ScientistLive.com, September 18, 2009  —   In two separate studies, a major component in green tea, epigallocatechin-3-O-gallate (EGCG), has been found to help prolong the preservation of both stored blood platelets and cryopreserved skin tissues. Published in the current double issue of Cell Transplantation (18:5/6), now freely available on-line at http://www.ingentaconnect.com/content/cog/ct, devoted to organ preservation and transplantation studies from Japan, the two complimentary studies have shown that EGCG, known to have strong anti-oxidative activity, can prolong platelet cell “shelf life” via anti-apoptosis (programmed cell death) properties and preserve skin tissues by controlling cell division.

Dr. Suong-Hyn Hyon, lead author on both studies and associate professor in the Institute for Frontier Medical Sciences in Kyoto, Japan, says that EGCG, a green tea polyphenol, is a known anti-oxidation and anti-proliferation agent, yet the exact mechanism by which EGCG works is not yet known. However, some of the activity of EGCG is likely to be related to its surface binding ability.

Enhanced platelet preservation

Using standard blood banking procedures, the storage duration for platelet cells (PCs) is limited to five days internationally or three days in Japan. During storage, PCs undergo biochemical, structural and functional changes, and PCs may lose membrane integrity and haemostatic functions, such as aggregability and affinity for surface receptors. Thus, PC shortages often occur. When EGCG was added to blood platelet concentrates, aggregation and coagulation functions were better-maintained after six days, perhaps due to EGCG’s anti-oxidative ability. Researchers suggested that EGCG inhibited the activation of platelet functions and protected the surface proteins and lipids from oxidation.

“Functions were restored by the maintained surface molecules with the detachment of ECGC by washing,” noted Dr. Hyon. “EGCG may lead to an inhibition of platelet apoptosis and lower rates of cell death, offering a potentially novel and useful method to prolong platelet storage period.”

EGCG enhances life of cryopreserved skin grafts

Another team of Japanese researchers studied the effects of using EGCG on frozen, stored skin tissues. As with platelet storage, the storage of skin tissue for grafting presents problems of availability and limitations on the duration of storage.

“To provide best outcomes, skin grafts must be processed and stored in a manner that maintains their viability and structural integrity until they are needed for transplantation,” explained Dr. Hyon. “Transplant dysfunction often occurs as the result of oxidation. A better storage solution could prevent this.”

It is known that polyphenols in green tea promote the preservation of tissues, such as blood vessels, cornea, islet cells, articular cartilage and myocardium at room temperature. Also, it is known that ECGC has stronger anti-oxidant activities than vitamin C because of its sterochemical structure and is reported to play an important role in preventing cancer and cardiovascular diseases.

This study examined how EGCG might help extend the preservation duration of frozen rat skin tissues and found that skin grafts could be protected from freeze-thaw injuries when EGCG was absorbed into various membrane lipids and proteins. Results of the study showed that EGCG enhanced the viability and stored duration of skin grafts up to seven weeks at 4 degrees C.

“The storage time of skin grafts was extended to 24 weeks by cryopreservation using EGCG and the survival rate was almost 100 percent,” noted Dr. Hyon.”

“These studies highlight the benefits of using natural compounds such as ECGC to enhance the preservation of stored tissues, possibly due to their anti-oxidative properties” said Dr. Naoya Kobayashi, guest editor of this double issue of Cell Transplantation.

Source: Cell Transplantation Center of Excellence for Aging and Brain Repair

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Margaret Hamburg speaking at the RAPS 2009 Conference

 The-Scientist.com, September 21, 2009, by Bob Grant  —  The US must bolster study on how to best craft regulations that bring drugs, medical devices and vaccines to market, the commissioner of the US Food and Drug Administration stressed in a speech delivered yesterday (September 16th) in Philadelphia.

Margaret Hamburg, the former New York City health commissioner who was named FDA commissioner earlier this year, was speaking at the annual Regulatory Affairs Professional Society conference to approximately 850 representatives from pharmaceutical companies, biotechs, and medical device manufacturers.

“Just as biomedical research has evolved in the past decades, regulatory science — the science and tools we use to assess and evaluate product safety, efficacy, potency, quality and performance — must also evolve,” she said.

Hamburg added that too little attention and resources are paid to regulatory science as a discipline that can help the FDA protect and benefit American citizens. “Our efforts will be seriously compromised if we don’t significantly increase the sophistication of our regulatory science soon,” she said. “A strong and robust field of regulatory science is essential to the work of FDA, and I believe it represents an important driver of our nation’s health.”

