Amino Acid Gymnastics and the Evolution of Influenza Virus Resistance to Oseltamivir

In previous posts, I discussed, respectively, the use of selection to generate an antibody of potential value in treating influenza A virus infections (1) and the relevance of protein dynamics to the evolution of protein function (2).   A recent paper in Science (3) offers evidence suggesting that internal protein dynamics play a crucial role in shaping the evolution and spread of resistance to the influenza neuraminidase inhibitor, oseltamivir (Tamiflu®). (more…)

Therapeutic Selection

It has been roughly fifty years since the humoral immune response was first conceived of as a compelling example of evolution via selection of individual cells on a time scale that is short relative to standard organismal evolution (Talmage, 1957, Burnet, 1957; reviewed by Forsdyke, 1995).  Multiple lines of evidence supportive of this concept were forthcoming over the next fifteen years (briefly reviewed in Talmage, 1986).   Instead of individual organisms competing for multiple resources that facilitate reproduction through mating, B lymphocytes compete, through cell surface versions of the immunoglobulin molecules they will ultimately secrete, for binding to antigen molecules that with other inputs stimulate cellular proliferation.  The descendants of the B cells expressing the receptors best able to complex noncovalently with the antigens introduced into the body will tend to dominate the B lymphocyte population at subsequent times.  Thus, the B cell population evolves in a neo-Darwinian fashion, i.e. the clonal composition of the population changes over time.

Numerous methods have been developed to exploit similar processes in vitro for the purposes of research.  A previous post (http://evomed.org/?p=145) provided one example of such in vitro selection which was used for the purpose of producing an antibody able to bind to the hemaggluitinin molecules of multiple type A influenza virus subtypes.  An article that appeared in March of this year by Bostrom et al.(2009), at Genentech, describes a novel application of selection techniques to producing a an antibody capable of potential use as a therapeutic agent in cancer.  Elsewhere (Greenspan, 2009), I have explained why some of the claims made for the broader significance of this paper were over-stated, but my dissatisfaction with the paper on that score does not diminish my appreciation for the originality of the question addressed or for the impressive manner in which an array of sophisticated methods were deployed.

Herceptin® (trastuzumab) is an antibody with specificity for the human epidermal growth factor receptor 2 (HER2) that is used to treat patients whose tumor cells overexpress HER2. (more…)

The Dawn of Darwinian Psychopharmacology

We usually consider medicine as a predictive scientific endeavor, as methodical in application as noble in purpose.  But for some diseases, such as schizophrenia, the first treatments showing any effectiveness, including lithium, chlorpromazine, and even electroconvulsive therapy, were discovered entirely by accident.  After the discovery of the first antipsychotic treatments, a period of allegedly rational schizophrenia drug development ensued, focusing on drugs that block the brain dopamine receptor DRD2 that was considered, based on very limited evidence, as the critical lock for chemical antipsychotic keys.  Some of the drugs worked – more or less, with serious side effects.  Truly rational drug development, however, required understanding of the causal basis of disease, which for brain diseases like schizophrenia requires, to a considerable extent, understanding the dark inner workings of the brain itself.

But the causal basis of one relatively-simple brain disease, Fragile X syndrome, has, in the past few months, been deciphered – a true milestone in the touted medical march from brain to computer, lab bench to bedside. Afflicting about 1 in 3000 children, Fragile X is the most-common known cause of both intellectual disability and autism.  A series of studies, led by researchers including Gul Dölen and Mark Bear at MIT (Dölen and Bear 2008) and Randi Hagerman at UC Davis (Hagerman et al. 2009), has identified the core neuronal defect caused by mutation of the fragile X gene, and shown they can fix it – literally cure it (Figure 1) – in mice.  The fix involves (more…)