Skip-a-BeatWords

--Nature of Love--

First the stars in the skies
Fell into our eyes,
and twinkled in wide iris pools.

Then the grass on the ground
Laughed in wind, pulled us down
And we rolled in its fingers like fools.

When the sea’s salt-sweet breeze
Hid and sought near our knees
You took my hand, pulled me to waves.

And as tides rushed o’er us
I fast learned to trust
Night-capped deep that encircled our blaze.

Oh, lightning and flame
Would be dull, would be tame!
Compared to the fire we spark…

When we roll on the floor
In the grass by the shore…
And let skip-a-beats light up the dark.


.MGW.

JAK/STATWords

--Somatic control of germline sexual development is mediated by the JAK/STAT pathway--

One of the world’s most important migrations ends in a place marked by no map: the gonad. This organ makes sperm and eggs, but it cannot perform this task- inherent to the success of sexual reproduction- unless germ cells first migrate to the gonad tissue, to receive the signals that will dictate their destiny as male or female. Despite the gonad’s role in shaping the sexual identity of germ cells, however, little is known about the molecular mechanisms underlaying this process. “For years, there has been this dance between somatic gonad cells and germ cells,” explained Johns Hopkins biology professor Mark Van Doren, “but we haven’t been able to identify the elements involved.”

Last July, however, Nature published a study in whichVan Doren and his colleagues identified one element- a “switch” for sexual identity. They demonstrated that in Drosophila, the JAK/STAT pathway- a cellular signaling route- mediates a critical signal from the male somatic gonad that is required for male germ cell development. In other words, no active JAK/STAT, no potential for a germ cell to become sperm.

Van Doren observed that STAT92E, a protein marker for JAK/STAT activity, was only expressed in male germ cells. This was the first tip that the pathway might play a unique role in male development. To confirm that presence of the STAT protein was due to JAK/STAT activation, however, Van Doren expressed a JAK inhibitor in his Drosophila. As expected, STAT92E expression was lost in the male germ cells. Interestingly, the presence of active JAK enabled germ cells – both male and female - to gain STAT protein expression. Female germ cells would normally not express STAT92E at all, leading Van Doren to his first conclusion:“The JAK/STAT pathway’s activity is necessary and sufficient for expression of STAT92E,” a protein seen in males.

But the JAK/STAT pathway is itself dependent on environmental factors for activation, as Van Doren observed. The pathway only “turned on” in germ cells that had completed their migration to the gonad. And just as contact with the gonad affected germ cell development, Van Doren found that sex of the gonad was influential, too. Normally female (XX) germ cells present in a masculinzed soma expressed the STAT92E protein characteristic of male germline development. Female germ cells also behaved uncharacteristcially in the presence of the JAK/STAT ligand, a binding molecule unique to the pathway. Typically, this molecule is expressed only in male gonads, reflecting that JAK/STAT activity (and all its components) is specific to males. When the ligand was expressed in female tissue, however, the female germ cells produced STAT like males would.

Male germ cell proliferation was also observed to be regulated by JAK/STAT acitivation, via the male gonad. Proliferation is specific to male germ cells during their early growth stages, but it was missing in male germ cells that lacked the somatic gonad. Additionally, female cells in a masculinzed soma proliferated early, as males would. This latter case could be problematic in an organism:“the sex of germ cells and the sex of the soma have to jive in order for sexual development to continue,” Van Doren explained. This understanding may provide rational for studies of drugs to help infertile couples.

Signals from the somatic gonad through JAK/STAT don’t act alone to influence malenss. Autonomous cues, like the male germline marker-1 (mgm-1), also play a part. On the whole, though, Van Doren’s study indicates that male germ cel development is first and foremost dependent upon non-autonomous cues via the JAK/STAT pathway. “But this isn’t the only pathway affecting the sex of germ cells,” Van Doren was careful to explain. And in the future, he hopes to identify additional somatic signals and germ cell autonomous cues that contribute to sexual development of the germline- the only means a species has to pass genetic cargo from one generation, to the next.

.MGW.

SmartWords

Intelligence-enhancing drugs?

In the 1970s, psychologist Corneliu Giurgea stated that "Man is not going to wait passively for millions of years before evolution offers him a better brain."

Michael S. Gazzaniga, director of the Center for Cognitive Neuroscience at Dartmouth College, recently claimed that "if we are smart enough to invent technology that increases brain capacity, we should use that advantage."

