LINUS
PAULINGINSTITUTE
OREGON STATE UNIVERSITY
research newsletter
Fall–winter 2017

The new director of the Linus Pauling Institute is announced. look Insidebroccoli and longnon-coding RNAs
Exploring novel routes of EPIgenetic
regulation through nutrition
By Laura M. Beaver, Ph.D. and Emily Ho, Ph.D.

If you only take away one message from thisarticle, it would be this: Eat more broccoli.
Everyone knows that broccoli is good for you.
It is low in calories, packed with fiber and avariety of micronutrients, and is a part of the
cruciferous vegetable family (see page 5).
However, there is more to broccoli than this:And we want to share our exciting new
discoveries about broccoli that may help
convince you to put more of it on your plate.
Here we discuss sulforaphane, a phytochemical
your body can obtain from consuming broccoli,
and how it may relate to cancer prevention.
This is through changing the expression of genesthat were, until recently, thought of as junk.
In the past, researchers believed that the
DNA and RNA in our cells had only one known

function: providing instructions to make protein.
“Junk DNA” is a term that applies to the DNA
sequences that do not code for protein andtherefore considered unimportant, just random
junk found in chromosomes. However, some ofthese DNA sequences provide the code for RNA
molecules that can be found in cells. There are
multiple types of this ‘non-coding’ RNA, and in
this article we will explore a class of these RNA
molecules termed long non-coding RNA or lncRNA.
Although these RNAs do not produce proteins,there are thousands of lncRNAs in the humangenome (and likely many more still to bediscovered). Interestingly, lncRNAs tend to be
tissue specific; for example, lncRNA1 is foundonly in the prostate, while lncRNA2 is foundonly in the brain and spinal cord. But because
lncRNAs are often expressed at much lower
levels than most other RNAs that code forfunctionally significant proteins in the body,they have largely been ignored. Further, genesthat code for lncRNAs are not as conserved fromone species to the next, which is a traditionalsign of “important” DNA within the cell.
Continued on page 4

In This Issue
Broccoli and Long
Non-Coding RNAs............... 1
From the Director................ 2
Diet and Optimum Health2017........................................ 6
The LPI Prize for HealthResearch................................. 7
Combating Cellular
Senescence............................ 8
Ignose, Godnose, Hexuronic
Acid, Ascorbic Acid. . .
Vitamin C!............................10
Metabolic Monitoring inLaboratory Animals...........11

Farewell to Barbara
McVicar................................12
LPI Students........................14
Developments....................15

From the Director

Jan Frederik Stevens, Ph.D.
Professor and Interim Director
Linus Pauling Institute“This past year,
the combined LPI
faculty trained 34
graduate students,
29 postdocs andvisiting scholars, and57 undergraduate
students in theirlaboratories.”— Jan Frederik Stevens, Ph.D.

Fall has come to Oregon, after a very
productive summer for the Linus Pauling
Institute. This September, the LPI hosted
the ninth biennial Diet and Optimum
Health conference (see page 6). Over 180
participants from more than a dozen
countries came to hear from a select group ofrecognized experts in the areas of molecularnutrition, vitamins, lipid metabolism, andgut microbiota. At the conference banquet,
we celebrated the 20th anniversary of the
LPI at Oregon State University with anamazing gift from Joahn H. Facey, wehonored Director Emeritus Dr. Balz Frei
with the LPI Prize for Health Research, andwe welcomed the new Director of the Linus
Pauling Institute, Dr. Richard van Breemen.
Overall, it was an extremely successful event.
With summer now over, more than 25,000
students have returned to campuses inCorvallis and Bend for a new academic year
at OSU. Many students are now seeking
health-related research opportunities in
LPI laboratories to gain hands-on experienceand to strengthen their applications foradmission to graduate school, medical
school, or other professional healthcare
programs. This past year, the combined
LPI faculty trained 34 graduate students,
29 postdocs and visiting scholars, and57 undergraduate students in theirlaboratories. In this newsletter, LPI students
Yang Zhang, Bharath Sunchu, and Lea Sophie
Ullrich are telling their stories on page 14.
The reorganization of the LPI Core
Laboratories I mentioned in the previous
newsletter is now complete. Focusing
on metabolomics, bioinformatics, andmetabolic phenotyping, with strong ties
to clinical and translational research, weare positioning ourselves better for federal
funding opportunities. With help from
Oregon State University’s Research Office,
the College of Public Health and Human
Sciences, and the College of Pharmacy, we
are now operating a Promethion metabolic
phenotyping system in our BiologicalModels and Translational Research Core.
Dr. Kate Shay has more in this newsletteron what this system can do to foster
research on metabolic health and physicalactivity (see page 11).

2

Federal grants are still difficult to obtain.
LPI faculty have applied for more grants
this past year than the year before. Six LPI
proposals seeking support from the National
Institutes of Health (NIH) scored in the
top 15% nationally, and three of these wereselected for funding. Two of the NIH award
winners, LPI Principal Investigators Viviana
Pérez and Kathy Magnusson, plan to study
cellular aging in the brain and what it meansfor our understanding of Alzheimer’s
disease. See more about Dr. Pérez’s workand their grant in this newsletter, startingon page 8.
And now for the “Changing of the Guard”:
It gives me great pleasure to announce
that the next director, Richard van Breemen,
Ph.D., will start his appointment in January
2018. By way of introduction, Dr. van
Breemen, currently a Professor of
Medicinal Chemistry and Pharmacognosy
at the University of Illinois at Chicago, is
one of the foremost leaders in thequalitative and quantitative analysis ofbotanicals and dietary supplements usingmass spectrometry techniques. Dr. van
Breemen and his group have developed
innovative methods for chemical analysisof botanicals and novel technologies for
rapid identification of bioactive
compounds in botanicals and dietary
supplements.
This area of research is important because
dietary supplements may be harmful tohuman health if they interact with drugmetabolizing enzymes and if they containtoxic natural products due to herbal
misidentification or due to adulteration
with cheaper but harmful ingredients.
For the past seven years, Dr. van Breemen
has directed the NIH Center for Botanical
Dietary Supplements Research in Chicago,
which has a focus on botanical dietary
supplements used by women seeking
alternatives to hormone therapy for reliefof menopausal symptoms. His group willcontinue studying the safety and efficacy
of dietary supplements at the LPI. All of us
at the Institute support Dr. van Breemen,
and we are looking forward to working withhim and his group. Please feel free to contact
Dr. van Breemen in the coming months,

