LINUS
PAULINGINSTITUTE
OREGON STATE UNIVERSITYRESEARCH NEWSLETTERSPRING 2021

NEW WEBINARS FROM THE LINUS PAULING INSTITUTE LOOK INSIDE
Photo credit: Hannah O’Leary

EAT, LIVE – EAT, DIE:

IN THIS ISSUE

An Interview with Dr. David E. Williams
Each year, Oregon State University names
two University Distinguished Professors.
This is the highest honor granted toprofessors at the University.

Much of your career has focusedon dietary indoles. What are they,and how did you start working withthem?

Previous University Distinguished
Professors at the Linus Pauling Instituteinclude Drs. Donald Reed (1990), GeorgeBailey (1995), Balz Frei (2010), and Joseph
Beckman (2013).

When we talk about dietary indoles, weare referring to indole-3-carbinol, which isalso known as I3C. Cruciferous vegetables
contain a compound called glucobrassicin.
When we chew these vegetables, anenzyme in the plant cells called myrosinase
reacts with glucobrassicin to form I3C.

Dr. David E. Williams, the Helen P. Rumbel
Professor for Cancer Prevention at theLinus Pauling Institute, joined the ranks of
University Distinguished Professors at theInstitute in 2020.
We sat down with Dr. Williams todiscuss his career achievements, which
include discovering how certain dietarycompounds might cause or preventcancer.

I began working with I3C with Dr. Roderick
Dashwood and the late Dr. George Bailey,
two cancer investigators at the Linus
Pauling Institute. We wanted to know how
I3C and other plant compounds might beprotective against certain carcinogens,making them dietary anticarcinogens.
Continued on page 4

Eat, Live – Eat, Die:
An Interview with
Dr. David E. Williams...1
From the Director......2
LPI Student Highlight:
Dr. Brian Head...........3
Reader Questions.......5
Vitamin C and Health:
New Frontiers...........6FROM THE DIRECTOR
We are excited to celebrate the 25thanniversary of the Linus Pauling Instituteat Oregon State University with a seriesof virtual events.
Photo credit: Hannah O’Leary

In February, we held our first webinarof 2021. Vitamin C and Health: NewFrontiers featured four world-renownedexperts, including the Institute’s
Dr. Maret Traber. A summary of thediscussion can be found on pages
6 and 7.
Emily Ho, PhD
Endowed Chair and Director,
Linus Pauling InstituteVitamin C and Health:
New Frontiers
lpi.pub/VitCWebinar2021
Why a Healthy Immune
System Needs Vitamin D
lpi.pub/VitaminD2021

In May, Dr. Adrian Gombart, theInstitute’s expert on vitamin D andimmune function, presented our second
webinar, Why a Healthy Immune SystemNeeds Vitamin D. Given the latest
research on the COVID-19 pandemic,
this topic was especially pertinent andwell received.
Our next webinar, Why You and Your
Dog Can’t Find Your Keys: This is Your
Brain on Aging, will be July 8 (see below).
Presented by Dr. Kathy Magnusson,
this webinar will address the changes
our brains go through when we age –both good and bad – and how diet andlifestyle can improve brain function.

2

Additionally, we will host a series ofscientific webinars this fall in place of
our in-person biennial Diet and Optimum
Health conference. These sessions willcontain more technical content and will
focus on the role of nutrition in threeareas: healthy aging, gut health and themicrobiome, and immunity. Please visit
lpi.pub/DOHonline for future updates
and additional details.
Finally, I am proud to share that theLinus Pauling Institute raised more than
$13,000 during Dam Proud Day – theannual day of giving for Oregon StateUniversity. Most donations went to theCaron and Donald Reed Fellowship Fund,which supports young scientists at theInstitute.
This is a very exciting year for theInstitute, and we are looking forward
to sharing our science with all of you incelebration.
Sincerely,
Emily Ho

LPI STUDENT HIGHLIGHT
Photo credit: Hannah O’Leary

Graduate students at the Linus Pauling Institute must complete andsuccessfully defend their dissertation to fulfill the requirements of a PhD
program. Their success is also that of the Institute and all of the donors who
supported their work.
We will feature research projects of graduate students supported by Linus
Pauling Institute fellowships. We begin with Dr. Brian Head, our most recent
graduate from the laboratory of Dr. Maret Traber.

