June 10, 2012
Fewer Mutations Needed For Cancer Than Previously Thought The number of mutations needed to make a cell go cancerous may be fewer than previously thought. This is a sort of Achilles' Heel in our genomes that we should fix so we are less at risk of cancer.

Chromosomal deletions in DNA often involve just one of two gene copies inherited from either parent. But scientists haven't known how a deletion in one gene from one parent, called a "hemizygous" deletion, can contribute to cancer.

A research team led by Stephen Elledge, a professor in the Department of Genetics at Harvard Medical School, and his post-doctoral fellow Nicole Solimini, has now provided an answer. The most common hemizygous deletions in cancer, their research shows, involve a variety of tumor suppressing genes called STOP genes (suppressors of tumorigenesis and proliferation) that scatter randomly throughout the genome, but that sometimes cluster in the same place on a chromosome. And these clusters, said Elledge, who is also a professor of medicine at Brigham and Women's Hospital, tend to be deleted as a group. "Eliminating the cluster gives a bigger bang for the deletion buck," he said.

So I've got a modest proposal for genetically reegineering the human genome to reduce the risk of cancer: make big deletions of multiple oncogenes lethal for the cell. How? Mix absolutely essential genes in between the oncogenes. If the oncogenes get deleted in a big block then the cell should die due to loss of essential genes. Basically, do genetic layout so those big deletion mutations are lethal.

Your new word for the day: haploinsufficient. Try to mix it into everyday conversation.

This finding is especially interesting in light of the two-hit model of cancer formation, which holds that both copies of a recessive gene need to be inactivated to trigger a biological effect. Thus the loss of a single tumor suppressor copy should have little or no influence on tumor cell proliferation because the remaining copy located on the other chromosome is there to pick up the slack.

Elledge's research points to a different hypothesis, namely that STOP genes in a hemizygous deletion aren't recessive but are instead haploinsufficient, meaning that they depend on two copies to function normally. "If a tumor suppressor is haploinsufficient, then a single gene copy lacks the potency needed to fully restrain tumorigenesis," Elledge explained, who is also a Howard Hughes Medical Institute Investigator. "So by removing clusters of haploinsufficient genes all at once, the cancer cell immediately propels its growth forward without having to wait for the other copies to also be lost."

Perhaps 10 or 20 years hence stem cells intended for therapies will get genetically enhanced to be far less susceptible to mutations that could turn them cancerous. My rearranging the genome the number of mutations needed to make a cancerous cell could be greatly increased, with cells becoming more likely to die than become cancerous when they lose genes involved in protection against cancer.

Since some rare people have immune systems which aggressively attack cancers we should also figure out what makes their genomes better in this regard. Then we should develop gene therapies and cell therapies that enhance our immune systems to snuff out early stage cancers.

Share |      Randall Parker, 2012 June 10 08:39 PM  Biotech Cancer

PacRim Jim said at June 11, 2012 1:05 AM:

Protecting our species against various diseases will effectively terminate its evolution by means of natural selection, because everyone, not just the fittest, will be considered adapted and thus selected for survival.
Speaking as a human becoming unfitter with every passing birthday, it's OK by me and none too soon.

Paul said at June 11, 2012 1:38 PM:

That's not how evolution works, Jim. Fitness is a fluid thing including more than just surviving disease.

Humanity will likely, at some point, go back to a situation of malthusian equilibrium, where reproduction just matches various checks. Removal of disease just means other checks will take over. If the check is some global control on reproduction, then evolution will select for willingness and ability to evade the controls or game the system. If the check is starvation, evolution will optimize for energy efficiency and ability to acquire nutrients. If the check is homocide, evolution will select for the characteristic needed to win this direct battle for survival, either by avoiding death or dealing it first.

Even tiny differences in fitness will be exploited by evolution, over long enough periods of time.

PacRim Jim said at June 11, 2012 3:24 PM:

The sole relevant metric here is survival to reproduction.
If medical research develops treatments/cures that allow people to reproduce despite pathogenic genes that would otherwise have prevented reproduction, those maladaptive mutations will remain in the gene pool, unless the therapy repairs the mutations.
That's about as dead as Darwin's evolution could get, wouldn't you say?

Mthson said at June 11, 2012 7:52 PM:
"The sole relevant metric here is survival to reproduction."

Basically everybody survives until reproduction age already.

The most relevant metric for evolutionary success today is low IQ, because medium and high IQ people tend to value other stuff above raising multiple kids. Thus geniuses like Steven Pinker have zero kids, and guys like this have 30 kids with 11 partners.

The big picture is that the regions that contribute the least to human advancement, like Africa, are expected to double in population by 2050.

So if "Darwin's evolution was dead," that'd be a big step forward from where we've been for a long time, which is reverse evolution.

Mthson said at June 11, 2012 8:06 PM:

(That being said, the variation within clusters is larger than the variation between clusters, etc., so individual metrics are more important than cluster membership.)

PacRim Jim said at June 12, 2012 3:19 PM:

"The most relevant metric for evolutionary success today is low IQ"

You take my breath away. Look around you. Do you find anyone so dumb--not ignorant, dumb--as to be incapable of reproduction?
The fact that most people now survive long enough to reproduce is proof that evolution as defined by Darwin is no more.
Thanks to our scientific method, we humans are now learning to control evolution, which is poised to accelerate beyond our understanding within this century.
Designer genomes will be just the beginning.
Whatever eventuates, humans qua Homo sapiens are unlikely to survive the century.

Mthson said at June 12, 2012 5:23 PM:

PacRim Jim,

My point is that population growth has inversely correlated with IQ for a long time, and that's the main evolutionary pressure in the modern era. It matters

Agreed that reprogenetics on a broad scale will probably fix a lot of things, but it's far away.

Randall Parker said at June 12, 2012 8:47 PM:

PacRim Jim,

You are completely wrong with this statement:

The fact that most people now survive long enough to reproduce is proof that evolution as defined by Darwin is no more.

Selective pressures have radically changed since we left the Malthusian Trap and they changed even more with the development of the welfare state. Traits are still being selected for and against. This is still happening at a rapid rate, probably even faster than before. The selective pressures are just in reverse directions.

Read Gregory Clark's book A Farewell To Alms. It is obvious that the selective pressures so obvious from that book have reversed.

Tj Green said at June 14, 2012 3:18 PM:

Survival strategies are genetic variation, and strategic alliances with other species. Therefore we can stop the arms race with our prey, but we cannot stop random mutations.

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