The four directors of the Linus Pauling
Institute (from left to right): Dr. Don
Reed, Dr. Balz Frei, Dr. Fred Stevens,and Dr. Richard van Breemen

and you will undoubtedly be hearing much
more from him and his group in the spring.
Our Executive Assistant, Barbara McVicar,
has announced her retirement from theLinus Pauling Institute. Barbara has beenwith the Institute for nearly all of its
history at Oregon State University, serving
all three directors to date: Donald Reed
(1996-1997), Balz Frei (1997-2016), and me.
With such an astounding career at LPI, her
contributions to our success are difficult
to summarize. Dr. Frei once wrote: “It is
not an exaggeration to say that neither myown effectiveness and accomplishments as
LPI Director nor the rapid progress of theInstitute itself would have been possible
without Barbara.”
For over two decades, we have relied
upon Barbara for all the Institute’s needs.
Her commitment and initiative show
clearly in her tireless efforts to help us
achieve success. Reflecting upon a careerat LPI, Barbara has seen the Institutechange from humble beginnings at OSU
after leaving Palo Alto. One of her favorite
parts of the job was being able to help
you – the reader – when you call or email
looking for answers to a question, more
information, or just a friendly ear. All of us
will miss her presence at the front desk at
the LPI. I encourage everyone to read moreof her recollections about her time at theInstitute on page 12.
Barbara’s last day working for theInstitute is at the end of this year. Althoughthat day is fast approaching, we have
her successor in training: Caitlyn Reilley,
formerly a volunteer worker with our
Healthy Youth Program, is learning manyof Barbara’s daily duties. Caitlyn is also a
recent graduate of OSU’s College of Public
Health and Human Sciences, and thus isvery familiar with the University and LPI.
For those of you who have interacted with3

Barbara over the years, please introduce
yourself to Caitlyn when you call or email.
Finally, I would like to thank you all foryour support in my time as interim director.
It has been an honor and privilege to serve
the LPI in this role, and I am pleased withthe successes we have achieved in myshort tenure in this office. Though I am
stepping aside, I am not going far. I will
resume my academic activities as
professor, principal investigator, andjournal editor. You will continue to see
advances and developments from mylaboratory in the future.
Sincerely,

Jan Frederik Stevens, Ph.D.
Professor and Interim Director
Linus Pauling InstituteContinued from cover — Broccoli and Long Non-Coding RNAs

Laura M. Beaver, Ph.D.
LPI Investigator

Then came a turning point: the discovery
that individual lncRNAs were found tohave specific functions. These functions
could be diverse, such as creating
subcellular structures or regulating theexpression of genes that code for proteins,but IncRNAs may have critical roles incells. Furthermore, recent advances in
RNA sequencing led to the discovery
that lncRNAs are dysregulated in many
diseases, including cancer, and may be
key components of epigenetic regulatory
networks.

with genes that regulate cell cycle, signaltransduction, and metabolism – allimportant players in cancer development.
So, we took a step further and explored therole of just one of these lncRNAs called
LINC01116, an RNA that is relatively high inaggressive prostate cancer cells and also inother types of cancer cells. Sulforaphane
treatment appeared to do exactly what we
expected: It decreased the expressionof LINC01116 about 50% compared tountreated cells. Artificially reducing thelevels of this lncRNA shows that LINC01116

Compounds from the food that we eat have thepotential to alter the expression of lncRNAs, andthis may play a role in our health.
–Laura M. Beaver, Ph.D.

Emily Ho, Ph.D.
Professor, School of
Biological & Population
Health Sciences;Endowed Director, Moore
Family Center for Whole
Grain Foods, Nutrition &Preventive Health;
LPI Principal Investigator

As it turns out, some of these non-coding
RNAs aren’t junk after all.
This is when our laboratory began to
explore the possibility that lncRNAs mightalso have a role in cancer prevention.
We did this using sulforaphane because it
can prevent and suppress cancer in animalmodels. Sulforaphane is toxic to prostatecancer cells in culture, but non-toxic innormal (non-cancerous) prostate cells.
Using RNA sequencing, we tested the
hypothesis that sulforaphane changes theexpression of cancer-associated lncRNAs inhuman prostate cancer cells. Interestingly,
the treatment altered the expression of
about 100 different lncRNAs and evennormalized the expression of some lncRNAs
that were dysregulated in prostate cancer.
The lncRNAs that changed withsulforaphane seemed to correspond

Graphical representation of LINC01116.
This is one of the possible configurations
the molecule could adopt that would allow
it to interact with proteins and DNA.

4

participates in regulating the expressionof some genes involved in glycolysis,
autophagy, and chromatin structure.
These studies also showed that reducing
LINC01116 levels decreased the ability of
prostate cancer cells to grow and formcolonies. This is a positive outcome incancer, where you want to inhibit theability of the cells to grow or invade newareas of the body.
Although we still are unsure about
exactly how LINC01116 functions in cells,
our work suggested that it might form afolded structure (see image below) thatinteracts with the DNA of potential target
genes by creating an RNA-DNA triplex, andthis may influence how neighboring genes
are activated.

