[biomed] No Solution to Cancer - Have Our Genes Evolved to Turn Against Us?

[Eugen Leitl]

http://www.physorg.com/printnews.php?newsid=95950931

Figure 1: The costs and benefits of DNA repair may be illustrated as
alterative strategies on a race track. The green car always stops for repairs
when a problem is indicated, whereas the red car ignores all warning lights.
The green car may have the better strategy under ordinary conditions (A)
because it always has a faultless engine, whereas the red car accumulates
errors. Fore the same reason, it may also seem rational that harsher
environments favour the repair strategy of the green car. Paradoxically,
however, the answer may be exactly the opposite. Imagining your body as a war
zone where tobacco smoke, an unhealthy diet and excessive sunbathing attack
the genes with heavy ammunition (mutagen in figure B). Damages appear faster
than can be removed, and the green car gets trapped in the check point. To
stop for repairs is thus a fatal strategy, and it is better to keep on going
despite accumulating errors. The model thus explains why mutagenic
environments favour the rise of genetically unstable cancer cells within our
body (Reproduced from Breivik, Proc Natl Acad Sci USA 2001; 98: 5379–81).
Cancer is a natural consequence of human evolution. Our genes have not
developed to give us long and happy lives. They are optimized to copy
themselves into the next generation - irrespective of our personal desires.
According to Jarle Breivik, an associate professor at the University of Oslo,
Norway, we are therefore unlikely to find a final solution to cancer.

Doing research at the Institute of Basic Medical Sciences, Breivik explores
the connection between cancer development and Darwinian evolution. In a
recent interview with Scientific American, and the research magazine Apollon,
published by the University of Oslo, he concludes that “Cancer is a
fundamental consequence of the way we are made. We are temporary colonies
made by our genes to propagate themselves to the next generation. The
ultimate solution to cancer is that we would have to start reproducing
ourselves in a different way.”

[No Solution to Cancer - Have Our Genes Evolved to Turn Against Us?] Genes
that repair genes

As a medical student at the Norwegian Radium Hospital, Breivik discovered a
curious phenomenon. He found that cancer cells that developed in the upper
colon had other types of mutations than those found in tumours closer to the
rectum. This finding was confirmed by other researchers and could be traced
to mutations in particular DNA repair genes. Such genes have evolved to
prevent mutations in other genes and play a vital role in defending the
organism from cancer. But why do cells in the upper region of the intestine
lose a different type of repair mechanism than those further down?

Breivik was determined to find an explanation. After several years of data
mining and theoretical modelling, he was able to demonstrate a connection
between loss of DNA repair and harmful environmental factors in the
intestines. Curiously however, the cancer cells appeared to have lost the
repair mechanisms that would protect them from DNA damage in their particular
environment. Breivik thus proposed the following hypothesis: Although DNA
repair is favourable to the organism; it may not be favourable to the
individual cell. The theory was developed in several science papers,
including an invited Commentary in the Proceedings of the National Academy of
Sciences USA, and may be illustrated as the effect of alternative strategies
in a car race (figure 1).

“Deciding when to stop for repairs and when to keep on going is a difficult
challenge. Making repairs assures an optimized vehicle, but it also consumes
valuable time and resources. At first thought, it may seem obvious that a
damaging environment calls for more repair. Paradoxically, however, the
effect may be exactly the opposite. Imagine that you are racing through a war
zone with constant bombardment. Stopping for repair can then be a fatal
strategy, and it is better to keep on going with flat tires and a screaming
engine than to stop for repairs,” says Breivik.

This illustration thus explains why genetically unstable cancer cells are
favoured in hostile environments—such as in the lungs of a heavy smoker. The
model may also be described mathematically and has been experimentally
confirmed in cell cultures and animal models by leading research groups in
the field.

“Cells exposed to particular carcinogens die if they have the relevant repair
mechanism, while genetically unstable cancer cells continued to grow,”
Breivik explains.

Evolution within

This research shows how the environment influences the selection of genes
inside of the body and is identical to the principle that Darwin found to
explain the origin of species.

“The body is not a static system. Our cells are in a constant state of
development, and new genetic variants arise every day. Many of these mutants
are removed by the immune system but, sooner or later, a cell will break
through the defences and develop into a tumour of wild-growing renegades.”

Cancer development is an evolutionary process within the multicellular
organism, but it is also related to the general process of evolution through
the generations. Life begins when our parent’s genes are united in the
zygote. These genes have been selected through millions of generations for
their ability to create a functional organism, but few days after
fertilization the genes split up in two different directions. Some end up in
the germ cells (sperm and ova) that will bring them to the next generation,
while the rest end up in the somatic cells that make up our body. The somatic
cells are initially programmed to cooperate, but as we age and new mutations
arise, the evolutionary process will favour cells that break ranks and
propagate freely within the body. Thus, according to Breivik, the division
between germ cells and somatic cells represents the Darwinian explanation to
cancer (figure 2).

Time bombs

Natural selection favours genes for their ability to replicate in their given
environment. Through the course of evolution, they have thereby developed
increasingly more complex mechanism for self-replication, first as single
celled organisms and later as cells that cooperate in complex colonies.

“This is where humans belong. We are cell colonies developed for propagating
our genes from one generation to the next. As soon as our children can take
care of themselves, we are irrelevant to the genes. Caring grandparents may
be good to have, but dozens of enduring ancestors will not increase a gene’s
chance for survival—on the contrary, they may represent a waste of valuable
recourses. The entire human genome is therefore probably developed to give us
a limited lifespan,” says Breivik.

He believes that many of our genes are constructed such that they protect
against cancer in the first part of our lives, but that they are programmed
for destruction as we get older.

“We see that DNA repair genes, which protect us from cancer in early life,
contain unstable DNA sequences that increase their probability for breakdown
as time passes. These sequences are ticking time bombs in our genome and
represent a paradox if we consider what is best for the organism. If we take
the perspective of the genes’, on the other hand, the phenomenon is quite
logical,” says Breivik. He is currently studying the molecular and
evolutionary mechanisms that lead to such unstable repair genes.

The next step in evolution

Despite important advances in therapy, all statistics show that the cancer
incidence will continue to rise.

“The better we get at treating cancer, the older we become and the more
cancer there will be in the population. Additionally, better therapy for
children and young people implies that more cancer genes are passed on to the
next generation. From what we know about evolutionary dynamics, I believe
it’s impossible to find a therapeutic solution to cancer. The basic problem
is that we are trapped in a body that the genes have made to be disposable. A
solution will therefore be something much more radical than a new drug,” says
Breivik.

He argues that cancer therapy is an attempt to counteract the natural decay
of the body. If we think about it, however, it is not really the body we care
about. After all, most people are more than happy to trade in a defect organ
for a new one.

“It's the mind, our thoughts and consciousness that we desperately want to
preserve. If we look at technological developments as a whole, that may be
exactly what’s happening. The ongoing revolution in information and
biotechnology may be interpreted as the mind’s liberation from the genes.
It’s difficult to imagine the alternative, but if I could see a thousand
years into the future, I would be very surprised if earth is still dominated
by two-legged creatures with a limited life span,” says Jarle Breivik.

Source: University of Oslo




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