. Technological advances have made bioprinting – a process in which biological elements like cells in a liquid form can be laid down upon each other in complex, three-dimensional formulations – more feasible, but nobody’s making anything yet that resembles a turkey breast or pork chop. Indeed, Modern Meadows short-term goal is to print edible slivers of meat two centimeters by one centimeter, less than half a millimeter thick.

Sounds tasty.

The big cell Proponents of the “3D Virtual Cell” hope the imagined project will do for biology what the Large Hadron Collider did for particle physics – without the cost and time involved in digging a giant hole in the ground. The idea is to create a virtual, rather than physical, framework and resource to gather together every studied and known aspect of molecular and cellular biology in a way that can be understood and used by practicing scientists. It’s a major undertaking, and with support from the National Science Foundation (NSF), researchers at the University of California, San Diego are taking some first steps with a year-long series of workshops. The first – “Toward the 3D Virtual Cell” – is scheduled for December 13-14 at the California Institute for Telecommunications and Information Technology (Calit2) on the UC San Diego campus. “Many of the top names in cell biology and cyberinfrastructure will join us to explore critical areas and challenges facing anyone who attempts to build a resource of this magnitude,” said Phil Bourne, principal investigator on the NSF grant and a professor of pharmacology at UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego. “Cell biology occurs at many scales, and a resource for modeling and visualization must operate on an increasingly large, diverse, complex and widely-distributed body of digital biological data.” To explore this field, conference attendees will be asked to address the grand challenges facing whole-cell modeling, and what computational, sociological or other obstacles must be overcome in order to the resource. “You can think of it as a giant app store of freely-available, open-source software, data, educational materials and expertise that would become the go-to resource for researchers in the life sciences, no matter what biological scale they are working at,” said Bourne. The workshop is open to university researchers as well as scientists from other La Jolla institutions that focus on life sciences research, among them the Salk Institute for Biological Studies, Sanford Burnham Medical Research Institute, The Scripps Research Institute, La Jolla Institute for Allergy & Immunology and the Sanford Consortium for Regenerative Medicine. Click here for registration information or contact Stephanie Hagstrom at 858-534-1219 or sthagstrom@ucsd.edu.
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The big cell

Proponents of the “3D Virtual Cell” hope the imagined project will do for biology what the Large Hadron Collider did for particle physics – without the cost and time involved in digging a giant hole in the ground.

The idea is to create a virtual, rather than physical, framework and resource to gather together every studied and known aspect of molecular and cellular biology in a way that can be understood and used by practicing scientists.

It’s a major undertaking, and with support from the National Science Foundation (NSF), researchers at the University of California, San Diego are taking some first steps with a year-long series of workshops. The first – “Toward the 3D Virtual Cell” – is scheduled for December 13-14 at the California Institute for Telecommunications and Information Technology (Calit2) on the UC San Diego campus.

“Many of the top names in cell biology and cyberinfrastructure will join us to explore critical areas and challenges facing anyone who attempts to build a resource of this magnitude,” said Phil Bourne, principal investigator on the NSF grant and a professor of pharmacology at UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego.

“Cell biology occurs at many scales, and a resource for modeling and visualization must operate on an increasingly large, diverse, complex and widely-distributed body of digital biological data.”

To explore this field, conference attendees will be asked to address the grand challenges facing whole-cell modeling, and what computational, sociological or other obstacles must be overcome in order to the resource.

“You can think of it as a giant app store of freely-available, open-source software, data, educational materials and expertise that would become the go-to resource for researchers in the life sciences, no matter what biological scale they are working at,” said Bourne.

The workshop is open to university researchers as well as scientists from other La Jolla institutions that focus on life sciences research, among them the Salk Institute for Biological Studies, Sanford Burnham Medical Research Institute, The Scripps Research Institute, La Jolla Institute for Allergy & Immunology and the Sanford Consortium for Regenerative Medicine.

Click here for registration information or contact Stephanie Hagstrom at 858-534-1219 or sthagstrom@ucsd.edu.

