The grapefruit is a subtropical citrus tree grown for its fruit which was originally named the “forbidden fruit” of Barbados. The fruit was first documented in 1750 by Rev. Griffith Hughes describing specimens from Barbados. All parts of the fruit have uses. The fruit is mainly consumed for a tangy juice. The peel is expressed into an aromatherapy oil and is also a source of dietary fiber. The seed and pulp as a by-product of the juice industry is sold as cattle feed and is manufactured for use to make an extract. GSE (grapefruit seed extract) was originally developed by Dr. Jacob Harich, a nuclear physicist. In 1963, Harich journeyed to Florida, the heart of grapefruit country, and began researching and later marketing of GSE. Aubrey Hampton, founder of Aubrey Organics, has promoted citrus seed extract, a component in “Aubrey’s Preservative”, for more than 25 years.


In Pakistan and India grapefruit pulp was believed to prevent and cure dysentery, diarrhea enteritis, typhus and other digestive tract disorders. Also believed to cure fatigue was a glass of equal parts of lemon juice and grapefruit juice. Grapefruit juice was also felt to be an effective diuretic, and to help eczema sufferers when it is drunk. Grapefruit also lowers cholesterol levels. It is felt that grapefruit stimulated the appetite. Grapefruit seed extract is a compound made from the seed, pulp and rind of the fruit in most cases.


In Chinese medicine, citrus fruits are contraindicated when combined with certain herbs. According to traditional Chinese medicine, grapefruit has a cooling effect on the body. Eating grapefruit is thought to be especially helpful for those people suffering from weak digestion, a decreased appetite, stomach fullness, alcohol intoxication, and dry cough.


For stomach problems like nausea, vomiting, stomach ache, diarrhea and digestive obstruction the following was prescribed: Simmer the whole fruit, including the peel, with honey and drink as a tea. For phlegm disorder especially of the lung;


Bronchitis with viscous yellow phlegm: Mix grapefruit skin with inner white pulp chopped with honey and rice wine. Take this morning and evening


Itching skin, unexplained rash: Wash one sour grapefruit, place inside a pot, add water, boil, then switch to slow fire, boiling sap to slag juice. Wash area of skin itch or rash, with this solution, 3 times a day.


Pain caused by inflammation: 5-8 grapefruit, about 500 ml of honey, about 100 grams of crystal sugar, about 10 ml of ginger. Grapefruit peel to core, twist juice, into a pot, boil, then switch to slow fire, fry thick, add honey, rock sugar and the ginger with the revolve paste, cool, bottle and reserve. Take 20 ml of this medicine, 2 times per day, along with boiling water Chongfu.


Treatment of abdominal pain and diarrhea: Take 1 ripe grapefruit and cut the top off. Remove the flesh and put into 100 grams of green tea and then cover and put in a cool place for more than 1 year. After 1 year, take this with boiling water, as a tea.


Grapefruits come in three colors, yellow or blond, pink and red, the colors describing the flesh and not the rind. It is believed by some that the red grapefruit, which contains lycopene, has medicinal value for prevention of prostate health for men as well as for erectile dysfunction. Grapefruit of all descriptions contain a lot of vitamins C, E and A as well as B-complex ones and minerals such as calcium, copper, iron, magnesium, manganese, potassium, phosphorous, selenium and zinc. Grapefruits also contain some Omega -3 and -6 fatty acids and 16 amino acids. Some people still think that grapefruit has potent antioxidant properties and are good to ward off and help cure colds and flu as well as having anti-inflammatory properties so good for osteoarthritis, rheumatoid arthritis and asthma. It is also still believed by some that grapefruit is cardiovascular protective and protects against strokes and cancers.


Grapefruit contains large quantities of a simple polyamine called spermidine, which may be related to aging. It is known to be necessary for cell growth and maturation, and as cells age their level of spermidine is known to fall. Scientists have shown that feeding spermidine to worms, fruit flies and yeast significantly prolongs their lifespan. In addition, adding spermidine to the diet of mice decreased molecular markers of aging, and when human immune cells were cultured in a medium containing spermidine, they also lived longer.



New Rheumatoid Arthritis Drug Targets NIH-Discovered Protein


Editor’s note: Why shouldn’t NIH get “a percentage” of any drug product developed with government funds. Think about it. It might make healthcare “free” in the US.


Affecting nearly 1.5 million adults, rheumatoid arthritis (RA) is an inflammatory disease that causes pain, swelling, stiffness, and loss of function in the joints. It occurs when the immune system, which normally defends the body from outside invaders such as bacteria and viruses, attacks the membrane that lines the joints.