A DEVELOPING BRAIN NEEDS VITAMIN E
By Brian Head, PhD
Vitamin E is necessary for embryonicdevelopment of all vertebrates. As a
fat-soluble antioxidant, vitamin E helps
prevent the oxidation of fatty acids inthe cell. This is especially important forcell membranes rich in polyunsaturated
fatty acids, which are abundant in thenervous system.
Normally, embryonic development is ahighly regimented process: the orderof events is very tightly controlled tocarefully construct groups of cells thatwill eventually become the organs andbodily structures. Without vitamin E, thisprocess breaks down.
Using a zebrafish embryo model, I
discovered that vitamin E is necessary
for proper development during a very
critical window: the first 24 hours afterfertilization. In humans, this corresponds
to the first three weeks after fertilization.
My work indicates that embryos without
vitamin E experience uncheckedoxidative damage. This places a heavy
burden on other antioxidant systems likevitamin C and glutathione.
To continue functioning, cells must
spend their precious energy reserves tomaintain these antioxidants. Energy is avery limited resource in young embryos,so this is a very costly process.
We believe that the zebrafish embryosenses the lack of vitamin E with aprotein complex called mTOR. This is an
important signaling protein at the nexusof redox balance, energy status, and cellsurvival.

Embryos without vitamin E do not turnon their mTOR pathway at the righttime, and most don’t survive. Embryosthat do survive have severely delayed or
disrupted nervous system development.
Adequate vitamin E is critical throughout
our lifespan. I expect that future
research on vitamin E will show how it isnecessary for protecting an adult brain,
especially as we progress into old age.
I am grateful to have received both theMark Sponenburgh and Marion T.
Tsefelas Endowed Fellowships fromthe Linus Pauling Institute. With thesefellowships, I did not have to take timefrom my project to seek out otherfunding to support my position. Instead,
I was able to spend more time in thelab studying critically timed events inembryonic development.
I hope that other graduate students
at the Institute will get similar
opportunities.

Dr. Head started a newposition at the National
Institutes of Health. He
currently works in theNational Institute ofChild Health and HumanDevelopment studying
lipoprotein metabolism,
cholesterol transport,
and other rare genetic
defects.

Fellowships at the Linus Pauling Institutehelp us foster the next generation ofnutrition scientists.
If you are interested in supporting the future of graduate
student education, please go to lpi.pub/Donate
For more information, contact
Andrew.Norwood@osufoundation.org

3Photo credit: Hannah O’LearyContinued from coverYour first cancer studies were introut. Why use a fish model?
At that time, it was standard practice toconduct carcinogen studies in rodents.
But these trials typically used very highdoses of carcinogens. It was the mosteffective way to study tumor formation
in a small group of animals.
But those high doses did not reflect“normal” human exposures. The doses
used were quite excessive, andtoxicologists had to extrapolate down to arelevant range for typical human exposurelevels. It was a lot of guesswork.
“To perform low-dose
carcinogen trials, youneed a large number ofanimals. With rodents,
this is prohibitivelyexpensive.”“Our first trial with trout
used 40,000 animals,
and we were able toincrease the sensitivityof tumor detection by 50
times that observed inother animal models.”Dr. Bailey suggested using trout, where
the large number of animals allowed us
to use significantly lower, more realistic
carcinogen doses.
We could also do dietary intervention
studies with trout. In other words, wecould ask whether dietary factors could
help prevent or modify the developmentof cancer. It turned out that I3C was one
such compound.

You then moved from fish to mice,creating a transplacental cancer
prevention model. Can you explainthat work in more detail?
When this work began, we knew thatcarcinogens given to a pregnant animal
could be carried to the developing
offspring. A maternal carcinogen exposure
just days before birth could result insevere and often fatal cancers in the pups.

4

We were attempting something different inour cancer studies: to see if a maternal dietcould protect offspring from carcinogens.
Could anticarcinogens derived from foodprotect the expectant mother and thedeveloping fetus?
I’m pleased to say that these animal trials
were very successful. Some compounds
that we tested were highly protective forthe young mouse pups.
I am still amazed by the fact that thedeveloping pups that never ate theseanticarcinogen compounds themselves
could be protected by the components of
their mother’s diet.

And dietary indoles played astarring role in this model as well?
I3C was the most protective of all of thecompounds we tested. Chlorophyll andgreen tea extracts also seemed to bemoderately protective, but the effects ofthe latter might have been related to thecaffeine content.

Now you are working withdiindolylmethane or DIM. What isDIM, and how is it formed?
DIM is essentially two I3C molecules joined
together. It is only formed when two I3C
molecules come together in an acidic
environment like your stomach.
In general, only a modest amount of DIM
is created in these reactions. There areestimates that about 40% of the I3C thatyou consume reacts to form DIM.

