SLA Biomedical & Life Sciences Division Blog

The Observed Psychosocial & Psychopharmacological Commonalities Between Schizophrenia & Bipolar Disorder Seem More Than Just A Coincidence: Can We Now Add A Common Genetic Basis?

A recent article by  Lichtenstein et al.  and an accompanying commentary by  Owen & Craddock (both cited below)  in the January 17, 2009, issue of the The Lancet  bring up an ongoing controversy: Are schizophrenia and bipolar disorder much more biologically related to one another  than current mental disorder classification  schemes like DSM-IV would suggest? Do they share  a similar genetic pathway that would ultimately make treatment for both more alike and more effective?

THE DIFFERING DIAGNOSTIC   CRITERIA & CLINICAL CONCEPTUALIZATIONS

OF SCHIZOPHRENIA & BIPOLAR DISORDER

Schizophrenia tends to be categorized as a cognitive disorder where patients may have one or more of the following: strange thoughts, hearing  voices when they’re not there, see things that are not there,   erratic speech patterns ( sometimes wildly jumbled syntactically, sometimes  lapsing into non-communicative catatonia), and especially a severe lack of logic in their cause-and-effect thinking, all to the degree that they significantly affect their life and relationships.

Bipolar disorder tends to be classified as a disturbance of mood levels. Moods swing way up and often then go way down. Generally, bipolar patients are   observed to have abnormally heightened feelings about themselves that simply are not likely to be   proportional with reality ( they believe that they can rule the world; they have I boundless  energy; they’re think they’re  tremendously productive or creative; they can go without sleep, sometimes for days at a time; they can spend money like it’s going out of style,  feeling there’s not really any good reason to stop at the moment ; and often exhibit markedly increased libido).

These highs are  followed by abnormally low feelings about themselves that are also not likely to be proportional (they are suddenly of no consequence to anyone; they have no energy at all; they can’t accomplish anything ever again ; they sleep all the time; they have no interest in pleasurable activities, including sex). 

While there are certainly variations in the presence or absence of given symptoms, and even intermixing of  up-and-down  symptoms in some patients at the same time, bipolar disorder for the most part,  is about the patient feeling ebullient at one point and then feeling totally flat at another, to such a degree that it  impairs their ability to function in the real world.

THE SHARED CO-MORBIDITIES & REAL-LIFE CONSEQUENCES OF LIVING WITH THESE DISEASES WHEN THE PATIENT DOES NOT COMPLY WITH EFFECTIVE TREATMENT ARE NUMEROUS & PERHAPS NOT COINCIDENTAL

The idea that these mental illnesses  may be  closer than the way they are framed as distinct clinical entities, comes at least in part from shared maladaptive behaviors that are thought to be predisposing or concurrent to the long-term bad outcomes of letting either disease go without effective treatment.

Both schizophrenics and bipolars tend to abuse alcohol and drugs, and many times they are the same ones,  although the dominant choice of substance  differs somewhat by diagnosis.  There is some evidence that in recent decades, schizophrenics have been significantly greater users of marijuana, while bipolar patients have favored methamphetamines, quite possibly because they can give a low mood state bipolar person a feeling of exhilaration and high energy, not unlike their high or manic moods. 

A SMALL (& OFTEN MISTAKENLY EXAGGERATED)  BUT NOT INSIGNIFICANT SHARED PROPENSITY FOR IRRATIONAL VIOLENCE

Likewise there are accounts that a small proportion of patients with   either of these disorders (5%-10% depending on the study, but disproportionately reported as  being commonplace in the popular press in any case), commits a violent act against innocent bystanders, caretakers or family members.

The truth is that most persons with serious mental disorders are not violent, and are more often the victims of violence themselves.

Nonetheless in studies of that small proportion of schizophrenics who commit acts of violence the cause is thought to be based on a  typically bizarre belief that  the victim of the assault was someone who somehow was mysteriously persecuting them, or monitoring or stealing their thoughts.

With bipolar patients, the victim is often a person who forcefully contradicts the bipolar patient’s assertions of  the patient’s vast superiority, or who tries to intervene in a destructive behavior (such as a spending spree or drinking binge) or someone who reports  to a rapidly speaking manic bipolar patient that they are  simply  not making any sense and cannot be understood, whereupon the manic person strikes out in frustration of the audience’s “slowness”  of comprehension.

The underlying motive seems to be rage on the part of the bipolar perpetrator,  that their particular view of the state of affairs or evaluation of their exalted status  is just not being  taken seriously by the rest of the world.

SHARED DISINTEGRATION OF FAMILIES, SCHOOLING & EMPLOYABILITY

There is also a commonality of familial, educational, and occupational breakdowns   between poorly managed schizophrenics and bipolar patients.   Marriages are often strained to the point of  dissolution (and severe mental illness is grounds for a virtually automatic  divorce in most states).