The FDA has recently approved a new oral medication for the treatment of RA that represents a new class of drugs for the disease. The drug, tofacitinib (Xeljanz), provides a new treatment option for adults with moderately to severely active RA who have had an inadequate response to, or who are intolerant of, methotrexate, a standard therapy for RA. Tofacitinib is from a new class of drugs developed to target Janus kinases. One member of this family, JAK3, was discovered in the early 1990s by a NIH laboratory in the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Subsequent studies carried out at the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the NIAMS, showed that genetic defects in JAK3 can cause severe combined immunodeficiency. This discovery led to the idea that drugs blocking Janus kinases would suppress the immune system and might be protective against the damaging inflammation of rheumatoid arthritis and certain other autoimmune diseases.


The approval of tofacitinib represents the first time in a decade that the FDA has approved an oral disease modifying antirheumatic drug, or DMARD, for the treatment of RA. This broad class of drugs slows or halts the progression of damage from the disease, rather than merely providing relief from symptoms. Unlike biologic treatments for RA — which are also DMARDs and target immune system proteins — tofacitinib is a pill, not an infusion or an injection. It is the first Janus kinase inhibitor to receive an FDA approval for RA.


JOHN J. O’SHEA, M.D., scientific director of the NIAMS, is the NIH researcher who discovered JAK3 and first cloned the human form of the protein. In 1993, shortly after O’Shea and his team discovered the JAK3 protein and established its role in inflammation, O’Shea learned that scientists at Pfizer were searching for drug targets to tackle autoimmunity and transplant rejection. Subsequent discussions led to an innovative public-private collaboration between NIH and Pfizer, through a cooperative research and development agreement. This agreement allowed teams from both organizations to work together toward the common goal of finding a new immune-suppressing drug for this debilitating disease.


WARREN J. LEONARD, M.D., director of the Immunology Center in NHLBI, is a pioneer in immune research whose group first identified the genetic mutations that are responsible for X-linked severe combined immunodeficiency (XSCID), commonly known as the “Bubble Boy Disease.” Leonard, in collaboration with O’Shea, then demonstrated that the protein that is defective in XSCID associates with JAK3, and that humans with mutations in JAK3 have a form of immunodeficiency clinically similar to XSCID. That discovery led to their hypothesis that JAK3 inhibitors might be potent immunosuppressive agents, as is the case for tofacitinib.

Drug Resistance and Pseudoresistance: An Unintended Consequence of Enteric Coating Aspirin


Roughly one-fifth of Americans take low-dose aspirin every day for heart-healthy benefits. But, based on either urine or blood tests of how aspirin blocks the stickiness of platelets – blood cells that clump together in the first stages of forming harmful clots – up to one third of patients are deemed unlikely to benefit from daily use. Such patients are called “aspirin resistant.” Clots are the main cause of most heart attacks and strokes.


Despite this concern, no clear definition of “aspirin resistance” has emerged and estimates of its incidence have varied remarkably. As a result, a study published online in Circulation (4 December 2012), was performed to determine the commonality of a mechanistically consistent, stable and specific phenotype of true pharmacological resistance to aspirin – such as might be explained by genetic causes.


For the study, 400 healthy volunteers were screened for their response to a single oral dose of 325 mg immediate release or enteric coated aspirin. Response parameters reflected the activity of aspirin’s molecular target, cyclooxygenase-1. Individuals who appeared “aspirin resistant” on one occasion underwent repeat testing and if still “resistant” were exposed to low dose enteric coated aspirin (81 mg) and clopidogrel (75 mg) for one week each. Variable absorption caused a high frequency of apparent resistance to a single dose of 325 mg enteric coated aspirin (up to 49%) but not to immediate release aspirin (0%). All individuals responded to aspirin upon repeated exposure, extension of the post dosing interval or addition of aspirin to their platelets ex vivo.


According to the authors, pharmacological resistance to aspirin is rare and the study failed to identify a single case of true drug resistance. However, pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric coated but not immediate release aspirin administration.

Long-Term Effects of Continuing Adjuvant Tamoxifen to 10 Years Versus Stopping at 5 Years After Diagnosis of Estrogen Receptor-Positive Breast Cancer


For women with estrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. As a result, according to an article published in The Lancet, Early Online Publication (5 December 2012), a study was performed aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years.


In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimization. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. The current report is based on breast cancer outcomes among the 6,846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues.


