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Oregon State University
The Linus Pauling From the Director Balz Frei, Ph.D. LPI Director and Endowed Chair Distinguished Professor of An Interview with Biochemistry and Biophysics Sharon Krueger, Ph.D. Joan H. Facey LPI Professor Assistant Professor (Senior Research) I n my last column I told you about the strategic Q. Where did you earn your doctorate?
planning process that the Linus Pauling Institute A. I earned my doctorate in genetics and crop science from
embarked on about a year ago and promised to update Oregon State University. you on the emerging key goals and initiatives. We are now in the process of finalizing the plan, which will be released Q. Did you work on plant breeding at OSU?
in May. As we move on to the all-important implementation A. I did. I got my master's degree in plant breeding in
phase, there will be numerous changes in how we do Wisconsin, and then I moved here to pursue my Ph.D. business here in the Institute. For instance, future Research My master's degree was involved with traditional Newsletters will be published online only, to allow for genetics and plant breeding, and I wanted to come greater flexibility in content, linking to other articles and to OSU to study genetics at a population level. I was web-based resources, and to save expenses for printing and working with a rather obscure plant called Cuphea, mailing, which are considerable for over 14,000 copies. which was being developed for its unique spectrum of Therefore, if we do not have your email address and you
would like to continue to get our Newsletter, please send
Q. How did you become involved in the Department
an email to If you do not have access
of Fisheries and W
to email and would like to continue to receive a hard copy A. When I was here as a Ph.D. student, I was diagnosed
of the Newsletter, please use the enclosed card to let us with a rare genetic enzyme deficiency that causes a know. We'll be happy to send you a copy by regular mail. metabolic muscular dystrophy. I was preparing for a As part of the strategic plan, we first developed a new career as a Mendelian geneticist doing traditional crop vision and mission for the Institute. Our vision is breeding that would have placed me out in the field, "Discovering how to live longer and feel better," which but that was not going to be compatible with my many of you will recognize from the title of Linus Pauling's condition. Although my underlying interest was in best-selling book touting the many health benefits of genetics, I really wanted to change my research focus vitamin C and other dietary supplements as part of a to work on metabolism, which would be compatible healthy diet and lifestyle. Our vision thus links back with the constraints of muscular dystrophy. That led to our founder and his ground-breaking concept of me to Fisheries and Wildlife, where I could establish orthomolecular medicine—the right molecule at the right my ability to work with animals. concentration to achieve optimal health and prevent Q. How did that lead to you working in
disease—and at the same time looks ahead to what we are environmental and molecular toxicology?
trying to achieve through our work, as explained in our A. I was aware of Dr. Williams' work—who's now an
new mission statement: LPI Principal Investigator—and he had an opening for The mission of the Linus Pauling Institute is to promote someone to work on the metabolism by enzymes of optimal health through cutting-edge research and trusted both endogenous and exogenous compounds, including public outreach. To accomplish this, we will: pharmaceutical drugs and pesticides.
continued on page 2 continued on page 2 Continued from cover — From the Director • Discover basic mechanisms underlying the biology academic institutions around the country, LPI has of aging and the causes of metabolic and age-related experienced a steady decline in federal research funding over the past five years. While we will continue to pursue grants from the National Institutes of Health, it will be • Develop effective approaches to slow aging and postpone metabolic and age-related diseases through imperative for LPI to aggressively diversify and increase diet, micronutrients, and phytochemicals funding from other sources. We will have to explore business opportunities, pursue grants from private • Advance the principles of healthy living and healthy industry, and increase philanthropic support to sustain aging in the public arena, thereby empowering people our current work and realize the many new initiatives of everywhere to add years of health and our strategic plan. vitality to their lives The third goal is to communicate the LPI Advancing healthspan, not just message and raise LPI's visibility. To this end, lifespan, is our passion. we will develop and implement a comprehensive communications and marketing plan that will The overarching theme emerging from advance knowledge, understanding, and our strategic plan is for LPI to create, how to live support of LPI, especially among our donors, communicate, and implement new the general public, health professionals, and knowledge that will advance human longer and the media. We will also realize the full healthspan. Health is defined here not potential of the Micronutrient Information just as the absence of disease but as feel better" Center (—the optimal health, vitality, and resiliency into Institute's "public face"—our comprehensive, advanced old age, free of disability and online database for scientifically accurate the deficits of daily living. The focus is on information on the roles of micronutrients and other quality of life—healthspan, "feeling better"—and on dietary factors in health and disease. closing the widening gap between lifespan and health- span in the US population and around the world. Finally, we will help improve public health through The strategic plan identifies four major goals for the community engagement. We will support and expand Institute. The first is to establish LPI's leadership role the efforts of LPI's Healthy Youth Program to empower in advancing human healthspan through cutting-edge youth and their families to achieve lifelong health and research. This goal will be pursued through our research wellness. An important initiative will be to validate and programs in healthy aging, cancer prevention and disseminate the high-quality outreach programs intervention, and cardiometabolic disease prevention, developed by the Healthy Youth Program so that they supported by cross-cutting facilities offering state-of- can be duplicated in communities around the country. the-art tools and technologies. One of these core You will hear a lot more about all the exciting new laboratories will develop unique screening models to initiatives going on here at LPI over the years to come. identify dietary factors and other novel compounds In the meantime, enjoy reading this Newsletter, and as that advance healthspan. always, feel free to contact us with any questions you The second goal is to diversify and increase funding may have about our work. Here's to your good health for LPI research and outreach. Like so many other and a great spring and summer! LPI
Continued from cover — Metabolizing Drugs and Toxins found where you are first exposed to a drug or a foreign chemical—the skin, lungs, liver, kidneys, and Q. When did you become a research assistant
intestine. All of these organs contain flavin-containing professor in LPI?
A. In 2007.
Q.What do FMOs do in the body?
Q. You've been interested in a group of enzymes, the
flavin-containing monooxygenases, or FMOs, for
A. FMOs are similar to another family of enzymes called
a long time. What do these enzymes do, and
the cytochromes P450s. They are located in similar how many of them are there?
places in the cell and have similar functions— metabolizing foreign substances like drugs and toxins. A. There are five different forms of flavin-containing
FMOs and cytochrome P450s add an oxygen atom to monooxygenases with activity in humans. They are these molecules that makes the resulting metabolite more readily excreted from the body. 2 spring/summer 2014

Q. What stimulated your interest in FMOs?
There is a developmental switch from FMO1 activity A. I wanted to work on enzymes that were important in
in the fetal liver to FMO3 activity in the adult liver. metabolism.
FMO1 declines very quickly—within three days—after birth. FMO3 is detectable by one to two years after birth Q. Are there ethnic or gender differences in the
and approaches adult levels during the teenage years.
activity of FMOs?
Q. Are FMOs affected by diet?
A. There are five different families of FMOs in humans,
and much of the work that I've done has been with Yes, they can be. There have been a couple of studies FMO form 2. This form is primarily located in the where people were given about 300 grams (10.6 lungs of humans and most other mammals. There is a ounces) a day of Brussels sprouts to eat, and that major mutation in this particular enzyme in people of depressed FMO3 activity in the liver.
African or Hispanic descent. Everyone else who has Q. Does that have to do with the indole-3-carbinol
been tested so far has a version of the FMO2 that is in the Brussels sprouts?
nonfunctional. Other FMOs also have different A. Yes, that is what we think, since indole-3-carbinol
versions, called polymorphisms, but none are as wide- reduces FMO activity in animal studies.
spread as the FMO2 variant.
