Should Worldwide Stock Markets Stop Electronic Trading Using Algorithms?

We’ve entered the age of the Algorithm, which is the age when computer programs run and make decisions that affect our lives. These Algorithms have already become quite good at beating most experts at games such as chess, poker and checkers, but there are others that can also beat the common investor in stocks. Currently we’re witnessing the Darwinian battle of the remaining Algorithms in the trading of stocks. These successful Algorithms have made a great deal of money for their investors, so there is a reluctance to abandon them, but we are in unique and unprecedented times that require us to think about the higher order effects on the overall equilibrium and stability of the global markets.

Many successful Hedge funds have used stock trading algorithms to make billions of dollars. Now that many investors have learned that the way to make a small fortune in the stock markets is to start with a larger one, these trading algorithms are left and pitted against one another. However, there are flaws with regulators allowing these scenarios to be played out. One flaw is that the overly successful algorithms will extract billions of dollars in wealth out of the markets. Any market strategy that wins repeatedly will eventually ruin the markets for everyone else. This has to be recognized by the market regulators and eventually corrected in order to maintain orderly markets.

Previously, some market rules and regulations may have functioned as brakes on the rapid electronic trading using these algorithms. Unintended consequences that may have made algorithmic trading more difficult may have resulted from the suspension of these rules such as the uptick rule. These have to be carefully considered by market regulators as necessary brakes on these powerful funds.

An interesting evolutionary perspective from these epic Darwinian struggles suggests that it isn’t necessarily for the best to eliminate all competition in evolving systems. Of course this raises many questions, such as: “What is the best?” and “What is the purpose of evolving systems?”, that can’t be answered here in terse and nonphilosophical words. Even the purpose of competition, itself, becomes a philosophical conundrum in this context, so I should stop here.

Credit Default Swaps and the Financial Crisis

A couple months ago, most of us never heard about credit default swaps (CDS), but now we learn that they may be at the heart of the financial crisis. This is primarily because many banks and financial institutions have credit default swaps on their books and no one knows how to value them or how much these financial institutions may owe.

According to Wikipedia (http://en.wikipedia.org/wiki/Credit_default_swap):

A credit default swap (CDS) is a swap contract in which a buyer makes a series of payments to a seller, and in exchange receives the right to a payoff if a credit instrument goes into default or on the occurrence of a specified credit event, for example bankruptcy or restructuring. The associated instrument does not need to be associated with the buyer or the seller of this contract.

Estimates of the credit default swap market has grown to the tens of trillions, (yes, that’s trillions), of dollars. It is now estimated to be larger than the world’s GDP. This has caused many institutions to hoard cash and not lend to others for fear that many have these “toxic debts” on their books.

Why don’t we make credit default swaps illegal? They will always remain as a source of doubt about financial institutions. Those who’ve engaged in these unregulated practices will just have to eat their loses, which they appear to be doing now. Just look at the recent auction of Lehman Brother’s credit default swaps, which yielded about 8 cents on the dollar. Wouldn’t we be better off legislating them all away and starting again from zero?

The Market Mess

Having been glued to the set last week watching the financial crises, I can’t help but wonder if we have finally come to the end of this problem... Perhaps we need to stop the whole mortgage derivative business and go back to the more simple time of mortgage lending...

The Structure and Function of G Protein-Coupled Receptors

For those who may wish to understand my and my collaborator's work on the structure and function of G protein-coupled receptors, I’ve provided the following links to the papers that are most important for understanding this work. I like to bunch them into groups of three. First are:


Weber's Law Modeled by the Mathematical Description of a Beam Balance, Mathematical Biosciences 122: 89-94 (1994)

Method for determining drug compositions to prevent desensitization of cellular receptors, US Patent # 5,597,699 (1997)

Activation of G Protein-Coupled Receptors Entails Cysteine Modulation of Agonist Binding, J. Molecular Structure (Theochem), 430/1-3: 57-71 (1998)

The next three papers are:

Compositions to enhance the safety and efficacy of bio-pharmaceutical drugs. US Patent# 6,593,094 (2003)

Optimal Agonist/Antagonist Combinations Maintain Receptor Response by Preventing Rapid Beta-1 adrenergic Receptor Desensitization Intl. J. Pharmacol., 1(2): 122-131, (2005)

Molecular dynamics of a biophysical model for beta-2-adrenergic and G protein-coupled receptor activation Journal of Molecular Graphics and Modelling 25: 396-409 (2006)

The Calcium Gate Hypothesis of Cancer

In 1978 I was finishing my Masters in Public Health at the University of Michigan School of Public Health. I had fallen under the spell of Dr. Bruce Chin who was enthusiastically studying the mechanisms of carcinogenesis. I took his advanced class in understanding the cellular mechanisms of cancer three times. During this time, I also developed my ideas that there must be a crucial switch that turns this cancerous process on and off and that the most likely candidate for this switch was an as yet unknown calcium gate that could be controlled by phosphorylation and dephosphorylation. This gate would be analogous to the then known cardiac gate controlled by phospholamban, which was discovered by Dr. Madeleine Kirchberger at the Mount Sinai School of Medicine in New York. I wrote this hypothesis into a paper that I submitted to the Journal of Theoretical Biology, but it wasn’t accepted for publication.

