Prime Time Replay:
Dr. George Michalopoulos
on Tissue Regeneration
MsgId: *breakthrough(7)
Date: Wed Jun 25 21:00:54 EDT 1997
From: moderator At: 152.163.194.163
Hello, and good evening. This is Madeleine Lebwohl, moderator for Breakthrough Medicine. Tonight I'll be speaking with Dr. George Michalopoulos, chairman of Pathology at the University of Pittsburgh. Dr. Michalopoulos has done extensive research on tissue regeneration in the liver, and will discuss the complex biological processes behind this intriguing phenomenon. Welcome, Dr. Michalopoulos!
MsgId: *breakthrough(9)
Date: Wed Jun 25 21:05:59 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
Hello! I am looking forward to tonight's discussion on liver regeneration, tissue remodelling and tissue engineering issues.
MsgId: *breakthrough(10)
Date: Wed Jun 25 21:08:13 EDT 1997
From: moderator At: 152.163.194.163
Tissue regeneration is a seductive idea: regrowth of what we've lost. The liver seems to have no problem with regeneration. Why can't other systems do the same?
MsgId: *breakthrough(11)
Date: Wed Jun 25 21:10:36 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
The truth is that many other tissues regenerate besides liver, although liver seems to have the largest regenerative capacity. Many scientists are studying regeneration of kidney, lung, skin and even brain tissue.
MsgId: *breakthrough(12)
Date: Wed Jun 25 21:12:20 EDT 1997
From: moderator At: 152.163.194.163
When you cut off part of your liver, it grows back. It seems that when you lose part of your lung, you don't get the same effect. What's the difference?
MsgId: *breakthrough(13)
Date: Wed Jun 25 21:14:17 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
Experiments with rats and clinical studies with humans have shown that after lung resection, the remaining lung tissue expands to fill the rest of the chest cavity. Obe remaining lung often expoans to 1.5X size. This is done by expanding existing anatomic units, in other words we don't get new bronchi etc, but rather expanded alveolar (small anatomic unit) spaces.In kidneys, removal of one kidney is associated with dramatic anlargement of the kidney of the other side. With brain, though we do not have restoration of anatomic ctructures, we have for the last 5 years discovered several growth factors that control growth of individual cell types in the central nervous system.
MsgId: *breakthrough(15)
Date: Wed Jun 25 21:19:45 EDT 1997
From: moderator At: 152.163.194.163
Cell regeneration seems to stop short when it comes to nerve cells in the spine. Why can numerous systems have some regeneration, but not the spine?
MsgId: *breakthrough(16)
Date: Wed Jun 25 21:22:51 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
There are two issues with regeneration of tissues in the spine. One is the replacement of the cell body of the neuron. The other is the establishment of correct fibre connections so that the pathways of nervous conductance become properly restores. We do not have any solutions for either of these two problems in the human. On the other hand, we only learned in the last two to three years what are the growth factors (or some of them) that control growth of neurons. To everybody's surprise, one of the neuron growth factors was the same as the one involved in liver regeneration (called Hepatocyte Growth Factor, HGF).
MsgId: *breakthrough(17)
Date: Wed Jun 25 21:24:40 EDT 1997
From: moderator At: 152.163.194.163
What would be the evolutionary reason that cells in the liver can establish connections between each other, but nerve cells can't?
MsgId: *breakthrough(18)
Date: Wed Jun 25 21:26:15 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
Establishing "connections" in the liver is not very important. The only thing that the body cares is that the liver mass is restored. On the other hand in the brain, the whole essense of the function depends on the right cell to cell connections. This is not the case for the liver.Liver is the first organ that sees toxic substances in the food once they become absorbed. This often causes liver toxicity, much more often than the brain. The "evolutionary mechanism" designed to cope for taht was regeneration. For the brain however, since the "toxicity" issues are rare, the evolutionary solution was to encase the whole nervous system inside protective bone structures, such as skull and spine.
MsgId: *breakthrough(20)
Date: Wed Jun 25 21:30:49 EDT 1997
From: moderator At: 152.163.194.163
In reptiles, they can regrow limbs. What is preventing in humans, on a cellular level, when the bulk of the liver can be regrown?
MsgId: *breakthrough(21)
Date: Wed Jun 25 21:32:44 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
The capacity to regenerate limbs is extensive in amphibia (slalamanders, frogs etc.) and limited in reptiles. It is non-existent in mammals and birds. We do not undertand the mechanisms for that discrepancy. We have designed culture systems that these elements can be grown together or separately. The association of the different cell types into tissue is what we are studying. We have found that the whole association depends on growth factors and tissue matrix proteins.The elements that compose liver tissue are the functional cells (hepatocytes) and the supportive cells (blood vessels, connective tissue cells, etc.) Each of these cell types can now be gropwn in pure cultures separately. The difficulty is to make them associate in a meaningful way in culture so that tissue of the liver can be restructured.
MsgId: *breakthrough(25)
Date: Wed Jun 25 21:40:46 EDT 1997
From: moderator At: 152.163.194.163
Is this a universal kind of growth factor that when isolated can be used in other systems? Or is it only limited to the liver?
MsgId: *breakthrough(26)
Date: Wed Jun 25 21:43:33 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
In fact, there are no specific growth factors that work only in one tissue, with the exception of the growth factors of the central nervous system. The same growth factors appear to control regeneration of liver, kidney, lung, skin, etc. What differs is the relative importance of each growth factor for each tissue and the time in regeneration in which they appear to play a role. For example, Epidermal Growth Factor (EGF) and the other members of that family (including TGFa, cripto , amphiregulin, an others ) appear to play a role in most tissue regeneration systems.The Hepatocyte Growth Factor (HGF) appears to stimulate growth in many cells types besides hepatocytes, including skin, kidney cells, bile duct cells, breast cells, and even neurons of the spinal cord.