Q. Another detoxification system is the cytochrome
Q. How prevalent is the FMO polymorphism in
P450 monooxygenase (CYP) family that
Hispanics or African-Americans?
metabolizes foreign substances, including
A. It can run from about five to seven percent of
antibiotics. Do FMOs act on the same kinds
Hispanics, and among people who are from Africa, it is of xenobiotics?
highly dependent upon the specific region. Active FMO A. They do, and we spent a number of years determining
is most prevalent in sub-Saharan Africa, where there which FMOs could metabolize different compounds. can be an incidence of up to 50%. Very often we also have to determine whether CYPs Q. Can these genetic polymorphisms or differences
metabolize the same compounds.
be easily detected by blood tests or some
Q. And metabolism prepares them for excretion from
other assay?
the body?
A. The assay that we have used requires the isolation
A. Right. This is a system your body has to help deal
of DNA from blood or saliva. We can then amplify the with foreign compounds. The object is to render them DNA to detect specific sequences. less toxic and then to eliminate them. The FMOs Q. What are the consequences of this genetic
metabolize many plant alkaloids and synthetic drugs heterogeneity of FMOs in terms of drug therapy
but don't act on a lot of known endogenous compounds. or exposure to toxins?
Cytochrome P450s are a lot more abundant and, as a family, more diverse in the compounds that they A. The FMOs primarily metabolize nitrogen- and sulfur-
metabolize. Some FMOs we don't know much about. containing compounds, including some antidepressants For instance, FMO5 does not metabolize drugs, that are based on tricyclic amine structure and some although it can be present in quite high amounts. It is sulfur-containing antibiotics. Genetic heterogeneity probably a product of the ancient ancestral form of the contributes to differences in drug response.
gene, but its endogenous role is not known. Q. Does that mean that people who have this
continued on page 4 variant, the polymorphism in FMO2, process
drugs or toxins in a more effective or less effective
way than people who do not have the mutation?
On one hand, oxygenation by FMO may speed up
the excretion of the metabolite in the urine. But FMO metabolism is sometimes required to activate a molecule and, therefore, may generate a more toxic metabolite.
Q. Why?
When FMOs metabolize sulfur-containing compounds,
they generate a sulfenic acid metabolite that can cycle with glutathione—an important antioxidant that protects cells. This leads to glutathione depletion in vitro and potentially in vivo, as well.
Q. Does the activity of FMOs change with age?
We probably can't say that FMO2 changes a lot with
age, but there are other FMOs that do change with age.
The Linus Pauling Institute 3 Continued from page 3 — Metabolizing Drugs and Toxins Q. With Dave Williams of LPI and others you've
investigated the role of FMO's metabolism of
Q. You mentioned that the FMOs act on
tamoxifen, a drug used to treat breast cancer.
xenobiotics or toxicants that contain sulfur or
What did you find?
nitrogen. Is there anything else special about
A. Tamoxifen is oxidized by FMO, a reaction that
certain toxicants, environmental pollutants, or
detoxifies and eliminates tamoxifen. In contrast, drugs that target them from metabolism and
cytochrome P450s hydroxylate and activate tamoxifen. excretion from the body by FMOs?
FMO metabolism could reduce non-target toxicity but A. Aside from the targets provided by sulfur- , nitrogen- ,
might also reduce efficacy, while CYP metabolism could and some selenium-containing compounds, the size and increase both drug efficacy and toxicity. bulkiness of the compound is a major constraint on its Q. Also with Dave Williams and others, you've
metabolism by FMOs. studied the effect of FMOs on the metabolism of
Q. Is there an example of a toxicant, environmental
the anti-tuberculosis drug ethionamide in mice.
pollutant, or drug that FMOs target that is not
You mentioned that FMOs metabolize this drug.
targeted by the cytochrome P450 system?
A. Yes, the FMOs, including FMO1, FMO2, and FMO3,
A. Ethionamide, which is a drug used to treat tuberculosis.
metabolize ethionamide. We were particularly It was not metabolized by cytochrome P450s in our interested in looking at this because people who have studies. FMO3 is the primary enzyme that metabolizes active FMO2 are primarily in sub-Saharan Africa. sulindac sulfide, an NSAID. FMOs also metabolize the The primary incidence of tuberculosis is also in sub- pesticide phorate very quickly, with the highest activity Saharan Africa, so there's a convergence of TB and we have ever been able to measure. FMO2 metabolism.
Q. What inhaled drugs might be metabolized by FMOs?
Q. What is the practical outcome of that observation?
Does this have any impact on drug therapy for
FMO2, the form in the lungs, metabolizes some of the TB patients?
compounds in cigarette smoke like nicotine.
A. Yes, it could very well. Ethionamide is a sulfur-containing
Q. Do FMOs play a role in protecting against
drug, and this is one of the cases where instead of seeing colorectal cancer in patients with familial adenoma
detoxification, something more toxic might be formed. polyposis (FAP) who take the drug sulindac?
Ethionamide is a pro-drug that needs to be activated A. Yes. Sulindac seems to be more effective in FAP patients
to have bactericidal activity. FMOs add an oxygen with FMO3 genetic variants that reduce activity—they to form sulfenic acid, which converts more slowly to had fewer colon polyps. Dr. Gayle Orner, who used to sulfinic acid. But that first step to form sulfenic acid work at the Linus Pauling Institute, and I had a small can lead to depletion of glutathione, as I mentioned, project to look at whether we could use cruciferous by cycling—forming the oxidized version—which leads vegetables like Brussels sprouts to alter the level of the to an almost suicidal cycle of continuous depletion, at FMO3 in the liver to reduce the rate of the sulindac least in vitro. In Africans who have the active form of the enzyme FMO2, oxidative lung damage might result Q. How does FMO3 metabolize sulindac?
from taking the drug and might reduce the amount of ethionamide available to combat the TB mycobacteria. A. Sulindac is an oxygenated drug: sulindac sulfoxide.
When that's swallowed and passes to the intestine, the Q. Would that suggest that suppression of FMO
microbes in the gut reduce it to sulindac sulfide, which expression might be beneficial to people
is the active form of the drug. This reduced form gets undergoing drug therapy for TB?
absorbed into the blood stream, circulates back to the A. It may reduce the amount of oxidative stress to the lung.
liver where the FMO3 is, and then FMO3 re-oxidizes it. Q. Are there any dietary interventions to suppress
It's a recycling process that happens several times before FMO activity?
the drug is finally eliminated from the body. A. I'm not aware of any, other than cruciferous vegetables,
Q. Does that mean that people could take less
that contain indole-3-carbinol and suppress FMO3. sulindac for an effective outcome?