We as a bird Almost 50 years ago, UC San Diego neuro-psychiatrist Harvey J. Karten, MD, then 30 years old and working at Massachusetts Institute of Technology, and colleagues discovered that a region of the avian brain (he was studying auditory and visual pathways, in particular) was surprisingly similar to a distinctly different looking region of the mammalian brain, including humans. Notably, they reported that neural inputs and outputs into the dorsal ventricular ridge (DVR), a cluster of neurons found in bird (and reptile) brains, was strikingly similar to the functioning of the neocortex in mammalian brains. Here’s the kicker: The neocortex is a part of the brain’s outer layer where higher-order processing is thought to occur. Research at the time posited that the neocortex was unique to mammals, and perhaps responsible for their presumed greater cognitive powers. Karten’s findings threatened to upend that notion of singularity. More importantly, it suggested a shared evolutionary history with mammalian cortex, one that predated the evolutionary separation of mammals and birds. And it proposed a mechanism of cortical development in mammals that was clearly at odds with the prevailing notions. Ever since, the debate over similarities (and their significance) between the brains of mammalian and non-mammalian vertebrates has rumbled along. Karten has steadfastly pursued it, most recently in a 2010 PNAS paper that demonstrated that the microcircuitry in the region of the avian brain that processes auditory signals (hearing) is similar to the region of the mammalian brain responsible for the same function. Final confirmation that Karten and colleagues were right, however, may have come earlier this month with the report (also in PNAS) by researchers at the University of Chicago, who tested Karten’s 47 -year-old hypothesis by using new molecular markers capable of identifying specific neuron types in the mammalian cortex, then looking to see if the same marker genes were expressed in DVR nuclei in the brains of chickens and zebra finch. They were. The neurons of the avian DVR are homologous to those of the mammalian neocortex. “Here was a completely different line of evidence,” said Clifton Ragsdale, PhD, an associate professor of neurobiology and senior author of the study. “There were molecular makers that picked out specific layers of cortex; whereas the original Karten theory was based just on connections, and some people dismissed that. But in two very different birds, all of the gene expression fits together very nicely with the connections. It’s welcome, if expected, news for Karten. “I recall that my mentor, the distinguished neuroanatomist Walle J. H. Nauta, cautioned me about not hoping for much of an enthusiastic reception. He said that for really novel, iconoclastic ideas, it can take 40 years before they are accepted. This is closer to 50 years! The most exciting part of the story will be watching how this may serve as a foundation for exciting new research into the evolution and development of the mammalian cortex by the next generation of bright young scientists.” Confirming functional similarities between avian and mammalian brains does more than just end an old argument. It opens up new avenues of investigation for neuroscientists, who now have another animal model to study. They can compare developmental steps between more, diverse organisms. They can look at how neurons take different form to provide the same function and how their differences impact behaviors and abilities, notably communication skills. More fundamentally, scientists are slightly closer to addressing the ultimate question of evolution: How did humans get from there to here? Part of the answer, it now appears, lies in the part of your brain that behaves like a bird’s.
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We as a bird

Almost 50 years ago, UC San Diego neuro-psychiatrist Harvey J. Karten, MD, then 30 years old and working at Massachusetts Institute of Technology, and colleagues discovered that a region of the avian brain (he was studying auditory and visual pathways, in particular) was surprisingly similar to a distinctly different looking region of the mammalian brain, including humans.

Notably, they reported that neural inputs and outputs into the dorsal ventricular ridge (DVR), a cluster of neurons found in bird (and reptile) brains, was strikingly similar to the functioning of the neocortex in mammalian brains.

Here’s the kicker: The neocortex is a part of the brain’s outer layer where higher-order processing is thought to occur. Research at the time posited that the neocortex was unique to mammals, and perhaps responsible for their presumed greater cognitive powers. Karten’s findings threatened to upend that notion of singularity. More importantly, it suggested a shared evolutionary history with mammalian cortex, one that predated the evolutionary separation of mammals and birds. And it proposed a mechanism of cortical development in mammals that was clearly at odds with the prevailing notions.

Ever since, the debate over similarities (and their significance) between the brains of mammalian and non-mammalian vertebrates has rumbled along. Karten has steadfastly pursued it, most recently in a 2010 PNAS paper that demonstrated that the microcircuitry in the region of the avian brain that processes auditory signals (hearing) is similar to the region of the mammalian brain responsible for the same function.

Final confirmation that Karten and colleagues were right, however, may have come earlier this month with the report (also in PNAS) by researchers at the University of Chicago, who tested Karten’s 47 -year-old hypothesis by using new molecular markers capable of identifying specific neuron types in the mammalian cortex, then looking to see if the same marker genes were expressed in DVR nuclei in the brains of chickens and zebra finch.

