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Doctors Develop Life-Saving Drugs from Coral Reefs


Cancer fighting sponges



The chemicals that help corals and 1) ___ survive are also helping people. Halaven, a drug derived from a sea sponge compound came on the market two years ago, and has improved survival among women who have metastatic breast cancer, NBC reported.


The kaleidoscope of life in the coral reefs under the turquoise waters of the Florida Keys is a magnet for tourists, but it’s not just a pretty view.


The same chemistry that helps corals and sponges survive is also helping 2) ___ fight cancer. “What we’re doing is taking advantage of that chemistry and turning those chemicals into drugs to save lives,” said Stephanie Wear, director of coral reef conservation at the Nature Conservancy. Wear describes the reefs as the “New York City” of the oceans, “where everything is happening,” because it is 400 to 600 times more likely to find a source for a drug in the 3) ___ than on land — and the densely packed coral reefs are an even more plentiful source.


But climate change and waterway pollution threaten the sea life that house these healing properties.


“The [coral reef] population is diminished by about 90% across the Caribbean,” said James Byrne, the marine science program manager at the Nature Conservancy. With 4) ___ under siege, scientists at the Nature Conservancy have created coral farms — currently supporting more than 30,000 corals across Florida and the U.S. Virgin Islands — to sustainably harvest the life-saving properties of the reef. “We’re taking these corals and growing them out in 5) ___ just like a tree farm would and replanting them back on the reef and doing it in a way that we’re really maximizing that potential for reproduction in the future,” said Byrne.


In the clear waters of the Florida Keys, scientists glue some of the corals to cinder blocks on the ocean 6) ___, and hang others from a rope resembling a laundry line, allowing them to float in the water. Eventually, they hope to put out up to 4,000 corals a year – all to battle some of the worst diseases known to humankind: cancer, leukemia, AIDS — and perhaps even Lupus, Alzheimer’s, and Parkinson’s.


The Staghorn coral population has been decimated by warming oceans and disease. The Nature Conservancy scuba team is working to regrow coral in nurseries on the ocean floor.

Arden O’Connor, a 34-year-old who lives in Boston, Mass., beat leukemia with help from Ara-C, a chemotherapy 7) ___ originally derived from sea sponges that thrive in the coral reefs. Without it, O’Connor said, she could have died at age 26. “I’ve spent most of my life swimming in the ocean but absolutely didn’t assume it would have anything to do with my cancer,” said O’Connor, who has been cancer-free for seven years.


8) ___, another drug also derived from a sea sponge, came on the market in Nov. 2010, and has improved survival among women who have metastatic breast cancer. “Without the reefs and without doing that biodiversity conservation, we have no starting points,” said Dr. Edward Suh, who develops new drugs at Japanese pharmaceutical company Eisai, the lab that produces Halaven (Eribulin) .


The Earth’s oceans are 9) ____ chests and scientists derive medications from sea sponges to treat diseases like breast cancer, said Dr. Linda Vahdat, Director of the Breast Cancer Research Program at Weill Cornell Medical College, as she discussed Halaven, a new cancer drug. Using the chemicals present in the sea sponge saves time during the drug production process, Dr Suh added. “In order to make this natural product a drug by synthesis, we would require over 60 steps,” he said. “And the typical drug is about 10 steps or less.”


For many doctors, the drug has proven to be an exciting option for their patients.


“Sometimes patients are interested in where the drugs come from and it’s interesting because when you mention to them that it’s derived from a natural product they seem to be a little bit better with the concept of getting these types of therapies,” said Dr. Linda Vahdat, the director of the breast cancer research program at Weill Cornell Medical College. “For millennia there have been natural products used to treat tumors and we know it from the ancient Egyptian writings — and certainly moving into contemporary space we use a lot of natural products to treat our patients with 10) ___ cancer.”


Halaven (Eribulin) is approved in the European Union, USA, Switzerland, Japan, and Singapore. In Europe, Halaven has received pricing authorization and been launched in Austria, Denmark, Finland, Germany, Iceland, Italy, Norway, Sweden, Switzerland, Slovenia, and the UK.


ANSWERS: 1) sponges; 2) people; 3) ocean; 4) corals; 5) nurseries; 6) floor; 7) drug; 8) Halaven; 9) medicine; 10) breast


Breast cancer treatments from under the sea



Editor’s note: With this subject matter going back 4,000 years, it seemed like important medical history to be informed about.


Source: The New York Times, December 2, 2012, by Nathaniel Rich


Nathaniel Rich is an author whose second novel, ‘‘Odds Against Tomorrow,’’ will be published in April 2013.


Graphic: Takashi Murai -The “immortal jellyfish” can transform itself back into a polyp and begin life anew



After more than 4,000 years – almost since the dawn of recorded time, when Utnapishtim told Gilgamesh that the secret to immortality lay in a coral found on the ocean floor – man finally discovered eternal life in 1988. He found it, in fact, on the ocean floor. The discovery was made unwittingly by Christian Sommer, a German marine-biology student in his early 20s. He was spending the summer in Rapallo, a small city on the Italian Riviera, where exactly one century earlier Friedrich Nietzsche conceived “Thus Spoke Zarathustra”: “Everything goes, everything comes back; eternally rolls the wheel of being. Everything dies, everything blossoms again.”