 Likewise,  students of high-school ( and even of  college age), are not likely to have their odd and generally disruptive behaviors tolerated by their peers, even if under ADA, the school (or university)   is required to make reasonable accommodation for the  student if they are notified in advance officially by the student or their parent or guardian that they require special treatment.

 While employers are now also under similar strictures, they are not required to keep on the payroll a patient who simply can no longer do the job or any available comparable work, or who cannot conform their behavior sufficiently to work alongside colleagues or with customers.

Often in either the educational or occupational setting, extended periods of unexplained or unexcused patient absenteeism is the reason for dismissal.  There is some good news in that today Social Security disability is more readily attained by those with intractable mental disorders.

SHARED PROPENSITY FOR SHORTER LIFESPANS & SUICIDE

Unfortunately there is a shared prevalence of suicide (depending on the study in the teens of percentage), and an equally dramatic lifespan reduction of between 15-20 years on average, among noncompliant  bipolars and schizophrenics. The lifespan reduction  may well be tied to concurrent trend among schizophrenics and bipolars towards homelessness or living in single-room occupancy settings in marginal neighborhoods that are poorly served by any form of healthcare.

SHARED PROPENSITY FOR RESPONDING WELL TO THE SAME DRUGS & SHARED PROPENSITY FOR DOWNWARD SPIRALS WHEN THE PATIENTS STOP TAKING THEM

Still another commonality between bipolar patients and schizophrenics is their increasingly common pool of prescribed medications. Clozapine, olanzapine, risperidone, ziprasidone, and ariprazole which were  once used primarily for psychotic episodes among schizophrenics,  are now also being used for longer term bipolar patients with more severe symptoms,  with a great deal of  success.

The fact that these drugs work when they are taken religiously suggests that the diseases may operate via similar neurochemical pathways. Unfortunately, frequent noncompliance of both schizophrenics and bipolar with their medications, is another shared trait between the two patient populations. The frequency, speed and degree  of symptomatic recurrence also appear to be about the same among bipolar and schizophrenics, and the untoward side-effects of the drugs also show a striking similarity.

IF MANY OF THE BEHAVIORS,  OUTCOMES & EVEN SOME OF THE EFFECTIVE MEDICINES ARE THE SAME,  MIGHT THERE BE A COMMON GENETIC BASIS?

While  any one of these commonalities might be explained away individually, the common collective pattern between the two clinical groups increasingly suggests a common causation, probably at the molecular level, given the common effectiveness of the pharmacology.  

In other words, a genetic load for either schizophrenia or bipolar disorder is said to be  “prodromal,” meaning very highly predictive of development of the disease despite various educational or social interventions.

 The first objection to this genetically prodromal argument is that it smacks  to some civil liberties, educational association,  and nonmedical therapist groups as  “biological determinism”  meaning that the patient is inevitably destined (or labelled as destined) to get the disease, no matter what else happened  to the patient, and often despite all therapeutic interventions designed to avoid the development of the illnesses.

Some feel that too strong a genetic explanation underplays the role of bad environmental influences such as indifferent parenting, poor  schooling, poverty, childhood trauma, malnutrition, the presence of drugs and alcohol in the environment, and even toxins in the food and water,   or shared epidemic exposure to influenza or other infectious diseases that are known to cause cognitive damage to children and even to fetuses --------all of which have their scientific or social work adherents as agents of causation of one or the other of these mental illnesses.

But this can be answered by far more rigorous and empirical  studies (particularly studies of twins reared apart, and adoption studies where the family environments & schooling are very different) that suggest that the causations proposed by classic psychoanalysis and social critics of psychiatry seem to account for very little that would deflect a straightforward genetic explanation. Most convincing is the opposite case: there  are  few large statistically reliable reports of a pattern of  adopted kids from “normal” birth parent routinely developing bipolar disorder or schizophrenia, even  when they are raised by adoptive parents who have one or the other disorder. The odds of seemingly normal adoptees developing these disorders later in life are vastly closer to that of the random population.

Nonetheless, even in the most deterministic genetic analyses, a few percentage points ( from 4.5%-7.4% for schizophrenia; 3.4%-6.2% for bipolar disorder)are allocated today towards “epigenetic” or environmental  factors.

What makes the Lichetenstein et al. study cited below so important , and so very definitive, is that  it involves an incredible 9,009, 202 individual studied from more than two million different families. The study of these very highly detailed and standardized government health  insurance  records turned up 35,985 clearly diagnosed schizophrenics and 40, 487  clearly diagnosed bipolars , which generated  a follow-up examination of the same records for   any patterns of mental health  disorders among relatives of varying degrees of closeness, whether living together or living apart.

The statistical inheritability of schizophrenia was placed at 64% (versus 1%  occurrence in the general population) and 59% for bipolars  (versus 3% in the  general population).