Even as our work in prostate cancer
was progressing, a parallel story wasdeveloping in labs of our collaboratorswith respect to colon cancer. The researchbegan with the sequencing of RNA from
sulforaphane-treated human colon cancer
cells and non-cancerous colon cells. With
sulforaphane treatment, a non-coding RNA
named NMRAL2P increased dramatically,
also appearing to have an anti-cancer
function. NMRAL2P appears to be under
the control of Nrf2, a master regulatory
protein in stress response and aging.
Further, NMRAL2P regulates theexpression of a gene called NQO1, which
participates in the protection of cells
against oxidative stress. By manipulating
NMRAL2P levels, we found evidence that
sulforaphane has cancer suppressive
properties in colon cancer cells in partthrough NMRAL2P.
Our findings highlight some of theexciting new ideas that have been
emerging about non-coding RNA. The firstis that lncRNAs are promising new targets
that could be manipulated for cancer
prevention. The second is that compounds
from the food that we eat have thepotential to alter the expression oflncRNAs, and this may play a role in ourhealth. Eating cruciferous vegetables is
associated with a decreased risk of cancer
in some studies – is this through the
involvement of lncRNAs?
We thus arrive back at our take-homemessage: Please eat more broccoli,
broccoli sprouts, Brussels sprouts, bokchoy, cabbage, or any other cruciferous
vegetable that appeals to you. Most ofthem are reasonably priced, easy to find,and taste pretty good. For many reasons,
including the production of sulforaphane,they are generally good for your health.
Enjoy!
References:
Huarte, M and Rinn, JL, Hum Mol Genet.
19 (2010) doi: 10.1093/hmg/ddq353
Beaver, LM et al., J Nutr Biochem. 42 (2017)
doi: 10.1016/j.jnutbio.2017.01.001
Johnson, GS et al., Mol Nutr Food Res. 61 (2017)
doi: 10.1002/mnfr.201600769

The Health Benefits of
CRUCIFEROUS VEGETABLES
from the Micronutrient Information Center
Nutrients and phytochemicals in
cruciferous vegetables like broccoli
synergistically contribute to healthpromotion. Broccoli is healthful for manyreasons: It is a good source of vitamins(like folate, vitamin C, and vitamin K),
minerals (magnesium and potassium),and dietary fiber. Like other cruciferous
vegetables, broccoli also contains
glucosinolates that can form
sulforaphane – an isothiocyanate that
may have cancer-fighting properties –and many other bioactive compounds.
Glucosinolate compounds are thesource of the bitter taste found inbroccoli and other cruciferous vegetables.
Glucoraphanin, a glucosinolate, can beconverted to sulforaphane. This only
happens when the vegetable is chewed
or chopped, because an enzyme released
from the plant is necessary for the process.
Cooking the vegetables inactivates the
enzyme needed for this conversion, butlight cooking (i.e., steaming for no morethan 5 minutes) will preserve some of the
enzyme activity.
Cruciferous vegetables are a family ofBrassica vegetables that also includes

5

Brussels sprouts, bok choy, cabbage,
cauliflower, kale, arugula, horseradish,radishes, turnips, watercress, andwasabi. High intakes of cruciferous
vegetables have been associated withlower risks of cardiovascular disease andseveral site-specific cancers, including
prostate, stomach, colorectal, bladder,lung, kidney, pancreatic, and breast
cancer. However, the evidence
supporting these effects is not particularly
strong due to the nature of the studies
that were conducted. Thus, this topic
requires more research.
Learn more about cruciferous
vegetables and their bioactive compounds
in these recently updated articles in the
LPI Micronutrient Information Center:
lpi.oregonstate.edu/mic/
food-beverages/cruciferous-vegetables
lpi.oregonstate.edu/mic/
dietary-factors/phytochemicals/
isothiocyanates
lpi.oregonstate.edu/mic/
dietary-factors/phytochemicals/
indole-3-carbinol

diet and optimum health 2017
The Linus Pauling Institute’s 9th biennial conference

The Linus Pauling Institute held theDiet and Optimum Health conference on
the Oregon State University campus in
Corvallis from September 13-16, 2017.
The conference featured 39 speakers frommany different countries, presenting in
13 different sessions around the central
theme of the conference: Innovative
Approaches to Improving Health.
The conference started with A Tributeto Balz Frei, a session dedicated to ourdirector from 1997-2016. Dr. John Keaney,
who worked with Dr. Frei before he cameto the Linus Pauling Institute, started thesession with a background on vitamin C
and its roles in protecting the vasculature.
Dr. Roderick Dashwood, formerly of theLinus Pauling Institute, then spoke about
his projects on dietary indole compounds
and sulforaphane from cruciferous vegetables– work influenced by Dr. Frei’s involvement.
Lastly, Dr. Helmut Sies, LPI Prize award
winner from 2013, talked about the “Redox
Code,” detailing electron reaction systems
prominently featured in Dr. Frei’s work overthe past few decades.
Components of our diet that promote or
inhibit the growth of beneficial bacteria
in the colon were outlined in Dietary
Components and the Microbiome.
The Metabolism of Bioactives continued
this theme, focusing on how polyphenolic
compounds may be altered by an interplay

Diet and Optimum Health consisted of 13 sessions
focusing on many innovative approaches toimproving health. A full conference program,with videos, photos, and sponsors can be foundat lpi.oregonstate.edu/DOHof our microbiome and our cells,
transforming them into a number ofdifferent molecules with properties that weare just beginning to explore. The impact
bioactives may have on human health was
elucidated further in Bioactives andCancer Prevention, with a focus
specifically on modifying epigenetic signals.
Lipid Metabolism challenged our views
on how fats behave in the body, including
the benefits of medium-chain fatty acids
and how lipid oxidation might trigger a
newly described form of cell death. Next,
An Update on Vitamin E, with threepresentations followed by a round-tablediscussion, was dedicated to understanding
new roles and requirements of this poorly
understood lipid-soluble vitamin.
Nutrition and Brain Health had adiverse set of talks that investigated various
aspects of the diet on cognitive function,
including the impact of certain herbal
supplements, high-fat diets, and vitamin C
deficiency. The oxidation of a mitochrondriaspecific phospholipid, cardiolipin, was also
indicated as a target for therapies intraumatic brain injury.
The Linus Pauling Institute was particularly
excited to host the last full day of theconference: an all-day session on vitamin C,
addressing Mechanisms of Vitamin C in
Cancer, Intravenous Vitamin C Therapy
in Cancer, and Intravenous Vitamin C
Therapy in Sepsis. These sessions built upon
Linus Pauling’s seminal work with vitamin
C starting in the 1970s, extending out into
the mainstream, but they also covered newfrontiers that expounded on the theories
of Pauling and many other early vitamin C
pioneers. The case reports of individuals who
6