Sommer was conducting research on hydrozoans, small invertebrates that, depending on their stage in the life cycle, resemble either a jellyfish or a soft coral. Every morning, Sommer went snorkeling in the turquoise water off the cliffs of Portofino. He scanned the ocean floor for hydrozoans, gathering them with plankton nets. Among the hundreds of organisms he collected was a tiny, relatively obscure species known to biologists as Turritopsis dohrnii. Today it is more commonly known as the immortal jellyfish.


Sommer kept his hydrozoans in petri dishes and observed their reproduction habits. After several days he noticed that his Turritopsis dohrnii was behaving in a very peculiar manner, for which he could hypothesize no earthly explanation. Plainly speaking, it refused to die. It appeared to age in reverse, growing younger and younger until it reached its earliest stage of development, at which point it began its life cycle anew. Sommer was baffled by this development but didn’t immediately grasp its significance. It was nearly a decade before the word “immortal” was first used to describe the species. But several biologists in Genoa, fascinated by Sommer’s finding, continued to study the species, and in 1996 they published a paper called “Reversing the Life Cycle.” The scientists described how the species – at any stage of its development – could transform itself back to a polyp, the organism’s earliest stage of life, “thus escaping death and achieving potential immortality.” This finding appeared to debunk the most fundamental law of the natural world – you are born, and then you die.


One of the paper’s authors, Ferdinando Boero, likened the Turritopsis to a butterfly that, instead of dying, turns back into a caterpillar. Another metaphor is a chicken that transforms into an egg, which gives birth to another chicken. The anthropomorphic analogy is that of an old man who grows younger and younger until he is again a fetus. For this reason Turritopsis dohrnii is often referred to as the Benjamin Button jellyfish.


Yet the publication of “Reversing the Life Cycle” barely registered outside the academic world. You might expect that, having learned of the existence of immortal life, man would dedicate colossal resources to learning how the immortal jellyfish performs its trick. You might expect that biotech multinationals would vie to copyright its genome; that a vast coalition of research scientists would seek to determine the mechanisms by which its cells aged in reverse; that pharmaceutical firms would try to appropriate its lessons for the purposes of human medicine; that governments would broker international accords to govern the future use of rejuvenating technology. But none of this happened.


Some progress has been made, however, in the quarter-century since Christian Sommer’s discovery. We now know, for instance, that the rejuvenation of Turritopsis dohrnii and some other members of the genus, is caused by environmental stress or physical assault. We know that, during rejuvenation, it undergoes cellular transdifferentiation, an unusual process by which one type of cell is converted into another – a skin cell into a nerve cell, for instance. (The same process occurs in human stem cells.) We also know that, in recent decades, the immortal jellyfish has rapidly spread throughout the world’s oceans in what Maria Pia Miglietta, a biology professor at Notre Dame, calls “a silent invasion.” The jellyfish has been “hitchhiking” on cargo ships that use seawater for ballast. Turritopsis has now been observed not only in the Mediterranean but also off the coasts of Panama, Spain, Florida and Japan. The jellyfish seems able to survive, and proliferate, in every ocean in the world. It is possible to imagine a distant future in which most other species of life are extinct but the ocean will consist overwhelmingly of immortal jellyfish, a great gelatin consciousness everlasting.


The most frustrating explanation for our dearth of knowledge about the immortal jellyfish is of a more technical nature. The genus, it turns out, is extraordinarily difficult to culture in a laboratory. It requires close attention and an enormous amount of repetitive, tedious labor; even then, it is under only certain favorable conditions, most of which are still unknown to biologists, that a Turritopsis will produce offspring. In fact there is just one scientist who has been culturing Turritopsis polyps in his lab consistently. He works alone, without major financing or a staff, in a cramped office in Shirahama, a sleepy beach town in Wakayama Prefecture, Japan, four hours south of Kyoto. The scientist’s name is Shin Kubota, and he is, for the time being, our best chance for understanding this unique strand of biological immortality.


“Turritopsis application for human beings is the most wonderful dream of mankind,” Kubota told me the first time I called him. “Once we determine how the jellyfish rejuvenates itself, we should achieve very great things. My opinion is that we will evolve and become immortal ourselves.”


One of Shirahama’s main attractions is its crescent-shaped white-sand beach. Worried that the town of White Beach would lose its white beach, Wakayama Prefecture began in 1989 to import sand from Perth, Australia, 4,700 miles away. Over 15 years, Shirahama dumped 745,000 cubic meters of Aussie sand on its beach, preserving its eternal whiteness – at least for now. Shirahama is full of timeless natural wonders that are failing the test of time. Visible just off the coast is Engetsu island, a sublime arched sandstone formation that looks like a doughnut dunked halfway into a glass of milk. At dusk, tourists gather at a point on the coastal road where, on certain days, the arch perfectly frames the setting sun. Arches are temporary geological phenomena; they are created by erosion, and erosion ultimately causes them to collapse. Engetsu is nearly matched in beauty by Sandanbeki, a series of striated cliffs farther down the coast that drop 165 feet into turbulent surf. Beneath Sandanbeki lies a cavern that local pirates used as a secret lair more than a thousand years ago. Today the cliffs are one of the world’s most famous suicide spots. A sign on the edge serves as a warning to those contemplating their own mortality: “Wait a minute. A dead flower will never bloom.”


But Shirahama is best known for its onsen, saltwater hot springs that are believed to increase longevity. There are larger, well-appointed ones inside resort hotels, smaller tubs that are free to the public and ancient bathhouses in cramped huts along the curving coastal road. You can tell from a block away that you are approaching an onsen, because you can smell the sulfur.