But what is even more striking is that in families where one sibling had bipolar disorder, not only did other siblings have an increased risk of bipolar disorder, but also of  developing schizophrenia, or developing both bipolar disorder and schizophrenia.

This  common biological-relatedness-propensity, or shared genetic load result even held up when a sibling with one or the other disorder was raised entirely apart from the birth family.

The  scariest  if entirely reasonable corollary of this study  may be the that a parent from a family that seemingly has a genetic history of one mental illness that marries into another family with the other, appears to convey to their children, not just a propensity for one or the other illness as the same rate as their parent’s generation, but  actually a higher rate of getting either or both.

This dangerous idea only makes sense only if the genes for one illness essentially pile on with the other, because it turns out that they are essentially the same genes that encode for the same structural (white matter) and metabolic (neurochemical) processes.

In other words, introducing more bad genes into a family clearly means more bad outcomes are likely in their children.

This starkly “eugenic” sounding formulation , if eventually proven true, however, has a really  sympathetic and beneficial effect on the patients themselves: if the diseases are essentially the same and  additively reinforcing in their genetic roots, and in subsequent brain structures and processes, then drugs treatments and future diagnostic procedures could one day be much more unified, and ultimately more beneficial to both variations of what, at its core, may be the same brain malfunction.  

This is particularly important given that the Diagnostic & Statistical Manual V, the tool with which the vast majority of the mentally are diagnosed and treated, is just around the  corner.

Tony Stankus, tstankus@uark.edu Life Sciences Librarian & Professor

University of Arkansas Libraries 223 E

365 North McIlroy Avenue

Fayetteville AR 72701

Voice: 479-40100021

Fax: 479-575-4592

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Brunette, M. F., Asher, D., Whitley, R., Lutz, W. J., Wieder, B. L., Jones, A. M., et al. (2008). Implementation of integrated dual disorders treatment: A qualitative analysis of facilitators and barriers. Psychiatric Services, 59(9), 989-995.

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Craddock, N., O'Donovan, M. C., & Owen, M. J. (2006). Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophrenia Bulletin, 32(1), 9-16.

Crow, T. J. (2007). How and why genetic linkage has not solved the problem of psychosis: Review and hypothesis. The American Journal of Psychiatry, 164(1), 13-21.

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Curran, G. M., Sullivan, G., Williams, K., Han, X., Allee, E., & Kotrla, K. J. (2008). The association of psychiatric comorbidity and use of the emergency department among persons with substance use disorders: An observational cohort study. BMC Emergency Medicine, 8, 17.

Duffy, A., Alda, M., Crawford, L., Milin, R., & Grof, P. (2007). The early manifestations of bipolar disorder: A longitudinal prospective study of the offspring of bipolar parents. Bipolar Disorders, 9(8), 828-838.

Etain, B., Roy, I., Henry, C., Rousseva, A., Schurhoff, F., Leboyer, M., et al. (2007). No evidence for physical anhedonia as a candidate symptom or an endophenotype in bipolar affective disorder. Bipolar Disorders, 9(7), 706-712.

Fallin, M. D., Lasseter, V. K., Avramopoulos, D., Nicodemus, K. K., Wolyniec, P. S., McGrath, J. A., et al. (2005). Bipolar I disorder and schizophrenia: A 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. American Journal of Human Genetics, 77(6), 918-936.

GAIN Collaborative Research Group, Manolio, T. A., Rodriguez, L. L., Brooks, L., Abecasis, G., Collaborative Association Study of Psoriasis, et al. (2007). New models of collaboration in genome-wide association studies: The genetic association information network. Nature Genetics, 39(9), 1045-1051.

Gallinat, J., Bauer, M., & Heinz, A. (2008). Genes and neuroimaging: Advances in psychiatric research. Neuro-Degenerative Diseases, 5(5), 277-285.

Hatfield, J. S. (2006). The genetic basis of hair whorl, handedness, and other phenotypes. Medical Hypotheses, 66(4), 708-714.

Ilgen, M. A., Hu, K. U., Moos, R. H., & McKellar, J. (2008). Continuing care after inpatient psychiatric treatment for patients with psychiatric and substance use disorders. Psychiatric Services, 59(9), 982-988.

Ishizuka, K., Paek, M., Kamiya, A., & Sawa, A. (2006). A review of disrupted-in-schizophrenia-1 (DISC1): Neurodevelopment, cognition, and mental conditions. Biological Psychiatry, 59(12), 1189-1197.

Kato, T., Iwamoto, K., Kakiuchi, C., Kuratomi, G., & Okazaki, Y. (2005). Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders. Molecular Psychiatry, 10(7), 622-630.

Lichtenstein, P., Yip, B. H., Bjork, C., Pawitan, Y., Cannon, T. D., Sullivan, P. F., et al. (2009). Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: A population-based study. Lancet, 373(9659), 234-239.