I don't think they have the same effect on FMO2. If you A. People with FAP develop resistance to sulindac. So there's
could reduce the level of FMO3 in the liver, then you less of a focus on taking less and more on getting a better might be able to deliver a higher therapeutic dose of outcome from the dose by being able to take it longer the drug to kill the mycobacteria, as FMO3 also more effectively. Theoretically, higher sulindac sulfide metabolizes this drug. Mycobacteria are actually levels would be achieved with certain mutations, and this quite interesting themselves because they also have would increase effectiveness.
an FMO—unlike most microorganisms—and FMO metabolism of the ethionamide by mycobacteria is responsible for their death. 4 spring/summer 2014 Q. What important questions about FMOs remain
rodent study where you give an astronomical dose of to be answered?
the carcinogen and then extrapolate down in a linear fashion to commonly encountered environmental levels. A. We need to get more definitive information on the
benefits of regulating FMO3 in familial adenoma Q. Are you planning a dietary intervention to see
polyposis and in cancer. There are still a lot of questions if indole-3-carbinol or cruciferous vegetables
remaining on the effect of FMO2 in tuberculosis. We've interfere with the metabolism of these carcinogens
had some promising results, although nothing yet as and offer some protection?
clear-cut as we would like to see. A third of the world's A. We are in the process now of working on the
population is infected, so there are a lot of people who investigational new drug protocol to submit to the are on drug therapy at any given time. There wouldn't FDA. Once we get approval from the FDA and OSU's be as much application in this country because the Institutional Review Board, we will probably get started number of people that have the active form of FMO2 is in about two or three months. We will have a small group of human volunteers who will swallow a small Q. You've worked on the dietary protection against
dose of radioactively labeled phenanthrene, which is cancer in the offspring of pregnant mice exposed
a non-carcinogenic polycyclic aromatic hydrocarbon. to environmental carcinogens. What dietary
We'll collect blood and urine for three days to learn the compounds might be useful in that role?
fate of the chemical. Then there will be a dietary wash-out period. We will ask the subjects not to consume any A. The long-time interest in the Williams lab is in crucifers,
cruciferous vegetables during the study, aside from what such as broccoli and Brussels sprouts, that contain we provide. After the first round we will determine the indole-3-carbinol. Our recent studies with LPI's Emily metabolic fate of phenanthrene when the subjects are Ho, Rod Dashwood, and Dave Williams have included not consuming crucifers, then they will take phenan- sulforaphane, which is typically found at higher levels in threne following consumption of indole-3-carbinol. broccoli, whereas indole-3-carbinol is at higher levels in Brussels sprouts. Q. What do you expect to find?
Q. In those experiments, did you feed the pregnant
A. We would expect to find that phenanthrene will be
mice the purified compound or the vegetable?
differently metabolized when indole-3-carbinol is present. Indole-3-carbinol should alter the amounts A. Our last study compared the effects of the purified
of different phenanthrene metabolites produced and compounds to a vegetable extract. In our particular possibly their time course, as well.
model, the highest benefit came from the indole-3- carbinol alone.
Q. If phenanthrene is around for less time, then
the probability for DNA damage is decreased?
Q. What carcinogen were these mice exposed to?
A. Correct. In the third cycle of the study, after another
A. They were given dibenzo[def,p]chrysene, a polycyclic
wash-out period, the subjects will go through the same aromatic hydrocarbon (PAH) formed from combustion protocol again but will eat Brussels sprouts every day in coal-burning plants and in vehicles. PAHs are for one week before they take the phenanthrene. So we common air pollutants and known human carcinogens.
will be able to compare the effects of the purified Q. Could they be responsible for causing cancer in
compound with the compound in its food matrix. children whose mothers may have been exposed to
Q. Most recently you developed an interest in
them when pregnant?
high-dose intravenous vitamin C to treat cancer.
A. It's possible that they are linked.
Is it similar to the work that Linus Pauling and
Q. How easily do you think that the results from
Ewan Cameron did with terminal cancer patients
these rodent studies can be extrapolated to people?
back in the 1970s?
A. Dr. Williams developed a very sensitive detection
A. It certainly uses that as the foundation. It involves a
method so that you can give a carcinogen to a human subject of interest to LPI Principal Investigator Joe at a level so small it's less than what you would get in continued on page 6 your daily exposure in the environment. The carcinogen can be tagged with a radioactive isotope with less radioactivity than what you would get flying across the Newly Updated Articles in the country or eating five bananas. We collect blood and Micronutrient Information Center urine for three days after the carcinogen or similar Articles on vitamin C, riboflavin, vitamin B12, fluoride, compound has been swallowed. Extracts of those samples and copper have been updated on the Micronutrient are sent to Lawrence Livermore National Laboratory, Information Center ( where they have an accelerator mass spectrometer that Pending updates include folate, vitamin D, magnesium, very sensitively measures the radioactive signature. and essential fatty acids. We encourage donations to This gives our group the ability to start looking at the help maintain and expand our MIC! kinetics of metabolism in a human being at a realistic exposure level. So for the first time, we're not doing a The Linus Pauling Institute 5 Continued from page 5 — Metabolizing Drugs and Toxins used. I've been very intrigued by various approaches to chemotherapy, where most people get very high Beckman, who has a series of copper compounds. doses and experience toxic effects and damage to Copper ATSM is a compound that chelates or binds normal organs. There is some interesting literature copper in either its oxidized (Cu II) or reduced (Cu I) suggesting that you can have very good outcomes if you form. Since it accumulates in tumors, a radioactive do long-term management of cancer at sustained low version is used for tumor imaging. Joe Beckman is levels of chemotherapeutic drugs rather than shorter using it in his research with an ALS animal model, bursts of very high levels. I am interested in looking at and he has produced a whole series of other copper- how these drugs, including copper, might be combined chelating analogs. Joe, Balz Frei, and I want to see if with vitamin C for a good outcome with fewer toxic these compounds might have anticancer effects—inhibit side effects. Whether vitamin C is compatible with tumor progression—in rodents. Copper is known to some traditional chemotherapy is still debated and is concentrate in tumors. It's believed that is due to the an area that warrants additional study.
acidic environment in a tumor and its hypoxia or lack of oxygen. The hypoxia drives the tumor to become Q. Pauling and Cameron didn't face that obstacle
more acidic, and that may explain why it retains copper. with their patient population in the 1970s
The most aggressive tumors have higher levels of because the cancer patients getting high-dose
copper than less aggressive tumors. The copper ATSM vitamin C were people who had been ruled out
increases copper levels in tumors. In the cell, oxidized for chemotherapy, surgery, or radiation, so there
copper can be reduced and, once reduced, can dissociate wasn't any problem with drug compatibility.
from ATSM and become trapped. Copper might then A. In cancer, we really want to prevent the disease. If cancer
interfere with mitochondrial function or generate occurs, we want to delay it and slow progression. I have hydrogen peroxide. If vitamin C concentrations are high, an interest in what we do when someone already has an additional mechanism could be copper-dependent a tumor because cancer is, unfortunately, still a oxidation of vitamin C, resulting in the formation of frequent diagnosis. It would be fantastic if we could hydrogen peroxide that then generates radicals that will use intravenous vitamin C as a sole therapy, but I kill cancer cells.
think it could be very important and synergistic in combination therapy. Q. Mark Levine's research at the National Institutes
of Health showed that high extracellular
Q. How has your work been funded?
concentrations of vitamin C generate hydrogen
A. The FMO work has been funded by the National
peroxide that then goes into the cancer cell and
Institutes of Health through the National Heart, Lung causes cell death. Are you proposing that the
and Blood Institute, and the National Cancer Institute hydrogen peroxide could react with copper inside
funded the work at LPI comparing dietary interventions cells to make radicals that kill cancer cells?
and supplements. The work on PAH carcinogens has A. I think that copper-dependent oxidation of vitamin C to
been funded by the National Institute of Environmental generate hydrogen peroxide could happen both inside Health Sciences.
and outside the cell. The first step for us is to show Q. How do you enjoy your free time outside the lab?
that these new compounds are not toxic in rodents. Then we want to find out if they affect tumor growth A. I like to go birding and enjoy visiting gardens.
rate. Lastly, we want to understand the mechanism and Oregon is a wonderful place for those activities, extend the work to humans if it's promising in rodents. with mountain meadows, the Iris Gardens, and ocean We will first do some cell culture studies, then we'll beaches. At this time of year, I'm often birding over take the promising compounds and put them into in the Albany-Millersburg Talking Water Gardens. immunocompromised mice that can be a host for a I moved from Wisconsin, in part, because of the cold human tumor, called a xenograft. These mouse winters with snow and ice and the hot, humid xenografts have turned up a lot of compounds that summers with lots of mosquitos. decrease the tumor growth rates or tumor size, but Q. What is it about LPI that you enjoy?
