IMPORTANT

1. Integrative Medicine • Vol. 14, No. 1 • February 201552 Krystal—Viewpoints
Gerald Krystal, PhD, is a distinguished scientist and
principal investigator in the Terry Fox Laboratory faculty of
the British Columbia Cancer Research Centre in Vancouver,
British Columbia, Canada. He received his doctorate in
protein chemistry in 1976 from McGill University in
Montreal, Quebec, Canada, and has published more than
150 articles and contributed to 27 books and textbooks.
Integrative Medicine: A Clinician’s Journal (IMCJ): What
originally drew you to examining the effects of diet on
cancer?
Dr Krystal: I had been working basically as a hard-core
protein biochemist in a cancer research center since 1978. I
came to Vancouver for a second postdoc in 1978 to explore
how normal cells are different from cancer cells in how they
get orders from outside the cell in terms of growth factors,
cytokines, and hormones. This is an area called signal
transduction in which we look at how signaling molecules
get into the cell to tell the cell what to do and how cancer
cells, through mutations, can signal themselves to proliferate
and divide without the need for normal exogenous signals
that come and tell a cell to divide.
I was quite happy and content doing all that very basic
research. Then I went to listen to 3 separate talks—we
have seminars every Monday, here. They were on PET
scanning—that is, positron emission tomography. The
upshot of that was that if you use a glucose analog, which
you typically do with PET scans—specifically a
radioactively labeled flourodeoxyglucose—you can
actually detect cancers because cancers take up more
glucose than normal cells—typically at more than 3 times
the rate. That got me really intrigued because I wondered,
“Can we exploit that to actually treat cancers?”
In my first studies, I actually started by trying to treat
tumor-bearing mice with a nonradioactive version of this
glucose analog, that is, 2-deoxyglucose. This glucose analog
is different from regular glucose in that it can be taken up
but it cannot be processed for energy. Actually it antagonizes
the use of regular glucose by the cancer cells. I thought,
“Why not just give cancer cells deoxyglucose?” It turned out
that you cannot do that. The mice died and when trials were
done with humans the same thing happened because it is
toxic. You need glucose for brain function and
2-deoxyglucose also piles up in the bladder and causes
toxicity there as well. So, that was a no-go from the start.
Gerald Krystal, PhD: The Effects of Protein and
Carbohydrates on Cancer
Interview by Craig Gustafson
VIEWPOINTS
Then I thought, “Okay, so we can’t do that, but is it
possible to lower the glucose levels in our bloodstream to
at least cause the tumor cells to grow slower?” They seem
to need glucose more, they take it up more readily, and
they need it more than normal cells to divide.
That is what got me interested. It was those 3 talks on
PET scans, basically, in a field totally different from what I
was working in. They led to all the diet studies. In
hindsight, this was quite funny because when I first started
asking myself the question, “Can you lower glucose levels
sufficiently just through dietary changes?”, I spoke to a lot
of colleagues—both physicians and scientists, like myself—
and it was very interestingly split. Most did not think you
could do that. Most thought that to make a significant
dent in blood-glucose levels you would have to be almost
at the point of starvation, and death. I moved forward
more on the basis of ignorance than anything else, which
worked in my favor. If I had been more sophisticated, I
might have dropped the whole premise because it is well
known—and I knew it at the time, too—that you have to
maintain blood glucose levels within a certain window.
You can typically vary blood glucose levels anywhere
from 4 to 6 millimolar without deleterious effect. If you
drop your blood glucose too much below this range, say by
half, you will actually lose consciousness because, as
mentioned above, it is an essential energy source for our
brains. I was concerned that if I went to a really extreme,
low-carbohydrate diet that maybe it would cause trouble
and the mice would go into shock, for example.
Fortunately, when you are on a high-protein diet you
can convert some of the amino acid building blocks that
make up proteins into sugars. So you can use a high-
protein, low-carb diet and still maintain your sugar levels
within this safe window.
IMCJ: Would that be gluconeogenesis?
Dr Krystal: Yes, exactly. The liver will convert certain amino
acids, such as alanine, into glucose by gluconeogenesis. This
acts like a safety valve to make sure you do not drop too low.