Ironically I came to New York in 1979 and later found myself working in Dr. Kirchberger’s lab on a project to isolate and purify phospholamban, but phopholamban is a membrane bound protein that was more difficult to purify than we initially thought and since I couldn’t reproduce my initial results, I had to drop this project and start a new project for a Ph.D. thesis. However, I very much admired the rigorous research integrity and intensity of Dr. Kirchberger’s lab and I learned a great deal about phospholamban and calcium signaling in the heart. I was still convinced that there must be a connection between the uncontrolled cell division in cancer cells and the control of the calcium gate in normal cells. I discussed this idea with many scientists because I wanted to find someone who was working in this area, but it still needed much more development to become a mainstream idea.

Years passed and I periodically scanned the literature to see if there had been more thought about the calcium gate hypothesis and cancer. The cancer field seemed to take off in the direction of a balance between kinase and phosphatase control of the cell’s metabolic machinery. This seemed to be promising since I had thought that the calcium gate would be controlled by the kinase and phosphatase molecules. The calcium field seemed to have its own direction and developed into an important field of research focusing on the myriad number of enzymes and kinases controlled by calcium signals. However, there didn’t appear to be a direct connection made between a particular kinase/phosphatase pair that were crucial in controlling a start/stop point in cell division.

This has now begun to change and suggests a redox sensitive switch -see:

http://www.ncbi.nlm.nih.gov/pubmed/18377233?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/17168752?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/18544350?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18372105?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18671159?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/18466777?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


Is it just coincidence that oncogenes and calcium control genes are near each other? The following list contains searches for oncogenes that happen to appear near to calcium control genes (clicking on the links give GOOGLE searches for the oncogene and the calcium gene and cancer):


27
Hs
ABL2
v-abl Abelson murine leukemia viral
oncogene homolog 2 (arg, Abelson-related
gene)
1q24-q25


777
Hs
CACNA1E
calcium channel, voltage-dependent,
alpha 1E subunit
1q25-q31

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%221q24-q25%22+1q25-q31&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



208
Hs
AKT2
v-akt murine thymoma viral oncogene
homolog 2
19q13.1-q13.2

773
Hs
CACNA1A
calcium channel, voltage-dependent,P/Q type, alpha 1A subunit
19p13.1-p13.2


51476
Hs
CABP3
calcium binding protein 3
19q13.33

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2219q13.1-q13.2+%22+19q13.33&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



867
Hs
CBL
Cas-Br-M (murine) ecotropic retroviral
transforming sequence
11q23.3

57010
Hs
CABP4
calcium binding protein 4
11



781
Hs
CACNA2D1
calcium channel, voltage-dependent,
alpha 2/delta subunit 1
7q21-q22
673
Hs
BRAF
v-raf murine sarcoma viral oncogene
homolog B1
7q34

674
HsBRAFP
v-raf murine sarcoma viral oncogene
homolog B1 pseudogene
7q34

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%227q34+%22+7q21-q22&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


12298
Mm
Cacnb4
calcium channel beta 4 subunit
2 33.9 cM
12170
Mm
Bmyc
brain expressed myelocytomatosis
oncogene
2


782
Hs
CACNB1
calcium channel, voltage-dependent,
beta 1 subunit
17q21-q22
1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3



54245
Rn
Crk
v-crk avian sarcoma virus CT10 oncogene
homolog
10
783
Hs
CACNB2calcium channel, voltage-dependent,
beta 2 subunit
10p12

12296
Mm
Cacnb2
calcium channel beta 2 subunit
2 14.5 cM

12298
Mm
Cacnb4
calcium channel beta 4 subunit
2 33.9 cM

12170
Mm
Bmyc
brain expressed myelocytomatosis
oncogene
2



773
Hs
CACNA1A
calcium channel, voltage-dependent,
P/Q type, alpha 1A subunit
19p13.1-p13.2

1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3+%22+19p13.1-p13.2&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



775
HsCACNA1C
calcium channel, voltage-dependent, L
type, alpha 1C subunit
12p13.3
1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3+%22+12p13.3&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

778
Hs
CACNA1F
calcium channel, voltage-dependent,
alpha 1F subunit
Xp11.23
867
Hs
CBL
Cas-Br-M (murine) ecotropic retroviral
transforming sequence
11q23.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2211q23.3%22+Xp11.23&as_q=cancer&btnG=Search%C2%A0within%C2%A0results



8911
Hs
CACNA1I
calcium channel, voltage-dependent,
alpha 1I subunit
22q13.1

1399
Hs
CRKL
v-crk avian sarcoma virus CT10 oncogene
homolog-like
22q11.21

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2222q11.21%22+22q13.1&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


782
Hs
CACNB1
calcium channel, voltage-dependent,
beta 1 subunit
17q21-q22

1398
Hs
CRK
v-crk avian sarcoma virus CT10 oncogene
homolog
17p13.3

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2217p13.3%22+17q21-q22&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


12295
Mm
Cacnb1
calcium channel beta 1 subunit
11 58.0 cM
12928
Mm
Crko
avian sarcoma virus CT10 (v-crk)
oncogene homolog
11 44.15 cM