Each morning, Shin Kubota, who is 60, visits Muronoyu, a simple onsen popular with the city’s oldest citizens that traces its history back 1,350 years. “Onsen activates your metabolism and cleans away the dead skin,” Kubota says. “It strongly contributes to longevity.” At 8:30 a.m., he drives 15 minutes up the coast, past the white beach, where the land narrows to a promontory that extends like a pointing, arthritic finger, separating Kanayama Bay from the larger Tanabe Bay. At the end of this promontory stands Kyoto University’s Seto Marine Biological Laboratory, a damp, two-story concrete block. Though it has several classrooms, dozens of offices and long hallways, the building often has the appearance of being completely empty. The few scientists on staff spend much of their time diving in the bay, collecting samples. Kubota, however, visits his office every single day. He must, or his immortal jellyfish will starve.


The world’s only captive population of immortal jellyfish lives in petri dishes arrayed haphazardly on several shelves of a small refrigerator in Kubota’s office. Like most hydrozoans, Turritopsis passes through two main stages of life, polyp and medusa. A polyp resembles a sprig of dill, with spindly stalks that branch and fork and terminate in buds. When these buds swell, they sprout not flowers but medusas. A medusa has a bell-shaped dome and dangling tentacles. Any layperson would identify it as a jellyfish, though it is not the kind you see at the beach. Those belong to a different taxonomic group, Scyphozoa, and tend to spend most of their lives as jellyfish; hydrozoans have briefer medusa phases. An adult medusa produces eggs or sperm, which combine to create larvae that form new polyps. In other hydroid species, the medusa dies after it spawns. A Turritopsismedusa, however, sinks to the bottom of the ocean floor, where its body folds in on itself – assuming the jellyfish equivalent of the fetal position. The bell reabsorbs the tentacles, and then it degenerates further until it becomes a gelatinous blob. Over the course of several days, this blob forms an outer shell. Next it shoots out stolons, which resemble roots. The stolons lengthen and become a polyp. The new polyp produces new medusas, and the process begins again.


Kubota estimates that his menagerie contains at least 100 specimens, about 3 to a petri dish. “They are very tiny,” Kubota, the proud papa, said. “Very cute.” It is cute, the immortal jellyfish. An adult medusa is about the size of a trimmed pinkie fingernail. It trails scores of hairlike tentacles. Medusas found in cooler waters have a bright scarlet bell, but more commonly the medusa is translucent white, its contours so fine that under a microscope it looks like a line drawing. It spends most of its time floating languidly in the water. It’s in no rush. Kubota feeds the Medusas artemia cysts – dried brine shrimp eggs harvested from the Great Salt Lake in Utah. Though the cysts are tiny, barely visible to the naked eye, they are often too large for a medusa to digest. In these cases Kubota, squinting through the microscope, must slice the egg into pieces with two fine-point needles, the way a father might slice his toddler’s hamburger into bite-size chunks.


It is a full-time job, caring for the immortal jellyfish. When traveling abroad for academic conferences, Kubota has had to carry the medusas with him in a portable cooler. In recent years he has been invited to deliver lectures in Cape Town; Xiamen, China; Lawrence, Kan.; and Plymouth, England. He also travels to Kyoto, when he is obligated to attend administrative meetings at the university, but he returns the same night, an eight-hour round trip, in order not to miss a feeding.


Given Kubota’s obsessive focus on his work, it is not surprising that he has been forced to neglect other areas of his life. He never cooks and tends to bring takeout to his office. At the lab, he wears T-shirts – bearing images of jellyfish – and sweat pants. His office is a mess. The door opens just widely enough to admit a man of Kubota’s stature. It is blocked from opening farther by a chest-high cabinet, on the surface of which are balanced several hundred objects Kubota has retrieved from beaches – seashells, bird feathers, crab claws and desiccated coral.


Kubota grew up in Matsuyama, on the southern island of Shikoku. Though his father was a teacher, Kubota didn’t get excellent marks at his high school, where he was a generation behind Kenzaburo Oe. “I didn’t study,” he said. “I only read science fiction.” But when he was admitted to college, his grandfather bought him a biological encyclopedia. It sits on one of his office shelves, beside a sepia-toned portrait of his grandfather. “I learned a lot from that book,” Kubota said. “I read every page.” He was especially impressed by the phylogenetic tree, the taxonomic diagram that Darwin called the Tree of Life. Darwin included one of the earliest examples of a Tree of Life in “On the Origin of Species” – it is the book’s only illustration. Today the outermost twigs and buds of the Tree of Life are occupied by mammals and birds, while at the base of the trunk lie the most primitive phyla – Porifera (sponges), Platyhelminthes (flatworms), Cnidaria (jellyfish).


Until recently, the notion that human beings might have anything of value to learn from a jellyfish would have been considered absurd. Your typical cnidarian does not, after all, appear to have much in common with a human being. It has no brains, for instance, nor a heart. It has a single orifice through which its food and waste pass – it eats, in other words, out of its own anus. But the Human Genome Project, completed in 2003, suggested otherwise. Though it had been estimated that our genome contained more than 100,000 protein-coding genes, it turned out that the number was closer to 21,000. This meant we had about the same number of genes as chickens, roundworms and fruit flies. In a separate study, published in 2005, cnidarians were found to have a much more complex genome than previously imagined.