We have tested everything from total ketogenic diets, with no
carbs at all, to diets with low carb levels. We actually made a
conscious effort to avoid ketogenic diets because in our
experience it is very hard for people to stick to those diets. We
wanted to come up with a diet that was not too onerous so
that it could be a permanent lifestyle change.

2. Integrative Medicine • Vol. 14, No. 1 • February 2015 53Krystal—Viewpoints
There is a lot of good to be said for ketogenic diets, but
in my opinion, it is very hard to stick to that kind of diet.
IMCJ: Did you find that the ketogenic diets were more
effective or just fractionally? Is it still an ideal, but just not
a realistic ideal?
Dr Krystal: My main interest was cancer and not
weight loss. When you are studying cancer, if you are
trying to compare different diets you have to be pretty
rigorous about ensuring that the mice do not lose
weight. It is well known that if you starve yourself the
tumors will grow slower. That is a confounding issue if
you are trying to figure out
which diet is best for slowing
tumor growth.
I could give them any kind of
diet and just restrict how much
they eat—like a starvation diet—
and the tumors will grow slower,
but that is not a fair comparison.
When you have cancer you do
not want to lose weight. There is
a phenomenon called cachexia,
when your cancer is quite
advanced, where the cancer
depresses your immune system
and at the same time increases
chronic inflammation. It leads to
certain cytokines, such as tumor
necrosis factor-alpha, TNF-α,
and interleukin 1-beta, IL-1β,
that lead to this phenomenon of
cachexia, where you get muscle
wastage to get more energy from
breaking down proteins—your
muscles—for the tumor cells to
use. Of course, that leads to a
shorter life span.
That is something we wanted to avoid. We made all
our chows isocaloric. When a mouse ate a gram of chow, it
got exactly the same amount of calories no matter what the
chow was. That way, we could measure the chows that are
left to get a measure of how much they ate. Then we could
say, “They all ate the same amount, they all got the same
level of calories. Now, what has happened to the tumor?”
Indeed, when we went to a ketogenic diet, even in a
short-term 3- to 4-week study, the mice lost weight. Even
when we started with an Atkins diet, where 8% of your
total calories are carbs at the beginning of this diet regime,
the mice lost weight. We kept increasing the carb level
until it hit 15%.
In these short-term studies you just inject rapidly
growing tumor cells, which is typically what researchers do if
they want to look at the effect of different treatments,
chemotherapeutic drugs, etcetera. You inject well-known,
different human tumor cells into an immune-suppressed
mouse or you inject well-known mouse-tumor cell lines into
an immune-competent mouse. You cannot put a human
tumor into a mouse that is competent immunologically
because it will just reject the tumor.
I was quite surprised by the results, actually, because
you have to remember we were just changing the chows, not
giving them any drugs. This was a short study; some tumors
that we injected—usually subcutaneously—grow like
wildfire. These are like runaway trains and so I was not sure
this was going to work. This was like the most extreme
example: If it was going to work on this, it was going to work
on almost any model we went with subsequently.
We started with these
extreme examples. As this was
a proof-of-principle study, I
wanted to go to an extreme
with my diets. I kept the fat
the same, because you do not
want to have too many
variables. The composition
and the percentage of fat was
always around 30%
kilocalories. Then, I just
switched the carbs for protein.
I did not want to change the
fat because I knew from the
literature that high-fat diets—
especially saturated fat—also
promote cancer growth. I said,
“Let’s keep fat a constant and
just switch the carbs and
protein.” In a Western diet, for
example, we get 55% of our
total calories from easily
digestible carbs. We only
consume, say, 15% protein. So,
we used a chow made up of
55% protein and 15% carb.
Now, I am not really proposing that people eat such a
high level of protein—55%. I would, however, promote in
the range of 35% to 40%. Protein at 35% has been shown
to be totally safe for healthy people in terms of potential
damage to the kidneys. I know that even if you go higher,
although the kidneys in humans and in mice might
enlarge—they might get a little hypertrophic—but that is
thought now to be a normal physiological response to a
heavy protein load rather than any pathology.
In fact, in our studies—although the kidneys were
enlarged, there was no leakage of any albumin or any other
protein in the urine. The kidneys were functioning
perfectly; the mice lived longer—longer than expected for
that strain of mice, and all their organs seemed to be fine.