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%2211+44.15+cM%22+11+58.0+cM&as_q=cancer&btnG=Search%C2%A0within%C2%A0results


1436
Hs
CSF1R
colony stimulating factor 1 receptor,
formerly McDonough feline sarcoma viral
(v-fms) oncogene homolog
5q33-q35
Links309
Hs
ANXA6
annexin A6
5q32-q34



776
Hs
CACNA1D
calcium channel, voltage-dependent, L
type, alpha 1D subunit
3p14.3

1894
Hs
ECT2
epithelial cell transforming sequence 2
oncogene
3q26.1-q26.2

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=%223q26.1-q26.2%22+3p14.3&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

12291
Mm
Cacna1g
calcium channel, voltage-dependent, T
type, alpha 1G subunit
11
13649
Mm
Egfr
epidermal growth factor receptor
11 9.0 cM


12295
Mm
Cacnb1
calcium channel beta 1 subunit
11 58.0 cM

13649Mm
Egfr
epidermal growth factor receptor
11 9.0 cM



24329
Rn
Egfr
Epidermal growth factor receptor, formerly
avian erythroblastic leukemia viral (v-erbB)
oncogene homolog (Erbb1)
14

12289
Mm
Cacna1d
calcium channel, voltage-dependent, L
type, alpha 1D subunit
14 8.0 cM

54234
Rn
Cacna1e
calcium channel, voltage-dependent, L
type, alpha 1E subunit



2002
Hs
ELK1
ELK1, member of ETS oncogene family
Xp11.2

778
Hs
CACNA1F
calcium channel, voltage-dependent,
alpha 1F subunit
Xp11.23

http://www.google.com/search?hl=en&lr=&suggon=0&safe=off&as_qdr=all&q=Xp11.2+Xp11.23&as_q=cancer&btnG=Search%C2%A0within%C2%A0results

A Creative Financial Fix to the Mortgage Crises?

Rick Santelli of CNBC (see - http://www.cnbc.com/id/15837966/) suggested that we create an opportunity for young home buyers to purchase foreclosed properties. There are pluses and minuses to such deals, but the underlying theme is that we need to create a way out of the mortgage crises. An interesting point that Rick made is that we (investors and financial institutions) must “bite the bullet” and step up to invest in new mortgage backed instruments. As a small investor, I agree that investors should invest some of their money to promote the greater good. However, this is sometimes difficult to see and reconcile with the capitalist creed to make money...

How to turn the mortgage crises around so that we have a win-win scenario? Perhaps there could be a way to interest REITs in the housing market if the offer was too good to ignore? Fannie and Freddie are sitting on large amounts of federal aid that are becoming more difficult for home buyers to access. If existing or new REITs could access these funds to buy, rent and sell homes, then perhaps we could create a creative way forward out of the current mortgage crises.

Active and Inactive Receptor States

When we write the set of brackets around a chemical species to represent a chemical concentration, it really represents a sum of probable chemical species that are grouped together. This is especially important when we consider the potential states of large protein molecules such as cellular receptors. In pharmacologic theory, we often characterize the active or inactive states of the receptor as initial quantities such as [R] and [R*]. This is convenient for mathematically manipulating these receptor states in order to derive information about how they behave in the presence of stimulating or inhibiting molecules such as agonists or antagonists, but conveys little about the underlying molecular species connected with these active and inactive states.

Even using specific and detailed molecular dynamic simulations, the meaning behind the [R] and [R*] receptor states becomes less clear when we explicitly model these states. Since there are a vast multitude of possible conformations, it becomes increasingly difficult to separate out those conformations that belong to the active or inactive receptor states. Ironically, this has brought us full circle to consider what [R] and [R*] represent as specific molecular species. The closer we are to understanding the details of these states from crystallographic structures, the further we are from understanding the molecular species that make up the active and inactive states.

Anyone who has truly studied pharmacologic theory and molecular modeling knows that we often wind up with this essential conundrum. Some have chosen particular molecular motions or interactions such as the breaking of a salt bridge or the twist or turn of a helix to describe what they think is the active receptor state. These descriptions may contain accurate descriptions of the active receptor state, but the fact that receptors exist in a sea of thermal noise and that activating drugs or ligands bind to their target receptors with only a 3-4 kcal/mol maximum energy difference and display different active molecular conformations suggest that we need a clearer on and off molecular switch for receptor activation.

These are not impossible physical constraints to accommodate in a biophysical molecular model for receptor activation (see - http://www.bio-balance.com/JMGM_article.pdf and http://www.bio-balance.com/GPCR_Activation.pdf ), but because receptors are complex molecular structures that exist in multiple domains, the teasing apart of the essential molecular signal is very difficult from both an experimental and theoretical perspective. This is particularly true if the biophysical models fail to accommodate major experimental findings such as the redox sensitivity of receptor systems or the reduction in desensitization by combining an antagonist with an agonist. A comprehensive molecular model for receptor activation should contain these findings.