had their lives changed by intravenous
vitamin C therapy were particularly moving
and served as a validation of the power
behind this fascinating molecule.
The final session of the conference was
the free public session, focusing on cancer
prevention and treatment, and featuring
Drs. Emily Ho and Jeanne Drisko. Dr. Hospoke of her work with sulforaphane(see front page) and dietary approaches
to cancer prevention, and Dr. Drisko
focused on the history and modern use of
intravenous vitamin C in cancer treatment.
The LPI’s Young Investigator Award, given
to graduate students and postdoctoral
researchers, went to four outstanding
young scientists: Yang Zhang from theLinus Pauling Institute (featured on page14), Shilpy Dixit from Vanderbilt University,
Martin Pearce from Oregon State
University, and Geoffrey Sasaki fromThe Ohio State University.
Major conference donors included LivOn
Labs, Bayer AG, TishCon Corporation,
Nu Skin/Pharmanex, and DSM Nutritional
Products. We would also like to highlightthe support of Ms. Karen Sharples from
Vancouver, Washington, who has supported
many of our conferences, as well as ourlong-time supporter, the Oxygen Clubof California.
Thanks to all who participated in andattended the conference this year. The nextDiet and Optimum Health conference will
be held in 2019.

linus pauling instituteprize for health research
The 2017 Linus Pauling Institute Prize
for Health Research was awarded to
Dr. Balz Frei, in honor of his dedication to
micronutrient and phytochemical research.
A respected name in many fields, Dr. Frei’s
contributions total over 350 publishedarticles, which together have been citedby his peers more than 23,000 times.
Papers noted by his colleagues include:• Ascorbate is an outstanding
antioxidant in human blood plasma(1989)• Vitamin C prevents metal
ion-dependent initiation andpropagation of lipid peroxidation inhuman low-density lipoprotein (1995)• Increase in circulating products oflipid peroxidation (F2-isoprostanes) in
smokers. Smoking as a cause ofoxidative damage (1995)• Does vitamin C act as a pro-oxidant
under physiological conditions? (1999)• Tea catechins and polyphenols: healtheffects, metabolism, and antioxidant
functions (2003)
As the director of the Linus Pauling
Institute, Dr. Frei grew the Linus Pauling
Institute from a small group of only six
people into a robust, thriving researchenterprise with 12 principal investigators
supported by a team of dozens of students,
scientists, and staff. Thanks to his direction,
the Linus Pauling Institute has become arespected name in molecular nutrition. In
addition to the scientific accomplishments,
under his leadership LPI established a105,000-square-foot facility with modern
laboratories, cutting-edge technologies,
and the space needed for LPI researchers
to interact and innovate.
And last, but not least, Dr. Frei established
two outreach programs at the Linus Pauling
Institute: the Healthy Youth Program andMicronutrient Information Center. The
Healthy Youth Program is dedicated to
implementing knowledge on healthfuleating and a healthy lifestyle in local

communities. Currently it has partnerships
with many community organizations,
including local hospitals, allowing it toreach upwards of 1,200 children andfamilies in just this past year.
The Micronutrient Information Center
is a website that disseminates freely
available, evidence-based information on
vitamins, minerals, phytochemicals, andother dietary factors in health and disease.
Averaging more than one million visitors
annually, this website is read by people
around the globe. Currently available in
English and Spanish, it soon will betranslated into Japanese.

“Doing basic research isimportant, but it is equallyimportant to come out of
the ivory tower and reallyhelp people make the rightdecisions regarding theuse of diet and dietary
supplements for their health.”–Balz Frei, Ph.D.

Although his early career focused on
vitamin C and atherosclerosis, Dr. Frei andhis lab team at the LPI made importantinroads into the mechanistic actions ofphytochemicals and polyphenols. Under
his leadership, LPI researchers broke
new ground in research on catechins intea, quercetin in onions, sulforaphane inbroccoli, and xanthohumol in hops, just to
name a few. Their findings have generated
new knowledge for preventing pathologicalconditions, such as cancer, metabolic
syndrome, neurodegenerative disease,and cardiovascular disease.
With the 2017 Linus Pauling InstitutePrize for Health Research, we recognize
Dr. Frei’s tireless efforts to build andtransform the field of micronutrient
research into what it has become today,and helping to advance the field of
molecular nutrition into the 21st century.

7

Dr. Balz Frei at the 2017 Diet andOptimum Health conference.

The Linus Pauling Institute Prize
for Health Research is awarded inrecognition of innovation and
excellence in research relating to theroles of vitamins, essential minerals,
and phytochemicals in promoting
optimum health and preventing or
treating disease, and the roles ofoxidative and nitrative stress andantioxidants in human health anddisease. The prize also recognizes
successful efforts to disseminate
and implement knowledge on diet,lifestyle, and health to enhance
public health and reduce sufferingfrom disease.
The award was presented to Dr. Frei
during the Diet and Optimum Healthconference this year, surrounded byhis friends and family. Many speakers
who spoke in other sessions alsomentioned the impact that Dr. Frei
had on their personal andprofessional lives. Dr. Fred Stevens,interim director of the Linus Pauling
Institute, made the award
presentation; the video of the award
ceremony and tributes to Balz Frei
are available online at
lpi.oregonstate.edu/freiCombating Cellular Senescence
A new function discovered for rapamycin, a compound that may help slow aging
By Alexander Michels, Ph.D.

