BioScience Biz

Researchers uncover possible link between avian flu and Parkinson's disease

Infection with the avian influenza virus might cause a predisposition to Parkinson's disease, according to research published this week in the Proceedings of the National Academy of Sciences. The following article is adapted from a recent report in The Scientist .

Epidemiological studies done in the 1980s showed that survivors of the 1918 Spanish influenza, a flu pandemic that killed more than 50 million people worldwide, had a greater incidence of Parkinson's disease later in life than the general population. Recent studies have suggested that the currently circulating strain of avian influenza has similar pathology to the 1918 flu. Though the subtypes of the viruses are different (Spanish flu shares the H1N1 subtype with the current H1N1 swine flu, whereas avian influenza has an H5N1 subtype), both viruses appear to enter the central nervous system (CNS) and can cause encephalitis, or inflammation of the brain. The study did not look at the ability of the current H1N1, or swine flu strain, to infect the CNS.

Richard Smeyne at St. Jude's Hospital in Memphis, Tennessee, and colleagues infected mice with avian flu and tracked how the infection progressed to the nervous system. "We thought [the virus] would get in [to the CNS] via the blood stream," through the blood brain barrier, said Smeyne. Instead, the virus entered "in a backdoor way," infecting the axon terminals of peripheral neurons first, specifically those of the gut and lung. The virus then traveled from the axon to the neuron cell body, where the researchers think it may be able to infect other neurons to eventually arrive in the brain.

Strikingly, said Smeyne, "this virus was mimicking the pattern of progression of Parkinson's disease." Some scientists think that Parkinson’s disease starts in peripheral neurons and slowly makes its way into the CNS, much like the progression of the flu infection. "It is interesting to me," said Tansey, that the virus "clearly infects the areas that are the most sensitive to chronic inflammation," such as the midbrain, where much of the neuronal death seen in Parkinson's disease occurs.

Smeyne observed a loss of about 17% of dopamine-producing neurons in the infected mice. Parkinson's patients normally lose between 50-80% of their dopamine-producing neurons, and the loss in Smeyne's mice suggests a predisposition to the disease, he said. Although all traces of the virus were cleared from the brain after about 20 days, and there was no evidence of further neuron loss, the virus appeared to have caused a prolonged activation of microglial cells, the immune cells that mediate inflammation in the brain. That effect -- observed 90 days post-infection -- suggests that these cells had become much more sensitive to subsequent neural insults, said Smeyne.

The biggest risk factor for Parkinson's disease, said Smeyne, is age. "We think what is happening with the influenza is that it's shifting the curve" to speed the onset of the disease. Tansey cautioned, however, that the study doesn't indicate the virus necessarily causes Parkinson's, nor does it suggest that more common strains of influenza may predispose people to the disease. It would be interesting to test whether the flu-infected mice would be more likely to develop full-blown Parkinson's disease if they were allowed to age, she said, and to repeat the study in non-human primates.

STUDY SUGGESTS H1N1 VIRUS MORE DANGEROUS THAN SUSPECTED

MADISON, WI - A new, highly detailed study of the H1N1 flu virus shows that the pathogen is more virulent than previously thought.

Writing in a fast-tracked report published recently (July 13, 2009) in the journal Nature, an international team of researchers led by University of Wisconsin-Madison virologist Yoshihiro Kawaoka provides a detailed portrait of the pandemic virus and its pathogenic qualities.

In contrast with run-of-the-mill seasonal flu viruses, the H1N1virus exhibits an ability to infect cells deep in the lungs, where it can cause pneumonia and, in severe cases, death. Seasonal viruses typically infect only cells in the upper respiratory system.

"There is a misunderstanding about this virus," says Kawaoka, a professor of pathobiological sciences at the UW-Madison School of Veterinary Medicine and a leading authority on influenza. "People think this pathogen may be similar to seasonal influenza. This study shows that is not the case. There is clear evidence the virus is different than seasonal influenza."

