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A man looks at the plastic rose in his doctor’s hand, and collapses
wheezing and gasping in the throes of an allergy attack. A woman whose back
was opened up for pain-relieving surgery swears that her pain has gone even
though the surgeon, unbeknown to her, stitched her up without doing a thing.
A group of women with terminal breast cancer survives twice as long as another
group, the only difference in treatment being psychotherapy.

This is the mind at work, and you’ve been hearing about it all your
life. Think of that elderly man who ‘lost the will to live’ when his pet
dog died; of the terrified villager who wasted away when cursed by the tribal
witch doctor; of the plucky mum-of-four who refused to give in to cancer.
The stories are fascinating and uplifting. But in the past scientists have
had precious little to say about them. Indeed, the whole subject of ‘mind
over body’ once languished on the far fringes of scientific respectability.

Now it has come in from the cold. Over the past decade, neurobiologists
and immunologists have amassed a hefty wad of research papers pointing to
links between the brain and the immune system. Today, such researchers are
winning government grants; they have a newly formed society for ‘psychoneuroimmunology’,
as they call it, and their abstracts fill up more and more pages of the
roster at each successive neuroscience meeting.

What is clear from all this research is that different moods turn the
activity of immune cells up and down, sometimes for long periods of time.
By these simple measures sleep and expressing your feelings are good for
your immune system; depression, chronic stress from work and insomnia are
often bad. The brain and the immune system ‘talk’ to one another. That much
is certain. The big questions now are: how they communicate and to what
extent their chatter influences our health (if it does so at all).

A couple of decades ago, researchers could barely begin to ask such
questions. The two disciplines of immunology and neurobiology were entrenched
in their separate university departments: immunologists poking at blood
cells in test tubes and dishes; neurobiologists prodding nerves in frogs
and squids. Historically, the two camps would ‘rather use each other’s toothbrushes
than use each other’s terminologies’, says David Felten, a neuroscientist
at the University of Rochester in New York state.

But even as early as 1926, the first glimmerings of a ‘mind-body’ science
were emerging. That year, Serge Metalnikov and his colleagues, working at
the Pasteur Institute in Paris, discovered something interesting. They would
scratch the skin of guinea pigs as they injected them with bacteria. As
expected, the guinea pigs would mount an immune response. More surprisingly,
the animals continued to respond to the scratch alone. It was as if the
animals had learnt that ‘scratching’ meant ‘bacteria’, just as Pavlov’s
famous dogs learnt that ‘bell’ meant ‘bone’.

Time passed and Metalnikov’s findings and some follow-up studies in
Russia languished in the musty pages of research journals. Then, in the
early 1970s, psychologist Robert Ader, now at the University of Rochester,
rediscovered the phenomenon. He too was studying conditioning, feeding rats
a noxious-tasting drug and saccharin. The idea was that the animals would
learn to dislike the saccharin when it was given to them without the drug.
The rats obliged. But they did something else: they died. And the more saccharin
they drank, the faster they died.

Ignorance can sometimes be handy in science. ‘I’m a psychologist, not
an immunologist – I didn’t know there were no connections between the brain
and the immune system,’ says Ader. ‘That meant I was free to make up any
story I wanted.’ The nasty-tasting drug, cyclophosphamide, was actually
an immune suppressant. So Ader reasoned that the rats had made a Pavlov-style
association between saccharin and cyclophosphamide, so that ‘saccharin’
had come to mean ‘turn down the immune system’. Somehow, the brain was able
to relay those orders to the immune cells, and the rats died.

ANSWERING THE CALL

How might this bizarre reaction work? To this day, Ader doesn’t know.
But he, his immunologist collaborator Nicholas Cohen and others have found
that in the conditioning paradigm a wide range of immune cells respond.
These include B cells, our antibody factories; T cells, the destroyers of
foreign, cancerous or virus-infected cells; natural killer cells, which
also attack virus-infected and cancerous cells; and macrophage cells, which
engulf and help to destroy invading bacteria. The scientists also know that
the requisite hardware is in place. The brain has chemicals that can communicate
with the immune system, while the immune system produces chemicals that
can reply to the nervous system.

