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Thursday, May 28, 2009

Wernher's Dreams & Milestones in Space

Today, we commemorate the 50th anniversary of the first humanoid excursion into space, ending with a happy splash in the Caribbean of the coast of the United States. National Public Radio's Morning Edition, broadcast a segment on the event this morning.

On this notable day in 1959, the squirrel monkey Baker and the rhesus monkey Able, both female, were hurled into space on top of a Jupiter rocket from Cape Canaveral, Florida, to return safely 15 minutes later. Able died a few days after the flight during a surgical procedure. Baker lived for another 25 years at the U.S. Space and Rocket Center in Huntsville, Alabama, and is buried there.  A stone in her memory is placed in front of the museum's old entrance on the right.


The memorable flight constituted the beginning of U.S. manned space exploration. At the time, the U.S. felt they were losing the space race to the Soviet Union, because the Soviets had successfully launched the first satellite named Sputnik 1 in 1957 and had sent the dog Laika into orbit on board Sputnik 2 in the same year. Laika perished during on reentry. The first human to reach outer space, orbit the earth, and return safely was going to be the Russian Yuri Gagarin on Apr. 12, 1961.

The U.S. space effort was led by Wernher von Braun. After the collapse of Nazi Germany, the legendary rocket engineer of V2 notoriety and about 100 colleagues managed to surrender to American forces and were whisked to the United States, along with hundreds of rocket components. Von Braun would become the United States' lead expert in rocket design and space exploration. I remember him talking down to me from the TV set, when I was a science fiction-loving youngster, gawking open-mouthed at the great man presenting animations of incredulous space adventures.

Wernher von Braun epitomized the serious, well-tanned, impeccably dressed icon of German engineering ingenuity who was about to help Americans accomplish unprecedented feats. He made Germans feel good about themselves. As German romanticism expounded: “Am deutschen Wesen soll die Welt genesen!”1 This was the theme Germans wanted Wernher von Braun and Germany remembered for, never mind that he had served as officer in the Waffen-SS and that his V1 and V2 rockets, built with slave labor, had laid waste to much of London. In his defense, it should be noted that he publicly deplored the abuse of the workers and almost fell victim to intrigue within the SS because of his attitude. Nobody liked to talk about these dark parts of German history when I grew up. Wernher von Braun was a German/American hero.

Of course, from the German side of the Atlantic we pictured the great explorer of space in Florida surrounded by palm trees or at the Control Center in Houston next to a lanky, jovial Texan U.S. President in front of banks of TV monitors. Little did we know! Many years later, my family and I stopped by the Huntsville U.S. Space & Rocket Center on a trip down Interstate 65, the home and resting place of Baker, the squirrel monkey. The shortened dummy of a Saturn V advertises the museum at a rest area nearby.

The museum is a truly interesting site to visit. In a comprehensive outdoor exhibit, the visitors can study generations of American rockets from the beginnings (Redstone) to the Apollo program (Saturn V), culminating in the landing on the moon. The rockets are life-size dummies built from left-over parts. I had never seen a more complete collection.

A whole Saturn V rocket is on display with capsule mounted on top. It is so colossal that it takes a minute to walk its full length. A Space Shuttle, much bigger than I imagined, has been added more recently to represent the latest epoch of manned American space flight.


The Marshall Space & Rocket Center at Huntsville used to be home of the Apollo program and builds parts for the  International Space Station, today. Compared with the Saturn V and the shuttle, the early models were tiny. The monkeys were essentially squeezed in the nose cone of a ballistic intercontinental missile. Two years later, and about a month after Gagarin's successful flight, Alan Shepard Jr. became the first American in orbit. He did not have much more room to move in his capsule either. The rocket was the size of small factory stack. The beginnings seem rough and simple in retrospect.


The first rocket on the left is a Jupiter missile. This type hurled Baker and Able into space. The example's payload is a satellite. The thin cylinder on top of the nose cone is a rotation device to stabilize the satellite. The monkey's capsule did not need it.  The second rocket from left is a Redstone equipped with a Mercury capsule; the same combination with which Alan Shepard blasted into space. The Redstone appears shorter than the Jupiter because it stands further back. In actuality, the height of both rockets is about equal. Realizing how tiny the capsules were, we quickly appreciate the brevity of the first traveler's voyage.