Dr. Viviana Pérez and her team(pictured: Bharath Sunchu) research thebasic biology of aging on a cellular level.

When cells accumulate significant
damage, they typically initiate a process ofcell death. Depending on the type of celland the amount and nature of the damage
involved, this is usually an orderly process,and neighboring cells do not suffer any
untoward consequences. However, there
are times when a damaged cell does notinitiate this process – instead, it stops cell
division in an attempt to survive the damage.
This is known as cellular senescence.
The problem is that senescent cells
are not always quietly active insideorgans – they can secrete a number ofpro-inflammatory molecules that alter theproper function of healthy, adjacent cells.
Researchers refer to this as thesenescence-associated secretory
phenotype, or SASP.
In other words, they become noisy
neighbors.
Senescent cells aren’t all bad – they
can play important roles in the body (seesidebar on page 9). Yet, SASP-positive cells
increase in tissues as we get older, so theprocess of cells turning toward senescenceis broadly linked to aging. And, an increasein cellular senescence has been linked withcardiovascular disease, diabetes mellitus, andcancer, among other age-related diseases.
Viviana Pérez, Ph.D., a member of the
Healthy Aging Program at the Linus Pauling
Institute, focuses on finding ways to preventor delay senescence as a possible route forpreventing disease. Her research groupfocuses on a compound called rapamycin.
Rapamycin, also called Sirolimus, is foundin bacteria and was initially investigatedfor its use as an anti-fungal treatment.
However, it was later discovered that
rapamycin had potent anti-inflammatory
and anti-proliferative properties thatallowed it to be widely used to prevent
tissue rejection in transplant patients. It
is also approved for use in treating a rare,
progressive lung disease.
Rapamycin became a compound ofinterest in aging research because it can
mimic the effects of dietary restriction,
which in some animals has been proven toextend their lifespan. It also has a clear rolein combating cellular senescence in animals.
“Increases in cellular senescence areassociated with aging. The associatedinflammation can set the stage for a wide
8

variety of diseases, including cancer, heartdisease, diabetes, and neurological disease,such as dementia or Alzheimer’s,” Dr. Pérez
explains. “In laboratory animals when weclear out senescent cells, they live longer
and have fewer diseases. And rapamycin
can have similar effects.”
Laboratory mice that have received
rapamycin have demonstrated increased
fitness, less decline in physical activity
with age, improved cognition andcardiovascular health, less cancer, and alonger life.
Researchers had previously determined
one mechanism of action for rapamycin in
preventing SASP: It boosts the activity of
Nrf2, a master regulator protein that can
induce the expression of up to 200 genes
responsible for cell repair, detoxification ofcarcinogens, protein and lipid metabolism,
and antioxidant protection. The culminationof these Nrf2-driven processes reducelevels of SASP in laboratory models.
Dr. Pérez’s group has now discovered a
new mechanism for rapamycin in stopping
cellular senescence. They concluded –in two newly published studies – that
rapamycin reduces SASP separate froma pathway involving Nrf2. This route of
rapamycin’s action could cause a direct
reduction of inflammatory markers in cells,
preventing senescence formation whendamage occurs. However, at present theuse of rapamycin to help prevent humandisease is limited due to the side effects,
like insulin resistance, that can occur.
Dr. Pérez has now brought her work on
senescence to neurological disease in a
newly funded grant from the National
Institutes of Health’s National Instituteon Aging. This 5-year grant will support
Dr. Pérez’s work on determining theimpact cellular senescence plays in thedevelopment of Alzheimer’s disease in
newly developed animal models.
In part of the grant, Dr. Pérez and hercollaborators will develop a new animalmodel for investigating the role senescentcells play in Alzheimer’s disease. In thismodel, the senescent cells that naturally
develop in the brain or other tissues canbe removed by administering a specificcompound to the animals.
Dr. Pérez’s collaborators in San Antonio
will assist by monitoring changes inmemory and behavior in these animals.
In the LPI, Dr. Kathy Magnusson will help
evaluate synaptic function in the isolated
brain tissue. If the team determines thatthe disease stops or slows when thesenescent cells are removed, it provides
evidence for their theory that Alzheimer’sor other neurological conditions may betreated by targeting senescent cells in the
body. They also plan to measure the impact
of compounds like rapamycin that are
purported to limit the negative effects ofsenescent cells.
The hope is that this will eventuallylead to new breakthroughs in treating avariety of neurological diseases in humans.
“We know that cells in the brain can bedamaged by SASP,” explains Dr. Pérez.
“Since these cells help protect neuronal
function and health, rapamycin could lead
us toward a new approach to treating
Alzheimer’s disease in the future.”
References
Yu, Z et al., J Gerontol A Biol Sci Med Sci. 70(2015) doi: 10.1093/Gerona/glu053
Wang, R et al., Aging Cell. 16 (2017) doi: 10.1111/
acel.12587

A cell can enter senescence as a
response to various types of damage.
As an alternative to inducing
programmed cell death, this adaptation
comes at a cost to neighboring cells.

What is Cellular Senescence?
Senescence is a form of aging that limits
the capacity of cells to divide. It is normal
for cells to stop dividing after they
undergo a certain number of divisions,especially when telomeres – the endsof our chromosomes – shorten past a
particular point. This is usually a signal
to the cell that it risks incurring
permanent damage if it undergoes
another replication cycle. Senescenceis a way for the cell to remain alive
and contribute to tissue functions
without dividing.
It is also extremely important for cells
that have undergone particular typesof stress, especially DNA damage or
oncogene activation, to limit their ability
to replicate – cells laden with damage

Wang, R et al., Exp Gerontol. 94 (2017) doi:
10.1016/j.exger.2017.01.026

9

could lead to the development of cancer.
Although cells would normally initiate
an orderly process of programmed cell
death called apoptosis, i.e., a systematic
removal of the troubled cell, apoptosis
is not always a viable option. Thus, somecells can remain in a senescent state fora prolonged period.
Senescence can also be part of aprogrammed series of events. For
example, senescence helps form certain
structures in the body in a developing
embryo. It also may be an important
process in wound healing. At this time,
it is not entirely clear how and whensenescence is preferred to apoptosis,
but researchers in this field are
currently examining these questions.