McIntosh, A.M., Job, D.E., Morehead, T.W., Harrison, L.K., Lawrie, S.M., Johnstone, E.C. ( 2007). White matter density in patients with schizophrenia , bipolar disorder, and their unaffected relatives. Biological Psychiatry  58: 254-257.

Mukherjee, O., Meera, P., Ghosh, S., Kubendran, S., Kiran, K., Manjunath, K. R., et al. (2006). Evidence of linkage and association on 18p11.2 for psychosis. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 141B(8), 868-873.

Niehaus, D. J., Koen, L., Galal, U., Dhansay, K., Oosthuizen, P. P., Emsley, R. A., et al. (2008). Crisis discharges and readmission risk in acute psychiatric male inpatients. BMC Psychiatry, 8, 44.

Ongur, D., Lin, L., & Cohen, B. M. (2009). Clinical characteristics influencing age at onset in psychotic disorders. Comprehensive Psychiatry, 50(1), 13-19.

Owen, M.J. & Craddock, N., Jablensky, A. (2007). The genetic deconstruction of psychosis. Schizophrenia Bulletin 33: 905-911.

Owen, M.J., & Craddock, N. (2009). Diagnosis of functional psychoses: Time to face the future.  The Lancet, 373 (9659), 190-191.

Prince, J. D., Akincigil, A., Kalay, E., Walkup, J. T., Hoover, D. R., Lucas, J., et al. (2008). Psychiatric rehospitalization among elderly persons in the United States. Psychiatric Services, 59(9), 1038-1045.

Rende, R., Hodgins, S., Palmour, R., Faucher, B., & Allaire, J. F. (2005). Familial overlap between bipolar disorder and psychotic symptoms in a Canadian cohort. Canadian Journal of Psychiatry - Revue Canadienne De Psychiatrie, 50(4), 189-194.

Ringen, P. A., Melle, I., Birkenaes, A. B., Engh, J. A., Faerden, A., Vaskinn, A., et al. (2008). The level of illicit drug use is related to symptoms and premorbid functioning in severe mental illness. Acta Psychiatrica Scandinavica, 118(4), 297-304.

Schulze, T. G., Ohlraun, S., Czerski, P. M., Schumacher, J., Kassem, L., Deschner, M., et al. (2005). Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: A first step toward a molecular genetic classification of psychiatric phenotypes. The American Journal of Psychiatry, 162(11), 2101-2108.

Sharif, Z. (2008). Side effects as influencers of treatment outcome. The Journal of Clinical Psychiatry, 69 Supplement  3, 38-43.

Sikich, L. (2008). Efficacy of atypical antipsychotics in early-onset schizophrenia and other psychotic disorders. The Journal of Clinical Psychiatry, 69 Supplement  4, 21-25.

Szatmari, P., Maziade, M., Zwaigenbaum, L., Merette, C., Roy, M. A., Joober, R., et al. (2007). Informative phenotypes for genetic studies of psychiatric disorders. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B(5), 581-588.

Is Fear Of Being Attacked In The Animal Kingdom Inherited Or Learned? If Forgotten, Can It Be Re-Learned? Joel Berger’s Book, “The Better To Eat You With” Offers Some Clues

Indiana Jones is a wildly popular daring-do movie-matinee adventurer,   known to millions,  but Joel Berger of the University of Montana and the Wildlife Conservation Society is  perhaps braver (and   crazier) , but very real, and ought to be better known by biomedical and life science librarians and their readers.

In his book, The Better to Eat You With: Fear in the Animal World (The University of Chicago Press, 2008. ISBN: 13: 9878-0-226-04363-0), uses exceptional ingenuity to find scenarios and develop tactics to test hypotheses about how prey animals, most commonly moose, elk, and buffalos come to fear and flee from (and occasionally to fight with) predators: mostly wolves, but also grizzly and black bears, and the occasional mountain lion, Siberian tiger or snow leopard.

Interviewing is pretty much out, the fictional Bullwinkle’s talkativeness aside, so observation is pretty much the only way to figure it out, but it is the behavioral and environmental manipulations that Berger uses that helps him create something like a laboratory of experimental animal psychology wherever he goes.

Here are some of the situations he explores in his book.

How can you tell when a prey animal is concerned about an approaching predator? What are good measurable indicators of initial predator awareness? Watchful waiting? Intention to flee?

If you have had a cat, you might have guessed that pilo- erection (the hair-raising of many mammals when being threatened or threatening others) is certainly one clue, but is it quantifiable?  And at what distance does such an observation become unreliable?  

Berger suggests that the time for some animals, particularly large hoofed game, the  which point the animal interrupts its browsing, and the duration of the interruption, and any repeated sequences of the interruptions,  are things that can be not only counted but timed to develop data points.

Prey animals that interrupt sooner, interrupt longer, and interrupt more often, have probably learned to be more wary, or were given a genetic endowment that favors wariness. He even offers a scenario how this might be tested, and the issue of learning  to fear versus inherited fear.