Meanwhile, Reginald Gorczynski at the University of Toronto and Novera
Herbert Spector at the National Institutes of Health in Bethesda, Maryland,
have shown that you can condition an animal to boost immune responses, as
well as suppress them. Both effects offer tantalising visions of future
therapies: revving the immune system up to help fight off diseases like
cancer for example, or, conversely, turning it down to help prevent the
rejection of grafts or development of autoimmune diseases such as lupus.
The drugs used to suppress immune reactions have nasty side effects. Conditioning
patients to lower their immune response and then maintaining a lower dose
of the drug might minimise them. In fact, it is clear that this therapy
can delay the onset of a lupus-like disease in mice, as well as extending
their lifespans.

RAVENOUS FERRETS

But ‘immune conditioning’ is just one strand of the story. Another
powerful way to influence immune cells is to disturb an animal’s peace of
mind by putting it under stress. How do you ‘stress’ a rat? You can’t fault
scientists for a lack of imagination on this subject. Over the years, they
have tethered rats in tight spaces, rotated them on turntables, popped them
briefly into freezers, even caged them next to ravenous ferrets. And they
have moulded a rat’s mood in more subtle ways, too – by giving it an electric
shock just once, in a special cage, then bringing the unfortunate creature
back to the cage where it knows nasty things are liable to happen.

Under such circumstances, the ability of B and T cells to divide is
reduced by as much as 90 per cent; natural killer cells attack tumours less
efficiently; and T cells produce less of key immune chemicals such as interleukin-2
and gamma-interferon. The aftereffects of one bout of stress can last for
days.

These kinds of treatments do make a difference to disease, it seems
– though not always for the worse. Putting a rat through ordeal by shock,
turntable or ferret leads to larger tumours and more of them, but only
if the tumours are transplanted into the animal before the stressful experience.
Transplanting the tumours after the stressful experience has the opposite
effect. It is as if the immune system by some unknown mechanism rebounds
after stress and overcompensates. Timing, it appears, is everything.

On the other side of the coin, rats that develop arthritis because they
have abnormally active immune systems fare better when the immune system
is damped down by stress. But that doesn’t mean people with arthritis should
all rush out to get jobs as air traffic controllers. ‘The human literature
seems pretty mixed,’ says Donald Lysle, the researcher behind the study
of arthritic rats and a biologist at the University of North Carolina. ‘Some
people report that their arthritis acts up when they’re under stress, and
others report that the disease gets better. It may be that stress does different
things at different points of the disease.’

Working out the details here will require researchers to pinpoint the
chemicals and nerves that enable the brain to communicate with the immune
system. Today it is clear that messenger molecules can leave the brain by
a ‘sea’ route or a ‘land’ route. Hormones called corticosteroids can ply
through the blood; other signals snake down nerves, delivering their messages
to the spleen and other watering holes for immune cells: bone marrow, the
thymus and lymph nodes.

First the sea route. Imagine you’re a rat, sitting in a cage waiting
for an electric shock. You see the bars of the cage, the decor of the room,
and instantly fear that trouble lies ahead. Within seconds, your hypothalamus
– a brain structure involved in emotions – releases a key chemical known
as corticotropin-releasing hormone, or CRH. Next, CRH travels to the pituitary
gland, sitting right below the hypothalamus, where it triggers the release
of another hormone, ACTH, which washes into the blood and sticks to receptors
nearby, in the adrenal medulla. Out washes corticosterone (in humans it
would be hydrocortisol), spreading through the bloodstream and sticking
to and entering T cells, natural killer cells and more. Out washes adrenaline,
growth hormone and sex hormones from sundry other sites, also binding to
cells. Inside many of these cells, proteins swivel into action, genes flicker
on and off, and immune responses are suppressed.