Ignose, Godnose, hexuronic acid,ascorbic acid…vitamin C!
By Jan Frederik Stevens, Ph.D.
In 1995, I graduated from the Universityof Groningen, the Netherlands. I have since
visited my alma mater a couple of times.
During my visit in 2010, I noticed a plaqueon the east wall of the old physiology
building where I took classes in applied
physics and pharmacology (see picture).
Dated June 2007, the plaque draws
attention to discoveries made by Dr. Albert
Szent-Györgyi in that very building. While I
stood there to take a picture of the plaque,
I was greeted by Professor Ben Westerink
who apparently recognized me and asked,“On a pilgrimage?”

Dr. Albert Szent-Györgyi,a Hungarian biochemist
interested in cellularrespiration, first isolated
vitamin C in search forbiological inhibitors ofoxidation. He won theNobel Prize in Physiology
or Medicine in 1937.

You see, one of the natural substancesthat was discovered in that building
ultimately turned out to be vitamin C.

thought he had discovered an essential
adrenal hormone, he actually had isolated
a carbohydrate.

Since that plaque was not in that facility
until recently, it left me wondering why it
took so long for the University to recognize
Dr. Szent-Györgyi’s early work. Although
his studies in this building (1922-1926)
resulted in six impactful papers publishedin Biochemische Zeitschrift, few professors
at the University thought much of his workat the time. One professor was of theopinion that Dr. Szent-Györgyi’s paper on
the respiration of plants ‘should be thrownin the wastepaper basket’ (J.J. Beintema,
Journal of the History of Biology, 2008,
volume 41).

Without knowing the exact structure of
the substance, Dr. Szent-Györgyi calledit ‘ignose’ – derived from Latin ‘ignorare’
meaning ‘to not know’ and the suffix ‘ose’
to indicate it was a sugar-like compound.
When he went to publish his results, theeditors of the Biochemical Journal asked him
to rename the compound. He then suggested‘Godnose’ (only God knows) as a name forthe molecule. This name was also rejected,
and the editors and Dr. Szent-Györgyi
finally agreed on the name ‘hexuronic acid.’
When hexuronic acid was discovered toprevent scurvy, it was later renamed‘ascorbic acid’ to reflect these anti-scorbutic
properties: in other words, it was vitamin C.

The compound Szent-Györgyi isolated
inhibited biological oxidations and wasabundantly present in adrenal glands.
Disappointed that the substance fromadrenal extracts did not rescue
adrenalectomized cats, Dr. Szent-Györgyi
left Groningen to work on the chemical
characterization of the compound at the
University of Cambridge. Although he
10

Dr. Albert Szent-Györgyi received theNobel Prize in Physiology or Medicine in1937 for his work in biological oxidation
reactions, including the discovery ofvitamin C. Other Nobel laureates from
Groningen are Heike Kamerlingh Onnes(Physics, 1913), Fritz Zernike (Physics, 1953),
and Ben Feringa (Chemistry, 2016).

Metabolic Monitoring in Laboratory Animals
By Kate Shay, Ph.D.
The purpose of metabolic monitoringis to get very precise information about
metabolic activity in an individual.
Metabolic monitoring can take many
forms, with a variety of methods used
to measure metabolism. Ultimately,
regardless of the technique used, theresults give you information about theenergy utilized by the body.
More accurate and detailed information
comes from more constant monitoring.
The most definitive information about
metabolism comes from individuals in a
metabolic ward, a controlled environment
where the calorie intake and output iscarefully monitored. However, for obvious
reasons, most people do not want to be
stuck in a hospital-like environment fordays at a time. Indeed, the demands ofthese types of experiments are often quite
impractical in humans; thus, we usually
make use of laboratory animals.
The Linus Pauling Institute recently
acquired a Promethion metabolic
phenotyping system, used to monitor
various aspects of metabolism inlaboratory animals. In general, this systemgives us a picture of energy use over time.
For our purposes, it is especially usefulto test how compounds of interest can
influence metabolic rate. If researchers
want to know whether lipoic acid cansupport weight loss, for example, thevarious features of the Promethion system
can tell us whether animal models fed thatcompound burn more calories.
The primary goal of using the Promethion
system is accurate tracking of energy
expenditure. The system has the capacity
for real-time monitoring of exhaled gases

The Promethion systemgives the Linus Pauling
Institute a greater capacity
to conduct high-quality
metabolic research inlaboratory animals.
– imagine a constant connection to a gas
analyzer for everything you do, even when
you sleep. In this case, however, continuous
monitoring of the entire animal housing
unit by an array of sensors does notinterfere with daily activity. The animal isunaware of the monitoring, and behaves as
it would normally.
The system estimates energy expenditure
by indirect calorimetry: a technique that
calculates calories burned by oxygen
consumption and carbon dioxide
production, two gases that are indicatorsof metabolic activity. Because these gases
are produced in different ratios when the
body burns protein, carbohydrate, or fat, thistechnique estimates what mixture of dietary
fuels an animal is using to produce energy.
Physical activity also accounts for no small
portion of the daily energy expenditure
in animals. In the Promethion system,
infrared sensors surrounding each cage
monitor the movements of the animalthroughout the day. Since all of therecords of activity and respiration data arecollected simultaneously, we can measure
how animals expend energy during a
resting period or when they are active.
Because we also record body weight(fuel reserves) and food intake (calories
consumed), this is a complete system formonitoring whole-body metabolism.
Animal monitoring studies can be shortor long-term (up to several days), to allow
the development of the best research
design to address the hypothesis at hand.
Since the Promethion system is so flexible,
it provides few limitations on study design
and allows researchers to ask the questions
that interest them.
The Promethion system gives the Linus
Pauling Institute a greater capacity to
conduct high-quality metabolic researchthat will provide greater opportunities forfederal funding. This certainly would nothave been possible without backing frommany supporting units at Oregon State
University, and we appreciate theinvestment in the future of health research.

