Academic Section 

The liver is one of the main organs of the body with numerous functions related to both  detoxification and secretion. When it becomes defective there are many possibilities for disease which are well documented in various web sites. http://cpmcnet.columbia.edu/dept/gi/disliv.html offers a starting point for the curious reader. Here we are only interested in dealing with those diseases and academic issues that relate to the work of Professor Habib and his colleagues.

As pointed out elsewhere in this web site cirrhosis, liver cancer and Hepatitis C are the main  target diseases. It is to the alleviation of these conditions that  Professor Habib wishes to deploy the full might of contemporary technology.        

In relation to cirrhosis aside from the possibility of transplantation, in which Professor Habib is interested but not presently active, the aim has been threefold.

• firstly, to attempt to alleviate portal hypertension by installation of an inline pump the better to impel blood through the cirrhosed organ.
• secondly, to attempt to provide hepatic stem cells in order to encourage more normal repair of the liver.
• thirdly, to provide by genetic engineering some of the secreted factors that the cirrhosed liver is producing in inadequate amounts. 

Liver Assist Device

Those working with the ailing heart have had considerable success working with assist devices consisting of accessory electric pumps  that provide supplementary pumping capacity. These devices have been termed Left Ventricular Assist Devices and they were initially intended as a bridge to heart transplantation. The outcome of the use of these pumps has been in many instances not only to fulfil the original intention but, surprisingly, to provide such relief to the ailing heart that transplantation in some instances has not been necessary.

There seems little reason why comparable technology should not be applied to blood flow through the cirrhosed liver. There are many problems most of which have been solved in principle. These in summary are as follows, not in order of importance,

• to invent a pumping device that will fit in the hepatic portal vein, the dimensions need to be seven millimetres in diameter and about thirty mm long.
• to design an impeller that is appropriate for an appropriate flow rate of blood without  destruction of cells passing through it.
• to provide a power source for the pump  (in time internal and rechargeable percutaneously, i.e. through the intact skin).
• to install monitors (microchips) of pump function the readout from which can be acquired telemetrically with, preferably, additional chips to provide information on liver function.
• to ensure that all devices can be installed without major surgery
• to  implant only materials that are biocompatible.

These problems have all been solved to the point where pilot pumps have been installed in pigs and shown to function well for short periods of time. At the moment the project is stalled due to  illness  and death among the participant teams but it is a viable possibility and as soon as the necessary funding can be obtained along with those willing and able to drive the project further it will regain momentum.

Liver Stem Cell Replacement

It is not known with any certainty why the liver faced with sustained destruction of its constituent cells eventually fails accurately to effect repair to restore the status quo. The cirrhosed condition is complex and not a simple reduction (or increase) of mass. It is often thought of as showing scarring comparable with that which can be seen on the skin following damage. In a sense this is correct in that there can  be seen a distortion of architecture, fibrosis and alteration of the pattern and effectiveness of blood flow. The liver is not unique in its response to chronic injury and it could be argued that all the major body organs can show comparable apparently irreparable degeneration in response to prolonged stress. The condition of the lung in patients with Chronic Obstructive Pulmonary Disease (chronic bronchitis) exemplifies this; the stress in this instance is usually inhalation of tobacco smoke.

It is argued by Professor Habib that part of the failure of the liver to regenerate to normal and instead to become fibrosed and relatively non-functional is due to a deficit of liver stem cells. It has been known for some time from studies of haematopoietic chimaeras that at least the Kuppfer cells in the liver are sometimes if not always replaceable from an haematogenous precursor . More recently it has been demonstrated that hepatocytes, the cells that characterise the liver, can similarly be replaced (Lagasse et al, Nat. Med.6, 1229-1234). The contemporary view of these replacements would be that cells from the bone marrow having pluripotent stem cell capacity are responsible.

Against such a background argument it is possible to argue that the liver contains stem cells and that these can  be replaced in times of deficiency from cells in peripheral blood. Professor Habib, acting on this argument, has attempted with considerable success to identify the relevant cells in the liver and to culture them in vitro.