As Hamburg was addressing an audience of regulatory professionals, she gave only a cursory definition for regulatory science. This left me wondering: What the heck is regulatory science?

For the answer, I turned to Alan Moghissi, the president of the Institute for Regulatory Science, a non-profit that advises universities, Congress, and state and local governments on matters of regulatory science.

“Regulatory science is a unique application of science, at all levels, to the societal decision process,” Moghissi told The Scientist.

He explained that regulatory science involves taking existing information or data and using it to hone and develop effective regulations, laws and judicial systems. When these social or industrial parameters are set using ideals or emotions rather than scientific inputs, Moghissi added, the public often winds up misled. “The moment you bring in societal objectives, as good as they may be, they mess [the regulatory or legal process] up.”

Moghissi noted that the problem extends beyond FDA and into other agencies tasked with developing meaningful and effective regulations. “I believe there’s a lack of recognition of the significance of regulatory science,” he said.

Indeed, there seems to be only a select few academic programs that specialize in turning out regulatory scientists. One such program, at the University of Southern California’s School of Pharmacy, bemoans the lack of regulatory science practitioners and uses the need as a recruitment device. “Industry and government cannot find sufficient numbers of skilled personnel to meet demands,” the program’s website reads. “Our program can help you get to the forefront, to become a leader in this emerging profession.”

Frances Richmond, director of the USC program, said that beyond being under-appreciated in terms of its importance to policy and regulation making, regulatory science is not a career “that people even recognize.” Richmond told The Scientist that improving the practice of regulatory science hinges on improving how we train its practitioners. “The investment should be more on the education side,” she added.

During her speech, Hamburg also pointed to the essential role that regulatory science plays in translating biomedical research discoveries to the clinic. “The goal is to place the emerging, very promising areas in science and technology, such as genomics and personalized medicine, the development of stem cell therapies and therapies that harness the power of nanotechnology fully at the service of public health,” she said.

Both Moghissi and Hamburg indicated that increased investment in the field of regulatory science is crucial to boosting sound rule-making in the drug and medical device industry. “Our nation has invested billions of dollars in biomedical research, an effort that’s indispensible for medical progress. But this research will not result in new therapies and cures unless it’s married to a robust investment in regulatory science,” Hamburg said. “We cannot afford to have a muscular investment in fundamental research and discovery with only a scrawny counterpart in regulatory capacity.”

“Some of the money that is being spent on R&D ought to be redirected with emphasis on regulatory science,” Moghissi concurred. “Maybe more resources would attract more people to attend to it.”

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GoogleNews.com, Washington, September 18, 2009 (ANI): US researchers may have moved a step further towards gaining a deeper understanding of the role of stem cells in liver cancer.

A team of experts from Penn State College of Medicine and the University of Southern California used a unique approach that involves study of individual cells, and became the first ever researchers to show a population of cancer stem cells in the liver prior to tumor formation.

Writing about their work in the journal Stem Cells, the researchers say that their findings suggest a potential link between liver stem cells and liver cancer.

Lead researcher C. Bart Rountree and colleagues have revealed that they used a liver-specific PTEN (phosphatase and tensin homolog deleted on chromosome 10) mouse model to study the microenvironment of the liver.

“The PTEN knock-out mouse is one model of chronic liver injury that ultimately leads to liver cancer. During chronic injury, liver stem cells proliferate, and at times of healthy liver, the liver stem cells are very rare. We were initially looking for what is driving liver stem cell proliferation during chronic liver injury,” Rountree said.

“We started investigating liver stem cells in many different liver injury models with the idea we may be able to help people with liver disease, but we discovered that some cells we isolated were malignant. It was quite a surprise for us because there were not any tumors in the mice when we isolated the cells,” Rountree said.

The liver is the only organ in the body that is able to fully regenerate itself. Its cells, including hepatocytes and cholangiocytes, can divide and repopulate themselves.

In cases of chronic liver injury, including by a virus or alcoholism, the hepatocytes lose the ability to make more of themselves. In such settings, liver stem cells proliferate and can make either of the cell types.

However, patients with chronic injury also develop liver cancer, opening the possibility that the stem cells are involved in tumor formation.

“There’s been a groundswell of interest in understanding the role of specific stem cells in the development of liver cancer. There is a cancer stem cell lurking out there that may be very bad. It has stem cell properties and is malignant, resistant to chemotherapy. These properties make it harder to treat these cancers,” Rountree said.

