New Cancer Solutions, From Lab to Clinic

Question: What are the potential applications of your RNAi studies in the field of cancer research?

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Gregory Hannon: Well, for a long time, we’ve been interested in using RNAi as a tool to silence genes of interest, whatever genes we want.  And in fact, my lab has built large collections of RNAi inducing agents, in fact, collections that can be used to turn off every gene in the human **** genome.  Now, the way that we use these to investigate cancer biology is essentially to take a set of cancer cells, engineer them so that each cell has a different gene turned off, and then we ask how those cells react under stress.  What genes do cancer cells require that normal cells don’t?   These are potential targets for therapy.  What genes modify the responsive cancer cells to chemotherapeutic agents, or targeted therapies?  What genes modify the ability of cancer cells to engrafted host to metastasize, etc.?

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Question: What new cancer therapies might be drawn from this research?

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Gregory Hannon: Well there are really two ways that one would move from the work that we’re doing to something that would be applicable in the clinic.  One is a process that is being repeated in many pharmaceutical companies.  Many labs really built on the foundation of understanding this basic piece of biology, which is searching for unique vulnerabilities in tumor cells.  Now, once one finds a cell upon which a particular subtype of breast cancer, for example, depends that the normal epithelial cells don’t depend on, then one can find targeted agents using standard pharmaceutical chemistry that could inhibit the activity of that particular target.  And there you have a potentially selective therapy in a way that things like Gleevec are selective for specific gene rearrangement upon with the tumor cells carrying that arrangement uniquely depend.

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Another promise of RNAi is that it can be used as a therapy itself.  And there is a tremendous interest in this, both in the academic and in the industrial communities.  The notion that pharmaceutical chemistry can only access only about 20% of the genes encoded in the genome being as we have a limited ability to regulate chemically, the activity of the proteins encoded by the other 80%.  RNAI doesn’t have such a limitation.  All it needs to be able to do is to specifically recognize the sequence of that gene in order to shut it off.  And so it is essentially, in some ways, a potentially universal pharmaceutical approach.  The difficulty is, and I think this is where many of us are focusing a lot of effort, is trying to figure out how to take this relatively large molecule compared to a normal pharmaceutical and get it efficiently delivered to the cells in which the therapy needs to operate.

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And so really, that is one of the major barriers to taking this basic science discovery and really exploiting it as a tool for improving human health.

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Question: How do you foresee this molecular delivery barrier being overcome?

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Gregory Hannon: Well, I think that the way this barrier to delivery will be overcome is chemistry.  So, it’s clear that we’ve pushed the biology of RNAI as a silencing tool sufficiently far that, given an inability to deliver this, we could shut off any gene that we wanted to and in fact, we could probably dial the activity of these inhibitors to the point that we could even figure out exactly how far down we have to turn a gene.  Maybe you don’t want to shut it off because maybe it’s essential.  Maybe you want to inhibit its activity 50% or 80%, and the tools **** in the biology is sufficient that we can achieve that with the tools that we have. 

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I think we will see advances in delivery come from is in changing the chemistry of the small RNA itself sufficiently that it can pass through cell membranes without the aid of a specific delivery agent.  Delivery agents are the other arm of research into RNAI delivery encapsulating RNAs and lipids and polymers, and that’s another strategy for getting small RNAs into cells. 

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But my own feeling is that the unformulated molecules probably have the best potential to be a future therapy, the simpler formulation in something where you’re mixing an RNA agent and a series, for example, of polymers, to try to get them across the cell.

Recorded on February 9, 2010

Interviewed by Austin Allen

The use of RNA interference (RNAi) as a gene manipulation tool may revolutionize cancer treatment. What barriers must be overcome before it produces new therapies?

Scientists discover how to trap mysterious dark matter

A new method promises to capture an elusive dark world particle.

Surprising Science
  • Scientists working on the Large Hadron Collider (LHC) devised a method for trapping dark matter particles.
  • Dark matter is estimated to take up 26.8% of all matter in the Universe.
  • The researchers will be able to try their approach in 2021, when the LHC goes back online.
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Yale scientists restore brain function to 32 clinically dead pigs

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.
Surprising Science
  • Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
  • They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
  • 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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