What is presently not known is how often and under what circumstances the stem cells for the liver are replaced and whether if liver stem cells are to be used therapeutically what are the optimal conditions for their deployment. There is no doubt however that if quantitative or qualitative deficiencies in liver stem cells are underlying the cirrhosed condition the approach of using injected stem cells has much to recommend it and indeed the first patients have already been treated. It remains to be seen what is the outcome.

Replacement of liver products by genetic engineering.

Of the various liver products that can be in short supply when the liver is cirrhosed, those of prime interest here are albumin and thrombopoietin. The former protein is if vital importance in maintaining fluid balance in the body and the latter is one of the important factors in maintaining platelet levels.

Albumin deficiency needs to be dealt with clinically and to do so by simple administration of the protein is very expensive in addition to requiring frequent patient attendance for treatment. In principle it should be possible to introduce the genetic information that codes for the production of the albumin in such a way as to provide a more long lasting palliation. The general difficulties are those of providing genetic material that is safe in that there are no unforeseen adverse consequence, and getting sufficient functional genes acting as required, often over long periods of time. This latter issue is particularly relevant in relation to albumin as the protein is present in very large quantities in the body and so far it has not proved easy with genetic engineering to obtain adequate yields of the desired product.

Professor Habib is in the process of exploring a variety of strategies designed to optimise the production of albumin. To date the problem is one of quantity not quality of product and further research is focussed on this issue.

As far as thrombopoietin is concerned the genetic material for its production is available and has been deployed in a number of experimental models. It has been found that gene therapy can be used prophylactically to prevent thrombocytopenia following the use of such cytotoxic anti-cancer agents as carboplatin.  This work is in its initial stages but is likely to be applicable clinically quite soon with patients suffering from viral hepatitis. The genetic constructs that are being adopted seem to have no toxicity and offer a relatively simple means of encouraging platelet production. Recently it was shown by Professor Habib and his colleagues, using a modification of a method called hydrodynamic therapy, that the thrombopoietin gene could be delivered in effective amounts in mice, pigs and humans. The problem now seems to be one of sustaining production by the delivered genes rather than  getting them to the production sites in effective amounts.

The fight against  viral Hepatitis C

Hepatitis C is caused by an RNA virus that is known in six different forms, (different rather like strains of hens or dogs differ) with an enormous number of described variants. It has only relatively recently been discovered and we are presently very short of information about the viruses concerned and how they interact with different kinds of humans.

The aim here will be to adopt the supposition that there is an interaction between the HepC viruses and their human hosts  which can  be thought of as an immunological reaction. This is a concept that is familiar to most people in the developed countries in that they will have been immunised against a variety of organisms that cause childhood diseases. Equally those who have travelled abroad, particularly to tropical countries will have been vaccinated against various organisms that offer threats in the countries they want to visit. The assumption is that vaccination affords protection from infection which may be true in the sense that infection itself is defined as invasion leading to harm. Most vaccinations are undertaken prophylactically, i.e. before encounter with the potentially harmful invader.

Unfortunately so far it has not been possible to find a vaccine that will  effectively prevent infection by HepC. This does not preclude the possibility that there will be found a suitable vaccine and many attempts are presently being made so to do.

Out strategy is three fold, all in various ways aiming at altering the host/virus immunological reaction to favour the host more than is presently the case.

• we are attempting to derive new methods of vaccination that given therapeutically, i.e. after the initial infection has occurred alter the capacity of the host to respond to the HepC virus
• we are exploring various chemical agents that are detrimental to the virus in the hope that if its numbers can be reduced the immune response will be more effective
• we are trying to use such natural antiviral agents as interferon again with the intent of affecting the host/virus immunological balance. 

HepC is particularly difficult to attack largely because it often invades the human body with no signs or symptoms for many years that betoken its presence. During the latent phase many changes can have taken place that make subsequent attack when the invasion is discovered a very complex problem. Professor Habib believes nevertheless that it should in the relatively near future be possible to propose effective strategies of control of the virus that will make it less of a hazard than it is at the moment. With some three hundred million people infected world wide HepC despite the fact that there are some moderately effective albeit expensive chemical treatments is a major threat to humanity.