The Promethion High-Definition Multiplexed
Respirometry System is produced by Sable
Systems International. The unit consists of 10
individual metabolic cages for mice (pictured
to the left) housed in a single system thatallows multiple animals to be monitoredcontinuously. The system is currently run
by the Biological Models and Translational
Research Core at the Linus Pauling Institute,and will support pre-clinical research at
Oregon State University.

11

Barbara McVicar was hired by theInstitute shortly after Dr. Donald Reedbecame the first interim director of the
LPI. Over the last 21 years, she has primarily
worked as executive support for Dr. Balz
Frei, but now assists Dr. Fred Stevens.
Barbara has been an outstanding memberof our team from the beginning, so ourgoodbyes are now bittersweet as we wish
her the best in her retirement years.

Barbara
McVicarAfter 21 years ofservice to the Linus
Pauling Institute,and 28 years employedby Oregon State
University, it is time
to say farewell.

All of the faculty and staff agree that the
LPI would not be the same place without
Barbara. As Dr. Frei often said “She was
the one who ran the Institute all theseyears… and I was given all the credit forit.” As this is the last newsletter that
Barbara will contribute to, we asked her
to write a few recollections of her timehere at the LPI:
When the Linus Pauling Institute came toCorvallis from Palo Alto in 1996, I had beenworking in the College of Oceanography
at Oregon State University. I was hired by
the LPI shortly after the move. For a year
or so, I was the lone person in the front
office – yes, just me. I did everything: fromhiring personnel, accounting, assisting with
grant applications, and building the first
LPI website.
It still surprises me to think how small
we were back then. The Institute wasonly eight people at the time, including
Stephen Lawson, Don Reed, and Ober Tyus
(our first director of development). I wasfortunate enough to have been involved in
the interviewing and hiring process for the
first permanent LPI director – it made a big
difference for the Institute.
Balz Frei was our first choice for the job,
and we felt so lucky that he accepted theposition. Balz certainly jumped in withboth feet and never looked back, and I
went with him every step of the way.
I loved working with Balz, and we made agreat team. He was always so supportiveand had faith in my abilities, and wetrusted each other to get the job done.

Dr. Balz Frei and Barbara McVicar,
celebrating a successful Diet andOptimum Health conference in 2015

Our team grew very quickly at that point.
One of Balz’s first initiatives was getting
new faculty hired for the LPI, and that
included the ‘fab four’: David Williams,
Maret Traber, Rod Dashwood, and Tory
12

Hagen. With their arrival and new people
joining their labs, it was very busy –although the whole Institute could still
all fit in one room, at least for the next
few years.
My favorite aspect of my job is the variety– I really enjoy doing so many different
things, whether it is helping plan events
like the Diet and Optimum Healthconference, arranging visits for donors,
helping people by phone or email when
they have questions, and even making
copies! The same could be said for working
with all the people here at the Institute.
Everyone is different, and it makes thework more fun and interesting. Variety iscertainly the spice of life.
As a non-scientist, I’m a bit of an outsider
at LPI… more of a “regular person.” I’ve
learned a lot about science over the years,
so I love to help people as best I can when
they call or email to ask questions. I thinkthey feel like they can talk to me and getsome information about the Institute inlay terms. Fortunately, the faculty arealways available to answer the more
technical questions!
The best part is when people call andtell me how grateful they are for the work
everyone is doing at the Institute. We all
really want to make a difference in people’s
lives, so we try very hard to get the best
information out to everyone.
After all these years, I still love doing
my job at the Institute. I really like being
the “go-to” person. After being at OSU for
28 years, I take great pleasure in helping
people who ask me questions, knowingthat I will likely be able to help them orat least steer them in the right direction.
Everyone at the LPI has been great towork with over the years. We are all so
committed to making LPI a great place towork and do research. It always seems
like we are on the same page together.
I appreciate all the support I havereceived from everyone over the years.
I will truly miss working here and being apart of LPI and OSU, and talking with all of
our supporters. But, I am looking forward
to retirement, playing with my grandkids,
and traveling. Thank you… it’s been agreat ride!

Thank You
For their years of dedicated service to the Linus Pauling Institute, we
express our sincere gratitude and appreciation to Balz and Simone Frei.
Under his leadership, Balz transformed the Institute into a world-classresearch program, recognized for research on the health benefits of
micronutrients and other dietary compounds. As the head of the Healthy
Youth Program at the LPI, Simone and her team brought the Institute’s
message touting the benefits of healthful eating and an active lifestyle.
All the faculty, staff, and students at the Institute wish the best to the Freisin their endeavors in the years to come.
Thank you again for your dedication.

13
13

LPI students

Yang Zhang

Lea Sophie Ullrich

Bharath Sunchu

Ph.D. Student, Nutrition Program, Collegeof Public Health and Human Sciences

Visiting Scholar, Institute of Pharmacy,
University of Regensburg

Ph.D. Student, Department ofBiochemistry and Biophysics

After obtaining her bachelor’s degree infood sciences and engineering in China,
Yang came to the United States to study
human nutrition at Utah State University.
After obtaining her master’s degree,
she decided to pursue a Ph.D. at Oregon
State University with Dr. Adrian Gombart,
principal investigator at the Linus
Pauling Institute.

Although she hails from Germany, Lea
is no stranger to the United States andto Oregon. As an exchange student, she
attended and graduated from a highschool in Grants Pass, Oregon. After her
acceptance into the pharmacy programat the University of Regensburg, she ishoping to be the first in her family to
pursue a career in science.

