Gene

Genetic risk of getting second cancer tallied for pediatric survivors

childhood cancer
RISK ROUNDUP Some pediatric cancer survivors carry genetic mutations that increase the risk of a later, second cancer.

WASHINGTON — A second cancer later in life is common for childhood cancer survivors, and scientists now have a sense of the role genes play when this happens. A project that mined the genetic data of a group of survivors finds that 11.5 percent carry mutations that increase the risk of a subsequent cancer.

“We’ve always known that among survivors, a certain population will experience adverse outcomes directly related to therapy,” says epidemiologist and team member Leslie Robison of St. Jude Children’s Research Hospital in Memphis. The project sought “to find out what contribution genetics may play.” The team presented their work at the American Association of Cancer Research meeting April 3.

“This is a nice first step,” says David Malkin, a pediatric oncologist at the University of Toronto. “The results validate the thoughts of those of us who believe there is a genetic risk that increases the risk of second malignancies.”

Five-year survival rates for kids with cancer have grown to more than 80 percent. But “there are long-term consequences for having been diagnosed and treated for cancer as a child,” notes Robison. Some survivors develop a later, second cancer due to the radiation or chemotherapy that treated the first cancer (SN: 3/10/07, p. 157).

The researchers examined 3,007 survivors of pediatric cancer who routinely undergo medical evaluation at St. Jude. About a third had leukemia as children. By age 45, 29 percent of this group had developed new tumors, often in the skin, breast or thyroid.

The team cataloged…

CRISPR had a life before it became a gene-editing tool

phages
Bacteria and archaea armed with CRISPR systems have been at war with viruses for eons. Here, hordes of viruses known as phages assault a bacterium to turn it into a virus-making factory.

WEAPONS OF MASS EVOLUTION

It is the dazzling star of the biotech world: a powerful new tool that can deftly and precisely alter the structure of DNA. It promises cures for diseases, sturdier crops, malaria-resistant mosquitoes and more. Frenzy over the technique — known as CRISPR/Cas9 — is in full swing. Every week, new CRISPR findings are unfurled in scientific journals. In the courts, universities fight over patents. The media report on the breakthroughs as well as the ethics of this game changer almost daily.

But there is a less sequins-and-glitter side to CRISPR that’s just as alluring to anyone thirsty to understand the natural world. The biology behind CRISPR technology comes from a battle that has been raging for eons, out of sight and yet all around us (and on us, and in us).

The CRISPR editing tool has its origins in microbes — bacteria and archaea that live in obscene numbers everywhere from undersea vents to the snot in the human nose. For billions of years, these single-celled organisms have been at odds with the viruses — known as phages — that attack them, invaders so plentiful that a single drop of seawater can hold 10 million. And natural CRISPR systems (there are many) play a big part in this tussle. They act as gatekeepers, essentially cataloging viruses that get into cells. If a virus shows up again, the cell — and its offspring — can recognize and destroy it. Studying this system will teach biologists much about ecology, disease and the overall workings of life on Earth.

But moving from the simple, textbook story into real life is messy. In the few years since the defensive function of CRISPR systems was first appreciated, microbiologists have busied themselves collecting samples, conducting experiments and crunching reams of DNA data to try to understand what the systems do. From that has come much elegant physiology, a mass of complexity, surprises aplenty — and more than a little mystery.

Spoiled yogurt

The biology is complicated, and its basic nuts and bolts took some figuring out. There are two parts to CRISPR/Cas systems: the CRISPR bit and the Cas bit. The CRISPR bit — or “clustered regularly interspaced short palindromic repeats” — was stumbled on in the late 1980s and 1990s. Scientists then slowly pieced the story together by studying microbes that thrive in animals’ guts and in salt marshes, that cause the plague and that are used to make delicious yogurt and cheese.

None of the scientists knew what they were dealing with at first. They saw stretches of DNA with a characteristic pattern: short lengths of repeated sequence separated by other DNA sequences now known as spacers. Each spacer was unique. Because the roster of spacers could differ from one cell to the next in a given microbe species, an early realization was that these differences could be useful for forensic “typing” — investigators could tell whether food poisoning cases were linked, or if someone had stolen a company’s yogurt starter culture.