There is always an extrapolation from mouse to human
that you make at your own risk, but I know a lot of people
on certain diets go up as high as 50% to 60% protein and

3. Integrative Medicine • Vol. 14, No. 1 • February 201554 Krystal—Viewpoints
they seem to be fine, as well. Again, I am not promoting
that. I am saying the literature suggests that 35% protein is
totally safe as far as the kidneys are concerned.
I do not know if you are aware, but there is a bit of a myth
about bone loss—calcium loss—occurring when you are on a
high-protein diet. That turned out to be incorrect. You do see
more calcium in the urine when you are on a high-protein
diet, but that is only because high-protein consumption
promotes calcium uptake in the gut. You end up, actually,
with stronger bones on a high-protein diet. The only reason
you see a little more calcium in the urine is because you are
absorbing more calcium on a high-protein diet.
IMCJ: What about the position that higher protein diets
present the body with an acidic state, acidosis?
Dr Krystal: That is actually a very good question and it is
very intriguing. It is true that when you break down amino
acids to get energy out of them you do generate more
protons—more ions—to lower the pH. There are lots of
ways to regulate that. If you have a normal, healthy kidney,
it will regulate it for you. The acidosis is a bit of a
misconception that people have. Your blood pH does not
change. You have a lot of good buffers, bicarbonate and
phosphate buffers, in your bloodstream so it is totally
controlled. The idea that you can take someone’s blood
and put it on a slide under the microscope to see whether
you are acidic or not—that is all hokum. In that regard,
concern about acidosis has been overblown.
Now, it is certainly true that there are some foods that
contribute more to acidic burden and some of these may be
counterintuitive. For example, if you drink orange juice, you
think that it is acidic and that would be bad, but it ends up
generating bicarbonate and being alkaline. It is hard to
predict. There are tables where you can look and see which
foods push towards one or the other and it is certainly true
that high protein will generate more acid, but your kidneys
can take care of that normally. I do not see the issue as being
as big as it has blown up to be right now.
I would like to say that what I am telling you is based
on what I know and what is known in the literature to
date. Things can change. If you called me in a year and a
lot of solid papers came out with good data saying that
what I am proposing is wrong, I would be the first to admit
it if the data are reasonable. This is a field that is in flux.
From my studies I feel confident, not so much that high
protein is good, but that high-carb is bad.
My real love and passion is chronic inflammation. So
a lot of my research, now, is attempting to reduce chronic
inflammation because just about all our ills as we age,
including cardiovascular disease, arthritis, inflammatory
bowel disease, Alzheimer’s and other forms of dementia,
and cancer—which is initiated by mutations that arise
from chronic inflammation-generated reactive oxygen
species, ROS. They can all be attributed to an increase in
chronic inflammation as we age.
One of the things that we—and many others—have
shown is that when you eat a diet that is very high in
simple sugars and/or easily digestible starches, which are
converted very quickly in our bodies to simple sugars, the
sugars cross-link to proteins that line our blood vessels.
This generates advanced glycation end products, or AGEs.
When you get these sugar-amino acid—typically lysine—
cross-links forming, it causes a stiffening of the blood
vessels. Stiffening of the blood vessels leads to higher
blood pressure, which in turn leads to strokes,
cardiovascular disease, and enlargement of the heart
amongst other pathologies.
Making things worse is that the immune cells
patrolling our blood vessels—especially the monocytes—
have receptors for these AGEs, called RAGE. That is funny
because RAGE is a good term for these receptors—when
they recognize these sugars covalently linked to proteins
in our blood vessel walls, they start attacking them, which
leads to the production of inflammatory cytokines.
Eventually you get plaque formation and cardiovascular
disease.
I firmly believe that one of the reasons, as we get
older, that chronic inflammation increases is eating a
Western diet over many years. My research is mainly on
cancer, but it has ramifications in other chronic
inflammatory-induced disorders, including rheumatoid
arthritis and cardiovascular disease. My research also
considers the effects of diet on chronic inflammation in
general. I am also very interested in the effects of adding
various supplements. We just had a paper come out
showing that if you combine a low-carb, high-protein diet
with an anti-inflammatory agent like celecoxib—Celebrex
is the brand name—which is a COX-2 inhibitor, it
dramatically reduces metastasis of various types of cancers.
That is really intriguing.