My greatest surprise, however, came when we entered the indoor museum. We stepped around a corner and found ourselves in front of a glass-walled office. On the desk was a sign that read "Wernher von Braun". The diorama was a replica of his office in Huntsville, where he spent perhaps the most consequential years of his career, as I was going to find out. Nobody told us about this in Germany. I doubt that many Germans would have been able to point out Alabama on the globe, before Mercedes Benz set up shop in Tuscaloosa. I am certain that Huntsville was never mentioned on German TV in the 1960s.

But, voilá, here was Wernher von Braun's legacy. They show you photographs of the Engineer in Chief and his whole original crew, wearing trench coats and broad-rimmed hats, upon arrival fresh out of Germany. On a bus tour through the Space Center we were shown the original test launch pad. Von Braun and his colleagues watched the launches through periscopes from a steel oil tank buried in the dirt fifty yards away. I could vividly imagine his voice ringing out hollow from the tank after yet one more failure, “Siegfried, Du Idiot hast das Zündkabel wieder falsch 'rum angeschlossen!”2 I cannot say for sure whether it happened exactly this way. But, there is no doubt in my mind that the teutonic presence left indelible marks on this part of the South.

Wernher von Braun adopted U.S. citizenship in 1955. As the architect of the Apollo program, he wrote to then Vice-President Johnson in a letter dated Apr. 29, 1961, “...we have an excellent chance of beating the Soviets to the first landing of a crew on the moon....I think we could accomplish this objective in 1967/68.” He fulfilled this promise only with one year delay. On July 20, 1969,  ten years after Baker and Able's first travel in space,  Neil Armstrong and Buzz Aldrin became the first humans to step on the moon.

Much has been achieved in human space exploration since then. Wernher von Braun's vision of a space station has become a reality. Only he had dreamed of a wheel design with hub and spokes. Stanley Kubrick used von Braun's vision in his epic movie "2001 - A Space Odyssey". However, von Braun could not have imagined that the present International Space Station would be the result of the joined effort of many nations, among them the greatest rivals of his time. Today, Russians help make the project work in instrumental ways. Moreover, just the other day astronauts spent long hours in space, repairing the Hubble Space Telescope. This telescope is one of the most influential instruments of our time. The clarity of its pictures of distant galaxies and nebulae have altered our views of the universe and our understanding of its origin in fundamental ways. Each picture contains myriad questions and may deliver as many answers. See for yourself here or watch the movie:
Despite the tremendous accomplishments, Wernher von Braun's dream of a visit to Mars still remains for us just that: a dream. In spite of the contributions of Baker, Able and their countless comrades as well as the experience gathered from people spending many months in microgravity, we still do not know how well we shall fare out there in the long run. I have written more about this in my post dated May 15, 2008.



Footnotes
  1. It is often extremely hard to translate a saying well. The rhyme means roughly translated: “From German groove, the world shall improve!” It reflects a popular German point of view at the beginning of the last century and has lost quite a bit of its luster.
  2. This would translate as: “Siegfried, you idiot reversed the ignition cable again!”

Addenda
  • Wernher von Braun's dreams are still alive and well as Kenneth Chang reports on a new generation of rockets for manned space missions in his post for The New York Times two days ago (06/19/09).
  • Buzz Aldrin just published a new book on his life experience entitled "Magnificent Desolation: The Long Journey Home from the Moon" and put forward a passionate plea supporting human Mars exploration in his commentary on CNN today (06/23/09).
  • Two days ago, we had the opportunity to visit the museum again. It has changed considerably since our first visit. A new exhibition hall has been added, housing the Saturn V lying on the ground. This time, it took me 2 min 15 secs to walk its length. An abbreviated history of rocketry is told in a wing of the new building. A second full-length version of the rocket is displayed upright out front.