The ability to infect the lungs, notes Kawaoka, is a quality frighteningly similar to those of other pandemic viruses, notably the 1918 virus, which killed tens of millions of people at the tail end of World War I. There are likely other similarities to the 1918 virus, says Kawaoka, as the study also showed that people born before 1918 harbor antibodies that protect against the new H1N1 virus.

And it is possible, he adds, that the virus could become even more pathogenic as the current pandemic runs its course and the virus evolves to acquire new features. It is now flu season in the world's southern hemisphere, and the virus is expected to return in force to the northern hemisphere during the fall and winter flu season.

To assess the pathogenic nature of the H1N1 virus, Kawaoka and his colleagues infected different groups of mice, ferrets and non-human primates - all widely accepted models for studies of influenza - with the pandemic virus and a seasonal flu virus. They found that the H1N1 virus replicates much more efficiently in the respiratory system than seasonal flu and causes severe lesions in the lungs similar to those caused by other more virulent types of pandemic flu.

"When we conducted the experiments in ferrets and monkeys, the seasonal virus did not replicate in the lungs," Kawaoka explains. "The H1N1 virus replicates significantly better in the lungs."

The new study was conducted with samples of the virus obtained from patients in California, Wisconsin, the Netherlands and Japan.

The new Nature report also assessed the immune response of different groups to the new virus. The most intriguing finding, according to Kawaoka, is that those people exposed to the 1918 virus, all of whom are now in advanced old age, have antibodies that neutralize the H1N1 virus. "The people who have high antibody titers are the people born before 1918," he notes.

Kawaoka says that while finding the H1N1 virus to be a more serious pathogen than previously reported is worrisome, the new study also indicates that existing and experimental antiviral drugs can form an effective first line of defense against the virus and slow its spread.

There are currently three approved antiviral compounds, according to Kawaoka, whose team tested the efficacy of two of those compounds and the two experimental antiviral drugs in mice. "The existing and experimental drugs work well in animal models, suggesting they will work in humans," Kawaoka says.

Antiviral drugs are viewed as a first line of defense, as the development and production of mass quantities of vaccines take months at best.

In addition to his appointment at UW-Madison, Kawaoka also is a professor at the University of Tokyo. The new study was funded by grants from the U.S. National Institutes of Health, and the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Caption: The pandemic H1N1 flu virus (red) has been shown to be more virulent than scientists previously believed. The filamentous shape of the virus, which in this image have recently budded from infected cells, is also unusual.

© 2009 Steven S. Clark, PhD, some rights reserved.  Articles contained herein, are meant to be distributed freely to interested parties. However, any use, including excerpts from any article, must credit Steven S. Clark and provide a link to the original article published in BioScience Biz.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

What’s new in stem cell research and therapy?

Stem cells are being tested in cardiovascular disease, stroke, diabetes, eye disease, Parkinson’s and to grow cartilage in damaged joints. Stem cells are also being made from blood, attached to sutures and authorities in Hungary crack down on unethical “stem cell tourism”.  Read about these and other recent advances in stem cell science here…

Is Alzheimer's caused by a presynaptic deficit in calcium mobilization?

This is adapted from a post by Jef Akst in The Scientist.

Researchers report a possible step forward in understanding the origins of Alzheimer's disease. Two genes that are commonly mutated in the early-onset form of Alzheimer's may cause the disorder by altering how presynaptic neurons release neurotransmitters, according to a study published this week in Nature.

The mechanism may apply to other neurodegenerative disorders as well, the researchers say.

"This is a new concept that's interesting to know," said molecular neurobiologist Ilya Bezprozvanny of the Southwestern Medical Center at Dallas, who was not involved in the work.

More than 100 different mutations in two genes coding for the proteins, presenilin 1 and 2, are associated with early-onset Alzheimer's disease, but the exact effects of these mutations on neural function is still unclear. "It's the first [study] suggesting that presenilins play a presynaptic role," Bezprozvanny said.