“There’s a shocking amount of genetic similarity between jellyfish and human beings,” said Kevin J. Peterson, a molecular paleobiologist who contributed to that study. From a genetic perspective, apart from the fact that we have two genome duplications, “we look like a damn jellyfish.”


This may have implications for medicine, particularly the fields of cancer research and longevity. Peterson is now studying microRNAs (commonly denoted as miRNA), tiny strands of genetic material that regulate gene expression. MiRNA act as an on-off switch for genes. When the switch is off, the cell remains in its primitive, undifferentiated state. When the switch turns on, a cell assumes its mature form: it can become a skin cell, for instance, or a tentacle cell. MiRNA also serve a crucial role in stem-cell research – they are the mechanism by which stem cells differentiate. Most cancers, we have recently learned, are marked by alterations in miRNA. Researchers even suspect that alterations in miRNA may be a cause of cancer. If you turn a cell’s miRNA “off,” the cell loses its identity and begins acting chaotically – it becomes, in other words, cancerous.


Hydrozoans provide an ideal opportunity to study the behavior of miRNA for two reasons. They are extremely simple organisms, and miRNA are crucial to their biological development. But because there are so few hydroid experts, our understanding of these species is staggeringly incomplete. “Immortality might be much more common than we think,” Peterson said. “There are sponges out there that we know have been there for decades. Sea-urchin larvae are able to regenerate and continuously give rise to new adults which might be a general feature of these animals. They never really die.”


Peterson is closely following the work of Daniel Martínez, a biologist at Pomona College and one of the world’s leading hydroid scholars. The National Institutes of Health has awarded Martínez a five-year, $1.26 million research grant to study the hydra – a species that resembles a polyp but never yields medusas. Its body is almost entirely composed of stem cells that allow it to regenerate itself continuously. As a Ph.D. candidate, Martínez set out to prove that hydra were mortal. But his research of the last 15 years has convinced him that hydra can, in fact, survive forever and are “truly immortal.” “It’s important to keep in mind that we’re not dealing with something that’s completely different from us,” Martínez said. “Genetically hydra are the same as human beings. We’re variations of the same theme.” According to Peterson, “If I studied cancer, the last thing I would study is cancer, if you take my point. I would not be studying thyroid tumors in mice. I’d be working on hydra.” Hydrozoans, he suggests, may have made a devil’s bargain. In exchange for simplicity – no head or tail, no vision, eating out of its own anus – they gained immortality. These peculiar, simple species may represent an opportunity to learn how to fight cancer, old age and death.


But most hydroid experts find it nearly impossible to secure financing. “Who’s going to take a chance on a scientist who doesn’t work on mammals, let alone a jellyfish?” Peterson said. “The granting agencies are always talking about trying to be imaginative and reinvigorate themselves, but of course you’re stuck in a lot of bureaucracy. The pie is only so big.”


Even some of Kubota’s peers are cautious when speaking about potential medical applications in Turritopsis research. “It is difficult to foresee how much and how fast Turritopsis dohrnii can be useful to fight diseases,” Stefano Piraino, a colleague of Ferdinando Boero’s, said. “Increasing human longevity has no meaning, it is ecological nonsense. What we may expect and work on is to improve the quality of life in our final stages.” Kubota sees it differently. “The immortal medusa is the most miraculous species in the entire animal kingdom,” he said. “I believe it will be easy to solve the mystery of immortality and apply ultimate life to human beings.”


Kubota can be encouraged by the fact that many of the greatest advancements in human medicine came from observations made about animals that, at the time, seemed to have little or no resemblance to man. In 18th-century England, dairymaids exposed to cowpox helped establish that the disease inoculated them against smallpox; the bacteriologist Alexander Fleming accidentally discovered penicillin when one of his petri dishes grew a mold; and, most recently, scientists in Wyoming studying nematode worms found genes similar to those inactivated by cancer in humans, leading them to believe that they could be a target for new cancer drugs. And so Kubota continues to accumulate data on his own simple organism, every day of his life.


It was a stressful time for Kubota. His eyesight was fading and he had begun to lose his hair. “Too old,” he said, scowling. “I want to be young again. I want to become miracle immortal man.” As if to distract himself from this trajectory of thought, he removed a petri cup from his refrigerator unit. He held it under the light so I could see the ghostly Turritopsis suspended within. It was still, waiting. “Watch,” he said. “I will make this medusa rejuvenate.”


The most reliable way to make the immortal jellyfish age in reverse, Kubota explained to me, is to mutilate it. With two fine metal picks, he began to perforate the medusa’s mesoglea, the gelatinous tissue that composes the bell. After Kubota poked it six times, the medusa behaved like any stabbing victim – it lay on its side and began twitching spasmodically. Its tentacles stopped undulating, and its bell slightly puckered. But Kubota, in what appeared a misdirected act of sadism, didn’t stop there. He stabbed it 50 times in all. The medusa had long since stopped moving. It lay limp, crippled, its mesoglea torn, the bell deflated. Kubota looked satisfied.


“You rejuvenate!” he yelled at the jellyfish. Then he started laughing.


We checked on the stab victim every day that week to watch its transformation. On the second day, the depleted, gelatinous mess had attached itself to the floor of the petri dish; its tentacles were bent in on themselves. “It’s transdifferentiating,” Kubota said. “Dynamic changes are occurring.” By the fourth day the tentacles were gone, and the organism ceased to resemble a medusa entirely; it looked instead like an amoeba. Kubota called this a “meatball.” By the end of the week, stolons had begun to shoot out of the meatball.