“What we ended up doing was shifting our understanding of liver stem cells and their role in malignancy. All work previously done was looking at patients, animal models or cell lines after the tumor already developed. What we did was identify malignant stem cells before there is evidence of the primary tumor. This gave us a new perspective on not only what the potential of stem cells for therapy is, but also in terms of what’s driving cancer formation. Imagine treating a cancer before a primary malignancy forms,” Rountree added.

For their study, the researchers created ten cell lines to study using a single-cell isolation technique. They separated cells that make a unique surface protein called CD133 by placing them in a liquid medium, and running through a flow cytometer.

Once identified, a robot took a single CD133-positive cell and placed it in a single drop into one well of a culture dish. Doing that several hundred times, the cell lines were established.

The researchers said that, when expanded up, the single cells were found to have stem cell characteristics, having markers of both hepatocytes and cholangiocytes.

When the researchers injected the lines into a mouse with a deficient immune system, the ttumorsthen formed.

According to Rountree, there is interest in targeting these stem cells with malignant potential.

“Can we target these cells in patients with hepatitis B or C, either before or after their cancer forms? The broader implication is very powerful. If you look at a patient with chronic injury and find a way to specifically target cells with malignant potential, you may be able to prevent liver cancer in the first place,” Rountree said. (ANI)

NewScientist.com,  —  Don’t try this at home. Several times a day, for several days, you induce pain in someone. You control the pain with morphine until the final day of the experiment, when you replace the morphine with saline solution. Guess what? The saline takes the pain away.

This is the placebo effect: somehow, sometimes, a whole lot of nothing can be very powerful. Except it’s not quite nothing. When Fabrizio Benedetti of the University of Turin in Italy carried out the above experiment, he added a final twist by adding naloxone, a drug that blocks the effects of morphine, to the saline. The shocking result? The pain-relieving power of saline solution disappeared.

So what is going on? Doctors have known about the placebo effect for decades, and the naloxone result seems to show that the placebo effect is somehow biochemical. But apart from that, we simply don’t know.

Benedetti has since shown that a saline placebo can also reduce tremors and muscle stiffness in people with Parkinson’s disease. He and his team measured the activity of neurons in the patients’ brains as they administered the saline. They found that individual neurons in the subthalamic nucleus (a common target for surgical attempts to relieve Parkinson’s symptoms) began to fire less often when the saline was given, and with fewer “bursts” of firing – another feature associated with Parkinson’s. The neuron activity decreased at the same time as the symptoms improved: the saline was definitely doing something.

We have a lot to learn about what is happening here, Benedetti says, but one thing is clear: the mind can affect the body’s biochemistry. “The relationship between expectation and therapeutic outcome is a wonderful model to understand mind-body interaction,” he says. Researchers now need to identify when and where placebo works. There may be diseases in which it has no effect. There may be a common mechanism in different illnesses. As yet, we just don’t know.  Read more at:

http://www.newscientist.com/article/mg18524911.600-13-things-that-do-not-make-sense.html?page=1

NewScientist.com  —  Madeleine Ennis, a pharmacologist at Queen’s University, Belfast, was the scourge of homeopathy. She railed against its claims that a chemical remedy could be diluted to the point where a sample was unlikely to contain a single molecule of anything but water, and yet still have a healing effect. Until, that is, she set out to prove once and for all that homeopathy was bunkum.

In her most recent paper, Ennis describes how her team looked at the effects of ultra-dilute solutions of histamine on human white blood cells involved in inflammation. These “basophils” release histamine when the cells are under attack. Once released, the histamine stops them releasing any more. The study, replicated in four different labs, found that homeopathic solutions – so dilute that they probably didn’t contain a single histamine molecule – worked just like histamine. Ennis might not be happy with the homeopaths’ claims, but she admits that an effect cannot be ruled out.

So how could it happen? Homeopaths prepare their remedies by dissolving things like charcoal, deadly nightshade or spider venom in ethanol, and then diluting this “mother tincture” in water again and again. No matter what the level of dilution, homeopaths claim, the original remedy leaves some kind of imprint on the water molecules. Thus, however dilute the solution becomes, it is still imbued with the properties of the remedy.