I am now involved, thanks to the Hecht Foundation,
in examining the effects of combining a Western diet
versus a low-carb, high-protein diet with anti-cancer
agents. Do you get a synergistic effect when you combine
any agent with a low-carb, high-protein diet versus
combination with a Western diet?
My big interest is not so much in chemotherapeutic
agents but in supplements like antioxidants and anti-
inflammatory agents that people can take throughout
their adult life. Again—coming back to my big love—can
we reduce chronic inflammation by going off a Western
diet? One of the things I want to test is whether you have
to go to a low-carb diet, or can you go to a more reasonable
carb diet, but just switch it to a more resistant starch form?
There are a lot of great foods that have lower glycemic
indices and one of the food types I am really interested in
is soluble fiber. Of course, I am very big on insoluble fibers
like cellulose and lignin, and there are lots of places to get
that. They are very important in giving you bulk and
actually speeding up peristalsis so your transit time is
quickened and you have less chance to absorb food.

4. Integrative Medicine • Vol. 14, No. 1 • February 2015 55Krystal—Viewpoints
This comes more to the obesity issue, which, of course,
causes chronic inflammation in itself. Soluble fiber is also
fascinating because it is resistant to digestion in the small
intestine, like resistant forms of starch. Normally when you
eat easily digestible starches such as white rice, white
potatoes, or white bread, you actually start digesting them
in your mouth. Your salivary glands produce alpha amylase,
which starts breaking down starches—basically long, linear,
covalently attached glucoses attached end to end.
You start breaking them down into a 2-unit glucose
molecule called maltose. In fact, if you keep white bread in
your mouth long enough, you will start to taste it as sweet
because your saliva is breaking it down to maltose.
Maltose does not taste nearly as sweet as sucrose, but it is
sweet enough. Then, when that gets past your stomach
into your small intestine, your pancreas secretes more
alpha amylase and the cells lining the gut—the
enterocytes—have enzymes that can break them down to
their single units: glucose. If you eat table sugar it will
break it into glucose and fructose by these enzymes.
That gets absorbed quickly through your small intestine
into your blood stream right away. If you have soluble fibers,
they are not broken down until they reach the large intestine
by the bacteria that live there. There is a huge interest right
now in this whole area called the microbiome. That basically
refers to the bacteria that live in your large intestine.
We, for example, are composed of about 10 trillion
cells, but we house about 100 trillion bacteria in our large
intestine. These bacteria actually have a huge influence on
our immune system, which is really fascinating. The kind
of bacteria you have in your large intestine is highly
dependent on what you eat, which makes a lot of sense. If
you give them foods that certain species of bacteria like,
those will proliferate and take over. If you give them other
foods, other kinds of bacteria take over.
The nature of your microbiome plays a big role in
whether you develop allergies and other pathologies. If you
eat a lot of soluble fiber, certain bacteria will take over and
they will break that soluble fiber down to what are called
short-chain fatty acids: things like the 4-carbon butyrate, the
3-carbon propionate and the 2-carbon acetate. They will
travel through the blood stream and they will actually—
especially butyrate—make it into the lungs and they can
reduce asthma. It is really fascinating that what you eat plays
a role—via changing the microbiome—in allergies and the
state of your immune system. It is really neat stuff.
IMCJ: It does seem like very divergent areas of medical
research can come together in very interesting ways.
Dr Krystal: It is very unique. I actually have 2 separate
areas of study in my lab. I have people who are working on
diet and I have people working on chronic inflammation—
in totally different systems. At the beginning of these
studies, I did not see much overlap. Now, they are totally
integrated. It is quite a lucky coincidence.
IMCJ: You said that combining the low-carbohydrate diet
and an anti-inflammatory, such as Celebrex, amplified the
beneficial outcomes. These powerful anti-inflammatories
often come with some significant side effects. Was the
dosage load you were using more or less than the dose for
the typical on-label use?
Dr Krystal: That is a bit tricky. All the studies are with
mice, so it is hard to extrapolate because there are different
clearance rates and different bioavailabilities—there is a
difference between mice and humans.