This method is, in a certain sense, cheating, as physical distress induces rejuvenation. But the process also occurs naturally when the medusa grows old or sick. In Kubota’s most recent paper on Turritopsis, he documented the natural rejuvenation of a single colony in his lab between 2009 and 2011. The idea was to see how quickly the species would regenerate itself when left to its own devices. During the two-year period, the colony rebirthed itself 10 times, in intervals as brief as one month. In his paper’s conclusion, published in the journal Biogeography, Kubota wrote, “Turritopsis will be kept forever by the present method and will contribute to any study for everyone in the future.” He has made other significant findings in recent years. He has learned, for instance, that certain conditions inhibit rejuvenation: starvation, large bell size and water colder than 72 degrees. And he has made progress in solving the largest mystery of all. The secret of the species’s immortality, Kubota now believes, is hidden in the tentacles. “Human beings are so intelligent,” he told me, as if to reassure me. But then he added a caveat. “Before we achieve immortality,” he said, “we must evolve first. The heart is not good.”


I assumed that he was making a biological argument – that the organ is not biologically capable of infinite life, that we needed to design new, artificial hearts for longer, artificial lives. But then I realized that he wasn’t speaking literally. By heart, he meant the human spirit. “Human beings must learn to love nature,” he said. “Today the countryside is obsolete. In Japan, it has disappeared. Big metropolitan places have appeared everywhere. We are in the garbage. If this continues, nature will die.” Man, he explained, is intelligent enough to achieve biological immortality. But we don’t deserve it. This sentiment surprised me coming from a man who has dedicated his life to pursuing immortality.


This is why, in the years since his “scare,” Kubota has begun a second career. In addition to being a researcher, professor and guest speaker, he is now a songwriter. Kubota’s songs have been featured on national television, are available on karaoke machines across Japan and have made him a minor Japanese celebrity – the Japanese equivalent of Bill Nye the Science Guy. It helps that in Japan, the nation with the world’s oldest population, the immortal jellyfish has a relatively exalted status in popular culture. Its reputation was boosted in 2003 by a television drama, “14 Months,” in which the heroine takes a potion, extracted from the immortal jellyfish, that causes her to age in reverse. Since then Kubota has appeared regularly on television and radio shows. In March, “Morning No. 1,” a Japanese morning show devoted an episode to Shirahama. After a segment on the onsen, the hosts visited Kubota at the Seto Aquarium, where he talked about Turritopsis. “I want to become young, too!” one host shrieked. On “Love Laboratory,” a science show, Kubota discussed his recent experiments while collecting samples on the Shirahama wharf. “I envy the immortal medusa!” gushed the hostess. On “Feeding Our Bodies,” a similar program, Kubota addressed the camera: “Among the animals, the immortal jellyfish is the most splendid.” There followed an interview with 100-year-old twins.


But no television appearance is complete without a song. For his performances, he transforms himself from Dr. Shin Kubota, erudite marine biologist in jacket and tie, into Mr. Immortal Jellyfish Man. His superhero alter ego has its own costume: a white lab jacket, scarlet red gloves, red sunglasses and a red rubber hat, designed to resemble a medusa, with dangling rubber tentacles. With help from one of his sons, an aspiring musician, Kubota has written dozens of songs in the last five years and released six albums. Many of his songs are odes to Turritopsis. These include “I Am Scarlet Medusa,” “Life Forever,” “Scarlet Medusa – an Eternal Witness,” “Die-Hard Medusa” and his catchiest number, “Scarlet Medusa Chorus.”


My name is Scarlet Medusa,

A teeny tiny jellyfish

But I have a special secret

that no others may possess

I can – yes, I can! – rejuvenate


Other songs apotheosize different forms of marine life: “We Are the Sponges – A Song of the Porifera,” “Viva! Variety Cnidaria” and “Poking Diving Horsehair Worm Mambo.” There is also “I Am Shin Kubota.”


My name is Shin Kubota

Associate professor of Kyoto University

At Shirahama, Wakayama Prefecture

I live next to an aquarium

Enjoying marine-biology research

Every day, I walk on the beach

Scooping up with a plankton net

Searching for wondrous creatures

Searching for unknown jellyfish.

Dedicate my life to small creatures

Patrolling the beaches every day

Hot spring sandals are always on

Necessary item to get in the sea

Scarlet medusa rejuvenates

Scarlet medusa is immortal


“He is important for the aquarium,” Akira Asakura, the Seto lab director told me. “People come because they see him on television and become interested in the immortal medusa and marine life in general. He is a very good speaker, with a very wide range of knowledge.”


Science classes regularly make field trips to meet Mr. Immortal Jellyfish Man. During my week in Shirahama, he was visited by a group of 150, 10- and 11-year-olds who had prepared speeches and slide shows about Turritopsis. The group was too large to visit Seto, so they sat on the floor of a ballroom in a local hotel. After the children made their presentations (“I have jellyfish mania!” one girl exclaimed), Kubota took the stage. He spoke loudly, with great animation, calling on the children and peppering them with questions. How many species of animals are there on earth? How many phyla are there? The karaoke video for “Scarlet Medusa Chorus” was projected on a large screen, and the giggling children sang along.