    It takes a lot of fuel to get away from our planet! The old museum continues to tell Wernher von Brown's story in detail. His office is still on display. A large LCD display shows a documentary of the time in Germany. On some footage Himmler's chilling face is lurking in the crowd of visiting luminaries. I am grateful we never met. In a corner opposite von Braun's office is a display dedicated to Baker and Able. The visitor can see the contraptions they were sitting in and inspect the nose cone they were traveling in. All pictures in this post were taken on our second visit (06/27/09).
  • This Thursday forty years ago, the journey began that would make Neil Armstrong the first person to step on the moon. You may enjoy a captivating real-time replay of the event at http://wechoosethemoon.org/ (07/13/09).

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Sunday, May 17, 2009

Amyotrophic Lateral Sclerosis & Iplex

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease in the U.S., is a devastating degenerative disease of the central nervous system, in which motor neurons die. Motor neurons are the nerve cells that innervate peripheral muscles and control our movements. Like most other nerve cells, motor neurons are not known to retain the potential to divide and replenish in the mature brain. They may die because of high oxidative stress and programmed cell death known as apoptosis. High oxidative stress results from an increase in free radicals. Free radicals are highly-reactive oxidative chemicals that can fatally damage the cell. On the other hand, apoptosis is a self-destruction mechanism of the cell that is triggered when the concentration of the excitatory neurotransmitter glutamate reaches abnormally high levels in the extracellular space. Therefore, therapies that lower free radicals and block the action of glutamate may offer benefits in the treatment of ALS.

Still we do not understand why the oxidative stress increases for motor neurons in ALS and why the extracellular glutamate reaches apoptotic levels. The motor neurons constitute the only nerve cells that reside inside the central nervous system, but make direct contact with cells outside. Perhaps, their endings pick up extrinsic molecules that increase their vulnerability in conjunction with a genetic predisposition.

Patient advocacy groups have recently petitioned the U.S. Food and Drug Agency to allow the compassionate use of Iplex developed by INSMED Inc. in terminally ill ALS patients. Amy Harmon reports the story of one family involved in her post for The New York Times published May 16, 2009. Iplex (mecasermin rinfabate) is a product of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) and has been used in th past to stimulate disrupted body growth in children. IGF-1 is known to promote proliferation and stifle apoptosis in cancer cells (Yu and Rohan, 2000). IGFBP-3 regulates IGF-1 action. Notably, it counteracts the growth factor's suppression of apoptosis. The protein may also inhibit tumor growth and stimulate apoptosis independent from IGF-1. Recent experience in Italy suggests that Iplex improves the condition of patients with ALS. How the drug interacts with motor neuron cell death is unclear at this point. Perhaps, the sum of its opposing effects slows the death of motor neurons. A lot more research needs to be done.

It is difficult to judge the wisdom of opting for such treatment, when the cause of the disease is entirely unknown. Faced with profound uncertainty, we are only left with hope.