The ‘land’ route works a different way, as David Felten and his students
discovered in the early 1980s. Staring at a piece of rodent spleen under
the microscope, the researchers noticed bundles of nerve fibres lacing between
T cells. Those nerves, the researchers later found, are linked to nerve
bundles called ganglia, then to the spinal cord and ultimately the brain.
They are important conduits between brain and body: damaging them can eliminate
certain effects of stress on immune cells. And researchers now have an inkling
as to how this happens.

WASHING AND LOCKING

As in the sea route, CRH probably plays an important part, indirectly
triggering an electrical impulse down the nerves to the spleen, the bone
marrow and the lymph nodes. There, the impulse directs the nerve-endings
to release noradrenaline. Some of the noradrenaline binds to receptors
on immune cells, altering the properties of the cells. And some washes
out into the blood, where it docks onto more cells in general circulation.

The overall effect of such stimulation is hard to predict. Yet even
this story is a simplification. The list of chemicals that can transmit
messages between the brain, adrenal gland and immune system grows longer
by the year. Flick through the 1218 pages of Psychoneuroimmunology by Ader,
Felten and Cohen, and you’ll get some idea. ‘The complexity is so incredible
that you wonder if there is ever any hope of working it out,’ says Felten.
‘What gives me hope is that there are some incredibly bright people making
outstanding efforts to bring it all together.’

And they will have to be – because the more you read, the murkier the
waters become. Today, it is clear that each type of immune cell reacts
to stress differently. In any one type of experiment, some cells will gear
up, and others down. Lysle, for instance, has recently reported that rats
anticipating an electric shock produce large amounts of nitric oxide from
their macrophages, a key type of immune cell. Nitric oxide suppresses the
immune system in one sense: it slows down T cell division. ‘But nitric oxide
also kills bacteria, and it’s involved in the inhibition of tumour growth,’
says Lysle. ‘Does that mean that these animals are more susceptible or less
susceptible to disease?’

And then, at least when it comes to human beings, it’s worth remembering
that there are as many moods as days in the year, that simplistic talk of
‘stress’ or ‘no stress’ is a pretty crude way to deal with the gamut of
emotions we experience in our lives. Candace Pert, a pioneering neurochemist
who is now at Georgetown University in Washington DC, believes every mood
might have its own concoction of chemicals that move from the brain into
the body. Which ones alter immunity? Which moods are good for us, and which
bad?

We don’t know that yet, but one thing seems clear: when it comes to
stress, we are as malleable as rodents. Just as the hapless rat fidgets
and waits for electricity to zap its feet, so do we walk into our office,
spot the burgeoning in-tray, the humming PC, and anxiety gnaws, nerves fire,
hormones rage. Nor does the stress of work evaporate when we leave the
office. It will often jolt us awake at two in the morning. You have to wonder
what we’re doing to our immune systems.

CONVERTED TO THE CAUSE

Psychologist Janice Kiecolt-Glaser and immunologist Ronald Glaser, a
husband-and wife team at Ohio State University College of Medicine, have
been tackling that question for the past decade. When first persuaded by
his wife to join her in a mind-body study, Glaser was convinced that the
experiment’s premise – that the mind could effect the immune system – was
poppycock. ‘Today, there’s no doubt in my mind that this is real,’ he says.

By taking blood samples from medical students at several points during
the year, the two showed that the students had sluggish immune responses
during exam time: their natural killer cells and T cells were operating
below par, and gamma-interferon, a protein that stimulates immune responses,
was also depleted. By contrast, the students’ immune systems were feistier
after the long, relaxing summer vacation. Medical students are not the only
ones to suffer immune suppression from stress. Elderly people caring for
partners who have Alzheimer’s disease are similarly affected.

THE LAST STRAW

Glaser and Kiecolt-Glaser had good reason to switch from studying healthy,
strapping medical students to elderly men and women. ‘Everybody now believes
that the immune system is modulated by the central nervous system,’ says
Glaser. ‘The big question is: what does it all mean in terms of health?’
In a young, healthy person the daily ups and downs of immune function won’t
matter much. But the immune systems of the elderly are already beginning
to weaken. Extra stress might push them over the edge.