In 2007, molecular geneticist and neuroscientist Jie Shen of Harvard Medical School and her colleagues created knockout mice that lacked both presenilin genes and found memory deficits and neurodegeneration in the brain -- two key features of Alzheimer's disease. In the current study, Shen set out to determine on which side of the synapse presenilins exert their effect by creating two strains of knockouts: one that lacked both presinilin genes only in the presynaptic neurons in the hippocampus -- a brain region that plays an important role in memory -- and another where the genes were knocked out just post-synaptically.

Measuring neural activity in dissected brain sections from the two strains of knockout mice, the researchers were able to compare the effects of presenilins on pre- and post-synaptic activity. In presynaptic presenilin knockout mice, the researchers found drastically reduced long-term potentiation (LTP) -- a physiological measure of memory formation. In postsynaptic presenilin knockouts, however, LTP was normal.

Knocking out presynaptic presenilins also altered other aspects of neuronal function and reduced the probability of neurotransmitter release. "Our earlier work led us to focus on NMDA receptors, which are postsynaptic receptors," Shen said. "This [work] led us to see the importance of the presynaptic function."

Neurotransmitter release depends on increases in calcium levels within the presynaptic neuron. By blocking the release of calcium from the endoplasmic reticulum -- an intracellular source of calcium -- the researchers mimicked the effects of the presynaptic presenilin knockouts in control mice. This result points to intracellular calcium mobilization as a possible mechanism by which presenilins regulate neuronal function.

"The main take home message is there is a difference in the way neurons process calcium levels in absence of presenilins, and that has an effect on synaptic [function]," said Bezprozvanny. However, he cautioned, it's not clear how directly the findings can be applied to Alzheimer's disease. "This is not an Alzheimer's mouse model. This is a presenilin knockout."

Researchers studying neurodegenerative diseases have long debated whether knocking out these genes is a good model for Alzheimer's because the exact role of the many presenilin mutations associated with the disease is unclear. Some argue that these mutations result in a 'loss of function,' in which case a knockout model would appropriately represent the changes that occur in Alzheimer's patients. Others argue that these mutations result in a 'gain of function,' or a change that cannot be replicated by knocking out the genes entirely.

If patients with Alzheimer's disease do indeed have non-functioning presenilin genes, the results of this study may suggest that presynaptic neurotransmitter release is a more general mechanism of neurodegenerative diseases. For example, Shen and her colleagues found a presynaptic effect in a mouse model of Parkinson's disease. These changes "might be a precursor to neurodegeneration," Shen said, and might therefore provide new targets for disease therapies.

Science and ethics in the embryonic stem cell debate

The Medieval philosopher, Boethius, tackled the esoteric question of what is a human and came to the conclusion that “human is born of human”. There is a certain circular, facile truth in this conclusion that reminds one of the modern right-to-life refrain that “life begins at conception”—an argument that seems as unsatisfying as any argument that has been reduced to a cliché. It is repeated so often and so glibly that the basis of the argument goes unexamined and unchallenged. 

This “life begins at conception” reasoning, leads to a casuistic rhetoric where harvesting embryonic stem cells (ESCs) from a five day old human embryo called a blastocyst, for the purpose of treating human ailments, is akin to killing a living adult in order to harvest his organs to transplant into someone else.  But how do we cross the chasm of logic to believe that a blastocyst is the moral equivalent of an adult human?  This is an unexamined and unspoken conclusion that looks very different in the light of modern biology.

Before exploring the premises underlying the right-to-life position let me acknowledge that at this point, some will ask, why revisit this debate?  Haven’t embryonic stem cells been rendered unimportant in the face of the research success of adult stem cells and in view of the fact that we can now reprogram adult cells to become stem-like, thereby avoiding the destruction of embryos to harvest ESCs?

Not so fast.

The fact is that we are rapidly driving, some would say careening, toward the day when ESCs will be used to treat patients. Despite the exciting advances in stem cell alternatives, ESCs still play a role that adult and reprogrammed adult cells cannot supplant—yet.

"...FDA recently approved the first ESC clinical trial..."