You can understand why Ennis remains skeptical. And it remains true that no homeopathic remedy has ever been shown to work in a large randomized placebo-controlled clinical trial. But the Belfast study (Inflammation Research, vol 53, p 181) suggests that something is going on. “We are,” Ennis says in her paper, “unable to explain our findings and are reporting them to encourage others to investigate this phenomenon.” If the results turn out to be real, she says, the implications are profound: we may have to rewrite physics and chemistry.  Read more at:

http://www.newscientist.com/article/mg18524911.600-13-things-that-do-not-make-sense.html?page=2

The gonad is an amazingly labile organ where male and female signals vie for dominance in the developing embryo


Editor’s Note: The gender of South African runner Caster Semenya is a major current topic of speculation.   While gender appears to be a cut and dried issue, in fact gonad development – the essential step in becoming female or male – is an extraordinary and flexible process.

In the article below, leading researcher Blanche Capel discusses the antagonistic molecular and cellular interactions in early embryonic development.  Her work paints a picture of complexity and antagonism as male- and female-directing signals vie for supremacy.  In some instances, neither program completely overwhelms the other.

This article is being posted ahead of publication in the October print issue of The Scientist magazine.

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The-Scientist.com, October 2009, by Blanche Capel PhD  —  The recent controversy over the South African runner Caster Semenya’s gender illustrates the complexity of how sex is assigned in humans. Experts must decide whether DNA, genitalia, or hormones should serve as the determining characteristic. Although there are cases of genetically XX females with male genitalia and vice versa, the three sex identifiers are aligned in most people. This is because, in humans and most mammals, genetic sex (i.e., whether you are XX or XY) controls development of a testis or ovary during fetal life, and all secondary sex characteristics (genitalia, musculature, sex ducts) are controlled by hormones and other secretions from the testis or ovary.1

In many animals, sexual characteristics are quite plastic-even in adult life. In some species of fish, all it takes is a glance, or lack thereof, to cause an adult female to change her sex and become male.  When the dominant male goes out of sight from the school, one of the females will undergo a sex change, taking on the coloration and behavior of the alpha male, and transition from making eggs to making sperm instead. A more subtle example is a species of mole that maintains “ovotestes” in adult life, changing from female to male characteristics and back again, depending on the season and whether it’s more advantageous to be submissive or to produce high levels of testosterone and exhibit aggressive behavior.2 

In some species of fish, all it takes is a glance, or lack thereof, to cause an adult female to change her sex and become male.

What accounts for the remarkable sexual plasticity seen in many animals? Perhaps it is the inherent plasticity of the gonad. For most developmental processes, there is only one possible outcome. For example, a kidney primordium can only make a kidney, and a lung primordium can only make a lung. In contrast, the gonad can develop into either a testis or an ovary.  This choice, “sex determination,” occurs during fetal life and is stable thereafter, but in other animals like some fish, this choice may be reconsidered later.

Another striking difference between sex determination and other developmental processes is that the genes that control most developmental mechanisms are tightly conserved across the animal kingdom. However, the mechanisms controlling sex determination seem to vary wildly across the animal kingdom. In some animals, the sex of offspring depends on population density, whereas in others, it depends on temperature. Humans develop inside the uterus, where they are (for the most part) protected from the vagaries of the environment. They use a genetic mechanism to determine sex based on their X and Y chromosomes. No unifying mechanism has been found that controls sex determination in all vertebrates, yet it seems impossible that such an essential process isn’t tightly conserved at some level.

When I began research in my own lab, it seemed to me that insight into this problem might come from a better understanding of how sex determination occurs at the level of the cell biology of organ development. How do the cells of the gonad decide to form a testis or ovary, and how do the different mechanisms of sex determination seen across the animal kingdom regulate this process?  Recent work from my lab and many others suggests that there may be a common underlying mechanism after all.

For me, the story began in 1991, with the discovery of the gene that governs sex determination in mammals. I remember it as an eventful week in Robin Lovell-Badge’s lab at the National Institute for Medical Research in London, where I was a postdoc.  We had journalists and photographers putting us in “busy scientist” poses and film crews grilling us about the details of our work. We had taken our candidate gene, the mouse Sry gene on the Y chromosome, and inserted it into the genome of an XX (female) mouse embryo, turning it into a male. In a play on that experiment, one newspaper sported a cartoon of a sex-reversing Minnie Mouse. 

In the reciprocal experiment, we showed that removal of the Sry gene from the Y chromosome of male embryos caused genetically XY male animals to develop as females.3 In collaboration with the Peter Goodfellow lab at the Imperial Cancer Research Fund (ICRF) in London (which worked on the human SRY gene), we paid a visit to the London Zoo to collect DNA samples from male and female horses, chimps, rabbits, pigs, cattle, and tigers. We found that all these animals carried the SRY gene on their Y chromosome, reflecting the wide conservation of this mechanism of sex determination in mammals.4

It was an eventful week in Robin Lovell-Badge’s lab, where I was a postdoc.  We had journalists and photographers putting us in “busy scientist” poses and film crews grilling us about the details of our work.