Addenda

  • According to Esha Dey's post on Reuters dated Jun. 25, 2009, phase II clinical trials showed that Iplex failed to significantly improve the condition of patients with myotonic muscular dystrophy (MMD). An Insmed press release specifies that 69 patients were treated over 6 months in a randomized, double-blind, placebo-controlled study. MMD is recognized as a genetic disorder. In contrast to ALS, the modified genes affect muscle cell function (07/24/09).
  • Learn about ALS from people who live with it. The acounts were recorded for The New York Times series "Patient Voices: A.L.S.", produced by Karen Barrow and published Oct. 19 (10/10/23).
  • A recent study of Kaspar and others (2005) supports the contention above that IGF-1 may facilitate nerve cell survival in ALS. The researchers showed in a transgenic mouse model for ALS that physical exercise or delivery to the central nervous system of the gene for IGF-1 slowed the progression of the disease. Both treatments combined had a synergistic effect on function and survival (10/25/09).
  • As of Jul. 29, 2009, Insmed has put clinical trials with Iplex on hold. The drug has been unavailable to new patients since then. The company ascertains that current supplies will suffice to maintain the treatment of patients who were already enrolled in ongoing trials for another two years. No new decisions have been announced to date (12/22/09).
  • The route of administration may be crucial to the effectiveness of Iplex in the treatment of ALS. A recent study with 330 ALS patients showed that subcutaneous injection of IGF-1, the main component of Iplex, did not statistically significantly improve the condition of the participants (Sorensen and others, 2008) compared with participants administered a placebo. A compound must cross the blood-brain barrier to affect motor nerve cells. Perhaps, too little IGF-1 reached the motor nerve cells to initiate a detectable effect. However, other routes of drug delivery may be more efficacious than subcutaneous injections. For example, rabies viruses are neurotropic. That is, the virus is taken up by the endings of motor nerve cells, transported into their cell bodies and further retrogradely into the nerve cells innervating the motor nerve cells. In the process of the disease, the virus multiplies in the nerve cell bodies, causing severe encephalitis and, ultimately, death. Because of its retrograde transport, rabies virus is used in animals to examine nerve cell circuitry (Taber and others, 2005). It is conceivable that deactivated forms of the virus can be used as vehicle to shuttle drugs like Iplex into the central nervous system. Herpes simplex viruses possess similar neurotropic properties and may constitute another option (03/19/10).
  • Yesterday, NPR's Talk of the Nation (Science Friday) broadcast a segment on recent advances in stem cell research entitled "Stem Cell Research Update".  New studies are discussed that provide evidence that glia cells derived from human stem cells implanted into rats after spinal cord injury help functional recovery (Sharp and others, 2010). The senior investigator of the study believes that one day in the near future stem cells can be used to replace nerve cells lost in neurodegenerative diseases. The therapy may be promising with diseases in which the causes are well understood. By contrast, the cause for motor neuron cell death in ALS is completely unknown. Hence, replacing them with new ones derived from stem cells may be short-lived (05/22/10).
  • If you are considering stem cell therapy, you may find the information on the International Society for Stem Cell Research site helpful (07/26/10).
References
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Thursday, May 7, 2009

Genes, Brain Plasticity & Memory

The strengthening of connections between nerve cells in the cerebral cortex has been associated with the formation of dendritic spines, that is, small protrusions of the nerve arbors on which mostly excitatory endings of other nerve cells terminate. The endings are called synapses. The excitation is mediated by the neurotransmitter glutamate released at the synapses. The number of spines is dynamic. Spines decrease with prolonged deprivation of sensory input (Valverde, 1967) and increase with prolonged experience-dependent stimulation of sensory input (Knott and others, 2006). With advanced optical imaging methods, Hofer and others (2009) were able to examine the dynamics of dendritic spine changes in the same preparation. They observed that the occlusion of one eye in adult mice resulted in decreases and subsequent profound increases in spine density on apical dendrites of pyramidal cells in visual cortex. The increases were presumably associated with prevailing input from the intact eye. With repeated eye occlusion, the first deprivation led to a two-fold augmentation of the rate of spine development, resulting in a net increase in spine density. The latter remained elevated after binocular vision was restored and did not increase further after the same eye was occluded for a second time. The authors concluded that the persistent spines were pertinent to the experience of the first deprivation, providing perhaps a mechanism for a lasting memory trace.

In this week's issue of the journal Nature, Ji-Song Guan and others at the Picower Institute for Learning and Memory provide evidence that the gene Hdac2 plays a crucial role in spine and synapse formation in as much as in the enhancement of memory. Hdac2 encodes type 2 histone deacetylase. Histones are proteins that are attached to coiled DNA, regulating access to the genetic code. Histone deacetylases are enzymes that remove acetyl groups at the tails of histones. The authors report that overexpression of the gene in mice diminished spine density, decreased the number of synapses, and degraded memory. Inhibition of histone deacetylase 2 augmented synapse number and improved memory. Conversely, lack of Hdac2 enhanced the number of synapses, spine density and memory; treatment with histone deacetylase 2 inhibitors was ineffective. Furthermore, the authors established that other genes known to influence synaptic formation promote the expression of Hdac2. Hence, we have come one step closer to the understanding of the molecular mechanisms that underlie brain plasticity and memory.


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