Saturday, September 15, 2007

Large Hadron Collider: Apocalypse Soon?

Probably Not

While looking over my site visit statistics, I found that many of my visits are to my article a few months back about the Large Hadron Collider under construction in France and Switzerland. A quick glance through the search terms that have led people to the article yield the following:

  • LHC Black Hole
  • Large Hadron Collider Doomsday
  • Large Hadron Collider Apocalypse
  • Large Hadron Collider Destroy Universe
  • Harge Hadron Collider End of the World
  • CERN destroy world
These searches are coming from the UK, France, Texas, Massachusetts, get the point. It seems like a lot of people are worried about CERN's LHC destroying the world.

Since this seems to being weighing heavily on the consciences of many people, I thought I would address it with a little more detail.

The nature of black holes has been debated for quite some time. What most people know about black holes is that they are incredibly dense masses in the universe. Since the force of gravity is dependent on mass, a black hole has an incredibly strong force that is powerful enough to capture even electromagnetic waves like visible light. For me, this has always been a little bit preplexing becase I used to wonder why Black holes ever stopped engulfing everything around them. To my mind, if something was massive enough to capture anything of mass around it, then it would continue to add mass. If it continued to add mass, it would then have an even greater gravitational force. Why would it ever stop?

It seems that black holes do lose their mass. They emit radiation which is actually representative of the mass and energy consumed by the black hole. Eventually, they radiate into nothingness; particularly small black holes created by collisions of tiny subatomic particles.

Now, I cannot claim that these are unequivocal facts. Much of this has been debated since the early 1970's. Stephen Hawking himselfrecently retracted his postulation that the radiation out of black holes carries no information from the mass and energy captured by it. He now believes that the radiation does carry information about what the black holes is made out of. He hsays the only problem with the information is that it is so random and jumbled that piecing it together into something we can interpret is virtually impossible.

However, the idea of black holes quickly radiating their energy such that they lose their mass makes a lot of sense to me. Otherwise I can envision black holes ever growing and consuming the whole universe...there is no evidence of this in astronomy.

So in the case of the tiny little subatomic particle derived black holes generated by CERN at the Large Hadron Collider, it seems very unlikely that a sustained black hole can possibly be produced. It will lose its mass to radiation faster than it can collect mass do to its gravitational pull.

Tuesday, August 28, 2007

Counting Chickens: Cancer Still Tough to Crack

Pennsylvanian Inventor Touting Cancer "Cure"

Cancer is a challenge. It is a challenge to patients. It is a challenge to their families. It is a challenge to researchers.

A leukemia patient from Erie, Pennsylvania decided to take matters into his own hands. His name is John Kanzius and he doesn't have an MD, Phd, or even a bachelors degree. He is, however, a creative mind who has been a radio and TV engineer for most of his life. Kanzius put his experience with radio wave technology to use when he coupled it with cutting edge nanotechnology. He and his partners have created injectable nanoparticles which generate heat when they are exposed to low frequency radio waves. This is definately and interesting and inspirational story.

Kanzius's energy transfer technology sounds fascinating, it really does. The idea of being able to heat small particles with projected radio waves could have lots of uses. Unfortunately, I just don't think its a cure or even a particularly useful technology for the treatment for cancer. Sorry, Mr. Kanzius.

Basically, Kanzius wants to physically perturb the cancerous cells by cooking them. He says that cancer cells will die when exposed to temperatures over 130 degrees. Well, so will healthy cells. While that is an interesting idea, it really isn't very much different from killing the cancerous cells chemically with chemotherapeutics or with targeted radiation. One would still need to contend with the issue of cell/tissue specificity.

The biggest challenge, which Kanzius addresses/glosses over in interviews, will be the targeting of cancer cells only. How will he keep his nanoparticles from cooking the rest of patients' cells? How is this any different from chemotherapy which targets cancer cells in a rudimentary way by targeting dividing cells? Honestly, one could make a case to say that chemotherapies are ahead of Kanzius' radio nanoparticles because at least there is some specificity. I suppose the advantage of his technology is the fact that "treatment" can be turned off when the radio wave generator is turned off.