With the Sry work behind me, I started my own lab at Duke University in 1993. While other groups coming out of the Lovell-Badge and Goodfellow labs continued to characterize the Sry gene and other genes immediately downstream, I wanted to study the earliest cellular mechanisms that trigger the decision to develop a testis or an ovary, at the point when the SRY transcription factor is expressed in the gonad.

The first challenge was to set up a system where I could study the gonads as they developed in a controlled environment. It was no small task to figure out the right conditions to keep embryonic mouse gonads viable in a dish for several days while they made their fate decision.

Robin Lovell-Badge and a former post-doc of his, Katarina Nordqvist, came to visit my new lab in 1995.  The three of us were very interested in testing an old idea that a population of cells from the mesonephros-a nearby tissue that is closely associated with the gonad at this stage-migrates into the gonad. We made a recombinant organ by combining a mesonephros carrying a beta-galactosidasegene that makes all cells blue, with a “white” unlabeled gonad, and cultured the two pieces together for several days. To our excitement, blue cells from the mesonephros migrated into the unlabeled gonads-but only into male XY gonads, never into XX female gonads.  Once in the male gonad, the mesonephric cells surrounded the Sry-expressing Sertoli cells and formed testicular cords, the first morphological change that signals a commitment to testis development.5

We could see that cells had migrated, but it wasn’t clear whether that really mattered. One of my students, Christopher Tilmann, devised an experiment to test the importance of cell migration. He placed a membrane barrier between the cultured mesonephros and gonad, demonstrating that blocking the mesonephric cells from migrating prevented the early steps of testis development. We wondered what would happen if we induced migration into an XX gonad-could we make it develop more like a testis than an ovary?

After many failed efforts to test this idea, it finally dawned on me that we could make a “sandwich” organ culture. We would place a developing XX female gonad in between an XY male gonad on one side and a blue mesonephros on the other. We were excited to see that cells from the mesonephros crossed over the XX female gonad on their way to the XY male gonad. Along the way, these traveling cells induced the developing female gonad to activate some genes associated with male development and to form male-like structures resembling testis cords-all in the absence of the master Sry gene.6

These experiments and others in the lab were gradually changing the way we viewed the problem of sex determination. Although SRY lies at the top of the sex determination cascade in mammals, it was becoming clear that the pathways downstream of SRY are critical in controlling testis morphogenesis, and without a testis, the embryo develops all female secondary sex characteristics.

By the late 90s we had identified several developmental processes essential for gonad development, but still lacked a clear picture of the genes that controlled it. Luck took a hand when David Ornitz at Washington University Medical School called to tell me about a mutant mouse. A post-doc in his lab, Jenny Colvin, had generated mice incapable of producing fibroblast growth factor 9 (FGF9). Mice lacking Fgf9 died at birth because their lungs could not form properly. However, Jenny noticed that all of the embryos developed as females. This was a very exciting finding because it suggested that Fgf9 was one of the genes that control developmental processes important for testis development. While SRY-a transcription factor-can only act on the cell that expresses the protein, FGF9 is a secreted protein and acts as a signaling molecule to nearby cells. It sounded like it might be just the sort of signal that controls proliferation or attracts the migration of cells from the mesonephros. 

Further work in my lab showed that during the bipotential stage of gonad development-before the critical fate decision-Fgf9 is expressed in both XX and XY gonads.  But after Sry is expressed, Fgf9 is strongly up-regulated in XY male gonads, and down-regulated in XX female gonads.  In XY male gonads that lacked Fgf9, testis development was completely blocked and some aspects of ovary development could be detected.

Since FGF9 is a secreted factor, we wondered what would happen if we added it to the culture medium for female gonads. To our delight, soluble FGF9 induced mesonephric cells to migrate into the XX female gonads, pushing their development toward the testis pathway.7,8

All indicators were pointing to the idea that Fgf9 played an important role in testis development. But what controlled female development? To the great irritation of many female investigators in the field, female development had classically been referred to as the “default pathway”-suggesting a passive process. To most of us, this was not an attractive idea.