Where does such technology stand today?

Geneticists have recently isolated a gene on chromosome 6 that they believe is involved in intelligence... Neuroscientists are gaining clearer understanding of which neurochemicals are involved in learning and memory, important components of cognitive function. And, according to Gazzaniga, many "smart" drugs that improve intelligence, learning, memory, and recall are in clinical trials right now.

To gain a better sense of how intelligence-enhancing drugs work (or don't), and to understand what role they might play in society, I've been talking to a neuroscientist (Dr. Solomon Snyder), a pharmacologist (Dr. Craig Hendrix), and a geneticist (Dr. Georg Ehret) from various institutes at JHU's Med School...

Could we/ should we be smarter on drugs?

Upcoming... upcoming...in the works!


.MGW.

PictureWords

A picture's worth a thousand WORDsss. xoxoxo MGW

MarathonWords

Post-Marathon, I reflect!

[ Baltimore Marathon
Completed 10.15.05
3hrs, 53min, 10sec
115th/886 Females ]


Soon, ohhh soooo soon, I am going to craft a lucious exposé on distance running.

For running is rich.

It is
pain
pride
endorphins
vision
you me
him her
doubt
assurance
courage
summit

fast faster
live longer
love-you-in-the-shower-later

relief challenge
mind body
soul sweat
race pace
hours minutes
wild steady
ancient present
city trail
sun wind
solo team
hills highs
hearts muscles.
Running is beautiful.

My exposé is on its way!
I hope to address running science, too- the science of Kenyans, endoprhins, pacing and pulsing, sweating and salt. The science of winners. The science of drive.

Finished in 3:53! and what a small sliver of time to dedicate to something which has so greatly enriched my life...

If I've run with you before, much love to you. And if I've not, that still-same love, and hopes of striding together soon!


Yes,
In your element,
you can be
as fierce and as fast
as your will can see...


.MGW.

GammaRayBurstWords

Gamma ray bursts don’t loiter, and neither can the people who hunt them. That’s why astronomer Andy Fruchter’s cell phone rings every time one of these cosmic bursts – packed with the energy of a trillion suns – explodes in outer space. Though the origin of gamma ray bursts (GRBs) has eluded understanding since the 1960s, when scientists scanning the sky for elicit nuclear tests first witnessed these powerful explosions and miscontrued them for Russian bombs, Fruchter’s recent attention to cosmic detail has filled in a gap in the GRB mystery: what kinds of galaxies these massive explosions occur in.

Along with other astronomers from the Space Telescope Science Institute in Baltimore, Fruchter collected Hubble Telescope images which prove that long gamma ray bursts only occur in“scruffy environs.” This means there will be no mass exctinction of humans from cosmic GRBs anytime soon; our home galaxy, highly-evolved and metal-rich, is anything but scruffy. More importantly, though, Fruchter’s work co-localizes the occurrence of GRBs with supernovae, a second type of extremely energetic explosion.

Gamma ray bursts and supernovae occur at almost the same moment in time, in a quick and powerful one-two blow. Both result from the collapse of a massive star, with supernovae preceeding GRBs on the celestial timeline. “One would expect the two events to form in similar environments, too” Fruchter explains. But his Hubble images show that they don’t. In fact, the presence of a supernova doesn’t always indicate that a GRB will follow. To understand why the two aren’t always co-localized, Fruchter and his colleagues compared the locations – or, the galaxies- where GRBs and supernovae go off. They found that GRBs require a different set of characteristics from their host galaxies. The two explosions live in every different environments.

Though all GRBs are probably formed in supernovae, not all supernovae produce GRBs. Fruchter observed that if a supernova occurs in a massive galaxy, one which is aged, this supernova will not go on to produce a burst. He attributes this to the high metallicity characteristic of older galaxies, where metal ions have had years to accumulate, and suggests that GRBs can only be produced by supernovae in galaxies with low metal levels. Metallicity inhibits GRBS in two ways. First, metal ions in the atmosphere absorb emissions, or the gas jets constituting a GRB, and this smothers the burst. Second, the magnetic field generated by the metal ions opposes and slows the rapid spin needed to generate a GRB.

“Some supernova would like to produce GRBs,” explained Fruchter, “but they can’t.” These are the supernova seen in massive, metal-rich, evolved galaxies, like ours. Fruchter joked that “one of the conclusions of this study is ‘Relax!’ ” But even though we don’t have to worry about GRBs going off in our galaxy, we can still observe these massive explosions from Earth.