For his technology to work, aptamers will need to be developed. Aptamers are oligonucleotides or peptides which stick to cell specific molecules. In research, they are often bound to pharmacological agents or cell markers.

The aptamers, whether for Kanzius' superheated nanoparticle antennas or cytotoxic chemicals, would likely need to be different for each tumor type. The means that the problem remains a discovery biology dilemma. Discovery biologists and the pharmaceutical companies for whom Kanzius seems to express considerable disdain have been working on this same problem for years. They've just been trying to selectively target their chemotherapy drugs instead of superheatable nanoparticles. Discovery efforts to generate cell specific aptamers are almost as involved and expensive as any drug discovery effort. Also, the idea of verifying that an aptamer only binds to a tumor cell is a huge undertaking. Researchers would basically need to undertake an enormous protein specificity assay. Today, proteomics efforts are still cumbersome and expensive. If researchers try to take short cuts and bypass any of these experiments, we might have doctors saying, "Oops, I fried your kidney...Sorry, didn't think it was going to do that...". More concerns involve heavy metal poisoning, nanoparticle immunoreactivity, and the pharmacodynamics of the aptamer, just to name a few.

So while Kanzius should be commended for his ingenuity in introducing a new technology to the cancer fight, Joyce Savocchio (the former mayor of Erie) probably should not be declaring him a future Nobel Laureate or calling Erie the place where cancer was cured. Perhaps he should also temper his own rhetoric a little bit, particularly when he implies that no one else is working very hard on the cancer problem. He and Ms. Savocchio sound ignorant to the real issues.

Saturday, August 25, 2007

Absence Makes the Heart Grow Fonder

It has been far too long since I last posted. I have missed the Omnome project and the Science Blogging community as a whole quite a bit while I have been distracted. I realized in the first months after initiating this blog site that the diversity of discussion in the science blog community really expanded my scientific thinking.

I hope my experiences in the past few weeks that have caused me to be so absent from Omnome will have provided me some insights that will enrich my posts on a few subjects that are regularly addressed here.

So what have I been doing? First of all, to say that I have been doing anything is a gross overstatement as anything I do is as part of a massive team effort. Secondly, I am somewhat constrained by organizational confidentiality agreements so it would be unprofessional for me to say too much. However, I think I can safely tell you the following about my past month:

1) Data was finally compiled and made accessible to me from a very large gene expression profiling effort which took my group one full year to complete. The dataset is made up of about 9 million data points. Mining is fun! Spotfire software can be fun as a visualization tool of the data. However, the statistical power of the program is sorely lacking.

2) My research group used stem cells in an animal model of neurodegeneration. I am pretty sure that's all I can really say about that. However, I suspect I will interject more thoughts about the technology in future posts as a result of my experiences with these cells.

3) My research group has initiated two large scale gene therapy efforts in animal models of neurodegeneration using adenoviral vectors.

I hope I will be able to find the time to frequent Omnome a bit more again. I look forward to visiting my scienceblogs favorites again as well. However, the people who actually pay me at work will continue to have a say over that.

Thursday, July 19, 2007

Tangled Bank #84!

Please stop by Tangled Bank 84 at the Voltage Gate! Omnome got a nod for our post about life, chaos, and disease.

Monday, July 16, 2007

Cows of the World Rejoice!

A Step Toward Treating Prion Pathologies?

In 1997 Dr. Stanley Prusiner of the University of California at San Fransisco was awarded the Nobel Prize in Medicine or Physiology for his discovery of prions approximately 15 years earlier. Prusiner had characterized the first infectious agents that were not somehow regulated by DNAs or RNAs.

Prions are proteinaceous infectious particles which cause diseases in myriad animals by affecting the structure and, subsequently, the function of the brain and other neural tissues. All are fatal. Prions are actually made of a protein which exists normally in healthy humans and animals called PrPc. The infectious, or PrPsc, form is different in that it is folded differently such that it cannot be broken down by proteases; the body's normal protein degrading enzymes. Not only is this aberrant form of PrP undegradable, it can actually transform the normal healthy PrP into the pathological form. It is worthwhile to note that while prion diseases can be infectious, some can be familial and directly inherited.