many aren't successful in subsequent human trials. A. As soon as I heard that LPI was moving to OSU,
On the other hand, there are some reports of very good I wanted to be a part of it. I come from a family that outcomes when part of a tumor from a cancer patient embraced the idea of good nutrition and supplement was implanted into mice. Then the mice are tested on use. I was raised on a farm in Wisconsin where we different therapies to look at which therapy knocks grew most of the food we ate. Having a rare metabolic back that particular tumor. That mouse-guided muscular dystrophy made me want to make the most of treatment has led to some good treatment results. my health. The research that we do in LPI is about how Q. What other research projects are you planning?
we can improve everybody's health, and there is a real A. The copper literature has really been a fascinating story,
satisfaction working with a group of researchers whose as well as investigating xenografts and how they are shared goal is improved health. LPI
6 spring/summer 2014

The Case is Far from Closed for Vitamin and Mineral Supplements! In their recent editorial in the journal Annals of Internal Vitamins and nutritionally essential minerals maintain Medicine, "Enough Is Enough: Stop Wasting Money on normal cell function, metabolism, growth, and Vitamin and Mineral Supplements," the authors (Guallar, development through their roles as essential cofactors Stranges, Mulrow, Appel, and Miller III) conclude that "we in thousands of enzymatic reactions and other biological believe that the case is closed—supplementing the diet processes—their main biological function is not to of well-nourished adults with (most) mineral or vitamin prevent or treat chronic disease. Nevertheless, the supplements has no clear benefit and might even be largest and longest randomized control ed trial (RCT) of harmful." It appears that the authors themselves weren't MVM supplements conducted to date, the Physicians' quite convinced of their conclusions because Health Study II (PHS II), found a significant 8% they added numerous qualifiers, such as "we reduction in total and epithelial cell cancer believe" and "well-nourished adults," and put incidence in male physicians and a 12% "most" in parentheses. reduction in total cancer incidence, excluding prostate cancer. The PHS II While a well-balanced diet is the best also found a significant 9% reduction in way to get almost all of one's essential the incidence of total cataract. These nutrients, the reality is that Americans findings of PHS II are consistent with don't get enough of them every day those of several other RCTs and are through diet alone. From the National even more impressive given the fact Health and Nutrition Examination that the conventional RCT design is Survey (NHANES), we know that the strongly biased against showing benefits large majority of the US population is of essential nutrients, in contrast to not "well-nourished" and falls short of pharmaceutical drugs. Unlike drug trials in getting all of their vitamins and minerals which the control subjects have none of the from their diet in levels recommended by the drug in their bodies, subjects in vitamin trials Institute of Medicine's Food and Nutrition Board. will always have enough of the micronutrient present For example, more than 93% of US adults to prevent severe deficiency diseases—hence, there is 19 years and older do not meet dietary intake no true placebo control group in such studies. recommendations (called Estimated Average Requirement, or EAR) of vitamins D and E, 61% for Furthermore, most published vitamin studies and magnesium, about 50% for vitamin A and calcium, and trials have not measured the concentration of the 43% for vitamin C. Certain subpopulations, including vitamin in the subjects being tested but only assessed older adults, African Americans, and the obese, have intake. Many factors, including age, gender, disease, increased needs for some micronutrients. Other studies ethnicity, and genetic differences or polymorphisms, have shown that people who take a daily multivitamin/ affect the concentrations of ingested micronutrients mineral (MVM) supplement with the recommended in the blood, organs, and tissues of humans. Without doses of most vitamins and minerals can fill most of those measurements, it's difficult to estimate the effect these nutritional gaps safely and at very low cost—a of supplemental micronutrients. year's supply of a high-quality MVM can be purchased Taking a daily MVM supplement will not only help fill for less than a nickel a day. the known nutritional gaps in the average American In contrast, only a very small, non-significant fraction diet, thereby assuring normal biological function and (0.1%) of US adults exceeds the Tolerable Upper Intake metabolism and supporting good health, but may Level (UL) from diet and supplements combined for also have the added benefit of reducing cancer and vitamin E, putting Guallar et al.'s claim that "vitamin E cataract risk—which no existing pharmaceutical drug … supplements increase mortality" in perspective. can do. The benefit-to-risk ratio also favors MVM Contrary to the impression that the authors give in their supplementation, with plausible or demonstrated editorial, the US population is inadequate in many vitamins health benefits and little risk. To call "the case … and minerals, a result of the calorie-rich and nutrient-poor closed" and label MVM supplements as useless, dietary pattern of Western populations, rather than harmful, or wasteful is unscientific and does not over-consuming MVM and other dietary supplements.
serve public health. LPI
The Linus Pauling Institute 7

Many factors can affect bioavailability, including the current status of the substance in the individual, general health of the subject, delivery mechanisms, and interactions with other substances that may increase or decrease absorption. For example, vitamin C enhances the absorption of dietary nonheme iron (increasing the bioavailability of iron), but Alexander Michels, Ph.D. the absorption of vitamin C is inhibited by the flavonoid LPI Research Associate quercetin, found in apples, kale, and onions (decreasing the bioavailability of vitamin C). Bioavailability is also a fundamental issue in studies on flavonoids. Since there are Bioavailability is an important factor in understanding nutrition and micronutrient research. However, the no specific transport mechanisms for flavonoids in the gut, concept of bioavailability and its broader implications may the absorption of many of these molecules is slow and be unclear or confusing to many. In a broad sense, unfacilitated, resulting in very low concentrations in the bioavailability is a measure of the amount of a substance blood stream even after eating foods rich in flavonoid that is absorbed into the blood stream after it enters the compounds. In many cases, the concentrations of flavonoids body. When referring to nutrients, micronutrients, and achieved are not high enough to have a meaningful biological other dietary factors, bioavailability usually refers to effect. Therefore, flavonoids are often categorized as being absorption after oral administration, such as eating a food poorly bioavailable. The situation is further complicated by or taking a supplement. Depending on the question being the rapid chemical modification of flavonoids after absorption. addressed, researchers may use different methods to assess Another example of bioavailability comes from studies bioavailability and to answer questions about the behavior on vitamin C by Dr. Mark Levine's research group at the of a compound after it enters the body.
Absolute Bioavailability Relative Bioavailability Accurate measures of bioavailability require measuring National Institutes of Health. They performed very careful blood concentrations of the molecule of interest. Absolute pharmacokinetic studies using oral and intravenous bioavailability is the most precise measure of bioavailability. administration to determine the amount of vitamin C that In order to determine absolute bioavailability, separate can be absorbed from supplements provided at different trials of both oral and intravenous administration of a doses to healthy volunteers. They found that all of the particular dose of a substance are required. A comparison vitamin C is absorbed into the blood stream at oral doses of the plasma concentrations achieved after oral versus up to 200 mg—exhibiting complete (100%) bioavailability. intravenous dosing determines the fraction of the substance However, at larger doses the absorption declined, suggesting that is absorbed through the gastrointestinal tract in relation that the bioavailability declined as the dose increased above to the concentration after direct delivery into the blood 200 mg. This phenomenon can be explained by the stream. This fraction is defined as the bioavailability of existence of vitamin C transport molecules on the surface the substance. These experiments, called pharmacokinetic of cells that line the gut. These transporters limit the studies, are very accurate but elaborate and expensive. amount of vitamin C absorbed into the blood stream. Subtle genetic differences, called polymorphisms, between Because of these limitations, relative bioavailability is people affect the amount and activity of these transporters, often used in research. The experimental trials needed further complicating generalizations about bioavailability.