Bacteria use CRISPR/Cas as a form of immunity or self-defense against invaders. A bacterium builds a library of genetic material from past invaders so that, if the same invader attacks again, the bacterium and its offspring can disable it.

L. Marraffini/Nature 2015, Adapted by J. Hirshfeld

But curious findings piled up. Some of those spacers, it turned out, matched the DNA of phages. In a flurry of reports in 2005, scientists showed, to name one example, that strains of the lactic acid bacterium Streptococcus thermophilus contained spacers that matched genetic material of phages known to infect Streptococcus. And the more spacers a strain had, the more resistant it was to attack by phages.

This began to look a lot like learned or adaptive immunity, akin to our own antibody system: After exposure to a specific threat, your immune system remembers and you are thereafter resistant to that threat. In a classic experiment published in Science in 2007, researchers at the food company Danisco showed it was so. They could see new spacers added when a phage infected a culture of S. thermophilus. Afterward, the bacterium was immune to the phage. They could artificially engineer a phage spacer into the CRISPR DNA and see resistance emerge; when they took the spacer away, immunity was lost.

This was handy intel for an industry that could find whole vats of yogurt-making bacteria wiped out by phage infestations. It was an exciting time scientifically and commercially, says Rodolphe Barrangou of North Carolina State University in Raleigh, who did a lot of the Danisco work. “It was not just discovering a cool system, but also uncovering a powerful phage-resistance technology for the dairy industry,” he says.

The second part of the CRISPR/Cas system is the Cas bit: a set of genes located near the cluster of CRISPR spacers. The DNA sequences of these genes strongly suggested that they carried instructions for proteins that interact with DNA or RNA in some fashion — sticking to it, cutting it, copying it, unraveling it. When researchers inactivated one Cas gene or another, they saw immunity falter. Clearly, the two bits of the system — CRISPR and Cas — were a team.

It took many more experiments to get to today’s basic model of how CRISPR/Cas systems fight phages — and not just phages. Other types of foreign DNA can get into microbes, including circular rings called plasmids that shuttle from cell to cell and DNA pieces called transposable elements, which jump around within genomes. CRISPRs can fend off these intruders, as well as keep a microbe’s genome in tidy order.

The process works like this: A virus injects its genetic material into the cell. Sensing this danger, the cell selects a little strip of that genetic material and adds it to the spacers in the CRISPR cluster. This step, known as immunization or adaptation, creates a list of encounters a cell has had with viruses, plasmids or other foreign bits of DNA over time — neatly lined up in reverse chronological order, newest to oldest.

Older spacers eventually get shed, but a CRISPR cluster can grow to be long — the record holder to date is 587 spacers in Haliangium ochraceum, a salt-loving microbe isolated from a piece of seaweed. “It’s like looking at the last 600 shots you had in your arm,” says Barrangou. “Think about that.”

New spacer in place, the microbe is now immunized. Later comes targeting. If that same phage enters the cell again, it’s recognized. The cell has made RNA copies of the relevant spacer, which bind to the matching spot on the genome of the invading phage. That “guide RNA” leads Cas proteins to target and snip the phage DNA, defanging the intruder.

Scientists have divided the array of known CRISPR systems into five types and 16 subtypes based on DNA sequence data. The distribution of types differs in archaea and bacteria.

K.S. Makarova et al/Nat. Rev. Microbio. 2015, Adapted by J. Hirshfeld

Researchers now know there are a confetti-storm of different CRISPR systems, and the list continues to grow. Some are simple — such as the CRISPR/Cas9 system that’s been adapted for gene editing in more complex creatures (SN: 4/15/17, p. 16) — and some are elaborate, with many protein workhorses deployed to get the job done.

Those who are sleuthing the evolution of CRISPR systems are deciphering a complex story. The part of the CRISPR toolbox involved in immunity (adding spacers after phages inject their genetic material) seems to have originated from a specific type of transposable element called a casposon. But the part responsible for targeting has multiple origins — in some cases, it’s another type of transposable element. In others, it’s a mystery.

Given the power of CRISPR systems to ward off foes, one might think every respectable microbe out there in the soils, vents, lakes, guts and nostrils of this planet would have one. Not so.

Numbers are far from certain, partly because science hasn’t come close to identifying all the world’s microbes, let alone probe them all for CRISPRs. But the scads of microbial genetic data accrued so far throw up interesting trends.

