Prime Time Replay:
Dr. Gene Block
on the Human Biological Clock
MsgId: *breakthrough(5)
Date: Wed May 7 19:21:01 PDT 1997
From: moderator At: 206.80.164.8
Welcome to Breakthrough Medicine. I'm Madeleine Lebwohl, and tonight I'll be speaking with Dr. Gene Block, director of the National Science Foundation Center for Biological Timing at the University of Virginia, Charlottesville.
MsgId: *breakthrough(6)
Date: Wed May 7 19:22:44 PDT 1997
From: Gene_Block At: 128.143.208.112
Hello, this is Gene Block -- I am glad to be here. Looking forward to answering some questions this evening.
MsgId: *breakthrough(8)
Date: Wed May 7 19:30:57 PDT 1997
From: moderator At: 206.80.164.8
Dr. Block, let's begin by talking about the work your lab is doing on biological clocks. I understand you're working on clocks in both mammals and snails. What are the similarities -- and differences -- you're finding?
MsgId: *breakthrough(9)
Date: Wed May 7 19:34:24 PDT 1997
From: Gene_Block At: 128.143.208.112
We are very fortunate in that nervous systems are very conservative. The properties of inidividual neurons in both mammals and snails are similar. Thus, what we learn about the snail has great generality for mammals, including humans. The advantage of the snail is that the neurons are larger and therefore easier to study.While the biological clock in the snail is located within the retina, and the biological clock in the mammal (rodent) is located in the brain (within the hypothalamus), in both cases it appears that invididual neurons are responsible for generating the circadian rhythm -- that is, the biological clock property is contained within the cell and is not a property of cell circuits within the brain or retina. Thus, since neurons are a very conservative part of the nervous system and the biological clock is within the neuron, there is great similarity between the biological clock of rodents and snails.
We are not certain that there are going to be very many differences between snails and mammal biological clocks. The mammalian brain contains many more cells and the region of the hypothalamus containing the biological clock contains thousands rather than the hundreds of cells in the snail retina -- nonetheless, the underlying mechanisms of the clock appear very similar.
MsgId: *breakthrough(12)
Date: Wed May 7 19:45:04 PDT 1997
From: moderator At: 206.80.164.8
How do you account for this similarity? Do the basic needs of these species mirror each other?
MsgId: *breakthrough(13)
Date: Wed May 7 19:55:36 PDT 1997
From: Gene_Block At: 206.80.164.8
At a functional level, the requirements of both animals (rodents vs. marine snails) are very similar. Both are nocturnal, and must remain inactive during when they are at risk from predators. In each case the biological clock regulates the time at which they are active, producing a temporal niche that confers fitness on both species.
MsgId: *breakthrough(14)
Date: Wed May 7 19:58:34 PDT 1997
From: moderator At: 206.80.164.8
At this point perhaps we could talk about what a biological clock actually is: what's there, ticking along with the day or night?
MsgId: *breakthrough(15)
Date: Wed May 7 20:04:21 PDT 1997
From: Gene_Block At: 128.143.208.112
Only recently have investigators begun to "unwind" the biological clock. Studies on Drosophila and Neurospora, a bread mold, have been most revealing. Even in these cases, however, we do not know all of the components that are involved in consructing "the clock" Nonetheless, a picture is emerging that implicates protein synthesis and molecular transcription. It appears in both organisms that the clock involves a feedback loop in which a protein enters the acts to reduce the levels of its own transcript. This inhibiton occurs with substantial delay, leading to regular near 24 hour oscillations. How many proteins are involved is still an open question. In Drosophila to proteins and their genes have been identified -- the period protein and the timeless protein -- both act in concert in an autoregulatory feedback loop.
MsgId: *breakthrough(16)
Date: Wed May 7 20:08:21 PDT 1997
From: moderator At: 206.80.164.8
Are these proteins totally unique? Are they similar to any other cells--can you trace when organisms started needing clocks?
MsgId: *breakthrough(17)
Date: Wed May 7 20:12:34 PDT 1997
From: Gene_Block At: 128.143.208.112
The clock proteins that have been identified thus far are unique -- they do not precisely resemble other proteins that have been identified and the proteins for the Drosophila clock are not very similar to the protein identified for the Neurospora clock. We are just begining to understand the underlying biochemistry of these proteins and it is turning out to be an interesting story. Regions of the per protein, for example, appear specialized for dimerization with other proteins. This analysis has provided insights into how the per protein dimerizes with the timless protein which appears to be required for both to enter the nucleus and turn of their own transcription.I should add that clocks are very veery primitive, they show up in bacteria.
MsgId: *breakthrough(19)
Date: Wed May 7 20:16:40 PDT 1997
From: moderator At: 206.80.164.8
Are the oscillations -- the turning -- that you see also unique to biological clock proteins? Are there any theories about how this mechanism developed?