Kubota does not go to these lengths simply for his own amusement – though it is clear that he enjoys himself immensely. Nor does he consider his public educational work as secondary to his research. It is instead, he believes, the crux of his life’s work. “We must love plants – without plants we cannot live. We must love bacteria – without decomposition our bodies can’t go back to the earth. If everyone learns to love living organisms, there will be no crime. No murder. No suicide. Spiritual change is needed. And the most simple way to achieve this is through song. “Biology is specialized,” he said, bringing his palms within inches of each other. “But songs?”


On my last morning in Shirahama, Kubota called to cancel our final meeting. He had a bacterial infection in his eye and couldn’t see clearly enough to look through his microscope. He was going to a specialist. He apologized repeatedly. “Human beings very weak,” he said. “Bacteria very strong. I want to be immortal!” He laughed his hearty laugh.


Turritopsis, it turns out, is also very weak. Despite being immortal, it is easily killed. Turritopsis polyps are largely defenseless against their predators, chief among them sea slugs. They can easily be suffocated by organic matter. “They’re miracles of nature, but they’re not complete,” Kubota acknowledged. “They’re still organisms. They’re not holy. They’re not God.” And their immortality is, to a certain degree, a question of semantics. “That word ‘immortal’ is distracting,” says James Carlton, the professor of marine sciences at Williams. “If by ‘immortal’ you mean passing on your genes, then yes, it’s immortal. But those are not the same cells anymore. The cells are immortal, but not necessarily the organism itself.” To complete the Benjamin Button analogy, imagine the man, after returning to a fetus, being born again. The cells would be recycled, but the old Benjamin would be gone; in his place would be a different man with a new brain, a new heart, a new body. He would be a clone. But we won’t know for certain what this means for human beings until more research is done. That is the scientific method, after all: lost in the labyrinth, you must pursue every path, no matter how unlikely, or risk being devoured by the Minotaur. Kubota, for his part, fears that the lessons of the immortal jellyfish will be absorbed too soon, before man is ready to harness the science of immortality in an ethical manner. “We’re very strange animals,” he said. “We’re so clever and civilized, but our hearts are very primitive. If our hearts weren’t primitive, there wouldn’t be wars. I’m worried that we will apply the science too early, like we did with the atomic bomb.”


I remembered something he said earlier in the week, when we were watching a music video for his song “Living Planet – Connections Between Forest, Sea and Rural Area.” He described the song as an ode to the beauty of nature. The video was shot by his 88-year-old neighbor, a retired employee of Osaka Gas Company. Kubota’s lyrics were superimposed over a sequence of images. There was Engetsu, its arch covered with moss and jutting oak and pine trees; craggy Mount Seppiko and gentle Mount Takane; the striated cliffs of Sandanbeki; the private beach at the Seto Laboratory; a waterfall; a brook; a pond; and the cliffside forests that abut the city, so dense and black that the trees seem to be secreting darkness.


“Nature is so beautiful,” Kubota said, smiling wistfully. “If human beings disappeared, how peaceful it would be.”  Source: The New York Times, December 2012


Shin Kubota at Kyoto University‘s Seto Marine Biological Laboratory

Credit: Yoshihiko Ueda for The New York Times

This is Huge – Study Suggests Immune System Could Play a Central Role in AMD


Age-related macular degeneration (AMD) damages the light-sensitive cells of the macula, the central part of the retina that allows us to see fine visual detail. As the disease progresses, patients encounter great difficulty reading, driving, or performing hobbies and tasks that require hand-eye coordination. Treatments exist to prevent severe vision loss in certain types of advanced AMD, but none prevent or cure the disease. Currently, 2 million Americans have advanced AMD and another 7 million have intermediate stages.


Recent studies have identified several genes with alterations that increase the risk of developing the disease. In addition, environmental risk factors have also been suggested as possible causes of the disease. One explanation may be that environmental exposures influence DNA methylation, which regulates gene expression. Changes in this process may result in the production of too much or too little of a gene’s protein, leading to cellular dysfunction and disease. Changes in DNA methylation have been implicated in cancer, lupus, multiple sclerosis, and many other diseases.


According to an article published in Cell Reports (2012;2:1151-1158), it was shown that changes in genes in the immune system function may cause AMD. The study identified decreased levels of DNA methylation, a chemical reaction that switches off genes, on the interleukin-17 receptor C gene (IL17RC). The lack of DNA methylation led to increased gene activity and, in turn, increased levels of IL17RC proteins in patients with AMD. IL17RC is a protein that promotes immune responses to infections, such as fungal attacks. According to the authors, the study also suggests IL17- and IL17RC-mediated immune responses can be crucial in causing AMD, and that by measuring IL17RC gene activity in at-risk patients, there is the possibility to identify an early method to detect AMD.”


To test whether changes in DNA methylation might play a role in AMD, the study evaluated three pairs of twins — one pair identical and two pairs fraternal — where only one of the siblings had AMD. Identical twins have the same genetic makeup while fraternal twins share about half of their DNA. Because of their similar genetic backgrounds, identical and fraternal twins can be helpful in studying the differences between the effects of genetics and the environment. When compared with the unaffected twins, methylation patterns were altered in 231 genes of affected twins. This finding is consistent with the hypothesis that environmental exposures may epigenetically regulate expression of many genes and lead to AMD.


Among the 231 genes, the study found that DNA methylation was absent in a region of the IL17RC gene in twins with AMD. The lack of methylation in the IL17RC gene led to increased gene activity and, in turn, increased levels of its protein in circulating blood. The study further validated these findings by comparing seven siblings with and without AMD as well as 202 AMD patients and 96 control subjects without the disease. These studies also found increased IL17RC levels in circulating blood and, most importantly, in the retina of patients with AMD but not controls.