MsgId: *breakthrough(28)
Date: Wed Jun 25 21:46:08 EDT 1997
From: moderator At: 152.163.194.163
Are these factors being developed into therapeutic applications?
MsgId: *breakthrough(29)
Date: Wed Jun 25 21:47:55 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
In fact, there are many clinical trials going on in many institutions testing growth factors for therapeutic efficacy. There are studies of the effects of TGFbeta in retinal detachment, because TGFbeta stimulates scar formation. Other studies are looking into blood growth factors after treatment of leukemias or aplastic anemias.With liver, the most dramatic condition is known as "fulminant hepatitis". The whole liver is rapidly detroyed as a result of a serious toxic injury or viral infectin, etc. It is a rather rare condition. Growth factors relevant to liver are very high in the blood in that condition, but we do not know if they are active. Studies are beng conducted to find this and to perhaps provide ways to activate the existing growth factors.
The most effective treatment at this point for fulminant hepatitis (massive liver failure) is liver transplantation. This is however very costly and there is a shortage in organ supply. Tissue engineering in the future may be of use to alleviate this shortage.
I should not forget to mention that one of the most useful aspects of tissue engineering is to introduce genes into the cells to correct genetic defects.
MsgId: *breakthrough(33)
Date: Wed Jun 25 21:54:49 EDT 1997
From: moderator At: 152.163.194.163
Are there any clinical trials using gene therapy regarding liver disease?
MsgId: *breakthrough(34)
Date: Wed Jun 25 21:56:49 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
There are several trials involving liver. In some systems, liver cells are grown outside the body and are treated with gene vectors and then reinserted back into the patient. In other systems, gene vectors are inttroduced into the body so that they can "home in" to the liver. In other trials, just normal liver cells are infused so that these cells can function instead of a whole liver transplant to correct genetic defects.
MsgId: *breakthrough(35)
Date: Wed Jun 25 21:58:08 EDT 1997
From: moderator At: 152.163.194.163
How soon could someone expect to benefit from gene therapy?
MsgId: *breakthrough(36)
Date: Wed Jun 25 21:59:32 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
We are looking into some forms of established gene therapy to be of use within the next decade. Ironically, the first applications might come not so much for tratment of genetic defects, but for treatment of cancer. Genetic vectors are being designed that can only grow in cancer cells and kill them selectively.
MsgId: *breakthrough(37)
Date: Wed Jun 25 22:00:48 EDT 1997
From: moderator At: 152.163.194.163
Will there be any immediate gene therapy applications for liver disease?
MsgId: *breakthrough(38)
Date: Wed Jun 25 22:02:35 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
There are no immediate therapeutic applications for gene therapy in liver disease, specifically. On the other hand, we do now understand most of the enzymatic defects that cause familial types of liver (and other) diseases. Once we can overcome the limitations of gene therapy, anything applicable to any tissue can also be aplied to the liver.
MsgId: *breakthrough(39)
Date: Wed Jun 25 22:03:37 EDT 1997
From: moderator At: 152.163.194.163
Do you see hepatocyte growth factor being used in the near future to help brain regeneration?
MsgId: *breakthrough(40)
Date: Wed Jun 25 22:05:05 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
There was an article in a recent issue of the journal "Neuron" which showed that HGF is the most important growth factor for neurons of the spinal cord. Based on that paper I would expect that HGF would have a serious role to play in future therapeutic schemes involving resoration of spinal cord motor neurons.
MsgId: *breakthrough(41)
Date: Wed Jun 25 22:07:04 EDT 1997
From: moderator At: 152.163.194.163
Will the work on hepatocyte growth factor usher in a new era, where tissue regeneration can be something we can all expect?
MsgId: *breakthrough(42)
Date: Wed Jun 25 22:09:00 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
Hepatocyte Growth Factor is one of many growth factors that are very interesting. It is likely that any future theraputic schemes on tissue restoration will involve some or many growth factors. The interesting aspect of HGF is that it is the only one that seems to have a unique receptor that it does not share with other growth factors. Thus it is more likely to have specific therapeutic effects in responding tissues.
MsgId: *breakthrough(43)
Date: Wed Jun 25 22:12:15 EDT 1997
From: moderator At: 152.163.194.163
So are you saying that many growth factors work together, and to get reliable tissue regeneration on demand, many factors have to be identified, and their relationships worked out?
MsgId: *breakthrough(44)
Date: Wed Jun 25 22:13:51 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
This "ecumenical" message is indeed correct. The growth factors are expressed in cascades of events where one growth factor and then another come out in sequence to turn growth fis=rst of the functional elements and then of the supportive connective tissue elements, so that the tissue can be properly built with all its cellular elements in place.
MsgId: *breakthrough(45)
Date: Wed Jun 25 22:15:28 EDT 1997
From: moderator At: 152.163.194.163
Do you see this 'cascade of events' being fully understood in the near future?
MsgId: *breakthrough(46)
Date: Wed Jun 25 22:16:40 EDT 1997
From: Dr_George_Michalopoulos At: 136.142.150.25
Very likely by the end of the decade we should have such an understanding for liver and some other "easy" tissues, with perhaps the brain to be the most difficult frontier for the future.
MsgId: *breakthrough(47)
Date: Wed Jun 25 22:17:51 EDT 1997
From: moderator At: 152.163.194.163
Thank you so much, Dr. Michalopoulos, for joining me on Breakthrough Medicine.
MsgId: *breakthrough(48)
Date: Wed Jun 25 22:18:29 EDT 1997
From: gkm At: 136.142.150.25
Thank you and the audience for engaging in this lively conversation.
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