to establish relative bioavailability only require blood sampling over time after delivery (typically oral Overall, the results of studies on bioavailability are vital administration) of the compound being studied, so they to our understanding of the variety of molecular mechanisms are simpler and less expensive. Measuring relative involved in the absorption of vitamins, minerals, and other bioavailability is usually sufficient to answer the questions dietary constituents. These analyses are critically important most often asked in research on the human diet.
to understand the role that micronutrients and
phytochemicals play in human health. LPI
8 spring/summer 2014

Briefly. . Vitamin B12 and stomach acid-suppressing DrugsVictoria J. Drake, Ph.D. Manager, Micronutrient Information Center In humans, vitamin B population with a high incidence of atrophic gastritis that 12 or cobalamin is required for only two biochemical reactions in the body: to make the leads to food-bound vitamin B12 malabsorption because of amino acid methionine from homocysteine and to make a insufficient acidity in the stomach. A recent case-control compound that is involved in the production of energy study—published in the Journal of the American Medical and in the synthesis of hemoglobin, the oxygen-carrying Association—evaluated whether the use of prescription pigment in red blood cells. In these roles as an enzyme acid-suppressing drugs was associated with the diagnosis of cofactor, vitamin B 12 is involved in DNA synthesis, red 12 deficiency in adults of all ages (25,956 cases of blood cell formation, and maintenance of neuron integrity. vitamin B12 deficiency, 184,199 controls). This study found Inadequate intake of vitamin B use of PPIs for two or more years was associated with a 12 (dietary sources include food of animal origin and fortified food like cereal) or 65% higher risk of diagnostic vitamin B12 deficiency compared to nonusers, and this association was much 12 malabsorption can lead to deficiency of the vitamin, which impairs DNA and hemoglobin synthesis stronger (an eight-fold increased risk) in individuals and damages the myelin sheath covering younger than 30 years compared to older nerves. Clinical symptoms of vitamin B age groups and in women compared to deficiency include megaloblastic anemia men. The study also found that use of and neurologic problems, such as painful H2 blockers for two or more years was numbness and tingling of the hands and associated with a 25% increased risk feet, difficulty walking, memory loss, and for diagnostic vitamin B12 deficiency dementia. The anemia can be reversed compared to nonusers. Although this study examined prescription medications, 12 supplementation, but neurologic symptoms may not, especially acid-suppressing drugs are also if they have been present for a long time. available over-the-counter at lower Linus Pauling's mother, Belle, died from dosages. Apparently, no research on the pernicious anemia in 1926, the same year effect of acid-neutralizing compounds that Minot and Murphy discovered that like antacids on B12 absorption has liver—a rich source of B disease. Belle Pauling suffered from physical This study was an observational symptoms and became irrational and study and therefore cannot establish a delusional in the late stage, exhibiting cause-and-effect relationship between use "megaloblastic madness." of acid-suppressing drugs and vitamin Dietary vitamin B 12 is bound to proteins 12 deficiency, but there is biologic and must be released in the stomach for plausibility for such an association. absorption in the small intestine; the acidic As mentioned above, stomach acid is Belle Pauling, circa 1915 environment of the stomach and the enzyme needed to liberate vitamin B12 from pepsin are necessary to dissociate the vitamin from proteins in food; in contrast, stomach acid is not required proteins. Consequently, long-term use of drugs that reduce for absorption of the crystalline form. In other words, the production of stomach acid may lead to vitamin B individuals with food-bound vitamin B12 malabsorption deficiency. Pharmaceutical inhibitors of stomach acid can readily absorb the crystalline form found in fortified production include proton-pump inhibitors (PPIs; e.g., foods and dietary supplements. It seems prudent for Nexium, Prilosec, Prevacid) and histamine 2 receptor physicians to monitor vitamin B12 status in individuals antagonists (H2 blockers, e.g., Pepcid, Tagamet, Zantac). taking acid-suppressing medications long term. The These drugs are used to prevent or treat gastrointestinal Recommended Dietary Allowance (RDA) for adults is disorders, such as peptic ulcers, Barrett's esophagus, and 2.4 mcg/day of vitamin B12; for adults over 50 years old, gastroesophageal reflux disease (GERD), and to treat the this amount should be in the form of fortified food or rare disorder, Zollinger-Ellison syndrome. Excess vitamin supplements. Due to the higher incidence of food-bound 12 is stored in the liver, and symptoms of deficiency 12 malabsorption in older adults, the Linus usually manifest only after years of inadequate intake or Pauling Institute recommends that adults over 50 years use of acid-suppressing drugs. old take 100 to 400 mcg of supplemental vitamin B12 daily. LPI
Some, but not all, studies have associated long-term use of PPIs with vitamin B12 deficiency in the elderly—a The Linus Pauling Institute 9 various dietary sources or in different forms. Thus, there is a need to improve understanding of SFN bioavailability from the diet to accelerate the study of SFN's efficacy in disease prevention and treatment. SFN is not absorbed identically from all dietary sources. cancer Prevention Crucifers contain glucoraphanin (GFN), which is the Lauren Atwell, M.S., R.D. glucosinolate precursor of SFN. Chewing or chopping LPI Graduate Fellow those vegetables releases an enzyme, myrosinase, that converts GFN to SFN, which is the form associated with cancer prevention. Inadequate activity of this enzyme or the inability of the enzyme to make contact with GFN has been cancer is a devastating disease that affects millions of people worldwide, and over 1.6 million Americans shown to greatly decrease the amount of SFN available are projected to be diagnosed with some form of cancer in from vegetables. Myrosinase is inactivated by heat, so 2014. Fortunately, approximately one-third of cancers can cooking crucifers at high temperatures or for long periods be prevented, in part, by lifestyle modifications, including of time diminishes its activity and results in lower SFN diet. While a healthy diet is made up of a variety of food, absorption. Within crucifers, myrosinase is located in a consumption of certain food has been linked to specific cellular compartment separate from GFN, so disrupting the health benefits, including cancer prevention. In particular, tissue matrix by chewing or chopping—thereby exposing the consumption of cruciferous vegetables ("crucifers," GFN to myrosinase—is essential for SFN formation. e.g., broccoli, Brussels sprouts, cauliflower, kale) has been Different cooking techniques and degrees of chewing affect associated with a lower risk for several types of cancer. the amount of SFN absorbed from dietary sources. Among these are breast and prostate cancers, which affect Another major determinant of SFN levels is the amount more Americans each year than any other type of cancer. of GFN in the crucifer. GFN levels in vegetables are highly The phytochemical sulforaphane (SFN) has been isolated variable due to genetic variations among cultivars, growing from crucifers and is thought to be responsible for their and storing conditions, and other factors. Two batches cancer-preventing effects. However, it remains uncertain of the same cultivar grown in similar conditions can also how much SFN should be included in the diet to help have extreme variations in GFN content. This variation protect against cancer. Researchers are currently trying to and unpredictability are problems when trying to provide figure out what levels of SFN are associated with specific the same amount of SFN to participants in a human health benefits and how best to obtain these levels in the feeding study or clinical trial. Use of crucifers in these body from the diet.
studies would require testing each batch and providing Several researchers have demonstrated SFN's cancer- different quantities to each subject, which is not often preventive effects in cultured cells and experimental animal logistically feasible. For this reason, clinical researchers models. Yet, verifying these effects in human studies often use dietary supplements as a source of SFN. However, introduces unique challenges that researchers are currently SFN bioavailability from supplements currently on the trying to overcome. One of the major challenges in studying market is much lower than from whole vegetables. These the effects of any dietary compound relates to the ability of supplements contain GFN instead of SFN and are devoid of that compound to be absorbed into the blood stream from myrosinase activity. Our lab previously demonstrated about the gut and then delivered to sites of action in a bioactive a seven-fold lower SFN absorption from these supplements form. This overall process is often termed "bioavailability" compared to fresh broccoli sprouts. An important aspect (see article on page 8). Absolute bioavailability studies of my work has been to evaluate SFN absorption from a compare concentrations in the blood of a compound dietary supplement that instead contains preformed SFN, consumed orally to those after the compound is injected thus bypassing the need for myrosinase activity.