We try to go with doses that are on the low-ish side but
to be totally frank, they are not that low. They are on the
edge of what in humans, based on weight, would be on the
borderline of dangerous. It is in a range of 400 to 800
milligrams. We humans usually take 200-milligram tablets
and you are allowed 2 to 4 a day—something in that
ballpark. So, it is on the high side, but the reason we were
excited by that study is it might be extrapolate-able to
humans, where you might be able to get the beneficial
effects of Celebrex at a lower dose if you are on a low-carb
diet. Without thinking too much about dosing, because it is
certainly true that if you go to high doses you will have
thrombolytic-cardiovascular concerns, it is conceivable that
it would be more efficacious than it is now in humans if you
ate low carb. Regardless of what dose you are thinking of, it
might be more effective and therefore be less dangerous on
a low-carb diet, that is, you can go to a slightly lower dose
on a low-carb diet and still see the same benefits.
Now, I am specifically thinking of cancer, again, here.
What is really intriguing is that a lot of different types of
cancer cells actually synthesize and secrete prostaglandin
E2
, which is likely the most important prostaglandin that
COX-2 inhibits. Prostaglandins actually help tumors grow
in a number of ways. One of the ways prostaglandins help
tumors grow is by depressing the immune system’s ability
to kill them.
Since we thought our diets were mostly involved in
slowing tumor growth, we wanted something that worked
in a totally different way. So, if prostaglandin E2 is
inhibiting the immune system from killing the tumor,
what if we—at the same time—slowed the tumor growth
and we reactivated the immune system? Would that have
a beneficial effect? The answer appears to be yes.
The other area we are really interested in are
antioxidants. This gets not only to chronic inflammation
but it also gets to aging, which of course, as I get older,
becomes more and more interesting to me.
IMCJ: In the background of your paper, in addition to noting
that higher levels of saturated fat promoted tumor growth,
you also noted research that revealed that increasing protein
intake also helped to activate the immune system, correct?
Dr Krystal: It is true. I can go on forever about protein
because I love protein. I want to be a little conservative in

5. Integrative Medicine • Vol. 14, No. 1 • February 201556 Krystal—Viewpoints
pushing protein because there are some justifiable
concerns if you have issues with your kidneys. I do not
want to encourage people to say, “I don’t care if I have
some renal failure, I am going to go on a high-protein
diet.” I do not want to be irresponsible and suggest that.
If you want to go on high—anything above 35%—
protein, then you should see your doctor first to ensure
that your kidneys are functioning totally normally before
you start.
IMCJ: Given that caveat, can you talk a little bit about that
linkage to moderately higher protein consumption and
the immune system?
Dr Krystal: First of all I am going to ramble a bit. There was
someone called T. Colin Campbell1
and he wrote this book
called The China Study where he was comparing animal to
plant protein. There has been some misinformation about
protein based on that. A recent paper by Victor Longo2
suggested that low-protein in the range of 10% and less is
actually good for you. We take great issue with that paper. I
won’t go into that, here, because he will likely address that
in future papers. What he was actually seeing, I think, was
slower tumor growth because the mice were losing weight.
From my own studies, I know that is the case. I know that
if you go to those levels that he used—in fact he even says
it in his paper: “We had to drop this study because the mice
were losing too much weight.” His slower tumor growth, in
my mind, is totally attributable to not getting enough
protein to keep the cells able to divide.
So, just in terms of the animal versus plant protein, I
am a huge proponent of plant protein over animal protein,
but not for the same reason that T. Colin Campbell
discusses. He did some very flawed rat-liver-polyp studies
with aflatoxin B years ago, which he used to lead him to
The China Study. He went to China because it is a
relatively homogeneous population of Han Chinese.
He said, “Let’s look at people that eat animal versus
plant protein and see who has a greater incidence of
cancer, etcetera.” The problem is that the people who ate
animal protein, like pig and whatever, were richer—they
were fatter. The people who ate plant proteins were
skinny, as they were the farmers who were on the verge of
starvation. He did not take the weight into account, so
that led to a lot of misconceptions.
Nonetheless, what I am saying is that if you were just
looking at animal versus plant protein—just the protein
itself—I would say animal protein is slightly better than
plant protein because a lot of plant proteins are limited in
certain essential amino acids, especially lysine. Animal
protein tends to be more complete.