Tallies suggest that CRISPR systems are far more prevalent in known archaea than in known bacteria — such systems exist in roughly 90 percent of archaea and about…

Random mutations play large role in cancer, study finds

GROWING PAINS As cells divide and grow to replenish and repair organs, accidental mutations may crop up in cancer-associated genes. A new study suggests such random mistakes are the source of 66 percent of mutations in cancer cells (illustrated here) across the board.

Researchers have identified new enemies in the war on cancer: ones that are already inside cells and that no one can avoid.

Random mistakes made as stem cells divide are responsible for about two-thirds of the mutations in cancer cells, researchers from Johns Hopkins University report in the March 24 Science. Across all cancer types, environment and lifestyle factors, such as smoking and obesity, contribute 29 percent of cancer mutations, and 5 percent are inherited.

That finding challenges the common wisdom that cancer is the product of heredity and the environment. “There’s a third cause and this cause of mutations is a major cause,” says cancer geneticist Bert Vogelstein.

Such random mutations build up over time and help explain why cancer strikes older people more often. Knowing that the enemy will strike from within even when people protect themselves against external threats indicates that early cancer detection and treatment deserve greater attention than they have previously gotten, Vogelstein says.

Vogelstein and biomathematician Cristian Tomasetti proposed in 2015 that random mutations are the reason some organs are more prone to cancer than others. For instance, stem cells are constantly renewing the intestinal lining of the colon, which develops tumors more often than the brain, where cell division is uncommon. That report was controversial because it was interpreted as saying that most cancers are the result of “bad luck.” The analysis didn’t include breast and prostate cancers. Factoring in those common cancers might change the results, some scientists said. And because the researchers looked at only cancer within the United States, critics charged that the finding might not hold up when considering places around the world where different environmental factors, such as infections, affect cancer development.

In the new study, Vogelstein, Tomasetti and Hopkins colleague Lu Li examined data from 69 countries about 17 types of cancer, this time including breast and prostate. Again, the researchers found a strong link between cancer and tissues with lots of dividing stem cells. The team also used DNA data and epidemiological studies to calculate the proportions of mutations in cancer cells caused by heredity or environmental and lifestyle factors. Remaining mutations were attributed to random errors — including typos, insertions or deletions of genes, epigenetic changes (alterations of chemical tags on DNA or proteins that affect gene activity) and gene rearrangements. Such errors unavoidably happen when cells divide.

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Chance cancer

For many organs, more of the mutations that lead to cancer come from random mistakes in DNA…

Yale Researchers Find That Autism Genes Helped Us to Become Smarter

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Those with autism face distinct challenges. These usually have to do with certain social deficits. That might be why the results of a new study appear a bit puzzling. Genes linked to autism spectrum disorders (ASD) were actually preserved through the process of evolution, Yale researchers concluded. These genes actually made us smarter.

If you find these results strange, consider the large numbers of scientists and engineers known to have Asperger’s syndrome. There are autistic savants as well, as the movie Rain Man can attest, which was based on a true story. Or perhaps you’ve seen the work of mind-blowing artist Stephen Wiltshire, who can draw panoramic scenes of whole cities with perfect detail, from his memory alone.

This was a genome-wide study, zeroing in on gene variants associated with ASD. Researchers examined 5,000 cases of autism and analyzed the genome of each participant. They focused on evolutionary gene selection, particularly on which genes were positively selected. One clue which led researchers to these findings was that, more genes associated with autism were preserved by evolution than would have been through sheer randomness.

Autistic…

Competition, Cooperation, and the Selfish Gene

Richard Dawkins has one of the best-selling books of all time for a serious piece of scientific writing.

Often labeled “pop science”, The Selfish Gene pulls together the “gene-centered” view of evolution: It is not really individuals being selected for in the competition for life, but their genes. The individual bodies (phenotypes) are simply carrying out the instructions of the genes. This leads most people to a very “competition focused” view of life. But is that all?

***

More than 100 years before The Selfish Gene, Charles Darwin had famously outlined his Theory of Natural Selection in The Origin of Species.

We’re all hopefully familiar with this concept: Species evolve over long periods time through a process of heredity, variation, competition, and differential survival.