For this test, we need (and Berger finds)  three populations of moose, for example. 

1.     Those prey animals who have lived with wolves or bear or cougars around all their lives (e.g. moose in parts of the Canadian wilderness where predators were not extirpated). They should be the measurably the wariest, although sorting out whether or not learning or heredity is dominant would still be difficult.

2.     Those  prey animals that live in areas where there have never been predators, for example, those who live on remote islands that never had predators. They should be measurably  the least wary, although if they are unexpectedly very wary, a score in favor of inherited fear might be better made.

3.     Those prey animals who live in an area where predators are being re-introduced after an absence of many generations of prey animals. If the prey are very wary, right from the start of the reintroduction,   such fear is unlikely to be a learned behavior. It is likely to be inherited instinct. But , if the animals are initially clueless, and suffer great losses to predation, but then  learn to cope by being wary, fleeing sooner, or getting more combative, then we might say that fear is learnable and learned.

In numerous studies detailed colorfully in the book, Berger tends to come down on the side of fear being primarily learned.

He bases this on the early experiences of naïve prey in national parks where wolves are re-introduced. Large mother moose who could flee with their calves or fight on behalf of their calves, often lose a calf on their first encounter ever with a predator.

But the lesson is often learned by next calving season. Prey are by no means uneducable. In fact, in cases where their prey is more social (elk are gregarious more often than  moose and apparently can learn from observation or some form of communication) it appears that learning to be wary and flee sooner can somehow be transmitted to elk mothers who have not personally lost calves.

Seeing a wolf or a bear or a cougar attack a prey animal is not always a practical way to judge alertness and fear responses, quite possibly because you cannot count on either predator or prey showing up exactly at the same time, whenever you are ready  to observe them.

So Berger develops a number of proxy situations. He asks himself: Will moose in areas that have long had abundant predators predictably react more quickly to a recording of a wolf howl, than will totally naïve moose? (The answer is dramatically YES….for naïve moose often do not react at all). But will the time to demonstrate an alert response also be shown to decrease in animals that used to be naïve, but have had a new if sad experience with predators? (The answer is also yes.) This last suggest learning once again.

A trick question might be if it is just the noise that matters. But it turns out that recording of loud howler monkeys does not get much of a rise, despite equal blaring.

One surprise, however, is that the roar of the African lion uniformly causes an alert state of fear even in animals which have never seen a lion in a thousand years or recent history. Berger suggests that this anomaly is perhaps best explained by the fact that some fear responses are genetically preserved, perhaps because they were uniformly lethal for those who did not inherit that particular type of fearfulness.

Berger points out the fact that throughout pre-historic North America, a variety of giant lion-like predators, much larger than mountain lions, and presumably with vocalizations similar to the African lion, were clearly present.  This can be seen from fossil findings,  from the retrieval of bones from site like the LaBrea tar pits, and from human-made cave paintings or other artifacts.

In one of his most interesting speculations, he suggests that the timing of the of Asiatic migration to North America might have been  influenced by more than just the periods at which a land bridge existed or water-craft were invented.

He suggests it might have been held up until those Asiatic hunter peoples developed their own fear-and-experience-based ways of fending off predators in order for themselves to become predators on the large animal prey of the time (e.g. mammoths) more plentiful in the New World.

Berger also demonstrate that there is some evidence that prey animals can associate, and react with fear, to  the sounds of scavengers (like ravens or eagles or vultures)  with the presence  of the predators that initially killed the prey. In other words, some of them realize and internalized the notion that the  Lords of Leftovers had to be preceded by the Princes of the Prime cuts. If the one were around, the other could not be far away.

Of course, there are other pungent parts of the book, such as Berger’s expertise in tossing snowballs of lion’s urine or  bear crap in order to detect if olfactory cues also factor into different levels of awareness.

Do naïve prey ignore or dismiss odiferous signs of imminent danger (pretty much); do those raised constantly with predators respond more reliably and appropriately (yup!), and can a change in sensory awareness and signal processing be observed in animals transitioning to a new world that now includes predators? (it seems so.)

All along the way, are other interesting nuggets of animal behavior information, including the role of the influence of leaders.

 For example, there are pods where it appears that the lead whale learns to pick fish off of commercial fishing lines, and the rest of the group learns from him. However, when the lead whale dies, the pod simply forgets this new skill.

And clearly there are differences of intelligence and personality even among animals within the same species and pack.

For example,  leading life sciences librarians with  an interest in animal learning and the transmission of fear and flight behaviors, and a few bucks, will demonstrate their superior intelligence by getting this book as soon as they sense its importance!

The others, well, they  may could fall prey to critical  faculty customers who want to know why this valuable resouce was not already in place.