However, I prefer plant protein because, when you eat
it, it comes with fiber, which is good for you, whereas
animal protein comes with a lot of saturated fat—mainly
because of what we feed our cows. We no longer feed our
cows grass; we give them easily digestible grains because—
surprise—they get fat. If you let a cow just graze on grass,
it takes about 6 years to reach a certain adult weight. If you
put them on grains, cattle reach that weight in 18 months
and they are filled with saturated fat. All the marbling you
see when you get a cut of meat is saturated fat.
Now, a lot of people like the marbling because it gives
the meat more taste and juiciness, but that is what is
killing us. For me, it is not so much animal protein versus
plant protein, but what we are feeding our livestock. If we
put our cows back to graze on grass it would take them
longer so it is not as profitable for the farmers, but it would
be much healthier.
Then, of course, putting your steaks on barbecues
generates a lot of carcinogens. That is an extra reason not
to go that route. At the moment, I think it is wiser to go on
a plant-protein diet because of this. I eat a lot of nuts. They
say you are what you eat: I eat a lot of nuts … and I eat a
lot of tofu. I do eat a lot of fish. I do it in large part for the
omega-3 fatty acids.
IMCJ: You feel that plant protein is better because it is
delivered with fiber instead of along with poor-quality fat.
Dr Krystal: Right. There is a lot less fat in plants than in
animals and that is an interesting evolutionary
development. As you may know, fat has twice the calories
per gram compared to protein or carbs, so fat is a richer
source of energy. Now, that is not important if you are a
plant. If you are an animal and you are trying to survive,
carrying something that weighs less and gives you more
energy is a real survival advantage. That is why animals
have taken to storing their energy as fat rather than carbs.
It weighs less and if you are running you want to be as
light as possible, right?
Plants are fixed in place. Portability does not matter
and there are certain advantages to storing energy as
carbs. They store, of course, their energy as starch. We
have a little starch—we call it glycogen—that we store in
our liver, but our main way of storing energy as an animal
is in fat because it weighs less.
When you eat a plant you are not consuming nearly as
much fat, typically, as when you are eating an animal. That
is an advantage. Now, the disadvantage is that plants are
lower in certain essential amino acids, so there are certain
foods—as a matter of fact, gluten, which is a big thing in the
news, is one of the poorest proteins because it is really low
in lysine. Whenever anyone is considering becoming a
vegetarian—or a vegan, especially—I say, “Really try and
mix up what you eat; do not stick to just one kind of plant
diet. Especially, eat a lot of legumes.” That is very beneficial
because they tend to be a bit higher in lysine.
IMCJ: If you look at the way consumers get their plant
proteins, they are often having these proteins isolated into
protein bars and protein powder. That divorces the
protein from the fiber.

6. Integrative Medicine • Vol. 14, No. 1 • February 2015 57Krystal—Viewpoints
Dr Krystal: Right, that is true. I hate to be part of any
bandwagon, but I certainly agree that we should avoid
processed foods. That is primarily because all the
companies that make these are just interested in the
bottom line. It is very sad that our whole society has to be
built on profit. You probably have heard of bliss points:
just the right amount of fat and salt and sugar to reach a
taste that hits the bliss point. This is probably the worst
combination you could come up with nutritionally. I agree
with you there.
I am a big proponent or whey powder, however. I
supplement what I eat with a whey powder isolate. That is
milk protein with most of the fat removed. You are
basically getting the benefit of the protein, a nice mix of
branched-chain amino acid proteins, without a lot of fat.
Especially when you talk to cancer patients—getting
back to the issue of cachexia—if they are being treated
with radiotherapy or chemotherapy, their appetite goes
away. They just cannot look at a steak or look at chicken.
Protein that is difficult to digest really makes them
nauseated. Rather than going to these horrible things like
Boost or Ensure, which are just full of sugar, I encourage
them to have whey-powder shakes. You can just mix it
with water and get a nice, easily digestible protein. I find a
lot of cancer patients can drink whey powder isolate
drinks even when they cannot eat.
IMCJ: Doesn’t the cysteine in whey powder also help
promote glutathione production?
Dr Krystal: Yes; in fact, those are the key things to think
about in terms of the immune system. It is really neat.
When cancer cells first appear, they are very stressed cells.
They put stress signals at the surface, which natural killer
cells and antigen-presenting cells can recognize. An
antigen-presenting cell like a macrophage or a dendritic
cell can gobble up a cancer cell, then it can present a little
piece of it on its surface.
