Four-strand DNA May Hold the Secret to a Cancer Cure

Most of us have heard of the double helix. But quadruple helix DNA? 

 

We remember the double helix from science class, that elegant swirl of genes that make up all life on earth. By contrast, quadruple strand DNA sounds like something out of a sci-fi horror movie. Maybe something to do with a cloned monster that gets out and tears up the town, until a small band of plucky heroes take it down. Though it sounds fantastic, we all contain quadruple strand DNA. And it fact, it has been implicated in a real monster. But a plucky band of scientists who discovered it, may unlock its potential for fighting this serious and real disease that potentially, threatens us all. 


A recent study, out of the University of Cambridge in the UK, finds that four-strand DNA has the potential to offer new targets for cancer treatment. These control certain genes, particularly those associated with cancer. This discovery, published in the journal Nature Genetics, may also help to advance the small, but growing sector known as personalized medicine. The more information we have about the genetic makeup of a patient, the better we can diagnose, treat, and even prevent diseases.

One problem with cancer treatments today is that they attack all cells indiscriminately. Chemotherapy for instance, hurts healthy cells and cancerous ones alike. With targeted therapy, only the cancer cells are damaged, leaving healthy ones alone. To do so, researchers must find what is unique about cancer cells. They may now have found one important aspect.

Chemotherapy drugs have harsh side effects, and injure cancer cells and healthy ones alike. Scientists are looking for options that only target cancer.

Four-strand DNA is known as G-quadruplexes, because they occur in regions of DNA with a lot guanine or G. This is one of the four main nucleic acids that make up RNA and DNA. The others include adenine (A), cytosine (C), and thymine (T). Watson and Crick discovered the double helix some sixty years ago, a structure they described as a twisty ladder.

G-quadruplexes are more like a tower with many floors. Each floor is known as a tetrad. Guanine (G) resides at all four corners, on each floor, held in place by hydrogen bonds. Cambridge researchers also found that a strand of DNA can fold itself into a G-quadruplex.

Those scientists who first discovered quadruple-strand DNA a few years ago, are behind this present finding. Professor Shankar Balasubramanian was the senior author on the study. He is a professor of medicinal chemistry at the university, and an investigator at the Cancer Research UK Cambridge Institute.

At first, there were a lot of theories on how G-quadruplexes might be associated with cancer. "But what we've found is that even in non-cancer cells, these structures seem to come and go in a way that's linked to genes being switched on or off," Balasubramanian said.

Model of a G-quadraplex. Image by TimVickers at English Wikipedia (Transferred from en.wikipedia to Commons.) [Public domain], via Wikimedia Commons

In this study, the professor and his team used small molecules to alter pre-cancerous cells, in order to search for G-quadruplexes. About 10,000 were located, mostly in areas that control gene behavior. They were particularly prominent around those genes associated with cancer.

Dr. Robert Hansel-Hertsch was the lead author on this project. He is a postdoctoral research associate at the university. Hansel-Hertsch said that G-quadruplexes were discovered in areas of the genome known for transcription, or rewriting DNA into other cells. They also control functioning and ultimately, the fate of cells.

"The finding that these structures may help regulate the way that information is encoded and decoded in the genome will change the way we think this process works," he said. Researchers now think that quadruple strand DNA acts similarly to epigenetic tags, in a process known as methylation.

This study suggests that four-strand DNA could become the next target for novel and precision cancer treatment. According to Prof. Balasubramanian, cancer cells respond well to small molecules that interact with G-quadruplexes. This suggests that these structures may exist in large numbers in pre-cancerous and cancerous cells.

Someday, cancer treatment may come down to flipping a few biochemical “switches,” stopping the cancer from multiplying and spreading. On this, Prof. Balasubramanian said, "Figuring out the fundamental processes that cancer cells use to switch genes on and off could help scientists develop new treatments that work against many types of the disease."

To learn more about four strand DNA click here: 

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Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.

Still from John Stephenson's 1999 rendition of Animal Farm.
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  • Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
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  • The research raises many ethical questions and puts to the test our current understanding of death.

The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?

But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.

What's dead may never die, it seems

The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.

BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.

The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.

As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.

The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.

"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.

An ethical gray matter

Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.

The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.

Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.

Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?

"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."

One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.

The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.

"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.

It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.

Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?

The dilemma is unprecedented.

Setting new boundaries

Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."

She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.

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