Calling for Pharmacologists, Cell Biologists and Those Working in Cellular Signaling

Calling all pharmacologists, cell biologists and those working in cellular signaling to test agonist/antagonist combinations for their ability to reduce or prevent receptor tachyphylaxis, desensitization or tolerance. It is important to the field of pharmacology that the simple act of combining an antagonist with an agonist reduces receptor desensitization be independently tested. Those with suitable experimental systems that demonstrate receptor desensitization, tachyphylaxis or tolerance should consider testing agonist/antagonist combinations against the responses observed with the agonist alone.

Why Agonist/Antagonist Drug Combinations Work

At the most fundamental level, the reason that adding an antagonist to an agonist in a specific ratio greatly reduces or eliminates receptor desensitization is that the dynamic competition between the agonist and the antagonist allows the receptor to function with little or no desensitization. What this means is that by slightly inhibiting the receptor, we can make sure that it doesn’t become overly excited and desensitized by the agonist drug alone.

What’s unique about this is that we can calculate the optimal ratios of agonist and antagonist to create the effects we want from the stimulated receptors. This hasn’t been accomplished before, because the importance of the agonist/antagonist ratio on receptor desensitization has gone unnoticed. Although there is some initial progress is this area, especially by Richard Bond (see - http://tinyurl.com/5kexhe, http://tinyurl.com/66oce8, http://tinyurl.com/6yhvgv and http://tinyurl.com/6plywh), the idea that we can create useful agonist/antagonist combinations to reduce or prevent desensitization, tachyphylaxis or tolerance has been slow to enter current pharmacological thinking.

This may seem surprising since our patented and published works were the first to describe how to make and control such agonist/antagonist combinations to achieve desired effects such as reducing or preventing receptor desensitization (see - http://tinyurl.com/6744mr, http://tinyurl.com/5ahxgm, http://tinyurl.com/5z8an6 and http://tinyurl.com/5mpsf7). Although this body of work has been ignored by many subsequent researchers, our priority dates on our patent filings certify our claims to first to discover this important means of modification of the receptor response.

Ideas About Anthrax

Ideas are a dime a dozen, but when one of my suggestions are followed, it is heartening. As I grow older, I value the effort that must be expended to follow through with what we like to call “good ideas”. Those who follow through and test these good ideas are the unsung heroes of scientific research and development. That said, I had previously e-mailed the following suggestions to the federal authorities on the dates below:

11/2/01
With regard to tracing the source of the anthrax. Cross contamination of overseas postoffices and other mail may help to determine where the anthrax entered the global mail system. It seems to me that by cross checking databases listing laboratory personnel (such as the Lists of World Culture collections: http://wdcm.nig.ac.jp/hpcc.html) who are capable of producing anthrax with other databases listing terrorist sympatizers and extreme right fanatics such as the Tim McVeigh sympathizers, that we could narrow down the search to possibly a few hundred places where appropriate personnel could question people and take appropriate samples to determine if the strains match.

7/14/02
Efficacy Corporation
30 West 86th Street - 1B
New York, NY 10024
(212) 769-3877 * biobalance@aol.com * Fax. (212) 769-3877

In order to find the suspect who carried out the anthrax attacks may I suggest that a scientific approach may work best. The method would require the hepa vacuuming of a suspect's clothes, car, home, etc. Anywhere the anthrax spores may have been. This should obviously be done with a clean filter, then the samples should be divided into at least two to three groups. One group should be cultivated under conditions that favor the germination of the anthrax spores and if found, they should be compared to the strains sent to the Senators' offices. Another sample should be pretreated to kill everything but spores, and then cultivated and examined for the same strain as was used in the attacks. The third should be examined microscopically to determine if the spores are present.

In addition, any filtering devices from the suspects' living or working quarters should be examined by the methods given above.

This will take time, but may be the best evidence to definitively convict the person of the crime.

Sincerely,
Richard Lanzara, PhD
President & Chief Scientist
Efficacy Corporation

Dick Cheney and the Oil Executives

Over the past year oil has doubled in price yet industry reports show some companies reporting a decrease in oil production. We all know that we’re in a period of financial adjustment and pain. Personally, I’m waiting for Dick Cheney to reconvene his energy executive meeting that took place early in President Bush’s first term and provide new leadership for a sane energy policy. There’s still time.

My Discovery

Since filing my first patent on September 30, 1992 (see - http://www.freepatentsonline.com/5597699.html), those who do not understand pharmacological theory want to understand what it is that I’ve discovered. My discovery has been that by combining agonist (or activating) drugs with antagonist (or inhibiting) drugs in specific ratios we can modulate the dose-response relationship to achieve whatever effect we want. This means that we can design new drug combinations that work better than the agonist (or activating) drugs alone. This is a potentially huge market as these drugs comprise roughly more than 30% of all drugs currently being sold. My unique contribution is that by combining drugs, we achieve beneficial effects without having to design new molecular drug entities. These drugs are already on the market and have been FDA approved so their actions and side effects are well known. By using these specific drug combination ratios, we can create safer and more effective drugs now if only we had more interest from the investment community.

