Well, while we are on the subject of transgenics, the current news byte seems to be right on target. The latest in transgenic technology also represents a break-through in the development of animal models for testing of viral diseases. Scientists at the Salk institute in La Jola have managed to develop a mouse that has a human liver. This research was carried out principally by Dr. Inder Verma.What this means is, that the animal now sports a liver that is made up almost entirely of human hepatocytes. This will make it easier to use this mouse as a model to study human viruses affecting the liver such as Hepatitis B and C.

THe Humanised Mouse !

THe Humanised Mouse !

The problem with viruses is their host specificity. What this simply means is, viruses attacking a human being will generally have no effect on a mouse and vice versa. While this is good as the non- human viruses will not spread rapidly and infect humans, it does present substantial problems to scientists trying to study the pathology of human viruses and developing vaccines and drugs for the same. Since one cannot test therapies directly on human beings, a viable alternative needs to be provided. In the past, we have experimented with using in vitro cell cultures; liver cells grown in a Petri dish. However, this model has severe limitations due to the lack of proper organ structure and complete absence of the kind of interactions between cells and organs seen in a complete organism. Alternatives to this were to use animals such as mice that completely lacked a viable immune system (nude mice) for studying tumors of human origin. The tumors would be transplanted into these mice and their effects and probable curative measure would be studied.

However, this model has its side effects too. As Dr. Inder says, clinically speaking, a tumor does not start by acquiring millions of tumor cells from outside the system. It starts with one or two or ten cells that have lost control of their cell division cycle and hence keep on multiplying uncontrollably to give rise to a tumor. So, to that extent, transplanting a tumor into a mouse is really a fundamentally different process and may not yield real-time data as needed. However, with this new model where the mouse liver cells are literally taken over by human liver cells (Hepatocytes) so that they overgrow to give a liver that is almost entirely human, we will be able to study the actual process of tumorigenesis or viral infections along with the possible cures and vaccination methods.

This physiological change was confirmed when these ‘humanised’ mice were subjected to challenge with the Hepatitis B and C viruses. The normally resistant mice developed the infection clinically. As we have already discussed, the initial resistance to these viruses was due to the host specificity of the viruses. The receptors required by the HBV or HCV were not to be found in the mouse liver and hence the immunity. Now, however, with a human liver, these mice became susceptible to the infection just like their human counterparts.

Dr. Inder Verma: Salk Institute

Dr. Inder Verma: Salk Institute

What was even better, the current first line of treatment for Hepatitis C worked just as well as it does with the human liver. This treatment consists of using Pegylated Interferon. What is Pegylated interferon? Well, interferon is a natural protein produced by our bodies in response to a viral infection. It works by inducing resistance to the infecting virus in the cells surrounding a virally infected cell in the body. It is therefore like a chemical signal sent out by a cell that has already been infected to the other healthy cells to raise their defences. Now, this natural interferon molecule was coupled with the chemical Polyethylene Glycol via a process called Pegylation (Technical definition of the process1: PEGylation is the technique that involves the modification of a protein, peptide or nonpeptide molecule (drug) by covalent attachment of one or more PEG molecules for the purpose of enhancing therapeutic value. Advanced PEGylation10 involves attaching specific, modified polyethylene glycol (PEG) polymers to biomolecules) to yield what is known as Pegylated Interferon. The commercially available molecule is Pegasys (Pegylated Interferon Alpha 2a). The mode of action of this drug is as yet unclear. It is thought to bind to specific cell-surface receptors, suppressing cell proliferation and viral replication. It has also been observed to increase the effector protein levels and to reduce white blood cell (WBC) and platelet counts.

PEGylation is necessary for the reasons such as increasing the solubility, stability, circulation half-life, for minimizing the rapid kidney clearance, for achieving the controlled release, etc. Advanced PEGylation overcomes the drawbacks of the earlier technology. Four types of bioconjugates of PEG comprise conjugation with peptides and proteins, with lipids, with low molecular weight drugs and with biological macromolecules. PEGylation is widely applied in various fields viz. medical, diagnostic, synthesis of peptides and carrying out some organic synthetic reactions.1

The applications of this chimeric mouse are tremendous and it will boost research and investigations into viral disease, vaccination and cure. This study has been published on February 22 in the Journal of Clinical Investigation. Dr Inder M. Verma is a Professor, Irwin and Joan Jacobs Chair in Exemplary Life Science,  Laboratory of Genetics, at the Salk Intstitute. For a detailed profile please click here.

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1. www.kppub.com