Here I am, an antigen-presenting cell, which means I
am probably a dendritic cell that is in the tumor
environment. I have got a piece of the tumor and I have
gone off into the nearest lymph node. I have shown it to
various T cells. One T cell has a T-cell receptor that can
recognize it and now it is activated to divide and multiply
up, hugely. This is called a clonal expansion of a single type
of T cell. It takes about 3 days.
This is exactly what happens when we fight infections,
by the way. When you get a bacterial or viral infection,
again, an antigen-presenting cell like a dendritic cell or
macrophage takes a piece of it, presents it in the lymph
node, certain T cells expand, they generate killer T cells,
they come back, and they destroy the infection just like
they will destroy a tumor cell.
Now the T cells: To expand, they need the amino acid,
cysteine. You can imagine, now, your T cells are expanding
tremendously so you need to generate protein, fat, and
nucleic acids for cell division.. If you have a low-protein
diet you cannot expand up your T cells sufficiently to
attack the cancer cells.
Now it gets very tricky because the T cells cannot
actually take up cysteine. They have to be given cysteine
by the antigen-presenting cell. There is a whole fascinating
dance and the tumor cells try and skew the system so that
the T cells cannot get the cysteine. Now, the T cells need
the cysteine to generate glutathione to counteract any
ROS. It gets a bit tricky here, because the tumor cells also
want the cysteine. They are very stressed, since they are
generating a lot of ROS. Both cells need the glutathione,
the reduced glutathione, to neutralize that oxidative stress.
Glutathione is needed for the ability of the T cells to
kill the cancer cells. The more protein you eat, the better
your chance of getting enough cysteine to make
glutathione. Glutathione is just a 3 amino-acid peptide,
and the critical amino acid in that peptide is cysteine.
IMCJ: How does the system keep the tumor cells from
hijacking the cysteine?
Dr Krystal: That is the whole dance. The reason cancers
win is because they are able to steal it. There is a whole
interesting thing that happens in the tumor
microenvironment. When the tumor is growing, all the
normal cells around it can either kill the tumor or they can
be co-opted by the tumor cells to help the tumor grow.
You can tell if a tumor is winning if you look at the
macrophages, which tend to be the most abundant
immune cells in the tumor microenvironment. If those
macrophages have been skewed to what is called a healer
sub type—it is called an M2 macrophage—you know you
are in trouble. What it means is that the tumor cells are
secreting factors that skew the incoming immune cells to
turn them into cells that will actually help the tumor grow.
For example, there is a well-known cell that is co-opted by
the tumor cell called an MDSC, for myeloid derived
suppressor cell, because it suppresses the immune system.
You might ask, “How is a tumor able to do all of this?”
That is because all these suppressor cells that suppress
immunity happen normally. Say you get a cut in your skin
and bacteria get in. Your immune cells that are already
there, such as mast cells and macrophages, get activated
and try to destroy them.
If the bacteria are dividing too quickly for them to
destroy the invaders, they try and hold the infection at bay
and then, like I mentioned before, they get a piece of the
bacteria, go to the nearest lymph node, and they alert the
T cells. The adaptive immune system—the cavalry—
comes in about 3 days, after it has expanded, and it wipes
out the remaining invading microorganisms.
Once the microorganisms are destroyed—whether it
is done by what is called the innate immune system or
whether they need the cavalry, it doesn’t matter—you have
to switch over to promotion of healing. The trouble is that

7. Integrative Medicine • Vol. 14, No. 1 • February 201558 Krystal—Viewpoints
when the immune system is activated, it can kill invading
microbes, which it was evolutionarily designed to do. If
this goes on too long, however, it starts leading to chronic
inflammation and damages your own tissues—like in
rheumatoid arthritis where it starts attacking your own
bone and cartilage.
The immune system has to be able to switch from a
killer phenotype to a healer. There are a lot of interesting
signals in the normal cut scenario that do that. So you
switched off your immune system after you have
eliminated the danger—the invading bacteria.
Now, what happens in successful cancers—successful
in terms of the tumor’s point of view—a successful tumor
mimics those signals that you normally put out to start the
healing process. The phrase was coined in the 1800s that
cancer is like “a wound that never heals.”