The FDA recently approved the first ESC clinical trial to treat patients with spinal cord injuries. The California Institute for Regenerative Medicine that oversees the $3 billion stem cell investment that came out of Proposition 72 in 2004, recently awarded grants specifically for supporting research leading to FDA applications to use ESCs for experimental therapeutics. A medical doctor in India claims to have treated a quadriplegic with human ESCs, with modest results.  Doctors in other countries make similar claims, raising the specter of unregulated “stem cell” tourism and unfettered treatment of patients with insufficiently tested ESC therapies—unregulated clinical trials in reality.

As we rapidly approach the era of stem cell therapy, or regenerative medicine, if in fact we are not already there, the debate over whether this technology represents a “brave new world” or a Faustian bargain will only intensify and I believe it will do so very soon. At the moment, this debate seems to be in a latent period due to the recent discovery that adult cells can be reprogrammed into stem cells. Opponents of ESC research hope that this advance will negate their ethical concerns about destroying human embryos in order to obtain stem cells. After all, if you can pluck a skin cell from someone’s arm, put it in a broth and, presto, pull a stem cell out, why would anyone need or want to do research with stem cells obtained from an embryo? But, the inconvenient truth behind these reprogrammed cells has not been fully explained. The fact is that they, too, have the potential to develop into persons. A scientist at MIT reprogrammed a mature mouse blood cell into a stem cell and used it to derive a whole new mouse. Very recently, two groups in China reported doing the same thing beginning with mouse fibroblasts and ending up with cloned animals. Let us consider how this ability of these so-called induced pluripotent stem cells (iPS) affects the whole stem cell debate.

Unpacking the right-to-life argument

I’ll begin by unpacking the right-to-life argument that “life begins at conception. It is abundantly clear that when a sperm fertilizes an egg cell, a cellular entity is created that can grow into a fully developed person. So, in a sense one can indeed claim that “life” begins at fertilization. But this argument assumes, and leaves unstated, that society is, therefore, obligated to give the same level of respect to a fertilized egg as it gives to an adult human. 

"...when is society obligated to give full respect to human life."

Thus, the underlying ethical argument here really is not about “when life begins” (indeed there is no precise time where this happens—it is a process lasting a couple of days), but about when is society obligated to give full respect to human life. This is the essential ethical issue on which the whole debate should focus. 

Let me illustrate the idea this way: We all agree that a living woman deserves our full moral consideration; society cannot legitimately take her life or deny her other life-related freedoms without good cause, such as committing a crime. On the other hand, neither a live dog nor a clearly dead human elicit the same level of consideration from society. This means that simply being alive, as in the case of the dog, or simply having a human body, as in the case of the corpse, do not provide a sufficient basis for assigning the full moral consideration that we give the woman. It follows that there is something inherent in the adult woman that we all readily recognize, but that we, equally readily, do not see in a live dog or a dead person, which tells us she deserves a greater level of moral respect.  This inherent worth in the woman that we all innately recognize is the crux behind making sense of the embryonic stem cell debate.

Viewed in this way, the question with ESC research becomes this: does a blastocyst that was created by a human (through in vitro fertilization) and that lives in a petri dish and lacks a brain, personal history, personality or any recognizable human trait is the moral equivalent of a living adult human that enjoys all these attributes?  Do we innately recognize something in the blastocyst, like we do in the woman, which compels us to assign full moral recognition to a five-day old sphere of cells that is no larger than a period at the end of a sentence?

At this juncture, some will argue that the fertilized egg possesses a completely novel human genome that denotes a unique genetic human being, and that this makes it deserving of full moral consideration by society. But, this argument has this major problem; certainly, genetic makeup is necessary and sufficient for determining that an embryo is Homo sapien, but genetic makeup, no matter how unique, is not sufficient for determining moral standing. If it was, then skin cells, which have the same genes as the fertilized egg from which they came, should also have equal moral standing with the fertilized egg.  

"...to acknowledge that a fertilized egg has potential to become a person means
that, in fact, it is not a person at that time."

It also could be argued here that an important difference between a fertilized egg and a skin cell is that the former has the "potential" to develop into a mature human person, while the latter does not. But there are problems of both semantics and logic with this contention.  For instance, "potential" describes something that can, but has not yet come into being. In other words, to acknowledge that a fertilized egg has potential to become a person means that, in fact, it is not a person at that time.