Tony Stankus tstankus@uark.edu Life Sciences Librarian & Professor

University of Arkansas Libraries MUULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-0021

Fax: 479-575-4592

Functional Food Health Advertising : Is Everything that Is Claimed to Be "Bioactive" or an "Antioxidant" Really Essential in Such Great Quantities or from Specific Food Types? Plant-Based Sources Are Abundant But Evidence is Not

One way of defining functional foods is that they are consumed for day-to-day energy balance and bodily maintenance but “may” have additional health benefits.

Functional foods are like regular foods  in many ways. Just as in foods that do not advertise themselves as being nutraceutical or functional, their “Nutrition Facts” label  clearly indicates a number of calories,  along with quantities and percentages of  given types of carbs, fats, vitamins and minerals contained, and how much of the recommended daily needs are met by consuming a suggested portion.

The difference is that while there is widespread scientific and clinical consensus on the standards for accuracy of that Nutrition Fact Label information,   as well as support  for the efficacy and safety  of the nutrients that are mentioned on that label, there is often significantly less factual basis for much of the additional “scientific”-sounding terminology that appear elsewhere on package labeling or in advertising, that suggests those “additional health benefits.”

The most important new health claims are made in bold lettering and only partly offset by fine print warnings that these foods are “not intended or claimed to aid in the diagnosis or treatment of any specific diseases.”

Nonetheless, there is a great rise in the use of terms such as “bioactive ingredients” as if  all  substances tagged with this,   were clearly beneficial to a significant degree for human health.

“Bioactive” simply means that the ingested materials are likely to react chemically within the body, as opposed to being relatively inert. In point of fact, the poisons in  mushrooms and snake venom are also “bioactive”.

“Bioavailable” is actually a more useful term, in that it should indicate what proportion of  the purported active ingredient is actually released into the body in a way the body can use. In other words, a proposed functional food, like a fish,  may be potentially a good source of calcium if one eats the bones. This might be fine for sardines, but, apart from any choking it would cause,  swallowing the bones of a codfish would not likely cause for much release of the calcium in a form useable by the body, because the calcium in large fish bones is not particularly “bioavailable.”   

  And one increasingly finds  in nutraceutical and functional food marketing  mention of their products having specific   categories of  naturally occurring compounds that share some characteristic chemical structure or have purported pharmaceutical functionality. 

The technical definition, molecular formula,  and 3-D drawing of these compounds would make for a good test question for courses in advanced bio-organic chemistry. But the names of these compounds   are instead, tossed out to the lay public as if that knowledge was common or self-explanatory.

In reality these compounds  are  vaguely perceived as being “something medical and important”  to most consumers. These compounds  are consequently inferred by the consumer to be  something essential to their very survival, or at least something of which they ought to have more of, to avoid any “unhealthy deficiency.”

The Best Case Scenario: Antioxidants

Antioxidants are any chemical compound that reduces electron loss in chemical compounds ----- indeed “reducing agent”  would be an equally valid term, although not one in common usage in human nutrition. 

The aim of reducing oxidation is to stabilize the structure of many biochemicals within the body, which function best in an unoxidized state, or in some cases, seriously malfunction when oxidized.  

The causative agents promoting these malfunctions are generally termed “free radicals,” although in Cambridge, MA and Berkeley, CA, they are probably re-named “ bourgeois capitalistic tools, “ to avoid offending the bulk of the populace.

Antioxidants in general have the most conventional science in their favor. Indeed, it is now well established that vitamins A, C, E, beta-carotene, and the trace element selenium work at least partly through their antioxidant capabilities, and recommended minimum daily requirement have long been established.

There is indeed some evidence developing that they may work by helping to stabilize the process of DNA replication, and that some people could benefit even more from these antioxidants if an optimal match could be made between their genetic needs and the antioxidants that would best support this stability, fostering   a  new field of Nutrigenomics.

What is not clear is what are the specific levels of  total antioxidants of all types, one must have before there are  too many or too  few for good health.  The underlying goal   is to somehow have enough of a supply of antioxidants to avoid adverse effects, without shutting necessary oxidation activities (like breathing and digestion!).

There are, unfortunately, many more claims that antioxidants “boost immunological functioning”, “cognitive ability”, and “reduce infection and inflammation” and even cure the common cold, than there is evidence that any of these assertions are true.

There is some evidence that the body is less capable of handling   free radicals  with increasing age, but, unlike some claims made in advertising, it is not clear that  an insufficiency of dietary antioxidants causes aging (it is clear to me that living for a long time causes aging) as well as diseases of cumulative effects like some cancers, and macular degeneration.

There is a good deal of epidemiological information that people who consume diets naturally rich in antioxidants ------typically five or more servings of vegetables and fruits -----are healthier. And, at least in the case of macular degeneration, there is evidence that consuming mega-doses of certain antioxidant vitamins (specifically the Age-Related-Eye-Disease-Study or AREDS formulation) slows the progression of macular degeneration, although it is not clear that an absence of antioxidants was the cause of the disease in the first place.