Recently, you transitioned fromanimal models into trials in people.
Has this given you any new insights
about DIM?
Right now, we’re looking at the metabolismof DIM in our clinical study volunteers.
We’re hoping to find clues about how it
might counteract the effects of carcinogen
exposure.
To do this, our trials used a DIM supplement.
I thought it was prudent to use a dose
commonly used in supplement products.
Our estimates are that a person would needto eat more than 20 pounds of Brussels
sprouts to obtain a similar amount of DIM
from food.
It’s always tricky using compounds fromplants for studies in humans or animals
because metabolism complicates thepicture. Our bodies don’t often leave thesecompounds alone. Instead, they treat
them as something foreign and transformthem into metabolites that the body canhandle using some sort of detoxification orelimination mechanism.

This is why I think it is premature to
recommend taking DIM supplements.
Since the research in this area is notcomplete, we don’t know if DIM metabolites
have biological activity – it’s impossible topredict what effect they may have. We needto take the time to do these trials in humanvolunteers first.

Do you have any suggestions foranyone trying to get more DIM in
their diet by eating cruciferous
vegetables?

Dr. Williams
presented aretrospective
review of his
scientific careerwhen accepting
his University
Distinguished
Professor award.
The video recording
can be viewed at:
lpi.pub/williams

I would say that the best advice is to eat
them as raw as possible. Myrosinase
is easily destroyed by heat. Some lightcooking like steaming is okay, but any
heavy cooking can destroy the enzyme.
This enzyme isn’t just important for theformation of I3C from glucobrassicin.
It also reacts with glucoraphanin to form
sulforaphane, which also has anticancer
properties. Just one more reason to eat
cruciferous vegetables.

READER QUESTIONS
few years ago, the LPI recommended taking
Q. AlipoicQ.
acid and acetyl-L-carnitine for brain
health and memory. I have used it for years
and watch for updates on this work. Your
Winter 2021 issue addressed a study using
only lipoic acid. Is research continuing on thecombination? —K.S. via emailThe structure you show as alpha-lipoic aciddoes not indicate that it’s the R-form, as
captioned, because the bond attaching thering to the chain is a simple line segment,
not a wedge or any other means of depicting
the stereochemistry at the ring carbon where
the chain is attached. —H.W. via email

are absolutely right! The accurate structure
A. Youfor R-alpha-lipoic acid is below.

There are indications that the combination

A. of lipoic acid and acetyl-L-carnitine has somebenefits for older animals, but at the time of thiswriting, these studies have not progressed into
human clinical trials.
Our recently published trial on lipoic acid was
designed to explore the benefits of lipoic acidon energy metabolism but not specifically inolder adults.
While the Institute continues to have an interestin this combination of supplements, we await
funding opportunities to conduct studies in olderadults. For more information about lipoic acid,acetyl-L-carnitine, and the current state of theresearch, please stay tuned for Dr. Tory Hagen’s
webinar later this year (date TBD).
5

VITAMIN C AND HEALTH:NEW FRONTIERSOn February 27, the Linus Pauling Institutecelebrated Linus Pauling’s birthday with an online
forum on vitamin C and health. This webinar was
hosted by the Institute’s Director, Dr. Emily Ho,and moderated by our vitamin C expert,
Dr. Alexander Michels.

Vitamin C supplement formulation
is not a crucial factor.

At this event, four of the world’s top experts onvitamins and health (see below) answered questions
about the new frontiers in vitamin C research and also
addressed some questions that remain unanswered
about how vitamin C works in the body.

During the webinar, Dr. Anitra Carr noted that theabsorption of vitamin C from synthetic sources isequivalent to that from natural sources. Additionally,Dr. Jeanne Drisko noted that there is some evidence
that liposomal vitamin C is slightly better absorbed
than other supplemental forms, but the differences
are small.

In terms of absorption of dietary supplements,
there is little difference in what type of vitamin C
formulation you take, despite claims by vitamin
manufacturers.

Here, we present several key takeaways from theforum to give you insight into the current state ofvitamin C research. We strongly encourage you tocheck out the video at lpi.pub/VitCWebinar2021.
Transcripts of the event, copies of the slides, andsome of the answers to attendee questions areavailable upon request.

Supplement formulation may matter if you
experience heartburn after taking vitamin C
supplements. In this case, look for products labeled
as “buffered.” These products have less acid and are
therefore more gentle on the stomach.

Anitra Carr, PhD

Jeanne Drisko, MD, CNS, FACN

Associate Professor
Director, Nutrition in Medicine Research Group
University of Otago, Christchurch

Riordan Professor of Orthomolecular Medicine
Director Emeritus of Integrative Medicine
University of Kansas Medical Center

Dr. Carr worked at the Linus Pauling Institute as an
American Heart Association postdoctoral fellow
under the mentorship of former Institute Director,
Dr. Balz Frei. While at the Institute, she and Dr. Frei
authored several of high-impact publications on therole of vitamin C in human health and disease.