MsgId: *breakthrough(20)
Date: Wed May 7 20:23:23 PDT 1997
From: Gene_Block At: 128.143.208.112
I don't think there is much compelling speculation about how biological clocks originated. My suspicion is that before there were biological chronometers physiological processes were driven directly by the light/dark cycle. Perhaps the step from a driven rhythm (by the day/night cycle) to the self-sustained oscillator was not such a great jump. Certainly the rhythms driven by the daily solar cycle already had much of the cellular/molecular organization that was required. This is a most interesting question that, unfortunately, I cannot provide much insight to.
MsgId: *breakthrough(21)
Date: Wed May 7 20:28:53 PDT 1997
From: moderator At: 206.80.164.8
How does the human biological clock exactly follow the light cycle -- what is the cellular process going on?
MsgId: *breakthrough(22)
Date: Wed May 7 20:32:39 PDT 1997
From: Gene_Block At: 128.143.208.112
While we still don't know much about how the human clock is synchronized by light cycles we know quite a bit about how simpler clocks are synchronized. In the model that my laboratory studies, the snail retina, we have determined that light acts to depolarize the clock neurons. This decrease in membrane potential leads to calcium channels opening up and calcium entering the clock cells. The level of intracellular calcium increases and it is this change in intracellular calcium that leads to resetting the clock to -- in our case - - Eastern Standard Time.
MsgId: *breakthrough(23)
Date: Wed May 7 20:36:35 PDT 1997
From: moderator At: 206.80.164.8
Are any of these developments going to be helpful to people who have problems with shiftwork?
MsgId: *breakthrough(24)
Date: Wed May 7 20:39:59 PDT 1997
From: Gene_Block At: 128.143.208.112
I should mention that our Center is studying shift work in a heavy industry setting and these studies of factory performance, accidents, etc, should be of great use in predicting how best to perform shift work. On the basic research side, our work with a model clock, the retina, will be useful for understanding the action of pharmacological treatments which may be useful in helping individuals adapt to shift work. These models can be used to study the molecular and physiological mechanisms of possible treatments such as melatonin. We have the capability of understanding how different treatments affect the machinery of the biological clock.
MsgId: *breakthrough(25)
Date: Wed May 7 20:44:44 PDT 1997
From: moderator At: 206.80.164.8
How is your Center studying how genes affect the development of biological clocks?
MsgId: *breakthrough(26)
Date: Wed May 7 20:56:46 PDT 1997
From: Gene_Block At: 206.80.164.8
One of the most interesting applications of genetics the Center has employed is the production of a transgenic mouse, in which the firefly gene 'luciferase' has been inserted into the mouse's genome. Luciferase acts as a reporter gene and can indicate through the production of light, the activity of another gene under study. In our case, we have been studying genes controlled by the biological clock in the hypothalamus. In a brain slice of hypothalamic tissue we are able to measure specific genes turning on and turning off by measuring a rhythm in light production of the brain slice. The ability to dynamically measure the activity of genes provides new opportunities for understanding the molecular genetics of the biological clock.One of the most exciting future applications for the transgenic mouse model is to develop techniques to record light production in vivo, in behaving animals. This technique may allow us to observe genes controlling the biological clock, turning on and turning off as the animal goes through its daily activity cycle. This ability to watch the genes that are biological clock, turn on and turn off while the animal is behaving, should provide important insights into how the biological clock functions to control behavior and physiology.
In fact, it's quite remarkable that one can see the ears of the mouse glow dimly indicating the activity of this transgene.
MsgId: *breakthrough(29)
Date: Wed May 7 21:05:47 PDT 1997
From: moderator At: 206.80.164.8
Are reporter genes being used in any other context at your Center?
MsgId: *breakthrough(30)
Date: Wed May 7 21:08:40 PDT 1997
From: Gene_Block At: 206.80.164.8
The earliest use of reporter genes in our Center was by Dr. Steve Kay who used it to measure the activity of clock control genes in tobacco and in arabidopsis. More recently, Dr. Kay and Dr. Jeff Hall have combined forces to use luciferase as a reporter gene to measure the activity of the clock gene, 'period', in intact drosophila. The technology holds great promise for use in many systems and for the study of many problems in neurobiology.
MsgId: *breakthrough(31)
Date: Wed May 7 21:10:52 PDT 1997
From: moderator At: 206.80.164.8
Dr. Block, thank you for speaking with me on Breakthrough Medicine. The work on reporter genes sounds incredibly exciting!
MsgId: *breakthrough(32)
Date: Wed May 7 21:12:06 PDT 1997
From: Gene_Block At: 128.143.208.112
This was most enjoyable. Thank you for asking me to participate.
MsgId: *breakthrough(33)
Date: Wed May 7 21:14:30 PDT 1997
From: moderator At: 206.80.164.8
Great to have you! Good night!
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