Calming the Financial Markets

The Congress, Federal Reserve and Treasury Department want to calm the financial markets. One thing that would go a long way to calming these markets is to insure that any and all depositors are fully insured. This would reduce depositors fear that they will not be insured if their accounts are over $100,000 and would also reduce the banks bureaucracy regarding depositors having multiple accounts. This may also strengthen the banks deposits, because depositors wouldn’t have to move their money elsewhere in order to insure that they’re covered by the FDIC.

Enhanced Pharmaceuticals, GPCRs, Drug Safety

At Enhanced Pharmaceuticals, we’ve discovered that the rather simple act of combining an agonist with the proper amount of an antagonist allows for a general decrease in the observed drug-receptor desensitization, tachyphylaxis or tolerance. This modulation of the receptor response appears to be a quite general phenomenon applicable to many G Protein-Coupled Receptors (GPCRs), but because it is an unexpected result that differs from most pharmacological theories and clinical intuition, it hasn’t caught on in the last 16 years since the filing of my first patent on September 30, 1992. Although it was previously reported for the opioid and nicotinic receptors, no other research group has characterized and defined their experimental results using predictive biophysical and pharmacodynamic models as we have.

Although at least three companies including Enhanced Pharmaceuticals were formed around such findings, general pharmacological science has been rather slow to follow up on these findings. Truthfully, this puzzles me, because these findings represent a paradigm shift in the pharmacology field toward discovering and making safer and more effective drugs. Big pharma appears to be looking in all the wrong places to extend their patent franchises while ignoring or remaining unaware of technologies such as ours to improve their drugs.

There remains more experimental work to do, but from our studies it appears that these agonist/antagonist drug combinations work well in animals that desensitize differently and that they appear to work after desensitizing a targeted receptor system such as for the Guinea-pig trachea (an accepted experimental system for asthma studies). In our animal studies, there were also less cardiac arrhythmias with our drug combinations than with the agonist (activating) drugs alone. These studies are promising, but need further research. Because our work holds such promise for better asthma, heart failure and Parkinson drugs, we continue to hope that investors will see our potential and rise to the opportunities.

Richard G. Lanzara, M.P.H., Ph.D.
President Enhanced Pharmaceuticals, Inc.

Enhanced Pharmaceuticals

Recently, there was a blog about our company, Enhanced Pharmaceuticals, that elegantly described our technology and the hurdles that it faces for future development.

See - http://avelient.com/BioPharmBlog/2008/07/22/the-agonistantagonist-duel-for-enhanced-pharmaceuticals/#more-113

I couldn’t have said it better.

My wife, who is a doctor, suggests that I need a better way to describe this technology to the public. She has suggested that I use the example of a heroine addict who uses more and more heroine, but achieves less and less of an effect from the drug. Our research suggests that by using a specific combination of heroine and an anti-heroine drug, the effect of the heroine can be maintained and not diminished through continued use.

This research requires additional work, but it holds great promise for designing safer and more effective drugs that target receptors. In our research, we’ve found this to be a general phenomenon for a number of commonly used drugs (usually called G Protein-Coupled Receptor, GPCR, activating drugs, which comprise over 30% of all pharmaceuticals). These drugs include the drugs used to treat asthma, shock, heart failure and Parkinson’s disease among others. So the potential is vast, but alas our funding isn’t.

Anyone wishing to invest in this important venture should contact me at rlanzara@enhancedpharmaceuticals.com for further details.

Evidence for a free thiol necessary for GPCR activation

P2Y12, a G protein-coupled receptor that plays a central role in platelet activation is the receptor targeted by the antithrombotic drug, clopidogrel. The mechanism of action of clopidogrel involved cysteine 97 within the first extracellular loop of P2Y12. This provides supporting evidence for a free thiol or sulfhydryl group necessary for GPCR activation.

See - http://www.pnas.org/content/103/29/11069.full and http://www.bio-balance.com/Ref.htm

Esmin Green

Having worked in health care for more than two decades, I can say that a fundamental requirement is that all health care workers should have a minimum level of compassion for their fellow human beings. The video of Esmin Green shows no compassion for her. Unfortunately there are those health care workers who don’t seem to have this very basic requirement. All too often I’ve seen health care providers at all levels who do not appear to have the necessary compassion for their patients that translates into good patient care. We need more effective methods to remove them if we are to ever improve our current health care system.
Richard G. Lanzara, MPH, Ph.D.

A New Definition of Human Slavery?

Human slavery occurs through rape (see - http://www.nytimes.com/2008/06/15/opinion/15kristof.html?hp), kidnaping and human trafficking (see - http://ombamltine.blogspot.com/2008/06/ending-human-slavery-in-our-lifetimes.html). It can occur for an hour or for one’s lifetime, but it is still slavery when one human being absolutely controls another. We should all work together to abolish this abomination within our lifetimes.

Perhaps by combining rape, kidnaping and slavery together more lawmakers will recognize and respond to this barbaric criminality that exists everywhere in the world today. We should all try to work together to abolish this scourge that falls largely on our women and children within our lifetimes.

Ending Human Slavery in Our Lifetimes

I’d like to believe that there is a science to ending human slavery in our lifetimes. If not, then I’d like to begin such a process. Certainly the power of the internet could be harnessed to fight against such barbarity.