There is conversely some evidence that an overabundance of some of these antioxidants  (vitamins  A,  E and beta-carotene) can increase mortality in certain populations. Smokers with early macular degeneration are given a modified formulation of  AREDS vitamins for this very reason.

What specialized categories of antioxidants seem to be making the news most often as being parts of nutraceuticals or functional foods? Lets look briefly at a few categories.

Carotenoids

Lutein, zeaxanthin, and lycopene are among the most commonly mentioned antioxidants. They are called carotenoids, quite frankly because they were first isolated in carrots, although they are widely available in many leafy  green plants (but overshadowed by the green pigments). Most of these antioxidants are naturally colored with shades ranging from yellow (marigold petals are used in most AREDS formulations) to orange (carrots)  to red (lycopene, for example is particularly found in products made from ripe tomatoes).

The Polyphenols, Particularly the Flavonoids

The nomenclature for the flavonoids comes in part from the Latin term for  blond and indeed, a dynasty of Roman emperors, the Flavians, were all (real or bottled) blondes (and major league throwers of Christians to the lions.) .

In fact, this is another family of yellow to red colored compounds with antioxidant capabilities, although their organic chemical structure involves more carbon rings ( particularly phenolic rings) than the carotenes, and there is a branch of this  chemical family that also has blue and green tints.

Like the carotenes,  polyphenols are largely present   in fruits and vegetables, particularly highly colored berries, grapes and citrus.  But owing to that blue-green branch, they can also be found in tea and cocoa plants.

Not too surprisingly, the polyphenol  antioxidant resveratrol, which is found in darkly-colored grape skins , has suggested that red wines in particular, might well function as nutraceuticals. Peanuts, it turns out, also have a significant amount of this category of antioxidant.

Isothiocyanates

Sharing a blue-green coloring with one branch of the flavonoid family are for some members  the  Brassica or Cruciferous  family of plants. Broccoli, Brussel sprouts, cauliflower, horseradishes, kale, mustard greens, radishes, turnips, watercress and even wasabi   are included, although to date,  few functional foods seem based on these healthful, but frankly gassy plant foods.

Carbon Sulfides

While hydrogen sulphide, the smell of rotten eggs,  is arguably the strongest stink on the planet,  the organo-sulphides are another, and rather popular,   class of functional food antioxidants, despite their sometimes overpowering smell. The most famous of these are various garlic-based supplements.

The Need for Standards in Making Claims of Quantity, Quality & Efficacy

There is indeed, growing evidence that nutraceuticals and functional foods that contain antioxidants that do just what they claim to do: promote human health, although the extent is quite unclear.

But there is at least as much evidence that the so-called health-food and nutritional supplement industry sometimes plays fast and loose with the levels of the antioxidant  that are present, from batch to batch,  or which are in fact, truly “bio-available” and in general, exercises less quality control, by far, than the convention medical/pharmaceutical industry. The paper by Griffiths et al. in the January 2009 inaugural issue of the Journal of Functional Foods , below outlines an excellent proposal for this industry to adopt the Council-of-Experts” approach used by the US Pharmacopeial Convention, Inc.

Tony Stankus tstankus@uark.edu Life Sciences Librarian & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AT 72701-4002

Voice 479-409-0021

Fax 479-575-4592

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Cellular Reprogramming: The Extraordinary Potential of Transplanting Stem Cells Produced by Oocyte Stem Cell Factories Whose Own Nuclei Have Been Removed and Replaced by Specialized Adult Cellular Nuclei

According to the journal Science, (see Alberts,  and Gurdon et al. below) the most important story in all 2008 science was progress made in the understanding of the ability of some cells to be reprogrammed from being one kind of functional cell into another kind doing a very different job.  

The story includes a kind of time machine effect, whereby the nuclei of functionally specialized adult cells could, through the cooperation of young cells otherwise intended to become something else (namely eggs)  be turned instead into factories for making  young stem cells with great curative potential for jobs other than being a female  gamete.

Cellular reprogramming holds out great promise for a number of reasons, not the least of which is their  ability somehow  to grow corrected (as opposed to inherently faulty) replacement tissues for malfunctioning hearts, pancreases, and perhaps even brains.

This process does not work equally well using all types of cells as starting material.

In fact, the most direct adult-for-adult cellular replacement approach, often works the least well.

Attempts to go about replacing sick adult heart cells with other healthier adult heart cells, for example, has rarely succeeded thus far, for reasons of both “foreign” tissue rejection, and the fact that adult stage tissue when placed among other adult stage tissue already in place within the organism,  do not often go on to yield highly viable, self-reproducing healthy tissues.

A statistic recently reported is that only about one in 10,000 such transplants survives.

This held true even in some cases when it was the patient’s own “corrected” adult cells that had been cultured and reintroduced. Having essentially identical DNA did not seem reliably to guarantee success or even always to confer protection from immunological attack.  