Bharath grew up in Warangal, a city inSouth India. With his mother and father bothbeing science teachers, science was a logicalcareer choice. Completing his master’s
thesis examining the mechanisms of DNA
replication in bacteria further strengthened
his passion for scientific research.

Her project focuses on the combinationof xanthohumol with vitamin D in immune
health. She is currently testing ‘nanofiber’
bandages that contain both of thesecompounds to improve wound healing
and reduce infections. These bandages
can be placed at the site of injury,
directing therapy where it is needed themost. Yang is also looking at how thiscombination of compounds may
influence the gut microbiome.

Very interested in travel, Lea wanted
to explore the various aspects ofpharmaceutical research around theworld. She recently returned to Oregon
to work with Dr. Fred Stevens at the Linus
Pauling Institute, in partial fulfillmentof her rotation requirements of her
undergraduate program. After her rotation
here, she will complete the remaining
requirements to become a licensed
pharmacist in Germany. She is considering
an application to come back to Oregon
State University as a Ph.D. student.

Yang has the long-term goal ofestablishing her own lab in aninterdisciplinary research area thatincorporates “big data,” biology, andmedicine. Her hard work has paid off inthree scholarship awards, and she iscurrently a Marion T. Tsefalas Graduate
Fellowship awardee. This generous
financial support has helped propel her
research forward in her first two years at
the LPI. Yang has earned travel awards
from the College of Public Health andHuman Sciences and a Young InvestigatorAward from our Diet and Optimum
Health conference held in September.

For the past six months, Lea has taken
part in multiple research projects usingmass spectrometry techniques to monitor
the metabolism of xanthohumol – acompound from hops. She has been
pioneering new analysis techniques for
detecting xanthohumol metabolites inbiological samples, with the hope ofdeveloping new preservation techniques.
This may eventually foster collaborations
with the LPI around the world on
xanthohumol research.

14

An interest in human health and abackground in pharmacy led Bharath
to study the cellular biology underlying
aging. Attracted to the idea that age-relateddisease could be prevented by treating theunderlying causes of aging, Bharath is now
working with Dr. Viviana Pérez. Using acomparative biology approach to study
protein stability, Bharath has been working
to understand why cells from long-lived
species – like the naked mole rat – appear
to keep their proteins intact and functional
when under stress.
Figuring out how evolution has tackled
the problem of misfolded proteins ultimately
may help develop new therapies forage-related diseases, and Bharath isexcited about the possibilities of taking
this work into humans. Bharath is a Mark
Sponenburgh-LPI Endowed Graduate
Fellowship awardee, has received an
Oregon Retired Educators Association’s
graduate student scholarship, and was therecipient of a travel award from the OSU
graduate school. He is currently finishing
his research for his Ph.D. dissertation.

DEVELOPMENTS
The Linus Pauling Institute will bewelcoming Dr. Richard van Breemen as
its new director in January. As he brings
a wealth of scientific experience andadministrative credentials to theInstitute, we look forward to his arrival.
Beyond his years of experience as the
director of a botanical supplement
research center, he has also led several
NIH-funded clinical trials, been an author
on scores of research articles on botanicals,
and is a collaborator with countlesspartners throughout the world.
As we look forward, however, it seems
appropriate to take a moment to look backat everything the Linus Pauling Institutehas accomplished with our supporters.
When Linus Pauling first founded theLinus Pauling Institute of Science andMedicine, he was looking for a place toconduct research on the impact ofnutrition on health, especially with hiswork on vitamin C. When he could not
find support from other institutions, heturned to the public – and their support
carried his research forward for the
next 20 years.
Just before Linus Pauling’s death, at atime when the Institute was looking for a
new path forward in nutrition research, it
found a home at Oregon State University(OSU). In 1996, the Institute made its way
to Corvallis and within a year, Dr. Balz Frei
took over the reins of leadership.
Dr. Frei ushered in a new era of change at
the LPI, and the results were extraordinary.

Over the next 20 years, the newinvestigators and research programs at theInstitute have brought in dozens of federal
research grants and created opportunities
for OSU students to participate in research.
The LPI has advanced the pace and breadthof discovery, fostered the next generationof nutrition scientists, and seeded researchfacilities across the world with brilliant
young minds – and none of it would havebeen possible without the generous
support of our loyal donors.
I am sure that Dr. Pauling would be very
proud to know that each one of theseaccomplishments, the scientists, and theirwork are now a part of his legacy.
The LPI continues to thrive under
Dr. Stevens’ deft leadership. Every day,our students, faculty, and staff are working
to advance our understanding of thefundamental mechanisms of disease andthe role that micronutrients andphytochemicals play in health.
I invite you to join Dr. van Breemen andthe all the researchers at Linus Pauling
Institute as we embark on the next era ofscientific discovery.

The new director of theLinus Pauling Institute,
Richard van Breemen, Ph.D.

“Dr. Pauling would bevery proud to knowthat each one of theseaccomplishments, thescientists, and theirwork are now a partof his legacy.”— Amanto Marcotulli, J.D.

Sincerely,

Amanto Marcotulli, J.D.

If you want to learn more about the many
ways you can support the Institute, email
Amanto.Marcotulli@osufoundation.org orcall (503) 553-3400.

See us on Facebook
Facebook.com/
LinusPaulingInstituteFind us on Twitter
twitter.com/LPatOSU

15

Linus Pauling InstituteOregon State University
307 Linus Pauling Science Center
Corvallis, Oregon 97331
phone: 541-737-5075
fax: 541-737-5077
email: lpi@oregonstate.edu
website: lpi.oregonstate.edu

now is the time
In a climate where government
funding for research is dwindling,your support for micronutrient
research is more important than ever.
To learn the many ways you can help
support the LPI, please contact the
OSU Foundation at (800) 354-7281 or
go to osufoundation.org/GiveToLPIAnnouncing the winner of the LPI Prize
for Health Research for 2017. LOOK INSIDE