So, tumors that do not secrete these factors are wiped
out. Little nascent tumor cells pop up every day and we
put them down—we kill them—you never see them. We
only see the successful ones. The successful ones are the
ones that secrete factors into the milieu around them that
tell the immune system, “Hey, I am just a wound that is
trying to heal now. I have eliminated the bad
microorganisms so come in and heal.”
The immune system gets attracted into the tumor and
gets switched to a healer phenotype, which actually helps
the tumor grow. It gets co-opted to help take up cysteine
and keep it away from the T cells. Again, that is what you
would normally want to do if you were healing. You want
to inactivate the killer T cells—to come in and say, “Hey,
calm down.” We do not want to keep the immune system
going because that will lead to chronic inflammation.
IMCJ: Circling back to the beginning of our conversation
regarding your paper published in 2011,3
you did some
continuing experiments expanding from your initial foray,
trying to optimize what level of carbohydrate works best.
You mentioned that you started at about 8% and that you
worked up to 15%. Where did you end up at as far as
optimization goes at this point?
Dr Krystal: In the mice, we did find that 15% was more
effective in the short-term studies, without weight loss, than
25%. In our second follow-up paper—the 2014 study4
with
the Celebrex—we did notice that in long-term studies—so
these were where we used mice that were genetically
predisposed for prostate cancer in this particular case—that
a slightly higher carb diet, 25%, was a healthier long-term
diet. The problem was when you are on the 15% diet for 2
years—so this is the long-term study on the mice—you do
start to see significant differences in weight.
What is interesting is that there was a difference
between males and females. Males can lower their blood
glucose levels with a diet that is higher in carbs than
females. Females need a more drastic reduction in carbs to
make a dent in their blood glucose levels—at least in mice.
There is an evolutionary reason for that. It is that you
need carbs to grow. This is something I should mention: I
do not propose a low-carb, high-protein diet for kids. It is
a diet I am proposing for adults only because kids need
high-carbs—not a Western diet, but not down to 15%. In
fact, if we put pregnant female mice on our low-carb,
high-protein diet, the pups are born runted. So, for rapid
cell division in the embryonic stage, you need a lot of
easily digestible calories. I am not proposing a Western
diet for kids who are sitting in front of their computers all
day. You need exercise. It is critical.
IMCJ: You need the carbs but may not need the sugar.
Dr Krystal: Exactly. There is nothing intrinsically wrong
with eating even sugar if you burn it all off. I always tell
people—because I talk to a lot of seniors—after every
meal go for a walk. Then the blood glucose that is
generated goes into your skeletal muscles to use for
walking. Walk for half an hour after a meal. Your blood
glucose tends to spike between 20 and 30 minutes after a
typical meal, so go for a nice walk. The glucose will not
then be converted into fat stores. It will go towards
working your muscles.
So, in terms of optimization, when I went to 15% carb
and 55% protein that was a proof-of-principle study to
show that it works. For most humans I suggest 20% to 25%
carb and try to use low-glycemic-index carbs and soluble
fiber. Of course insoluble fiber does not count; you do not
get any calories from that. You should be in the range of
35% to 40% protein.
What we are now doing, thanks again to the Hecht
grant we just got, is comparing not only percentages of
proteins, fats and carbs, ie, macronutrients, but different
types. We are comparing different types of protein:
comparing soy to casein, so of plant to animal. We are
comparing different oils: comparing corn oil to coconut
oil to fish oil, because there is a huge controversy about
coconut oil. Even though it is full of saturated fats, they
tend to be shorter-chain fatty acids and that might be
beneficial. We will be able to test that.
References
1. Campbell TC, Campbell TM. The China Study. Dallas, TX: BenBella Books;
2006.
2. Longo VD, Levine ME, Suarez JA, et al. Low protein intake is associated
with a major reduction in IGI-1, cancer, and overall mortality in the 65 and
younger but not older population. Cell Metab. 2014;19(3):401-417.
3. Ho VW, Leung K, Hsu A, et al. A low carbohydrate, high protein diet slows
tumor growth and prevents cancer initiation. Cancer Res. 2011;71(13):4484-
4493.
4. Ho VW, Hamilton MJ, Dang NH, et al. A low carbohydrate, high protein
diet combined with celecoxib markedly reduces metastasis. Carcinogenesis.
2014;35(10):2291-2299.