The Sex Slave Industry:

The sex slave industry is one of the problems that contributes to human slavery (for some important links regarding this problem, see Stella Rotaru http://reverbiage.com/find/stella-rotaru http://criticaldemocracy.wordpress.com/2008/05/13/stella-rotaru-sex-slaves/ and http://www.google.com/search?hl=en&suggon=0&as_q=&as_epq=Stella+Rotaru&as_oq=&as_eq=&num=10&lr=&as_filetype=&ft=i&as_sitesearch=&as_qdr=all&as_rights=&as_occt=any&cr=&as_nlo=&as_nhi=&safe=off). By calling attention to this problem, which exists everywhere, yes everywhere, you may be able to put press on lawmakers and others to raise the awareness of such problems and begin processes to end it.

Human Trafficking:

Sites that can serve as beginning points for understanding the aspects of human trafficking are: http://www.apcss.org/core/Library/Bibliography/humantraf.htm http://www.outreachworld.org/resource.asp?curriculumid=1141 and http://www.google.com/search?hl=en&suggon=0&as_q=Human+trafficking&as_epq=human+slavery&as_oq=&as_eq=&num=10&lr=&as_filetype=&ft=i&as_sitesearch=&as_qdr=all&as_rights=&as_occt=any&cr=&as_nlo=&as_nhi=&safe=off

How to Stop Human Trafficking:

Although there are several sites suggesting ways to combat human trafficking, we need a higher level of response from everyone. Some sites that suggest ways to stop human trafficking are: http://www.stophumantraffic.com/ http://www.amnestyusa.org/violence-against-women/end-human-trafficking/page.do?id=1108428&n1=3&n2=39&n3=738 and http://www.google.com/search?hl=en&suggon=0&as_q=&as_epq=how+to+stop+human+slavery&as_oq=&as_eq=&num=10&lr=&as_filetype=&ft=i&as_sitesearch=&as_qdr=all&as_rights=&as_occt=any&cr=&as_nlo=&as_nhi=&safe=off . If you send anyone resources to stop human slavery or trafficking be sure to follow up and see whether or not your contribution is doing what you thought it was designed to do. Following up is very important whenever you give to charities or other causes, because unfortunately, there are always those who try to profit from others misfortunes.

Hopefully this can be the start of a resource for people committed to ending human slavery.

Writing on Helium

Lately I've been writing on the website Helium. See - Helium
for some examples of this site and my writing.

The Devilish Complexity of Cysteine Modulation in Protein Function

There exists a devilish complexity in the vast array of biological modifications that can alter the free thiol or sulfhydryl group, which is the reactive group of the essential amino acid cysteine an important amino acid of many important biological proteins. The thiol group is vitally important for its ability to form disulfide bonds with other thiol groups and to form either reduced or oxidized (redox) forms that may further interact reversibly or irreversibly with a panoply of other chemical and biological molecules. In addition, many of these forms have their own redox and pH-dependence that determines their successive reactivities with other chemical or biological molecules, which only adds further complexity to this already overly complicated picture.

Unfortunately the experimental expertise necessary to deal with this burgeoning complexity has fallen behind. Experiments often control for temperature and pH and occasionally for the redox environment and ionic strength. However, there are further complexities that are much more difficult to measure and control. These complexities include evaluating the previous exposure of thiol groups to thiol modifying agents and conditions that render them either reversibly or irreversibly modified. In addition, there are time-dependent factors such as the release of nitric oxide (NO) from S-nitrosothiols that may function as a storage form of NO (1) and the additional confounding factors that include successive thiol oxidations to sulfenic acids (R-SOH), sulfinic acids (R-SO2H) and sulfonic acids (R-SO3H) (2). These oxidations also change the pK of the thiol group towards successively lower values (3) .

In many important biological and cellular proteins, the free thiol group of cysteinyl side chains is particularly susceptible to oxidative modifications such as the formation of intermolecular or intramolecular disulfides between other protein thiols or other low-molecular-weight thiol molecules such as glutathione (4). This may also occur by thiol-disulfide exchange or disproportionation reactions. The modification of cysteine thiols by incorporation of NO moieties such as S-nitrosylation or incorporation of glutathione moieties (S-glutathionylation) functionally blocks thiol groups from additional oxidation reactions that could irreversibly block their biological functions. Some reversible modifications may be essential in preserving vital intracellular proteins and membrane receptors, thereby allowing them to eventually return to a functional, free thiol state.

Thiol modifications are produced by a number of reactions induced by a vast number of reactive species. These species include nitric oxide-related species, other proteins or organic molecules with or without free thiol groups and metals that can form reversible redox-cycles or that primarily complex with and deplete glutathione levels or directly bond with free thiol groups (5). These reactions all have their own pH and redox dependence, which further complicates experimental efforts to control for thiol reactivities toward these large number of potentially reactive molecules. Measuring how and under what conditions these reactions can be reversed requires much more experimental work.

Altogether, it is a bit like trying to reverse the development of a photographic plate. The photographic reactions leave their history as an imprint on the plate, but just like an incompletely fixed photographic plate, there may exist other areas or reactive groups that can undergo further reactions given the proper set of experimental conditions. Studying the reactivities of the thiol groups of biological tissues may be very similar to the photographic plate analogy. Once they’ve reacted, it is very difficult to bring them back to their functional in vivo state. Currently there is relatively little recognition of these problems and little or no attempts to address them with suitable experimental controls.