The first evidence for an active female pathway came in 1999, when Andy McMahon’s group at Harvard generated a mouse incapable of producing WNT4. Like FGF9, WNT4 is a secreted signaling molecule that can affect cells at a distance. In mice lacking the Wnt4 gene, even those that were genetically XX female, gonads developed with some characteristics of testes. For example, XX gonads from these mutants showed patterns of cell migration similar to XY gonads and, later in development, produced testosterone.9,10 This was particularly interesting because it was consistent with reported cases of genetically XX female humans who develop a testis in the complete absence of SRY.  One explanation suggested for these patients was that something had gone wrong with their active ovary-determining pathway-a pathway necessary to block testis development.

We found that, like Fgf9, Wnt4 is expressed in both sexes while the gonad is still bipotential, but it is up-regulated in XX gonads and down-regulated in XY gonads precisely at the time when the gonadal fate decision occurs-the opposite of Fgf9 expression.

About this time, we remembered a piece of evidence from organ-culture experiments done earlier in my lab suggesting that FGF9 could block expression of Wnt4. Could these two signaling pathways be acting antagonistically, staging the battle of the sexes in the gonad? Yuna Kim, another graduate student in my lab, planned a set of experiments to test this idea.

Other researchers had shown that the primary role of SRY is to up-regulate a closely related transcription factor, Sox9.  Various experiments showed that SOX9 is capable of substituting for SRY in activating testis development. The question was how WNT4 and FGF9 fit into the story. Yuna found that FGF9 and SOX9 reinforce each other’s signaling to establish the testis pathway in XY gonads. She showed that when Fgf9 is eliminated, XY male gonads switch sex and activate ovarian genes.  But our most exciting finding was when she discovered that SOX9 and FGF9 are both up-regulated in an XX female gonad when Wnt4 is absent. This clearly showed how the male pathway could be activated in an XX genetic female, in the complete absence of the Sry gene-just as those human XX male patients had predicted.11

Could these two signaling pathways be acting antagonistically, staging the battle of the sexes in the gonad?

Based on these experiments, we proposed a new model for mammalian sex determination. In both XX and XY primordial gonads, Fgf9, Sox9, and Wnt4 are all expressed simultaneously early in development, when the fate of the gonad is still undetermined. In an XX gonad, WNT4 dominates and turns off the testis pathway.  However, in an XY gonad, SOX9 and FGF9 get an extra boost from SRY, which allows them to dominate and repress WNT4.

The animal kingdom has many means of determining sex, from population density and behavioral cues in fish, to temperature in turtles, alligators and other reptiles, and hormonal influences in many egg-laying species.  Yet, surely a process as important as sex determination must be conserved at some level.

I and others have begun to suspect that although the primary gene controlling sex determination varies among species, perhaps what is conserved is an underlying pattern of antagonistic signals-such as the ones we’ve seen in mice with FGF9 and WNT4. This fundamental sex-determining mechanism could easily operate in response to a genetic switch (such as Sry in mammals) or to an environmental cue (such as temperature in turtles), as long as the initial decision is amplified and reinforced by downstream pathways that recruit all the cells of the gonad to one game plan.12

In an effort to learn from another species, we began to work with red-eared slider turtles, which determine sex via temperature. When their eggs are incubated at 26 degrees Celsius, 100% become male but when incubated at 31 degrees, 100% become female. (At temperatures in between, mixed sex ratios occur.) We have begun to explore the cellular basis for the development of the testis and ovary in the turtle, and to search for similar control signals by returning to our organ-culture methods.

This work has led us to suspect that the antagonistic signaling system that we uncovered is just the tip of the iceberg-that we should be looking at the workings of the entire complex system of signals that underlie sex determination and gonad development rather than at single genes. We are very excited about a new project to do just that, employing many of the new techniques and computational skills of systems biology.

Our understanding of sexual development is evolving along with our ability to test and measure the process. We have only begun to clarify the early genetic and cellular processes that influence the initial stages of gonad differentiation. The subsequent effects of hormones, environment, and neurological wiring all have critical roles in the eventual identification of an individual as “male” or “female.”

In the face of this complexity, tests used by many athletic organizations for the presence of SRY as the sole means of classifying contestants as male or female seem very simplistic. Among other things, this assessment does not provide a category for qualified individuals who possess some combination of male and female characteristics. Yet these individuals also represent the spectrum of human abilities. In the case of Caster Semenya, it is a pity that her impressive achievements might be overshadowed by accusations that may simply stem from her misalignment with Western standards of beauty rather than from purposeful deception with respect to her sex.

Blanche Capel is a Professor in the Department of Cell Biology at Duke University Medical Center. She thanks the many former and current members of her lab for their wonderful work, especially Lindsey Barske and Jonah Cool, who have helped edit this article.

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Sunset Over Piney Point, New York  (this past weekend)