Based on these results, the authors propose that chronic increased levels of the IL17RC protein in the retina likely promote inflammation and recruitment of immune cells that damage the retina and lead to AMD. The authors are planning to evaluate what environmental factors may be responsible for the regulation of IL17RC and how the epigenetic regulation leading to the chronic inflammation in AMD patients can be reversed by novel therapies. They will also evaluate the role of epigenetics in other eye diseases.

HIV Treatment Reduces Risk of Malaria Recurrence in Children


The Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) nevirapine has been recommended as the first-line treatment for HIV by the World Health Organization for children in developing countries. It is less expensive than the protease inhibitor combination and, unlike the protease inhibitors, does not need refrigeration. However, previous studies have shown that the lopinavir-ritonavir combination is more effective for treating HIV-positive infants than widely used treatment regimens based on nevirapine. Unfortunately, compared to nevirapine, the current liquid formulation of the protease inhibitor combination is unpleasant tasting. However, recent changes in the protease inhibitor formulation may overcome these barriers to expanding its use in resource poor settings. New formulations have been developed for the drug so that it can be sprinkled on food, tastes better, and doesn’t need refrigeration.


According to an article published in the New England Journal of Medicine (2012; 367:2110-2118), a combination of protease inhibitors lopinavir and ritonavir contributed to an overall reduction of 40% in the rate of malaria among a group of HIV-positive infants and children up to 6 years old in Uganda who were also being treated with anti-malarial drugs. This reduction was in comparison to malaria incidence among children receiving NNRTIs.


Protease inhibitors interfere with the reproduction of HIV by blocking the protease enzyme of HIV. The protease inhibitor combination used in the study did not appear to inhibit an initial bout of malaria–but reduce the chances of a recurrence of the disease following a successful treatment. The study also found that blood levels of anti-malarial drugs were higher in children who had received the protease inhibitors, which may help explain their effectiveness at preventing malaria’s return. According to the authors, it is possible that these protease inhibitors prevent antimalarial drugs from breaking down or have some other additive effect against the malarial parasite. The authors added that laboratory studies also suggest that protease inhibitors can block the malaria parasite outright.


More than 170 HIV-positive infants and children participated in the study. They received either an NNRTI (nevirapine for children under age 3, efavirenz for children over age 3) or the protease inhibitor-based treatment. In addition, the children received insecticide-treated nets to keep mosquitoes away while they slept, vitamins, a clean source of water, and medication to prevent infection with the malaria parasite, which is transmitted by mosquitoes.


Even with these measures, the study found that the children’s risk of developing malaria in the first six months of their anti HIV treatment was greater than 40%. Although the risk was slightly higher in the nevirapine-treated group, the difference was not significant statistically. However, of the children who developed malaria and were successfully treated for it during the study, 41% of those taking an NNRTI developed another case of malaria within 28 days of clearing their system of the parasite the first time. In contrast, only 14% of those on the combination lopinavir-ritonavir treatment developed another case of malaria within this time period. When comparing the two groups over a 63-day period, the authors found that 54% of the NNRTI group had a recurrence of malaria, compared with 28% of the group taking the lopinavir-ritonavir treatment. In addition, tests conducted one week after the start of malaria treatment showed that blood levels of an anti-malaria drug were higher among children receiving the protease inhibitor combination than among their counterparts taking the nevirapine-based treatment.

Outcomes of the Surviving Sepsis Campaign in the ICU in the USA and Europe


Mortality from severe sepsis and septic shock differs across continents, countries, and regions. As a result, a study published in Lancet Infectious Diseases (2012;12:919-924) used data from the Surviving Sepsis Campaign (SSC) to compare models of care and outcomes for patients with severe sepsis and septic shock in the US and Europe.


The SSC was introduced into more than 200 sites in Europe and the USA. All patients presenting with severe sepsis and septic shock 1) in emergency departments or hospital wards, and admitted to intensive care units (ICUs), and 2) those with sepsis in ICUs were entered into the SSC database. Patients included in the cohort were limited to those entered in the first 4 years at every site. Random-effects logistic regression was used to estimate the hospital mortality odds ratio (OR) for Europe relative to the US and to find the relation between lengths of stay in hospital and ICU and geographic region.


A total of 25,375 patients were included in the study. The US included 107 sites with 18,766 (74%) patients, and Europe included 79 hospital sites with 6,609 (26%) patients. In the US, 12,218 (65·1%) were admitted to the ICU from the emergency department whereas in Europe, 3405 (51·5%) were admitted from the wards. The median stay on the hospital wards before ICU admission was longer in Europe than in the USA (1.0 vs 0.1 days). Raw hospital mortality was higher in Europe than in the USA (41.1% vs 28.3%. The median length of stay in ICU (7.8 vs 4.2) and hospital (22.8 vs 10.5 days) was longer in Europe than in the USA. However, adjusted mortality in Europe was not significantly higher than that in the USA (32.3% vs 31.3%; p=0·468). Complete compliance with all applicable elements of the sepsis resuscitation bundle was higher in the USA than in Europe (21.6% vs 18.4%).


According to the authors, the significant difference in unadjusted mortality and the fact that this difference disappears with severity adjustment raise important questions about the effect of the approach to critical care in Europe compared with that in the US, and the effect of ICU bed availability on outcomes in patients with severe sepsis and septic shock requires further investigation.