Since this is a critical area for future research, suggestions for improving the experimental strategy may entail treating the cells or tissues with sulfhydryl chelating agents at various times during the experimental preparations so that we may begin to understand how successive handling and extraction procedures modify these critical groups. Using a protocol of successive sampling, the relative exposure of thiol groups could be determined at critical steps in experimental protocols that extract and purify biological proteins. Then the effects of these procedures on thiol modifications may become better understood and more readily controlled in future experiments.

Only by careful analysis and systematic experimentation can we begin to understand the role of thiol groups and their contributions toward the finely balanced control of a great number of critical biological functions (6-17).


References (Since this isn’t intended as an extensive review, these are only a minimal number and I apologize if I have left out other important references):

1) Alencar JL, Lobysheva I, Geffard M, Sarr M, Schott C, Schini-Kerth V, Nepveu F, Stoclet JC, Muller B. Role of S-nitrosation of cysteine residues in long-lasting inhibitory effect of NO on arterial tone. Mol Pharmacol 63: 1148–1158 (2003).

2) Kiley PJ, Storz G. Exploiting Thiol Modifications. PLoS Biol 2(11): e400 (2004).

3) Claus J, Holme AL, Fry FH. The sulfinic acid switch in proteins Org. Biomol. Chem., 2, 1953 - 1956 (2004). DOI: 10.1039/b406180b

4) Berndt C, Lillig CH, Holmgren A. Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. Am J Physiol Heart Circ Physiol 292: H1227-H1236, (2007). doi:10.1152/ajpheart.

5) Valko M, Morris H, Cronin MT, Metals, toxicity and oxidative stress. Curr Med Chem. 12(10):1161-208 (2005).

6) Smith JG, Cunningham JM Receptor-Induced Thiolate Couples Env Activation to Retrovirus Fusion and Infection. PLoS Pathog 3(12): e198 (2007).

7) Kokkola T, Savinainen JR,Mönkkönen KS, Retamal MD, Laitinen JT. S-Nitrosothiols modulate G protein-coupled receptor signaling in a reversible and highly receptor-specific manner. BMC Cell Biology 6, 21 (2005).

8) Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP. Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 101, 3908-3914 (2003).

9) LoPachin RM, Barber DS. Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants Toxicol. Sci. 94: 240-255 (2006).

10) Martínez-Ruiza A, Lamas S. Signalling by NO-induced protein S-nitrosylation and S-glutathionylation: Convergences and divergences Cardiovascular Research 75(2):220-228, (2007).doi:10.1016/j.cardiores.2007.03.016

11) Held KD, Sylvester FC, Hopcia KL, Biaglow JE. Role of Fenton chemistry in thiol-induced toxicity and apoptosis. Radiat Res.145(5):542-53 (1996).

12) Nagy L, Nagata M, Szabo S. Protein and non-protein sulfhydryls and disulfides in gastric mucosa and liver after gastrotoxic chemicals and sucralfate: possible new targets of pharmacologic agents.World J Gastroenterol.13(14):2053-60 (2007).

13) Lewandowicz AM, Vepsäläinen J, Laitinen JT. The 'allosteric modulator' SCH-202676 disrupts G protein-coupled receptor function via sulphydryl-sensitive mechanisms British Journal of Pharmacology 147: 422–429 (2006). doi:10.1038/sj.bjp.0706624

14) Moriarty-Craige SE, Dean PJ. EXTRACELLULAR THIOLS AND THIOL/DISULFIDE REDOX IN METABOLISM Annual Review of Nutrition 24: 481-509 (2004). (doi:10.1146/annurev.nutr.24.012003.132208)

15) Nozik-Grayck E, Whalen EJ, Stamler JS, McMahon TJ, Chitano P, Piantadosi CA. S-nitrosoglutathione inhibits {alpha}1-adrenergic receptor-mediated vasoconstriction and ligand binding in pulmonary artery. Am J Physiol Lung Cell Mol Physiol 290: L136-L143, 2006. doi:10.1152/ajplung.00230.2005

16) Rubenstein LA, Zauhar RJ, Lanzara RG. Molecular dynamics of a biophysical model for beta-2-adrenergic and G protein-coupled receptor activation. Journal of Molecular Graphics and Modelling 25: 396-409 (2006). http://dx.doi.org/10.1016/j.jmgm.2006.02.008

17) Rubenstein LA, Lanzara RG, Activation of G Protein-Coupled Receptors Entails Cysteine Modulation of Agonist Binding. J. Molecular Structure (Theochem) 430/1-3: 57-71 (1998). http://dx.doi.org/10.1016/S0166-1280(97)00387-4

Beta-Adrenergic Receptor in Two Molecular States

One Consuming Interest

Over the last several years, one of my consuming interests has been to understand how our cellular receptors function on the molecular level. Somewhat surprisingly, there is a rather simple two-state, acid-base model that accounts for a remarkable number of experimental findings.