And that is just what Glaser and Kiecolt-Glaser seem to be finding.
In one study, they discovered that upper respiratory tract infections were
more severe in a group of depressed, stressed-out carers than in a control
group. The carers had the same number of colds as the controls, mind you.
But by rights they should have had fewer, argues Glaser, because carers,
tied to the house by their helpless spouse, are less likely to be exposing
themselves to infection.

Now the Glasers are taking the study one step further, by testing the
ability of their subjects to raise antibodies to the influenza virus after
an inoculation. If the carers turn out to be less efficient at raising
an immune response, that could be a serious matter. ‘The flu is no small
potatoes for this bunch – it’s a leading killer for their age group,’ notes
Glaser.

Still, of us could be at heightened risk in smaller ways, even if it
only means keeling over with a cold the day after some test or deadline.
To test this theory, Sheldon Cohen, a psychologist at Carnegie Mellon University
in Pittsburgh, herded 154 men and 266 women down to the Medical Research
Council’s Common Cold Unit in Salisbury, before it closed in 1990. He assessed
their level of stress using psychological questionnaires, then sprayed
cold virus up their noses. Sure enough, the people scoring high for stress
came down with colds more often.

Colds are one thing, but when it comes to cancer the stakes are clearly
higher. Today there is tantalising evidence to suggest that alleviating
stress and depression makes a definite difference to the progression of
skin cancer, breast cancer and cancers of the blood and bone marrow. For
instance, Jean Richardson, a psychologist at the University of Southern
California in Los Angeles, found that patients with leukaemias and lymphomas
live significantly longer when they receive regular, supportive home visits
– and a large chunk of the effect can’t be explained away by things like
better adherence to medical treatment.

Fawzi Fawzi, a psychiatrist at the University of California at Los Angeles,
has similar findings. He divided 74 patients with melanoma into two groups.
One received only routine care, the other group also had six sessions with
a support group where they discussed the typical problems they encountered
as cancer patients, and learnt strategies to help them cope. Six months
later, the group that had undergone therapy was in better psychological
shape than the ‘routine care’ group, as measured by standard mood scales.
Not only that, but their natural killer cells – known to be key players
in fighting cancer – were more numerous and more active. Five years later,
three of them had died, compared with 12 in the ‘routine care’ group.

Even more striking survival differences appeared in a study by David
Spiegel, a psychiatrist at Stanford University in Palo Alto, California.
And his finding is ironic. Spiegel was fed up with New Age therapists blaming
patients for ‘causing’ their cancers through negative thinking – or even
‘wanting’ or ‘needing’ them at some level. So he set out to show that psychological
wellbeing, though clearly valuable, couldn’t cure anyone of terminal breast
cancer. To do that, he went back to a study he had conducted years ago with
psychiatrist Irvin Yalom, also of Stanford, aimed at improving the mental
wellbeing of women with breast cancer. What had become of those 86 patients?

No, they were not cured. But one glance at a graph was enough to spot
the trend. Those receiving group therapy and hypnosis as well as standard
cancer therapy survived twice as long on average as those who had standard
therapy alone – 36.6 months, compared with 18.9. Stunned, Spiegel asked
more than twenty sceptical scientists to study the data before he published.
None found a fatal flaw in the work.

Spiegel doesn’t know what ingredient of the therapy was crucial. Was
it social support? The freedom to express bottled-up emotions? Self-hypnosis
to control the pain of cancer? Pain is certainly bad for the immune system.
It suppresses natural killer cell activity. Self-expression on the other
hand seems to promote a healthy immune system: when actors play out roles
in which they are angry or joyful, their bodies release natural killer cells
from the spleen into the general circulation, where they can do their work.

BEING IN CONTROL

Exercising control over the world around you is also good for your immune
system. Two rats, in identical cages, given equal numbers of electric shocks,
will fare very differently if one rat can work the lever that turns off
the shocks for both of them. Even though both rats have the same total time
in shock, the rat with no control over the lever has been shown to have
T cells which divide more sluggishly when stimulated with growth factors,
as well as unusually slothful natural killer cells.