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First Seasonal Influenza Vaccine Manufactured Using Cell Culture Technology



Congratulations to our colleagues at Novartis Vaccines and Diagnostics.


Getting vaccinated each year remains one of the best ways to prevent seasonal influenza. The Centers for Disease Control and Prevention recommends that everyone 6 months of age and older receive an annual influenza vaccine.


Cell culture technology is another manufacturing alternative to conventional egg-based influenza vaccine production. Advantages of cell culture technology include the ability to maintain an adequate supply of readily available, previously tested and characterized cells for use in vaccine production and the potential for a faster start-up of the vaccine manufacturing process in the event of a pandemic.


The FDA has announced the approval of Flucelvax, the first seasonal influenza vaccine licensed in the US produced using cultured animal cells, instead of fertilized chicken eggs. Flucelvax, manufactured by Novartis Vaccines and Diagnostics, is approved to prevent seasonal influenza in people ages 18 years and older.


The manufacturing process for Flucelvax is similar to the egg-based production method, but a significant difference is that the virus strains included in the vaccine are grown in animal cells of mammalian origin instead of in eggs. Cell culture technology has already been in use for several decades to produce other U.S. licensed vaccines.


Flucelvax was evaluated in a randomized controlled clinical study conducted in the US and Europe that involved about 7,700 people ages 18 to 49 years who received either Flucelvax or a placebo. The study showed that Flucelvax was 83.8% effective in preventing influenza when compared to placebo. The use of Flucelvax in people older than 49 is supported by antibody responses in about 1,700 adults which showed it to be comparable to Agriflu, an egg-based seasonal influenza vaccine approved by FDA for use in people 18 years and older.


The safety evaluation included about 6,700 individuals who received Flucelvax in controlled clinical studies. Injection site and general reactions to Flucelvax were typical of those seen with current influenza vaccines. Pain, redness and soreness at the injection site and headache and fatigue were the most common reactions.

Baked Halibut with Red Pepper Sauce


This sauce is serendipitous. I first set out to copy a spread we had at a restaurant for our rolls, that had a large amount of butter mixed with red peppers.  After, eliminating all of the butter, I couldn’t get it exactly right, I realized that what I had done, was to create a darn good sauce that would be delicious on a light white flaky fish.   If you try this recipe, hopefully, you will feel the same way and like it as much as my family does.


First, here is how to roast the peppers:


1. To begin, fire up the grill, the broiler, or the open flame on your cooktop.  All are equally effective.



2. Charcoal all of the peppers.   Turn them to get as much done, as you can.



3. It may look awful, but you’ll see, it’s not



4. Whether under the broiler or on the grill, blacken them for about ten minutes, then remove them and set them on a plate for a few minutes.



5. After a few minutes, throw the peppers into a large Ziploc bag.     Get the quart size.



6.  Seal the bags.     Let the peppers sweat for about 10 minutes, while you do something else.



7. Remove peppers from the Ziploc bag…it’s time to peel the peppers



8.         Peel off the outer skin with your fingers. It should slide off really easily.     Don’t do this under the faucet, or you’ll rinse away the flavor



9. When they’re all peeled, cut off the tips and slice open the pepper.



10.       Run your knife along the inside of the peppers, to scrape out the seeds and membranes.



11.      Into your food processor or blender, throw in the peeled and seeded peppers.



12. Pulse several times until it’s pureed, and note that the mixture won’t be totally smooth –              it’ll have a wonderful red peppery texture.



13. Your pepper sauce should look, more or less, like this, just before you spread it over the halibut portions.




  1. 1.5 pounds halibut fillets (cleaned and cut into four pieces)
  2. 3 red bell peppers, roasted with skin peeled off
  3. 1 yellow bell pepper, roasted with skin peeled off
  4. 3 garlic cloves, peeled and cut in half
  5. 8 ounces tofu cream cheese (Tofutti)
  6. 1 can (15 oz) chickpeas, very well drained
  7. 1.5 teaspoons golden miso (same as traditional white miso)
  8. Pinch fine black pepper or 1 grind coarse black pepper
  9. Juice of 1/2 to 1 lime
  10. 1/3 cup chopped cilantro (save some for garnish)



  1. Roast and peel all of the peppers and cut into pieces. Follow the pepper directions, above.
  2. While the peppers are in the ziplock bag, prepare the halibut etc.
  3. Preheat the oven to 475 degrees F (245 degrees C).
  4. Clean the fish and cut into four portions
  5. Grease a 9×13 inch baking dish. (Dish with a cover)
  6. Season halibut with ground black pepper (salt optional)
  7. Place halibut portions in the greased baking dish.
  8. Now, in a food processor, put all of the pieces of pepper and combine the rest of the ingredients (save some cilantro for garnish). Pulse until smooth. If your food processor is not large enough, then puree the ingredients in portions, until everything is smooth.
  9. Spread the pepper mixture evenly over each halibut piece. If there’s some extra sauce, that’s fine, use it all.
  10. Bake in the oven, covered, until fish is opaque and flakes easily with a fork, about 20-25 minutes.
  11. Remove from the oven and let stand for 5 minutes before serving. Sprinkle with some cilantro.



Serve your halibut with, or over, jasmine or basmati rice and with a simple tossed salad.


Be sure to serve some warm bread or rolls because this sauce is delicious and you’ll want to sop it up.


A chilled glass of Chablis would be perfect with this entree.