These include everything from the Weber-Fechner law (see link) to the redox sensitivities of many receptors (see
Activation of G Protein-Coupled Receptors Entails Cysteine Modulation of Agonist Binding, J. Molecular Structure (Theochem), 430/1-3: 57-71 (1998) and Molecular dynamics of a biophysical model for beta-2-adrenergic and G protein-coupled receptor activation Journal of Molecular Graphics and Modelling 25: 396-409 (2006), for a picture of this model - Click here then also click on the picture). Over several years, I've tested many of the predictions from this model and found that it predicts and continues to explain a number of interesting findings. These include rapid receptor desensitization or tachyphylaxis (see link) and a method for preventing this desensitization (see link) and the phenomenon of "spare receptors", which is an old conundrum in pharmacology (see link).

Understanding how our receptors work at the molecular level is an awe inspiring undertaking, because these are the molecules that link our thoughts and senses to the universe. Understanding how they function may open new frontiers for us to truly understand our place in the cosmos.

I Could Be Wrong

I could be wrong.

This is something that every true scientist must face directly. Our mental constructs to explain the real world have assisted us greatly over many millennia. Today more than ever, we need to remind ourselves that our ideas can be mistaken. Scientists have a particularly difficult time with this, as they must become their own worst critic. Not everyone can do this.

What I do is to set my work aside for an extended period of time (dear reader, please forgive my blogging mistakes). Any period of time, from a day to years, helps to clarify issues that are initially unrecognized. This rest allows for the injection of new knowledge and a more objective perspective to grasp the larger picture.

Scientists have the additional burden of mathematics. Mathematics is a two-edged sword that can slice the Gordon's knot or cut off our hand. True science needs mathematics to objectively describe its findings. The problem with mathematics arises because there may exist more than one mathematical solution to a real world physical problem. Scientists have recognized this and decided that the simplest way to describe the real world problem is the best. This has been termed Occam's razor (sometimes spelled as "Ockham's razor" attributed to the 14th-century English logician and Franciscan friar William of Ockham).

If a scientist finds a mathematical solution that isn't so simple, then they often have a dilemma. The dilemma often occurs if they try to fit their data to some mathematical equation that fits the data, but only if they use higher and higher exponential powers of a particular parameter within their equation. The problem is that this process begins to lose the physical meaning behind that parameter and the logical connection to the underlying physical process becomes less clear.

Those who aren't scientists don't understand this dilemma and fail to recognize some of the serious implications for today's scientists. The old saying is, "Publish or perish"; however, my former mentor use to say, "Publish and perish!". This is a problem for both the experimental and theoretical scientists today because they have enormous pressures on them to publish their findings before they get scooped, or to get that grant, or to patent a promising technology, or to show a potential boss that they've published many papers. It is no wonder that the cold hard logic underlying the science often gets lost in these scenarios. It is also no wonder that if they have at least one mathematical equation that fits most of their data, then they will publish it without asking themselves what does it mean and what are the implications of using this equation. In other words the bigger picture often gets lost in the rush to publish and a scientist may lose their hand to the mathematical sword.

This leads one to consider the region of what I'll call "hard science". Hard science is the objective modeling of experimental findings using more than one model and then evaluating which model is best. Today this is almost impossible to do within one scientist's lifetime, because almost 90% of the scientists who've ever lived are alive today and they are exponentially adding to the scientific literature in their rush to publish so that there has been an exponential explosion in potential mathematical models in all scientific areas. No one scientist can test them all.

So what can hard science do? There are additional aspects within the mathematical equations to look for. First, the generality of the equation to other experimental findings is an important aspect. Second, the novelty of predictions arising from manipulations of the parameters within the equation and the experimental verification of these predictions. Third, the ability of the parameters within the equation to match with physical entities. This places the burden on the experimentalists to wisely choose the theory that they are testing. Thus are the scientific models that will lead us toward a better understanding of our universe proven true. This involves a lengthy process of give and take between theory and experiment to find the truth behind our scientific discoveries today.

I could be wrong.

Welcome

Welcome to my blog. First, a bit about what I'd like to share with those of you searching netspace:

I've discovered something truly remarkable. I'll try to explain it by suggesting that you first check out this gedanken experiment at http://www.bio-balance.com/SB_Gedanken_Exp.pdf and then http://www.bio-balance.com/Simple_Balance_PartI.pdf, and then http://www.bio-balance.com/Simple_Balance_PartII.pdf. These simple physical experiments demonstrate something very profound about a two-pan balance that to my knowledge hasn't been adequately explored or addressed before.

Although some of Archimedes' notebooks are lost, this discovery points to a fundamental equation of equilibrium that may have been previously discovered, but was lost (see - http://www.bio-balance.com/Anemone.pdf). This fundamental equation may revolutionize how scientists view everything from cellular receptor activation to complex, nonlinear systems (see - Weber's law or http://www.bio-balance.com/Weber's_Law.pdf and Graphics and http://www.bio-balance.com/A_Question_of_Balance.htm). Digesting this requires some time, but only a basic understanding of algebra. Those who try will be rewarded by the elegant simplicity of the fundamental equation of equilibrium that may hold the key to several complex problems today.