Results showed that among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3,428 women allocated to continue vs. 711 in 3,418 controls, p=0.002), reduced breast cancer mortality (331 deaths vs. 397 deaths, p=0.01), and reduced overall mortality (639 deaths vs. 722 deaths, p=0.01). The reductions in adverse breast cancer outcomes appeared to be less extreme during years 5-9 than after year 10 (recurrence rate ratio 0.90), and 0.75 in later years, as well as for breast cancer mortality (RR 0.97 during years 5-9 and 0.71 after year 10).


The cumulative risk of recurrence during years 5-14 was 21.4% for women allocated to continue treatment vs. 25.1% for controls. Similarly, breast cancer mortality during years 5-14 was 12.2% for women allocated to continue treatment versus 15.0% for controls.


Treatment allocation seemed to have no effect on breast cancer outcome among 1,248 women with ER-negative disease, and an intermediate effect among 4,800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected. For the incidence rates of hospitalization or death rates fo specific diseases, RRs were as follows: pulmonary embolus 1.87 (p=0.01), stroke 1.06 (ns), ischemic heart disease 0.76 (p=0·02), and endometrial cancer 1.74 (p=0.0002). The cumulative risk of endometrial cancer during years 5-14 was 3.1% (mortality 0.4%) for women allocated to continue versus 1.6% (mortality 0·2%) for controls.


According to the authors, for women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.


FDA:  Advancing Breakthrough Drug Therapies


The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012, gives FDA the authority to collect user fees from industry to fund reviews of innovator drugs, medical devices, generic drugs and biosimilar biologics. It also reauthorizes two programs that encourage pediatric drug development. This is the fifth authorization of the Prescription Drug User Fee Act or PDUFA, first enacted in 1992, and the third authorization of the Medical Device User Fee Act, or MDUFA, first enacted in 2002. Both programs have provided steady and reliable funding to maintain and support a staff of trained reviewers who must determine whether a proposed new product is safe and effective for patients and do so within a certain time period. The new user fee programs for generic drugs and biosimilar biologics build on the successes of these two established user fee programs.


Extracted From FDA Voice: By: Janet Woodcock, M.D.


Thanks to a recent law that went into effect on July 9, 2012, FDA now has a new program to help expedite the development of new drugs that could potentially offer a substantial improvement over existing therapies for patients with serious or life-threatening diseases. The new law is designed to get “breakthrough” therapies developed as quickly and safely as possible so they can be available to treat the patients who need them. Recently FDA has identified the first therapy to receive this special designation and there is lots of interest in the pharmaceutical industry in taking advantage of this new development tool. FDASIA defines a “breakthrough” therapy as one that is “is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.” In other words, a breakthrough drug is one that may offer important new benefits for patients with serious or life-threatening disease who are especially in need of new safe and effective treatments.


This new option will complement the three programs that FDA ahs used for many years to help speed up the development and review of especially important new drug therapies. They’re called “expedited drug development and review” programs, named Fast Track, Priority Review and Accelerated Approval. Each one is different, but for simplicity, think of them as various ways of bringing potentially important new therapies to patients sooner. These programs have been very successful and are part of the reason that FDA leads the world in first approvals of innovative new drugs.

Janet Woodcock, M.D. is the Director of FDA’s Center for Drug Evaluation and Research


Versatility of Grapefruit


Editor’s note: Just a note of caution to our readers, who may be taking any prescription drug(s).  Before you try any of the recipes, below, check with your doctor to see if you are at risk for any serious grapefruit/drug interactions.


Grapefruit Margarita




Grapefruit segments cut into quarters


3/4 cup of grapefruit juice

6 oz tequila

2 oz Cointreau or Triple Sec

2 cups cracked ice




1. Rub the cut grapefruit segments around the rim of cocktail glasses then swirl them in a mound of salt to coat the rims.

2. Blend the liquids until smooth.

3. Pour into cocktail glasses and garnish with a grapefruit quarter (or smaller)  and/or a slice of lime.



Red Snapper with Grapefruit & Tarragon




  • 1/4 cup minced shallot
  • Four 6- to 8-ounces fillet of Red Snapper
  • 1/4 cup plus 2 tablespoons dry white wine (cooking wine is not as good)
  • 1/4 cup plus 2 tablespoons bottled clam juice
  • 2/3 cup fresh grapefruit juice
  • 1/4 cup heavy cream or almond milk (lowest calories) or buttermilk or half&half or plain yogurt
  • 6 Tablespoons extra virgin Olive oil
  • 2 teaspoons minced fresh tarragon leaves or 1/4 teaspoon crumbled dried, or to save (save a little extra for garnish)
  • fresh grapefruit sections as an accompaniment


1. Sprinkle the shallots into an oiled shallow baking dish just large enough to hold the fish fillets in one layer. Be sure the dish has a cover.