Dr. Drisko helped build the Integrative Medicine
department at the University of Kansas MedicalCenter. She facilitated many of the studies to test
the safety and efficacy of intravenous vitamin C inthe treatment of cancer and infectious disease.
Dr. Drisko is a strong advocate for complementary
and alternative medicine. She has a wealth ofexperience using intravenous vitamin C in cancer
patients and has repeatedly demonstrated itsbenefits.

Upon returning to the University of Otago, Dr. Carrcontinued her research on vitamin C. She isparticularly interested in the roles of vitamin C in theprevention and treatment of infection and cancer.

6Oral vitamin C supplements cannot mimic
intravenous vitamin C infusions.

With intravenous vitamin C, the dosematters.

Intravenous vitamin C bypasses the vitamin Cabsorptive control mechanisms in the small intestine.
Dr. Jeanne Drisko emphasized that no amount oforal supplements can produce the same plasma
concentrations of vitamin C as IV infusion.

Clinical trials have explored the use of intravenous
vitamin C to treat various diseases, including cancer,sepsis, and other infections. However, work in theseareas has shown mixed results.

A single intravenous infusion results in bloodconcentrations of vitamin C that are at least 50 times
higher than that achieved with oral supplements.
The unique benefits of intravenous vitamin C are dueto the very high concentrations in the blood.
How does this work? Although there is much workthat needs to be done, it appears that the high bloodconcentrations of vitamin C lead to the productionof hydrogen peroxide. This is presumed to be an
important factor for the effects of IV vitamin C inthe body.

One reason we do not have a clear answer is thevaried amounts of vitamin C given in these infusion
trials. As Drs. Drisko and Fowler discussed, the doseof vitamin C and the timing of its administration arelikely key determinants of a trial’s success.

There is much we still do not know.
Dr. Maret Traber commented that limited funding
opportunities have slowed vitamin research, leading
many to believe that vitamin C has a limited impact onhealth. Our experts agree this couldn’t be further fromthe truth. There is still much more to be discovered
about vitamin C.

Alpha “Berry” Fowler, III, MD

Maret Traber, PhD

William Taliaferro Thompson Professor of Medicine
Division of Pulmonary Disease and Critical Care Medicine
Virginia Commonwealth University

Ava Helen Pauling Professor, Linus Pauling Institute
Professor, College of Public Health and Human Sciences
Oregon State University

Dr. Fowler’s research focuses on ways to mitigate thelung and vascular inflammation that occurs in acuterespiratory distress syndrome (ARDS) and sepsis.

Dr. Traber’s research interests lie in the functions
and properties of vitamin E, a major fat-soluble
antioxidant in the body. Her work seeks to better
define the interplay between vitamin C and vitamin E
in health and disease.

Dr. Fowler recently directed a multicenter trial using
high-dose intravenous vitamin C to treat acute lunginjury in critically ill patients with sepsis; he reviewed
the results of this trial during the webinar. Dr. Fowler
is also studying intravenous vitamin C as a treatment
for COVID-19-related lung injury.

Dr. Traber has long sought to better understand theeffects of low vitamin E status. Currently, her focus ison embryonic brain development (see page 3).

7

LINUS PAULING INSTITUTERESEARCH NEWSLETTER
Alexander Michels, Newsletter Editor
Victoria J. Drake, Associate Editor
Sandra Uesugi, Assistant Editor
Oregon 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

INSIDE: THE LINUS PAULING INSTITUTE’S WEBINAR ON VITAMIN C AND HEALTH

CREATE A LEGACY OF HEALTHWE CAN IMPROVE LIVES FOR GENERATIONS TO COME with ourresearch and outreach programs. Continuing the Pauling legacy,
the Linus Pauling Institute seeks to discover and share the new waysthat nutrition can help people everywhere achieve the best of health.
What will your legacy be?
Would you like to learn more about how thoughtful legacy
planning can help you:
•Create a tax-wise estate plan that is healthy forboth you and your family?

•Support the charities you love, while maintaining
healthy assets?

•Consider a charitable gift that creates a healthy
income for life?

If yes, please join our Create Your Legacy webinar on July 21
at 10 AM PDT. Register online at lpi.pub/Legacywebinar
For more details on the webinar, contact Andrew Norwood:503-936-0086 or Andrew.Norwood@osufoundation.org