I like to think of the PrPsc protein as if it were an unruly elementary school student with very rich parents who have funded the new wing to the school. The bad student (PrPsc) should be expelled, but the administrators can't do it because they will lose necessary funding (proteases are unable to degrade PrPsc). As a result, the bad student is a terrible influence and converts formerly good students (PrPc) to his bad behavior. They all eventually burn down the school (Central Nervous System disease eventually resulting in death).

OK, so the analogy is crude, but you get the point, right?

A recent publication in PNAS, describes a simple but only recently possible approach to slowing this protein's infectious misbehavior. The researchers first analyzed the thermodynamic stability of PrPc. They found that the normal protein is most unstable at residues which cause a cavity in the protein. These sites of instability seem to be correlated with mutated regions of the PrP protein in inherited prion diseases.

The researchers then embarked on a "dynamics-based" drug discovery strategy. My impression of the strategy is that they utilized proteomic informatics technology to find chemical structures which might bind to and stabilize the collapsible, unstable, residues of the healthy PrPc. If that isn't what they did, I think that might be a good idea...

The researchers eventually tested a handful of compounds in cell models and in animal models of prion diseases. They settled on one compound which did seem to stabilize the endogenous PrPc and reduced the rate of PrPsc induced degeneration in infected mice.

I have much interest in neurodegenerative protein conformation diseases because I work in amyotrophic lateral sclerosis (ALS) drug discovery. I have developed a bias where I am under the impression that the main key to unlocking neurodegenerative diseases lies in understanding the truth about protein misfolding, degradation, and aggregation and as such I find this publication to be very interesting. I may carry this bias as a result of having been heavily influenced by Dr. Susan Lindquist when my research group met with her about 4 years ago.

Dr. Lindquist is a leading protein misfolding expert and sums my feelings up best in the quote below:

"What do "mad cows", people with neurodegenerative diseases, and an unusual type of inheritance in yeast have in common? They are all experiencing the consequences of misfolded proteins. ... In humans the consequences can be deadly, leading to such devastating illnesses as Alzheimer's Disease. In one case, the misfolded protein is not only deadly to the unfortunate individual in which it has appeared, but it can apparently be passed from one individual to another under special circumstances - producing infectious neurodegenerative diseases such as mad-cow disease in cattle and Creutzfeld-Jacob Disease in humans."
--from "From Mad Cows to 'Psi-chotic' Yeast: A New Paradigm in Genetics," NAS Distinguished Leaders in Science Lecture Series, 10 November 1999.

Sunday, July 8, 2007

Cancer: A Mistep into Chaos Quicksand?

I spent much of this weekend pouring over two publications. The first, Probing Genetic Overlap Among Complex Human Phenotypes, was published in PNAS. Gene Expression has a nice post about the publication. While the paper itself focuses on genetic overlap between Autism, Schizophrenia, and Bi-polar Disorder, the scope of the work spans across over 150 diseases which were all compared in a pair-wise fashion. My personal interests in this work lie in their findings regarding Amytrophic Lateral Sclerosis which the authors included in their 200+ pages of supplementary materials. As I learn more about this work, I will share more about my understanding of the potential significance.


The second publication I spent a lot of time attempting to wrap my feeble mind around this past weekend was a fascinating conceptual "modeling" paper written by Dr. Ivo Janecka, MD, MBA, PhD (that's a lot of letters...). As I mentioned in my post about Miuro, I am very much intrigued by chaos mathematics and non-linear dynamics. It is the most ambitious of my many amateur interests.

The introduction of Janecka's publication starts with a quote by Fritjof Capra saying:

"The more we study the major problems of our time, the more we come to realize that they cannot be understood in isolation. They are systemic problems, which means they are interconnected and interdependent."
It is a sentiment which many scientists share, but is very easy to lose site of when we attempt to make our research efforts more manageable. We try to linearize our experiments. We pretend that we can study individual variables. We forget that we are usually attempting to solve complex problems rather than answer simple binary questions. In the twenty-first century, living systems and their "problems" are proving to be more complex than any systems humans have ever tried to understand.