directly into the blood stream, as the latter bypasses the We conducted a human feeding study to evaluate SFN absorptive processes in the gastrointestinal tract. However, absorption from fresh broccoli sprouts and broccoli sprout injecting a compound into the blood stream of human extracts (BSE) containing SFN. The SFN-rich BSE was subjects is not always safe and is rarely performed. Instead, produced by researchers at Johns Hopkins University by researchers evaluate the relative absorption of a given treating GFN-rich sprout extracts with myrosinase to compound by measuring levels that appear in the blood convert GFN to SFN. SFN content of the resulting SFN- following oral ingestion of a food, extract, or supplement rich powder was measured, and the powder was packed containing the compound. Comparisons between food into gel capsules. Thus, the SFN contained within this BSE sources and their forms (fresh vs. cooked vegetables vs. should be well absorbed, and BSE supplements should vegetable extract) contribute to our understanding of a provide more SFN than the GFN supplements we studied compound's relative bioavailability and help to identify previously. Our study enrolled healthy adults, ages 18-50 potent dietary sources for use in studies evaluating the years, who consumed equivalent amounts of SFN from compound's health benefits. The bioavailability of SFN either fresh broccoli sprouts or BSE supplements. Despite is not fully understood, and many researchers have the fact that myrosinase activity within the supplements demonstrated that SFN is not equally bioavailable from was no longer an inhibitory factor for SFN absorption, 10 spring/summer 2014 approximately three-fold less SFN was absorbed from BSE supplements compared to the sprouts. This observation suggests that myrosinase activity is not the only determinant of SFN absorption.
LPI's Dr. Maret Traber Honored Although derived from fresh broccoli sprouts, the BSE used in our study does not contain all of the plant Dr. Maret Traber, a principal investigator matter, nutrients, and phytochemicals that are naturally in LPI and an internationally renowned found in intact broccoli sprouts. The BSE was obtained expert on vitamin E, received the DSM by boiling sprouts, so only water-soluble compounds Nutritional Science Award 2013 in were retained in the supplement preparation. Also, high September in Grenada, Spain. Dr. Traber cooking temperature may have altered some chemical was honored for her "lifetime commitment and characteristics. Little is known about how the presence scientific achievements in the field of vitamin E of other dietary compounds in the gut can influence SFN research." The DSM judging committee stated, "Professor Traber has been providing seminal work absorption, so it is possible that some of the compounds and is a major contributor to our understanding of discarded along with the plant material could enhance SFN the role of vitamin E as an essential micronutrient in absorption. The exact reason for the differences in SFN human metabolism in health and disease." absorption between broccoli sprouts and the BSE remains unclear. Future studies investigating interactions between Dr. Traber, the Helen P. Rumbel Professor for SFN and other dietary constituents will be an important Micronutrient Research, has been with LPI since area of research.
1998 following stints at New York University School of Medicine and the University of California-Berkeley. Although the BSE did not deliver as much SFN as the From 1998 to 2000, she served on the Food and intact sprouts, they were an improvement over previously Nutrition Board's Panel on Antioxidants and Related tested GFN supplements that lacked myrosinase activity. Nutrients, which is part of the Institute of Medicine Despite the large difference in the amount of SFN of the National Academy of Sciences, and helped to absorbed between the BSE and sprouts, we did not observe establish the Dietary Reference Intakes for vitamin E. substantial differences in the effects of SFN on certain Dr. Traber is highly regarded for her work on the enzymes and proteins involved in cancer. Thus, these alpha-tocopherol transfer protein that specifically SFN-rich BSE supplements may be acceptable for use in recognizes that form of the eight-member vitamin E clinical trials. Once they become commercially available to family for distribution to tissues. She also published consumers, they may also be an important SFN source for landmark studies on the bioavailability of vitamin E individuals who do not consume cruciferous vegetables. and showed, for the first time in vivo, that vitamin C However, the safety and efficacy of this BSE have not recycles vitamin E from its oxidized to reduced form, been tested in all groups of individuals, and it may not thereby preserving its antioxidant functions.
be appropriate for certain populations, such as children,
adolescents, elderly individuals, or pregnant or lactating
women. Additional work is needed to evaluate the effects of
this BSE in these populations and others in order to identify
individuals who may derive health benefits associated with
their consumption. LPI
The Micronutrient Information Center Now in SpanishThanks to a generous donation to LPI from Bayer Consumer Care AG, Dr. Andrew Quest of the University of Chile spearheaded the translation of the articles on vitamins and minerals in the Micronutrient Information Center into Spanish. The Spanish version, available at, debuted in February 2013. We are very pleased that this useful information on the role of vitamins and minerals in health and disease is now accessible to Spanish speakers around the world.
The Linus Pauling Institute 11 Probiotics and Prebiotics: The Bacteria that Live in Your gut and affect health Giana Angelo, Ph.D., LPI Research Associate Over the past 30 years, evidence has accumulated that Energy balance/obesity. Although we each have a unique the microscopic organisms that live in our digestive bacterial "fingerprint," these many different bacterial tract play a prominent role in health and well-being. species fall into two major groups: Bacteroidetes and Although it is a complex relationship with much still to Firmicutes. The ratio of Bacteroidetes to Firmicutes be learned, we know that it is a two-way street: what inhabiting our colon has been linked to obesity—obese we eat influences the composition and activity of our gut individuals have fewer Bacteroidetes and more Firmicutes microbiota, and conversely, the nutritional value of food compared to lean individuals. But this ratio can be can be influenced by the microbes that inhabit our gut. modulated: after one year on a calorie-restricted diet (either fat- or carbohydrate-restricted), progressive The Gut Microbiota
weight loss in obese subjects The gut microbiota refers to the was accompanied by a shift collection of microbial species that in the skewed proportions of live in the lower gastrointestinal Microbe - a microscopic organism, such as a Bacteroidetes to Firmicutes to tract (see Terminology box at right).