Furthermore, it is not logical to assume that “potential” confers any a priori obligation--while I may have the “potential” to become President, that obligates no one to play “Hail to the Chief” when I enter a room. So, based on potential, there is no compelling reason to afford a blastocyst the same obligation we offer the adult woman.

Conditional potential of stem cells

It also is important to understand that a thing’s “potential” can be altered by circumstance. Thomas Aquinas, the great Catholic theologian and philosopher, made this argument about “potential” many years ago. He explained that for potential to be present, a thing must have the capability of realizing that potential. Thus, a piece of paper has the potential to be burned, because it is burnable. Conversely, a bucket of water does not have the potential to be burned because it is not capable of being burned.

Certainly we now know that water can be given the potential to burn, but only under specific electrolytic conditions that separate oxygen and hydrogen from the water molecules. So, the conditional circumstances in which water exists determine its potential to be burned.

In the laboratory, human ESCs are harvested from a blastocyst that has only lived in a tissue culture dish. As long as a blastocyst lives in the petri dish, it has zero potential to become a person. This can only happen if someone intentionally inserts it into the womb of a woman who has been hormonally manipulated to mimic pregnancy. Only after these human efforts, like the human efforts needed to make water burnable, can the tissue culture organism then acquire the potential to become a person. 

From animal cloning, which is now a common practice, we know that under the proper conditions, we can reprogram adult cells back to an embryonic state where they acquire the ability to grow into an embryo and a fully functioning animal. Therefore, modern science tells us that, like a blastocyst that lives in a petri dish, a blood cell that lives in your veins has conditional potential to develop into a person. Since we do not confer any special moral status to a blood cell what then compels us to confer such status to the blastocyst that was created in a laboratory and that lives in a petri dish or frozen in a liquid nitrogen tank? After all, they both have similar conditional potential to become a person.

Thus, like genetics, “potential” is not a sufficient basis to compel us to confer the same moral status to a fertilized egg that we reserve for a living person. 

At what point do we give a developing embryo full moral consideration?

It, admittedly, is very hard, if not impossible, to know when we ought to bestow full moral protection to a developing human embryo. But, I submit that we can know when the embryo does not enjoy the same consideration we give to an adult. To illustrate this point, consider this thought experiment—you walk past a building and see a fire raging inside.  Moreover, you also see a man struggling to get off the floor and escape the conflagration. You see that he is lying next to a tank that you know contains thousands of frozen human embryos.  What would you do if you only had time to make one trip into the burning building? 

"Most of would opt to rescue the man..."

Most of us would opt to rescue the man indicating that we recognize a greater moral responsibility to one anonymous living adult person than we do to a tank full of nascent persons. Indeed, most of us would opt to rescue a dog before the tank of embryos. In other words, we do not innately view thousands of five-day old embryos as moral equivalents to a single fully formed person any more than we view a live dog as the moral equivalent of the woman. To do so, we have to conjure up a special respect for embryos that is based on the imperfect arguments discussed above.

Unfortunately, poor Boethius, a Christian, ran afoul of the Visigoth rulers of Rome and was executed in an especially gruesome way. They wrapped a rope around his head, inserted a stout stick and twisted it until his skull burst. I suspect that when the right-to-life community becomes aware of the ability of reprogrammed adult cells to become people, the debate will flare once again generating Boethian-sized headaches on both sides.

© 2009 Steven S. Clark, PhD, all rights reserved. 

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.                                     

Who's your mama? (by Steven S. Clark)

Remember Jurassic Park—the Steven Spielberg sci fi flick in which a greedy businessman and his mad-scientist minions reached inside prehistoric amber to extract, and ultimately clone, dino DNA that had been sucked up by a sap-trapped bug? Seem far fetched?

Maybe not so much.

An international team of scientists from Germany, the US, Croatia and Finland just reported in the prestigious journal, Cell, that they had cloned and sequenced the Neanderthal mitochondrial genome. The DNA was isolated from a 38 thousand-year old fossilized leg-bone that was found in the Vindija Cave in Croatia in 1980.