When I decided to pursue a career in life sciences, it was because I could not imagine that any other field of study could offer systems as beautiful and mysterious as life. I also could not imagine a field that could offer so much promise to help fellow humans once some of the mysteries were unlocked.

In this publication, Janecka offers a conceptual model for life systems. He describes life as a "non-linear dynamical system following the principles of organized complexity" with a "health territory" defined by the the systems ability to self-organize and self-adapt.

OK, so what does that mean? Let's take it one part at a time.

What is a non-linear dynamical system?

This is a system where small changes to early conditions can directly result in hugely different results at some later time. Many people have heard of the concept of a butterfly fluttering its wings on the North American west coast resulting in dramatic changes to huge tropical weather system on the east coast. Weather patterns are good examples of non-linear dynamical systems.

What is self-organization?

A system that self-organizes is one that will find a way to go back to "normal" after it has been disrupted. Imagine a beehive that is completely buzzing with activity. Now, imagine throwing a very small pebble at that beehive and disrupting the activity of the bees. For a few moments, the bees buzz away and circle the hive, only to go right back to the hive. The hive then appears almost exactly as it had before it had been disrupted. The system always approaches an organized baseline of activity.

Life, specifically human life, is very much the same. Our bodies work to self-organize. When we suffer lacerations, bleeding stops and the lesion closes/heals. This propensity to self-organize is catagorized by Janecka into a "zone of order".

What is self-adaptation?

Self-adaptation can be described as a systems flexibility to change based on information received from outside to the system. If you have ever attempted to play the guitar, you will know that it hurts at first. Fingertips become raw. Forearms become very sore. Over time, the muscles in the hand and forearm become much stronger and the fingertips become calloused and less sensitive to pain. The system is self-adapting to the information conveyed from the environment. If we could not adapt the environment around us and we didn't have flexibility to express a variety of phenotypes, our species could not survive. This flexibility is catagorized by Janecka within the "inner edge of chaos".

If life is a self-organizing and self-adapting system, then, Janecka reasons, it can be described as a pendulum swinging back and forth through the "zone of order" and the "inner edge of chaos".

When life swings too far into the "zone of order", it is at the expense of adaptability. This can result in detrimental rigidity as in the case of ECG cardiac signalling. Lack of chaotic fluctuations in cardiac electical signalling invariably indicates cardiac disease because of its lack of adaptability to variable conditions of stress and strain. Imagine if your heart couldn't beat faster when you needed to run. You wouldn't be able to get oxygen to your blood and muscles fast enough. It would be detrimental to you as a "living system".

Likewise, when life swings too far past the "inner edge of chaos", the system loses its ability to self organize. This can be observed in cases of cancer where a subsystem of cells within the complete living system loses the ability to regulate expenditure of resources. In cancer, most cellular resources are allocated to reproduction instead of differentiation and functionality. The cancer cells replicate in exponential self-similar chaos fractal patterns like the common Mandelbrot geometic patterns of Merkel cell carcinomas.

Janecka suggests that many untreatable human diseases can be catagorized as pendulum swinging too far in either direction of the self-organizing/self-adapting systems. A swing in either direction plunges the living system into a stage of accelerating entropy ontil the system completely unravels at death. He goes on to suggest that scientists and clinicians could use the model to evaluate what needs to happen to a diseased patient to best bring them back to their healthy balance of order and chaos. In the case of cancer, Janecka proposes that efforts be made to re-educate the cancer cells to move back toward efficient energy consumption. Teach the cancer cells to differentiate again instead of reproduce. Re-balance the system.

The concept is fascinating and I look forward to following up on researcher who reference this publication.

Thursday, July 5, 2007

The Tangled Bank #83

The 83rd Tangled Bank has been posted at Aardvarchaeology. Omnome's Parkinson's gene therapy post was included in the carnival.