bacterium, virus, or fungus more closely resemble that of We are born germ free but quickly Biota - from Greek, meaning "all life" lean individuals. colonized by bacteria from our Microbiota - the collection of microbial So how might the proportions of mothers and the environment. species that live on and within an individual Bacteroidetes to Firmicutes affect Mode of delivery, early microbial Gut microbiota - the collection of microbial energy balance? By isolating and exposure, diet, and host genetics species that live specifically in the lower transplanting the fecal microbiota have all been implicated in shaping gastrointestinal tract (colon) (which accurately recapitulates the one's microbiota. Our gut gut microbiota) from obese and microbiota stabilizes by about age Microflora, gut flora - often used lean individuals into germ-free three, with trillions of different interchangeably with gut microbiota mice, scientists can now study how bacteria inhabiting our gut. Microbiome - all of the genes that comprise these microbial signatures influence various aspects of physiology. Probiotic - live cultures of beneficial microbes Recipient mice acquire the body The composition of the gut that can be ingested as a dietary supplement composition of the human donor microbiota changes rapidly in or food additive (i.e., increased body mass and response to diet. For example, one Prebiotic - non-digestible food ingredients that adiposity when transplanted with experiment showed that within two promote the growth of beneficial gut microbes the obese microbiota). Although days of eating an animal-based the gut microbiota from obese and versus a plant-based experimental Antibiotic - a medication that kills microbes lean donors differ metabolically, diet, microbial composition was we do not yet know how these altered such that certain clusters differences may influence energy balance. Certain types of bacteria characterized each dietary pattern. Upon with- of bacteria may be more efficient at generating energy drawal of the experimental diet, the microbial composition from food or may produce signals that influence satiety reverted back to its baseline state just as quickly. In addition to diet, incorporating probiotics and prebiotics (see below) are other strategies to modify the composition of the gut Atherosclerosis. Inside the dark, anaerobic environment of the large intestine, bacterial fermentation of undigested foodstuff yields short-chain fatty acids, alcohol, gases, and other small molecules. These metabolic products represent The bacteria in our gut provide many important one mechanism by which gut microbes can influence functions for the host. They protect against pathogens, extract nutrients and energy from food, contribute to Bacterial fermentation of dietary choline (found in eggs, normal immune function, and synthesize some vitamins, turkey, and beef) produces a compound known as including vitamin K, which is bioavailable to the host. trimethylamine (TMA). In the liver, TMA is enzymatically A growing body of evidence indicates that the functional converted to trimethylamine-N-oxide (TMAO). TMAO potential of the microbiota may go even farther than these has been implicated as a potential causative factor in the established roles. 12 spring/summer 2014 development of atherosclerosis because it increases We do know, however, that there is an interaction—we macrophage cholesterol accumulation and foam cell coexist with these microscopic organisms, and they can formation, early events in the development of help us or harm us depending on how they are treated. atherosclerotic plaque. New research suggests that one's bacterial community could affect the amount of TMAO As we await more scientific information, the good news that is produced upon exposure to dietary choline, thereby is that following the existing dietary guidelines will provide influencing the impact of diet on cardiovascular disease prebiotic and probiotic compounds, for example, from (CVD) risk. It's too soon to tell, but this "diet-microbiota fruit, vegetables, and yogurt. These recommendations interaction" could represent a new risk factor for CVD. establish a framework that is good for both your body and
the little microscopic organisms with which it coexists. LPI
Probiotics are live, beneficial microorganisms that can
be ingested as a dietary supplement or in food. Yogurt
products that state "live and active cultures" on the label
Do Probiotics Affect Bowel Regularity? contain probiotics. Other sources include naturally According to the Activia® website (, fermented foods like unpasteurized sauerkraut and kimchi, the product makers state: "Clinical studies show and traditionally cultured dairy products like kefir and that Activia® with B. Lactis DN 173-010 helps with acidophilus milk. Commercial probiotics typically provide slow intestinal transit or occasional irregularity when Lactobacilli or Bifidobacteria. Keep in mind that these consumed 3 times per day for 2 weeks as part of a bacteria colonize the gut only temporarily, making regular balanced diet and healthy lifestyle." consumption necessary to sustain their population in the gut.
A 2011 systematic review and meta-analysis of While many health benefits are touted (see box), strong 11 clinical trials with 464 participants reported that scientific evidence currently exists for the use of probiotics probiotic supplementation has a modest effect on for only two indications: as a supplement to antibiotic reducing bowel transit time, mainly in the elderly therapy to prevent acute diarrhea and adverse effects in and those with initial slow transit time. B. Lactis DN the intestinal environment and to prevent atopic dermatitis 173-010 (three trials, 139 participants) and B. Lactis (eczema) in infants. HN019 (two trials) were deemed to have the most significant treatment effects.
Prebiotics are food for gut microbes. A prebiotic cannot
Yogurt is an excellent package of nutrients, and the be broken down by human digestive enzymes but can be regular consumption of yogurt has been associated fermented by gut bacteria. These non-digestible substrates with many positive health effects, such as improved are thought to selectively stimulate the growth of beneficial cardiovascular health and successful weight bacteria in the colon. management. The presence of pro- and prebiotics in yogurt may even mediate these and other health Food products with prebiotic effects are typically effects; scientists are still gathering information. non-digestible carbohydrates. The two compounds most The possibility of reduced transit time may be yet extensively tested and with confirmed prebiotic effects are another reason to consume yogurt, but the benefit inulin-type fructans (ITFs) and galacto-oligosaccharides depends on the frequency of consumption and type (GOS). Both ITF and GOS selectively increase of probiotics.
Bifidobacteria and Lactobacilli, bacterial strains that are also available as probiotics. ITFs occur naturally in several foods, such as leeks, asparagus, artichokes, garlic, onions, chicory, wheat, bananas, and soybeans. Other sources of prebiotics include honey, oatmeal, red wine, and legumes. As with probiotics, the influence of a prebiotic ingredient on the gut microbiota is transient. Changes in microbial composition respond rapidly—within 24 hours of exposure—and disappear equally fast upon withdrawal of the prebiotic compound. Conclusion
We are at any early stage in the discovery process of
the effects of probiotics and prebiotics. It is difficult to
identify the explicit effects of your microbiota on your
health, and no specific recommendations can yet be made.
The Linus Pauling Institute 13 In Memoriam: Dr. emile Zuckerkandl Dr. Emile Zuckerkandl, former Biological Laboratory in Wood's Hole, Massachusetts, President of the Linus Pauling followed by a stint as a visiting Professor at the University of Institute of Science and Medicine, died Delaware. At Pauling's invitation, Zuckerkandl joined the at home in Palo Alto, California, on Linus Pauling Institute of Science and Medicine in Menlo Park, November 9, 2013, at the age of 91.
California, in 1977 and was elected by its Board of Trustees as President and Director in 1980. Under Zuckerkandl's Zuckerkandl was born in Vienna, guidance, the Institute expanded into new research areas, Austria, in 1922. His mother was a including molecular evolution, aging, virology, genetics, and painter and his father was a gene regulation in cancer, while continuing strong programs biochemist, and his grandparents were in orthomolecular medicine. After his retirement from the involved in anatomy, psychoanalysis, Linus Pauling Institute of Science and Medicine in 1992, he and the arts. Zuckerkandl was forced to flee Austria during founded the Institute of Molecular Medical Sciences in Palo WWII, but thanks to help from Albert Einstein, immigrated Alto to carry out research in molecular biology and genetics.
to the United States to continue his education.
On May 29, 1998, Rick Hicks, former vice president of Zuckerkandl received a master's degree in physiology in the Linus Pauling Institute of Science and Medicine and a 1947 from the University of Illinois and a doctorate in long-time colleague of Zuckerkandl and Pauling, hosted a biology from the Sorbonne in Paris. He worked initially at small dinner on the occasion of the Austrian government's the Marine Biological Laboratory of Roscoff in Brittany award of the Austrian Cross of Honour for Science and on hemocyanin, a copper-containing oxygen transport protein found in the blood of invertebrates like mollusks and crustaceans.