NASA employs a special spacecraft, known as Swift, to capture GRB images. They are difficult to capture, though. GRBs last only a few seconds – minutes at most- and occur randomly from all directions in the sky. To find them, the Swift spacecraft scans the sky. Its telescopes are designed to automatically detect the first flash of an explosion and then target that event as quickly as possible- usually in under a minute. It approximates GRB positions so that other telescopes, like the Hubble, can follow up and obtain pictures of the afterglow. Fruchter emphasized the difficulty of capturing such images. “There are well over 1000 gamma ray bursts known,” he explained, “but only 40 or so for which we have a good image.”

While charting these explosions has been difficult, Fruchter knows how to increase his odds. “My cell phone makes a really obnoxious noise, that I can’t ignore, if a gamma ray burst goes off” he laughed, pulling his phone from his pocket. Fruchter has followed the call of GRBs, elucidating their origins, and now we are all one step closer to understanding they mysteries surrounding these majestic explosions.

.MGW.

EP2Words

Deleting EP2 Could Be Good For You
-Hopkins Study Finds Deleting EP2 Receptor Reduces Symptoms of Alzheimer’s in Mice-

Scientists at Johns Hopkins recently discovered that deleting a single receptor in the brain reduces symptoms in mice with the equivalent of Alzheimer’s disease. The discovery might lead to development of anti-inflammatory therapies safer than those currently used in Alzheimer’s prevention, the researchers say.

Alzheimer’s disease is a gradually worsening condition that impairs older people’s ability to carry out daily tasks, eventually stealing all ability to function. Though scientists associate certain changes in brain tissue with the disease (i.e. plaque build-up and nerve cell inflammation), they still don’t know what causes it, nor is there a cure.

Research suggests that drugs like ibuprofen and naproxen prevent symptoms of Alzheimer's. Unfortunately, chronic use of these drugs, non-steroidal anti-inflammatories known as NSAIDs, can cause side effects like gastric ulcers and intestinal bleeding. Additionally, COX-2 inhibitors, a specific type of NSAID, can cause serious cardiovascular problems. Last December, the U.S. Food and Drug Administration withdrew the COX-2 inhibitor Vioxx from the market and issued a health advisory for those COX-2 inhibitors remaining on shelves.

This new work, however, suggests that Alzheimer’s symptoms could be prevented, without incurring negative side effects of NSAID use, by blocking a prostaglandin receptor known as EP2. The findings are described in a recent issue of the Journal of Neuroscience

“This is just the beginning of a model for treating Alzheimer’s,” emphasized Johns Hopkins neurologist Katrin Andreasson, “but the identification of downstream prostaglandin pathways that function in Alzheimer’s disease should assist in development of anti-inflammatory therapies that are more selective than NSAIDs.”

In general, NSAIDs work by inhibiting the cellular pathway that promotes inflammation, a hallmark of Alzheimer’s disease. “They inhibit the formation of the mother of all prostaglandins, molecules that cause swelling” Andreasson explained, and they do this by first inhibiting activity of the enzymes COX-1 and COX-2.

But because inhibiting COX enzymes has lead to health problems, Andreasson’s group studied downstream components of the COX pathway in their search for treatment. Earlier work in the field suggested an important role for one such component, the prostaglandin PGE2. Levels of this prostaglandin, which has EP2 as its receptor, are elevated in patients with probable Alzheimer’s This observation suggested that PGE2-EP2 signaling may function in Alzheimer’s development, and so the researchers developed a mouse that would be insensitive to PGE2’s effects by EP2, its receptor.

“The EP2 receptor,” explained Andreasson, “provides a novel and selective target for development of therapies in Alzheimer’s. There are no EP2 antagonists available now.”

Dr. Richard Breyer of Vanderbilt University knocked out EP2 in a population of mice. He found that their brains exhibited less inflammation and plaque build-up than did brains of mice with the EP2 gene intact.

Inflammation was measured by observing brain levels of free radicals, harmful oxygen species that disrupt neurons. Free radicals are generated indirectly by EP2; as Andreasson explained, “EP2 activation elicits an innate immune response in supporting cells in the brain,” and part of this immune response is free radical production. The study showed that mice without EP2 had significantly lower levels of free radicals in their brains, correlating to reduced inflammation.