They were. The neurons of the avian DVR are homologous to those of the mammalian neocortex.

“Here was a completely different line of evidence,” said Clifton Ragsdale, PhD, an associate professor of neurobiology and senior author of the study. “There were molecular makers that picked out specific layers of cortex; whereas the original Karten theory was based just on connections, and some people dismissed that. But in two very different birds, all of the gene expression fits together very nicely with the connections.

It’s welcome, if expected, news for Karten.

“I recall that my mentor, the distinguished neuroanatomist Walle J. H. Nauta, cautioned me about not hoping for much of an enthusiastic reception. He said that for really novel, iconoclastic ideas, it can take 40 years before they are accepted. This is closer to 50 years! The most exciting part of the story will be watching how this may serve as a foundation for exciting new research into the evolution and development of the mammalian cortex by the next generation of bright young scientists.”

Confirming functional similarities between avian and mammalian brains does more than just end an old argument. It opens up new avenues of investigation for neuroscientists, who now have another animal model to study. They can compare developmental steps between more, diverse organisms. They can look at how neurons take different form to provide the same function and how their differences impact behaviors and abilities, notably communication skills.

More fundamentally, scientists are slightly closer to addressing the ultimate question of evolution: How did humans get from there to here?

Part of the answer, it now appears, lies in the part of your brain that behaves like a bird’s.

Tidings of stem Yesterday’s announcement that John B. Gurdon and Shinya Yamanaka would share the 2012 Nobel Prize in Physiology or Medicine is the latest evidence that stem cell science has come a long, long way – though not yet where scientists, doctors and ordinary people hope it will someday be. Gurdon and Yamanaka were honored for a pair of landmark discoveries made almost half a century later. In 1962, Gurdon was the first to clone an animal. Taking an intestinal cell from an adult frog, Gurdon extracted its nucleus and inserted it into a frog egg whose nucleus had been removed. The frog successfully developed into a tadpole, upending dogma at the time that said adult cells were irrevocably assigned specific functions. Gurdon’s experiment showed that adult genes could be reprogrammed. (FYI: Gurdon conducted his experiment using the African clawed frog (Xenopus), a laboratory stand-by. The image above depicts ready-to-hatch red-eyed tree frog  tadpoles, not typically used in research, but infinitely cuter.) In 2006, Yamanaka followed up with an even-more astounding experiment. Using mice, he induced adult skin cells to revert back to stem cells, a state in which they are capable of developing into any kind of cell. So-called induced pluripotent stem cells (iPSC) are the workhorses of much stem cell science today. Researchers use them in hopes of one day being able to grow replacement neurons for neurodegenerative diseases like Alzheimer’s or new tissues for damaged organs, such as the liver or heart. Most recently, Japanese researchers showed the utility of stem cells in future fertility treatments, growing both egg and sperm cells from iPSCs, then combining them to produce healthy offspring.
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Tidings of stem

Yesterday’s announcement that John B. Gurdon and Shinya Yamanaka would share the 2012 Nobel Prize in Physiology or Medicine is the latest evidence that stem cell science has come a long, long way – though not yet where scientists, doctors and ordinary people hope it will someday be.

Gurdon and Yamanaka were honored for a pair of landmark discoveries made almost half a century later.

In 1962, Gurdon was the first to clone an animal. Taking an intestinal cell from an adult frog, Gurdon extracted its nucleus and inserted it into a frog egg whose nucleus had been removed. The frog successfully developed into a tadpole, upending dogma at the time that said adult cells were irrevocably assigned specific functions. Gurdon’s experiment showed that adult genes could be reprogrammed. (FYI: Gurdon conducted his experiment using the African clawed frog (Xenopus), a laboratory stand-by. The image above depicts ready-to-hatch red-eyed tree frog  tadpoles, not typically used in research, but infinitely cuter.)

In 2006, Yamanaka followed up with an even-more astounding experiment. Using mice, he induced adult skin cells to revert back to stem cells, a state in which they are capable of developing into any kind of cell.

So-called induced pluripotent stem cells (iPSC) are the workhorses of much stem cell science today. Researchers use them in hopes of one day being able to grow replacement neurons for neurodegenerative diseases like Alzheimer’s or new tissues for damaged organs, such as the liver or heart.

Most recently, Japanese researchers showed the utility of stem cells in future fertility treatments, growing both egg and sperm cells from iPSCs, then combining them to produce healthy offspring.