But Spiegel doesn’t yet know if the immune system is even responsible
for the different survival rates he chronicled in the breast cancer patients.
It is possible that the hormone, which is prolactin released during stress,
stimulates tumours directly. Or maybe sleep or diet were improved along
with mental wellbeing. Then again, poor sleep could be the cause of poor
immunity: Michael Irwin, a researcher at the University of California in
San Diego, has measured brain waves in sleep labs and shown that people
with the most disturbed sleep have the most sluggish natural killer cells.

Still, the order of business is first to check that Spiegel’s finding
is robust. That is why he and others have embarked upon two new experiments.
One, at Stanford, will offer support groups once again to a hundred women
with terminal breast cancer. This time, though, the researchers will take
regular blood samples and measure immune cell activity, hydrocortisol and
CRH levels, and record the patients’ sleep, diet and exercise regimes.

The other is a much larger study, involving 12 university hospitals
around the US, this time with women whose cancer was caught before it spread
from the breast. And while the first trial might not make a huge difference
to life expectancy the second one very well might. ‘It’s a hell of an interesting
question – and it’s one of the things that we’re going to be looking at,’
says Spiegel.

FIGHT OR FLIGHT

One question this kind of research can’t answer is why the nervous
system should be programmed to stomp on our immune system when we feel off
colour. Certainly, the ability to turn down the immune system can be useful:
hyperactive immune responses maybe just as bad for us as sluggish ones.
But why link this immune regulation to stress? An extreme form of stress
is the ‘fight or flight’ sensation we feel in response to danger. At such
times, argue some scientists, the best tactic is to concentrate biological
resources on the hormonal and physical needs of fighting or fleeing – not
on immunity to infections: in other words, to trade off long-term needs
against short-term needs. Also, fleeing or fighting is exactly what is likely
to lead to injury, so perhaps it is prudent for the immune system to wind
down to reduce the risk of inflammation.

Then again, the immune system is a complicated mix of cells which don’t
all behave the same way under stress. ‘We tend to think of the immune system
being up and doing its job, or being down and not doing its job,’ says Lysle.
‘But it’s far more sophisticated than that.’

This complexity, however, seldom surfaces on the pages of popular books
such as You Can Heal Your Life, by Louise Hay, or Love, Medicine and Miracles,
by Bernie Siegel. Discipline your mind, suggest the authors, and your disease
will melt away.

As evidence of the mind’s miraculous powers, such books will often point
to the research of Spiegel, Felten and company. ‘It bothers me greatly when
someone makes a blanket statement like ‘You can cure yourself of cancer’,’
says Felten. ‘Because you cannot cure yourself of a grade IV malignant glioma.’

In fact, it’s possible that some therapies might even make people worse.
Spiegel, Richardson and Fawzi use therapy to help a patient handle the illness,
not vanquish it. By contrast, in a common fringe therapy tool called visualisation,
a patient is instructed to visualise his immune cells attacking and killing
cancer cells. If a patient’s cancer worsens, he may well feel that he is
to blame for not visualising well enough, and will feel more stressed not
less.

EMOTIONAL BURDEN

And Bernie Siegel, who believes that loving thoughts can conquer disease,
asks the patient to ponder the question: why did you need the illness? ‘That’s
a psychonoxious question,’ insists Spiegel. ‘Nobody needs cancer and the
idea that you can’t get better until you’ve blamed yourself appropriately
is ridiculous. I could conceive of somepeople in that treatment getting
emotionally worse. And Lord knows, if the therapy makes people emotionally
worse it’s not likely to make them physically better.’

Today, few scientists need convincing that the brain communicates with
the immune system. The evidence mounts every day. Tomorrow’s agenda will
be to explore what this talk might mean for our health. What precisely does
it mean to halve one’s natural killer cell capability for several days,
or even for several decades? Does our immune system give a hoot? Does it
matter how we feel? ‘We don’t know how much difference mental wellbeing
could make to the outcome of a disease,’ says Spiegel. ‘But we’ve got
to get off this hook of saying either it has nothing to do with it, or that
you can cure your body if you just fix it in your mind.