Mitochondria are small bacteria-like structures found inside cells where they function as the cell’s powerhouse—they produce chemical energy that the cell uses to drive its biology. The relevant thing here is that mitochondria contain their own small, characteristic genome that is distinct from, and inherited differently than, the much larger genome in the cell nucleus. In your prototypical maternal/paternal genetic inheritance, a sperm fertilizes an egg and the nucleus of each contains one-half of the genome the embryo will need to function. Upon fusion of the two nuclei, the fertilized egg, called a zygote, acquires the full genome that it needs to function and grow.

In contrast to the inheritance of the nuclear genome from both parents, the mitochondrial genome is solely obtained from the mother. When a tiny sperm, that is not much more than a nucleus with a tail, fuses with the much larger egg cell, the subcellular organelles of the egg provide the necessary machinery to allow the zygote to survive, divide and do its thing. Hence, the zygote’s mitochondria are completely inherited from the mother. This means that by tracking lineage relationships through mitochondrial DNA (mtDNA) sequence analysis one is examining matrilineal descent between different biological species, genera and families. It is a lens into our past to Eve—the mother of us all.

This amazing feat of cloning and sequencing prehistoric DNA entailed careful and painstaking sterilization of the specimen and then, in a sterile room, carefully chipping away the mineralized bone’s surface to uncover small amounts of DNA that had been sequestered within the stone bone.

High tech DNA cloning and sequencing methods were used to unravel a DNA sequence that clearly came from mitochondrial DNA, but whose? Since we don’t have Neanderthals walking around today—no, not even the Troglodytes in Congress—how could the investigators be sure that the DNA was in fact from the bone’s original owner and not from say, the saber tooth tiger that gnawed on it eons ago or even from some plant matter that was trapped in the sediment that encased and fossilized the bone?

Fortunately, scientists have an extensive database of mtDNA sequences from extant humans as well as from many old and new world apes and other non-hominid animals for comparison. Comparing the Neanderthal DNA to this database revealed that the mtDNA clearly had a hominid origin, but was not from any known family of primates. This confers a high degree of certainty that the DNA was indeed from the fossil bone—the scientists were peering through a molecular window into the genetic history of a species that first appeared pre-history!

The first Neanderthal fossil was found in the Neander Valley near present-day Düsseldorf, Germany and the fossil record indicates that they are the closest known hominid relative to humans—closer even than chimps. The DNA sequence confirms this archeological conclusion. Genetic mutations occur at a predictable rate per generation, and once fixed in a genome, are subsequently inherited by the progeny while new mutations continue to appear at the predictable rate; thus, leaving a bread-crumb-like trail to the past from whence we came. From this, one can construct a “molecular clock” with which to estimate how long ago different hominid species diverged and this indicates, with a 95% statistical certainty, that humans and Neanderthals split off from a common ancestor between 520-800 thousand years ago. In contrast, humans and chimps diverged some six million years ago. The genetic data also showed that Neanderthals likely lived in very small numbers; maybe no more than 10,000 alive at any one time; they were in a distinct minority relative to humans.

Anthropologists have long known that Neanderthals and humans overlapped in history as well as regionally, raising speculation as to whether humans and Neanderthals interbred. However, you can rest easy since the Neanderthal mitochondrial genes "were distinctly different to modern humans, suggesting Neanderthals never, or rarely, interbred with early humans." Perhaps that fact is mostly of interest to a prurient anthropologist who has been in the field too long, but it also should still the salacious speculation from the History Channel of illicit communion between the two species. In other words, Great Grandma was not one of the knuckle-draggers, regardless of uncle Ned’s jutting jaw and flat forehead—that is just the luck of the draw from the Homo sapien gene pool and not due to genetic “contamination”.

Another upshot of this study is that the lessons learned about isolating and sequencing antediluvian DNA will be useful for the analysis of the entire Neanderthal genome that will soon come.

Can "Neanderthal Park" be far behind?