The researchers also assayed plaque deposition, a second hallmark of Alzheimer’s. Since free radicals boost activity of the enzyme that breaks plaque precursor protein into the smaller proteins forming plaques, the presence of free radicals (like those generated in EP2-PGE2 signaling) causes plaque build-up. The study found that deleting EP2 reduced this phenomenon up in mice.

Since EP2 deletion reduced symptoms of Alzheimer’s without interfering with COX activity, blocking it might help prevent Alzheimer's disease, while simultaneously avoiding health risks associated with NSAID use. “This work may be the mechanism by which NSAIDs prevent Alzheimer’s,” said Andreason.

She admits that there’s still more work to do, however. “We are looking at the function of other prostaglandin receptors in the Alzheimer’s mouse model.”

The researchers are also curious about the exact mechanism- direct or indirect- by which EP2 activation leads to plaques. “We are still trying to figure out exactly how the EP2 receptor promotes increased oxidative stress associated with free radicals,” Andreasson said. “We’re trying to figure out whether we can target those pathways therapeutically, too.”

The researchers were funded by the American Federation for Aging Research and the Nancy and Buster Alvord Endowment. Authors on the paper are Andreasson, Xibin Liang, Qian Wang, Tracey Hand and Liejun Wu of Johns Hopkins; Thomas Montine of the University of Washington, Seattle; and Breyer, Vanderbilit University.




.MGW.

SchizophrenicWords: DISC1 Gene

-Transgenic Mice Provide New Insight into Schizophrenia-

Akira Sawa has been messing with mice, and now they’re schizophrenic. Recently, the Johns Hopkins neuroscientist elimated expression of the DISC-1 gene in rodents, and he showed this to delay neuronal development. Sawa’s population of transgenic mice exhibits the same delayed neuronal migration seen in another group: schizophrenic humans.

Sawa hopes to use his transgenic models to better understand development of schizophrenia – a disease with no known cure. “There are no clear cut biological markers for the disease,” he explained, and as such, both environmental and genetic factors have been implicated in causing it.

While some researchers point to the delayed onset of schizophrenia (manifest at ages 15 to 30) as a sign that environmental factors are to blame, Sawa joins those who ascribe a larger role to genetic predisposition. “There are several candidate genes for schizophrenic susceptibility,” he said, and though he acknowledges that environmental factors (psychological stress in childhood, viral infection in the womb) have a role in schizophrenic development, Sawa’s take is that the disorder actually starts before birth, as the brain develops.

To prove this, Sawa sought to link genetics to poor neuronal migration- a hallmark of schizophrenia. In his study, he focused on manipulation of one gene in the candidate list: DISC-1. Why this gene? “There are a lot of false positives in these studies,” Sawa explained, in reference to the list of genes implicated in the disorder, and “90% of these are junk,” he said. However, Sawa selected DISC-1 because, unlike the other candidate genes, it was not a known gene with a known function. Additionally, “only DISC-1 has a clear-disease associated mutation.”

Furthermore, previous studies link a truncated DISC-1 gene to familial history of schizophrenia. In his experiment, Sawa had no power to truncate DISC-1, but he was able to observe what happened when something went wrong with the gene by eliminating its expression all together. To do this, he introduced Ribonucleic Acid Interference (RNAi) into mouse embryos. RNAi targets a specific gene and silences its expression by preventing protein synthesis. Sawa used electric current to open channels and insert the RNAi targetting DISC-1 into the heads of mice developing in the womb. At this stage, neuronal abnormalities could be observed in the mouse brains.

In normal brain development, neurons migrate from inside the chambers of the brain to its outer cortex at a certain rate. This process was significantly delayed in the transgenic mice, however, reflecting poor neuronal migration. This is what Sawa had hoped to see. A biological marker had been established in DISC-1.

Sawa’s mice models provide means for pharamaceutical companies to test new therapies, based on biological markers. Sawa stipulates that this just the beginning of understanding schizophrenia, though; more biomarkers must be found in people before schizophrenia can be cured. Sawa explained that with stem cells harvested from humans, more biomarkers will be able to be pinpointed. It’s good to know that these markers can be tested in the the minds of mice so that someday soon, the minds of men will be less plagued by disease. Sawa’s messing with mice may yet yield a masterpiece in the treatment of schizophrenia.