2. On top of the shallots arrange the fillets, skin sides down, and pour the wine and the clam juice over them. Sprinkle the fillets with salt and pepper to taste and bake them, covered, in the middle of a preheated 425°F. oven for 10 to 12 minutes, or until they are just cooked through. Just before the fish is done, raise the oven temperature and uncover the fish. Let it get a golden brown color and then take out of the oven. Transfer the fillets with a slotted spatula to a platter and keep them warm, and covered.


3. Strain the cooking liquid through a fine sieve into a small saucepan, and add the grapefruit juice, and boil the mixture until it is reduced to about 2/3 cup. Add the almond milk and boil the mixture until it is reduced by half. Reduce the heat to low and whisk in the olive oil, a little bit at a time, lifting the pan from the heat occasionally to let the mixture cool. (The sauce should not get hot enough to liquefy. It should be the consistency of thin hollandaise.) Whisk in the tarragon and salt and pepper to taste.


4. With a slotted spatula transfer each fish fillet, skin side down, to a plate. Pour one fourth of the sauce over each fillet and arrange some of the grapefruit sections around each plate. Garnish with a few sprinkles of fresh tarragon.


Serve with your favorite tossed salad, your most delicious pasta, and warm grainy rolls and/or bread to mop up the delicious sauce. I don’t think Chardonnay would go well with the grapefruit, so try a nice chilled Sauvignon Blanc or a Pinot Gris.


Pharmaceutically Speaking


Editor’s Note: Is the danger here the loss of the “right of free speech” or challenges to the “public safety”? One compromise is to promote off-label use of medications only to physicians, from peer reviewed journals like the article above on long-term use of tamoxifen for the treatment of breast cancer published in the Lancet.  With all of the discussion about “free speech” and “court opinions,” nothing is more important than the rights of patients and treatment outcomes. 


By Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.


In a decision sure to evoke passionate responses, pro and con, a US Appeals Court (Second Circuit) ruled in favor of a pharmaceutical industry representative and against the Government in a free speech case involving “off-label” promotion.


Basically, the Court has found that the Government does not have a compelling interest in forbidding speech about the use of a legally marketed product. The Court (Judge Denny Chin, quoted in the Wall Street Journal, Editorial December 5th, 2012, page A18), perhaps anticipating critics who will warn of risks to the public, noted that “The First Amendment directs us to be especially skeptical of regulations that seek to keep people in the dark for what the government perceives to be their own good.”


The FDA prohibition against pharmaceutical companies initiating discussions of unlabeled uses of approved medicines, uses that may be medically appropriate but not officially approved by the FDA, has long been a challenge for industry. It has also proven quite expensive for the firms and sometimes resulting in multiple billion dollar fines.


My impression is that the issue is less emotionally compelling for the broader practitioner community which, especially in the current environment, has an array of more practically impactful health policy concerns. However, it has been my perception over the years that physicians are often perplexed by constraints on the industry representatives that they see; the justifications for the restraints are often not intuitively obvious.


Irrespective of how one feels about the pros and cons of this unique speech prohibition, there is something seemingly “unfair” to Americans about someone telling you not to speak, because you are “not allowed to talk about that and to call Headquarters”. To some, it simply doesn’t feel right, despite the presumably salutary intent.


The profound implications of this ruling – it has the potential to transform the marketing of medicines, including advertising directly to consumers – make it likely that it will be appealed. Should the Supreme Court agree to address the issue it could be some time before we have closure.


The interim landscape promises to be interesting. Will FDA, for example, relax its enforcement of the prohibition against off-label promotion? If so, how will this be manifest? Will companies be aggressive and change marketing and sales strategies to exercise their (presumed) new freedoms, or will they act cautiously, perhaps fearful of angering regulators? These are unanswerable questions. It will be fascinating to watch, with much at stake, as companies and regulators reset their behavior in a changed, and potentially charged environment.


Whatever happens, the Court’s opinion seems (to me at least) consistent with the times. In an era of consumer empowerment and unfettered access to vast amounts of information on virtually any topic the prohibition on speech by industry about its own products increasingly seems anachronistic. Concerns that patients will be misled and put at risk by product information coming from a biased source, (likely to be expressed by many people of good will), while legitimate, have in many ways been superseded in a society that has apparently determined that free access to information is the higher value. However, the quintessential “American” challenge is to develop processes to assure that providers of information behave responsibly so that the public can accurately assess available information. This will not be an easy hurdle to overcome.

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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

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