August 15, 2010

Lance Becker on Modifying the Boundary Between Life and Death

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Lance Becker on Modifying the Boundary Between Life and Death

There is increasing evidence that the boundary between life and death is not a distinct cut-off, but rather is more flexible and modifiable than we have previously believed. If true, it may be possible to save tens of thousands of lives each year from premature death with novel therapies currently in development.

To develop these life saving therapies requires an understanding of the basic mechanisms of death. We understand relatively little about sudden death in humans and acute death in cells, and the physiological implications of cell death within a whole person remain unknown. A common pathway for sudden death is any condition that results in oxygen deprivation to tissues. Deprivation of oxygen, called ischemia, is the pathway for devastating conditions such as cardiac arrest, asphyxia, drowning, poisoning, severe blood loss, heart attack and stroke, among others. Conventional wisdom dictates that the best therapy for conditions of oxygen deprivation is to rapidly restore blood flow, delivering oxygen back to the body.. The restoration of oxygenated blood is called “reperfusion”. Rapid reperfusion is currently the universal treatment to these life-threatening emergencies.

But there is a problem with this approach: it does not work if the period of oxygen deprivation has been prolonged. Furthermore, the restoration of oxygen itself has been shown to cause tissue injury, a phenomenon known as “reperfusion injury”. Many scientists now believe that there is another approach which may restore life to those for whom our current methods of reperfusion and restoring oxygen are insufficient.

Over the last years we have developed some newer insights into the basic mechanism of cell death and the cause of reperfusion injury. It has been shown that many of these cellular pathways involve the mitochondria, the tiny organelle within our cells that is responsible for producing energy for the cell. A major breakthrough in our understanding has been that the mitochondrion also uniquely controls the initiation of cellular death, and it is the activation of this pathway upon reperfusion that results in reperfusion injury and cellular death. This control over cell death may be modifiable and more flexible that we currently believe. Understanding the hard wiring of the mitochondria, its ability to control the flow of electrons within our cells, and the chemical results of this activity are now within our grasp. If true, the implications on human therapies would be significant.

Our collective knowledge in this area suggests that a new combined approach to saving lives is required. We propose to simultaneously provide (a) artificial circulation plus (b) controlled reperfusion cocktails to victims of ischemia who currently do not survive all traditional methods of resuscitation. Studies using such an approach reveal that the brain can be restored to full function after a period of ischemia that is completely lethal to standard treatment. Studies to expand this approach to the resuscitation of whole animals and humans are now underway. There is reason for much optimism that we will soon have the ability to restore life to tens of thousands of premature deaths each year with these new approaches to resuscitation.

there seems to be intentional death of cells after they are deprived of oxygen for a long time but then have oxygen restored.

All study of intentional cell death leads to mitochondria.

mitochondria provides ATP (energy) but also seems to have a death switch.
Normally oxygen has an electron added to it in the mitochondria so that water can get formed.

When there is a lack of oxygen, there is buildup of electrons.

Cocktail of antioxidants, inhibit signalling cooling, turn it off.

Need a mitochondrial meter to know the state of the mitochondria.



Cooling can be used to reduce the time pressure in some surgery.
Cooling is time dependent.
New slurry generation devices can be used to reduce the temperature in minutes instead of 8 hours for 3 degrees of cooling.

Need to control the oxygen restoration.
Penn goal - emergency cardiopulmonary bypass plus controlled reperfusion.

re-establish safety before work.

Could allow people who are oxygen deprived for hours instead of four minutes. In pigs they have restored after 30 minutes.

It can also be used to solve the transplant shortage in 9 months with these techniques.

France bought 150 of the machines to solve the transplant problem.
Asia (Japan, Taiwan, South Korea...) are far ahead in this area. Tokyo has done hundreds. Lance Becker's team has done 6 people so far.

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