In 1959 Dr. Linus Pauling offered Zuckerkandl a post-doctoral fellowship in his lab at the California Institute of Technology in Pasadena and persuaded him to study hemoglobin, the iron-containing oxygen transport protein in humans, instead of hemocyanin. Pauling had been interested in hemoglobin for many decades, including his discovery of abnormal hemoglobin as the cause of sickle-cell anemia—the first disease to be described as a molecular disease—and studies that discovered the alpha-helix, a main structural theme of proteins. In the 1950s, Pauling became increasingly interested in evolutionary theory, stimulated by his interest in possible genetic mutations caused by exposure to radio-active fallout. Under Pauling's direction, Zuckerkandl began Dr. Emile Zuckerkandl and Dr. Linus Pauling applying electrophoretic and chromatographic techniques Art to Zuckerkandl. Among the guests were Margrit and to study differences in hemoglobin among primates. This Robert Mondavi and Nobel Laureates Edward Lewis of collaboration resulted in a number of important papers, Caltech and Henry Taube of Stanford.
including the 1962 seminal paper, "Molecular disease, The Linus Pauling Institute inducted Zuckerkandl into evolution, and genetic heterogeneity," that introduced the the Linus Pauling Institute Society in May, 2007, at the concept of the molecular clock, which was specifically Diet and Optimum Health Conference in Portland, Oregon. named as such in another paper in 1965. In this new field Zuckerkandl was honored for his "extraordinary vision of molecular evolution that Pauling and Zuckerkandl also and generosity," qualities that sustained and enhanced the called "chemical paleogenetics," the molecular clock was Institute in California for many years, and for his great invoked to calculate and time the divergence of species based personal sacrifices on behalf of the Institute.
on the assumption of a fairly constant rate of mutation (amino acid substitutions, coded by DNA) and comparisons Stephen Lawson, LPI's administrative officer and former of the amino acid makeup of hemoglobin among species. CEO of the Linus Pauling Institute of Science and Medicine, This paper played a crucial role in the origin of the field knew Zuckerkandl for many years and co-directed the of molecular evolution, and Zuckerkandl later became the Laboratory for Research in Gene Regulation with him. founding editor of The Journal of Molecular Evolution. Lawson remembers Zuckerkandl as a brilliant scientist, accomplished pianist, humanitarian, and exceedingly kind In 1964 Zuckerkandl returned to France for many years, and generous person with catholic interests spanning diverse where he founded a molecular biology research institute, the sciences and the arts. Research Center of Macromolecular Biology, in Montpellier. He spent 1976 working on gene regulation at the Marine Emile Zuckerkandl is survived by Jane, his wife for over
65 years. LPI
14 spring/summer 2014 New Biography of Ava Helen Pauling Ava Helen Pauling: Partner, Activist, Visionary by Dr. Mina Carson—the only Linus Pauling Institute
biography of Linus Pauling's wife, Ava Helen—was published by OSU Press in 2013. Dr. Carson, an expert on American s a supporter of the Linus Pauling Institute, you care about healthful eating—you may not think you can have your cake and eat it, too. But, social and cultural history, by choosing to make a life-income gift to support the is an associate professor Linus Pauling Institute, you can strengthen LPI and of history at Oregon State receive income for life. In addition to the satisfaction of creating an Linus Pauling met Ava enduring legacy, life-income gifts offer a variety of Helen Miller at their alma tax, financial, and estate-planning advantages. Many mater, Oregon Agricultural College—now Oregon State donors who contribute highly appreciated but low-yielding stock find that they are able to increase their University. They married in 1923 when Pauling was a annual income while making a very important gift. graduate student at the California Institute of Technology In addition, these gifts may: in Pasadena and had four children. Ava Pauling was interested in social and political causes and persuaded • Provide an immediate, large tax savings her husband to devote more time to educating the public • Reduce capital gains taxes for gifts funded about the dangers of radioactive fallout from the with appreciated property atmospheric testing of atomic bombs. Their joint efforts, • Reduce estate taxes including circulating worldwide a petition among notable scientists, were instrumental in the test ban treaty of 1963 These gifts aren't overly complicated. You transfer to end the atmospheric and underwater testing of atomic cash, stocks, real estate or other property to a trust bombs, signed by the U.S.S.R., the United States, and the designed to pay an income to you (and/or someone United Kingdom. In 1963, Pauling won the Nobel Peace of your choosing) for life or for a specified term of years. When the trust ends, the remaining assets Prize for 1962 in recognition of his important role in pass to the Oregon State University Foundation to securing the treaty. He often said that he thought his wife support research in the Linus Pauling Institute.
should have shared the award. Among the treasured items in the Ava Helen and Linus Pauling Papers at OSU is a If low rates on other investments have you trove of love letters that Linus wrote to Ava Helen looking for a good way to supplement your over decades. LPI
income—now or in the future—and at the same time you want to do more to help the Linus Pauling Institute, we invite you to discover the benefits of a life-income gift to LPI.
For more information about how these flexible gifts can benefit you and your family, please contact LPI's gift-planning specialists at the OSU Foundation. There is no obligation and, of course, your request will be respected as strictly confidential. If you have any questions or would like a confidential illustration on how a life-income gift can help support LPI research meaningful to you, please contact Jeff SEE US ON FACEBOOk Comfort, Vice President, Principal Gifts and Gift Planning, OSU Foundation at 800-354-7281 or LPI
VISIT THE LPI BLOG The Linus Pauling Institute 15 Linus Pauling Institute Non-Profit Org.
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Page 1 . From the Director
Page 1 . Metabolizing Drugs and Toxins—
An Interview with Sharon Krueger, Ph.D.
Page 7 .The Case is Far from Closed for
Vitamin and Mineral Supplements!

Page 8 .What is Bioavailability?

Page 9 .Briefly. . Vitamin B12 and Stomach
Acid-suppressing Drugs
Page 10 .Cruciferous Vegetables and
Cancer Prevention
Page 12 .Probiotics and Prebiotics

Page 14 .In Memoriam: Dr. Emile Zuckerkandl
Page 15 .Developments
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Active Music Therapy in Parkinson's Disease: An Integrative Method for Motorand Emotional RehabilitationCLAUDIO PACCHETTI, MD, FRANCESCA MANCINI, MD, ROBERTO AGLIERI, CIRA FUNDAR O, MD, EMILIA MARTIGNONI, MD,AND GIUSEPPE NAPPI, MD Background: Modern management of Parkinson's disease (PD) aims to obtain symptom control, to reduce clinicaldisability, and to improve quality of life. Music acts as a specific stimulus to obtain motor and emotional responsesby combining movement and stimulation of different sensory pathways. We explored the efficacy of active musictherapy (MT) on motor and emotional functions in patients with PD. Methods: This prospective, randomized,controlled, single-blinded study lasted 3 months. It consisted of weekly sessions of MT and physical therapy (PT).Thirty-two patients with PD, all stable responders to levodopa and in Hoehn and Yahr stage 2 or 3, were randomlyassigned to two groups of 16 patients each. We assessed severity of PD with the Unified Parkinson's Disease RatingScale, emotional functions with the Happiness Measure, and quality of life using the Parkinson's Disease Qualityof Life Questionnaire. MT sessions consisted of choral singing, voice exercise, rhythmic and free body movements,and active music involving collective invention. PT sessions included a series of passive stretching exercises,specific motor tasks, and strategies to improve balance and gait. Results: MT had a significant overall effect onbradykinesia as measured by the Unified Parkinson's Disease Rating Scale (p ⬍ .034). Post–MT session findingswere consistent with motor improvement, especially in bradykinesia items (p ⬍ .0001). Over time, changes on theHappiness Measure confirmed a beneficial effect of MT on emotional functions (p ⬍ .0001). Improvements inactivities of daily living and in quality of life were also documented in the MT group (p ⬍ .0001). PT improvedrigidity (p ⬍ .0001). Conclusions: MT is effective on motor, affective, and behavioral functions. We propose activeMT as a new method for inclusion in PD rehabilitation programs. Key words: music therapy, Parkinson's disease,rehabilitation.

spring 2013 / 5773 AssociAtion for cAnAdiAn Jewish studies AssociAtion des études juives cAnAdiennes A C J SA E J C spring 2013 / 5773 Volume 27:1 Louis Rosenberg Distinguished Service Award conferred on professor ira robinson Religion, the Association for Jewish Studies and the Canadian Society for