.MGW.

ScienceOfLoveWords

~On Shores of Amygdala~

Amygdala – a fine hotel
On Dopamine’s high coast.
All guests who come return again,
But pairs return the most.

Receptionist, she greets the guests,
Releasing to each pair
A garden key, a telling hint:
“Blooms oxytocin there.”

Amygdala – a fine hotel,
On shores of highest height.
Below its cliffs the waves do kiss,
And hearts swell, all the night.


.MGW. ;-)

TransplantWords

--One Man, Six Organs: Georgetown Transplant Patient Goes Home--


Greg Marshall is “dying for a sausage.” His digestive organs stopped working 2 years ago, and ever since, the 43 year old New York native has been fed intravenously. But solid foods will soon again be in his diet; on August 25th, Marshall underwent a rare 14-hour transplant surgery at Georgetown University Hospital. Last month, just three weeks after the operation, he walked out with a functional digestive tract. And six new organs.

"It's exceptional that we're able to take six organs and replace them and actually make them work," said Thomas Fishbein, head surgeon for Marshall’s transplant surgery.

Marshall had received a liver, kidney, pancreas, stomach, small bowel, and colon. Only 20 such transplants have been performed in the United States, according to the United Network for Organ Sharing. And not all of these transplants involved six organs. Because the intestine includes the small bowel, the colon, and the stomach, other surgeries categorized as “liver-kidney-pancreas and intestine” transplants may have only involved replacement of 1 or 2 of these three intestinal organs. In Marshall's case, all three were replaced. Doctors also replaced many of his immune cells in an effort to prevent his body from rejecting the transplants.

And today, several weeks later, he’s feeling just fine. “He’s got that twinkle back in his eye,” his wife told reporters. Before the transplant, Marshall had suffered from Gardner Syndrome, a rare immune disorder caused by a defect in the APC (adenomatous polyposis coli) gene. In America, only one person in one million is diagnosed with Gardner Syndrome each year. Characterized by abnormal production of polyps and tumors in the intestine, it ultimately results in organ failure, and makes digestion nearly impossible. Furthermore, it is inherited in an autosomal dominant pattern; if Mom has it, there’s a 50% chance that you will, too. In fact, Marshall’s mother does have the disease, and so does his sister. But neither of them had ever experienced a complete immune shutdown, like Marshall had before the surgery, when he was confined to the couch by his intravenous feeding tube.

In hopes of ending Marshall’s battle, Dr. Fishbein replaced his intestinal organs (stomach, small bowel, colon), and he also replaced his liver, kidney, and pancreas. Marshall needed replacements for these last three organs due to scarring left over from a 1997 operation. That year, his stomach had protruded oddly from his lean frame, and curious doctors located a basketball-sized tumor in his abdomen. Removing it meant that he’d need a bowel transplant, but Marshall’s body rejected the organ, resulting in so much scarring in his digestive system that his other organs began to stop working, too.

After that, Marshall waited several years for a new set of organs. In multiple organ transplants, patients can be given organs from multiple donors, but doctors at Georgetown prefer that all organs come from one donor. “When we get to these sort of numbers more than four... five, six organ transplants in a single setting, it works much better if we are able to have the organs attached to one another," Dr. Fishbein explained. Naturally, the number of available donors is low.

“I didn’t believe it was ever going to happen,” Marshall said. Then, last August, doctors phoned to inform him that a donor with six compatible organs had indeed become available. Marshall would be getting a multiple-organ transplant the following day.

“I was happy for us, but sad for the people who had lost someone,” said Marshall’s 16 year old son, Brandon, referring to the donor’s family. Brandon also acknowledged how lucky his father is; many people “are still waiting for organs.” The telephone call was clearly a relief for the family. For a year, the intravenous line that fed him had limited Marshall’s movements. He’d rarely been able to leave the couch, and he’s never gotten to play with his 18 month old granddaughter. “I’m looking forward to spending time with her,” Marshall says now, after the surgery.

For the time being, he’s staying in a hotel near Georgetown University Hospital so that his progress can be monitored. Because of careful precautions (i.e. organs from just one donor, replacement of immune cells), there is little chance that Marshall’s body will reject the transplanted organs. However, it is always a possibility, and rejection usually occurs within the first three months. According to his family though, Marshall is “in good spirits” and among other things, he looks forward to soon eating his first real meal.

.MGW.