For years, it was thought that the closeness of genetic match, for example, using human cells ( as opposed to say, mouse cells)  for human cellular replacement, would be  the only or at least key feature making  cellular transplants more successful.

But that genetic relatedness notion told only half the story. The environment in which the very same genes function   can yield very different results in terms of what tissues develop or get reprogrammed.

Stem cells -----pre-adult-cells that have wide range of potential capabilities, even if they ultimately turn into a particular type of adult cellular functional specialist --------- work much better, even if they are not as fully trained for the particular specialty job which they will eventually assume upon transplant.

First, they have an advantage in that they appear to generate much less immunological attack. (Being very young appears to render them somewhat harmless appearing to many immune systems).

And, stem cells are like very bright college students   before they have definitively   decided on a college major. They are amenable to being trained one way or another, even if they all have the same DNA at the start.

Take identical twins, who are somehow assigned different training tracks in their freshman year in terms of what group of mentors with which they come into contact.

Through exposing one of   them to a working group in chemistry, and the other to  one in economics,  an academic dean has a higher rate of turning them separately into chemists or economists, even though they both had an essentially identical genetic repertories.  

The trick is first, to develop a production system that will make stem cells abundantly; second, it is to influence the resulting stem cell to take on the role you want.

The best, but no longer only,   cellular factory for creating new stem cells is the oocyte. Ooctytes are essentially egg cells about one step from becoming independently viable mature eggs capable of fertilization, after which they would turn into embryos.

Today it has been recognized that timing with ooocytes, if not quite everything, is really important. Using too mature an egg cell does not work as well as using these young oocytes.

 It appears that oocytes present a window of opportunity for  having their own nuclei extracted without having too much of their own original  genetic propensities remain residually in a manner that would inhibit,  or work at cross purposes with the purpose of the DNA introduced by a transplanted nucleus.

In other words, an oocyte which has its own DNA removed, and is then injected with the nucleus of another mature cell, seems to offer fewer “objections” to making stem cells that are more influenced by the injected nucleus.

How then are resulting stem cells made to orient themselves in a manner to get the job required done?  In other words, how does one recruit or transform the best starting material once it has begun being made in some quantity?

While there are several approaches possible, three  appear  more practical at this time.

·        The first is to find the  best available subpopulation of cells within the original source of the more specialized cells, even when dealing with very sick individuals, and to culture them to obtain enough healthy nucleic for transplant into oocytes.

To continue our college analogy:  Even among some very badly performing high schools, are likely to be some heroically performing, over-achieving  individual students who ought  to be selected.  They ought to be taken out of their otherwise hopeless underperforming environment, and be bolstered by association with other successful “despite-the-odds”  students. As we have repeatedly seen, throwing high school overachievers directly into the adult world through direct injection  rarely works (the 1 in 10,000 statistic). They need instead, to get a fresh start where allowance for growth in ability and some shelter from immunological attack can be had by first   attaining stem cell status.

These  overachievers are to be excised from their sick  tissue, multiplied in the lab, and then instead of being directly injected back into the patient, have their nuclei injected into oocytes whose own nuclei have been removed immediately prior. These oocytes then go on in a maternal way to reproduce the next generation of what would otherwise have been their own egg cells as instead, stem cells having a propensity for achievement.

Being exposed to the best and the brightest tends to multiply natural propensities, in a sense “ the collective genetic and epigenetic environment” steers the resulting stem cells successfully,   so that eventually the resulting cell culture is not seen as a clone of a failing system but as the stem cell of a particularly promising “campus culture” that tends to have a great propensity for functioning as chemists or economists, so to speak.

·        The second approach is to encourage the nucleus-transferred oocytes to develop into early stage embryos with multiple types of harvestable stem cells in different areas of the proto-fetal body.

 

In other words, let the process of embryonic development   build an assortment of easily harvested of quasi-specialized  tissues with some degree of potential already: nervous system-oriented  stem cells could be harvested for brain and neurological transplants,  proto-blood cells (hemoblasts)  could be used for blood or marrow transplants, etc.

·        The third approach is to use either method one or  method two, and find a chemical agent, or a benign virus bearing some added genes,  that amplifies the effectiveness or favors the production of stem cells in a manner that yield a desired disproportion of more vibrant cells for transplant.  This is the method that probably has the most promise at this point.

Ultimately, the new thinking is that introducing a fresh supply of many healthier, more viable stem cells that have a chance for reproducing is likely to work better than attempts to someone do single gene replacement or single gene silencing therapy. Healthy tissue that reproduces well in the patient after transplantation, is likely to become a more viable option than hoping that a newly  altered gene will not be shut down or revert to “wild” or “carcinogenic” or otherwise dysfunctional status.

Tony Stankus tstankus@uark.edu Life Sciences Librarian & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice 479-409-0021

Fax: 479-575-4592

 

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