The mechanism of heredity was invisible to Darwin, but a series of scientists, not without a little argument, had figured it out by the 1970’s: Strands of the protein DNA (“genes”) encoded instructions for the building of physical structures. These genes were passed on to offspring in a particular way – the process of heredity. Advantageous genes were propagated in greater numbers. Disadvantageous genes, vice versa.

The Selfish Gene makes a particular kind of case: Specific gene variants grow in proportion to a gene pool by, on average, creating advantaged physical bodies and brains. The genes do their work through “phenotypes” – the physical representation of their information. As Helena Cronin would put in her book The Ant and the Peacock, “It is the net selective value of a gene’s phenotypic effect that determines the fate of the gene.”

This take of the evolutionary process became influential because of the range of hard-to-explain behavior that it illuminated.

Why do we see altruistic behavior? Because copies of genes are present throughout a population, not just in single individuals, and altruism can cause great advantages in those gene variants surviving and thriving. (In other words, genes that cause individuals to sacrifice themselves for other copies of those same genes will tend to thrive.)

Why do we see more altruistic behavior among family members? Because they are closely related, and share more genes!

Many problems seemed to be solved here, and the Selfish Gene model became one for all-time, worth having in your head.

However, buried in the logic of the gene-centered view of evolution is a statistical argument. Gene variants rapidly grow in proportion to the rest of the gene pool because they provide survival advantages in the average environment that the gene will experience over its existence. Thus, advantageous genes “selfishly” dominate their environment before long. It’s all about gene competition.

This has led many people, some biologists especially, to view evolution solely through the lens of competition. Unsurprisingly, this also led to some false paradigms about a strictly “dog eat dog” world where unrestricted and ruthless individual competition is deemed “natural”.

But what about cooperation?

***

The complex systems researcher Yaneer Bar-Yam argues that not only is the Selfish Gene a limiting concept biologically and possibly wrong mathematically (too complex to address here, but if you want to read about it, check out these pieces), but that there are more nuanced ways to understand the way competition and cooperation comfortably coexist. Not only that, but Bar-Yam argues that this has implications for optimal team formation.

In his book Making Things Work, Bar-Yam lays…

Human gene editing therapies are OK in certain cases, panel advises

bubble boy
EDITING OUT DISEASE Gene therapy can cure a genetic disease called severe combined immunodeficiency, or “bubble boy,” disease. Using new gene editing techniques like CRISPR/Cas9 to treat genetic diseases is fine under certain conditions, but it should not be used to enhance people, a panel of experts says.

Human gene editing to prevent genetic diseases from being passed to future generations may be permissible under certain conditions, a panel of experts says.

Altering DNA in germline cells — embryos, eggs, and sperm, or cells that give rise to them — may be used to cure genetic diseases for future generations, provided it is done only to correct disease or disability, not to enhance people’s health or abilities, a report issued February 14 by the National Academies of Sciences and Medicine recommends. The decision contradicts earlier recommendations by organizers of a global summit on human gene editing, who concluded that gene editing with molecular scissors such as CRISPR/Cas9 should not be used to produce babies (SN: 12/26/15, p. 12).

Heritable gene editing is not yet ready to be done in people, says Alta Charo, a bioethicist at the University of Wisconsin‒Madison Law School who cochaired the panel. “We are not trying to greenlight heritable germline editing. We’re trying to find that limited set of circumstances where its use is justified by a compelling need and its application is limited to that compelling need,” says Charo. “We’re giving it a yellow light.”

National Academies reports carry no legislative weight, but do often influence policy decisions in the United States and abroad. It will be up to Congress, regulatory agencies such as the U.S. Food and Drug Administration, and state and local governments to implement the recommendations.

Supporters of new genetic engineering technologies hailed the decision.

“It looks like the possibility of eliminating some genetic diseases is now more than a theoretical option,” says Sean Tipton, a spokesman for the American Society for Reproductive Medicine in Washington, D.C. “That’s what this sets up.” Diseases such as cystic fibrosis and Huntington’s, which are caused by mutations in single genes, could someday be corrected by gene editing. More complex diseases or disorders caused by changes in multiple genes, such as autism or schizophrenia, probably would not be the focus of genome editing.

Others worry that…