Eczema Update - July

Update on the Human Genome Project

The human genome has been sequenced to provide a "map" of the genetic makeup of humans. It is widely anticipated (and hoped) that the human genome map will allow investigators to identify the specific genes associated with diseases that have a genetic basis, in turn providing information to better understand those diseases and develop effective treatments.

Background

The sequencing of the human genome was conducted by a publicly funded group of laboratories under direction from the National Institutes of Health and a private venture led by Celera Genomics, a biotechnology firm. Results of the efforts and human genome "maps" were published in the American journal Science for February 16, 2001, and the British journal Nature for February 15, 2001. The maps are raw data which researchers in many disciplines will use for many purposes, including investigation of human diseases.

Some Surprising Findings

A surprise for the Human Genome Project investigators and many other scientists was the total number of, about 32,000, human genes reported by both the NIH and Celera groups. It was previously believed that humans carry about 100,000 genes. The current estimate of most investigators is that the final total of human genes after "dotting all the i’s and crossing all the t’s" will be between 32,000 and 40,000.

Some Implications of the Findings

The number of genes carried by a human is now known to be only about twice as many as the number of genes in the nematode C. elegans—a tiny, worm-like organism found in wet soil that is also a favorite organism for genetic studies. The entire genome of the C. elegans was sequenced earlier, providing scientists with one of the earliest models for gene sequencing.

The finding of a surprisingly small number of human genes supports studies in evolutionary genetics indicating that many genes carried by humans (1) developed early in evolution and, (2) were preserved and "recycled" through increasingly complex organisms up to and including humans. The conservation, recycling and adaptation of genes that were "road tested" for survival value over millions of years may have been a good evolutionary strategy as organisms became more complex. An analysis of protein families (proteins are a major product of genes) supports the concept that most human genes were conserved from a distant evolutionary past when there were no organisms more complex than bacteria, fungi and yeasts: of the 1,278 protein families specifically identified with human genes, only 94 are specific to vertebrates (animals with a backbone). [Baltimore D. Our genome unveiled. Nature 2001; 409:815-816.]

In complex organisms such as humans, genes may have single or multiple functions. Genes that seem to have a single function often work in concert with other genes to perform complex functions or a variety of functions. Gene researchers have observed, and reported, that human genes do a lot more work than the genes of simpler organisms—even though they may be genes carried over from more ancient organisms. When comparing gene sequences of about the same size that are found in humans, nematodes and fruit flies, the human genes shuffle the sequences into an amazing number of combinations to perform a great variety of functions that are not observed in the simpler organisms.

The genetic building blocks of humans and older, simpler organisms have great similarity, but the human genome produces structure of great complexity. Greater complexity creates the possibility for more error.

Before discussing genes, genetic defects and disease, some definitions are in order.

Incorrect and therefore confusing definitions of words and terms can make it difficult to understand what scientists are talking about. For example, it is technically incorrect to talk about "the gene for (a given disease)…". The more correct usage is to refer to "the gene defect (mutation) or variation that increases the odds for a given person to get (a disease)." In very few if any instances does a gene defect or multiple defects confer a 100% probability for getting the associated disease. The odds that disease will appear are influenced by inheritance patterns and other factors.

Gene Defects and Disease

Some genetically-based human diseases may be mapped to a defect or variation in a single gene. However, the single-gene disease may be a complex puzzle for investigators. For example, prior to the sequencing of the human genome investigators mapped cystic fibrosis to a gene in the terminal third of chromosome 7—a task that required seven years because neither a human genome map nor super-fast computers were then available. Cystic fibrosis is an example of the complexity of a single-gene disease.

Genes and Multifactorial Diseases

As complex as single-gene diseases may be, multifactorial diseases are even more complex. Many diseases with a genetic context are already known to involve multiple genes and gene mutations as well as environmental factors. Atopic dermatitis falls into this category.

So-called single-gene diseases are different from multifactorial diseases in very important ways:

• In single-gene diseases, mutation in a single gene is both necessary and sufficient to produce the disease. Whether or not one "gets" the disease depends heavily on inheritance patterns and other factors, but genetic risk for the disease can be assessed.
• In multifactorial (multiple gene plus environment) diseases such as atopic dermatitis, variations in a number of genes may produce a genetic predisposition for the physical, biochemical and physiologic make-up that may respond to environmental factors in such a way as to produce the disease. Gene mutation(s) are often not necessary or sufficient to explain the clinical response. A tendency for inheritance within families is observed but the inheritance patterns are not Mendelian (not in a pattern that can be readily assessed for risk). Environment is often observed to be a major contributor to onset of the disease. [McKusick VA. Mendelian Inheritance in Man. Baltimore: Johns Hopkins University Press, 12^th ed.; 1998].

A number of genes involved in atopy are already known or suspected, as discussed in more detail later.

In order to search the human genome map for genes involved in multifactorial diseases such as atopic dermatitis, investigators need a great deal of information that will give them clues as to where to begin.

• Animal models can provide important information if investigators can find an animal in which the disease can be reliably reproduced and/or genes can be "knocked out" to indicate the relative importance of gene function and products in producing the disease.
• Epidemiologic data can help to establish genetic patterns in large populations.

Investigations of atopic dermatitis have often been difficult because there is disagreement of the features of this syndrome, which is defined as a combination of clinical symptoms that occur together. There is no single outstanding feature and no precisely defining laboratory test. There has not been a reliable animal model. Epidemiologic studies have often lacked precision due to a lack of defining features for the disease—i.e., atopic dermatitis can have a clinical appearance similar to a number of other skin diseases.

In general, atopic dermatitis is recognized as a chronically relapsing skin disease that often is associated with a personal or family history of atopic dermatitis, allergic rhinitis and/or asthma, and confirmed by elevated level of serum (IgE) antibodies. Environmental factors are the key to the pre-disposed individual response to the condition, as well as the onset, chronicity and severity of the disease. It has even been suggested that atopic dermatitis is not a single disease but rather a number of conditions that have similar symptomatic expression.

Atopic dermatitis is known to have a genetic component, but as in all multifactorial diseases the pattern of inheritance is not clearly definable. Neither is it known with precision which genes and gene defects are involved in atopic dermatitis, but clinical and genetic studies have yielded a list of "most likely suspects." On the basis of numerous studies, candidate genes for involvement in atopy include those associated with antibody globulins, antibody receptor molecules, messenger molecules that mobilize immune cells, and molecules involved in inflammatory processes. [Leung D Y-M, Tharp M, et al. Atopic dermatitis (atopic eczema). In: Freedburg IM, Eisen AZ, Wolff K et al. (eds). Fitzpatrick’s Dermatology in General Medicine, 5^th ed. New York: McGraw-Hill; 1999:1464-1480].

Of interest, perhaps, is that all of the current candidate genes are part of the "adaptive immune system" of disease fighting cells (e.g., T cells) and immunity (e.g., antibodies). The so-called adaptive immune system is a late development in evolution. Its elegantly complex cellular and immune protection is not found in older organisms from which we inherited so much of our genome. The adaptive immune system may have evolved from the more ancient system known as "innate immune response," an inflammatory reaction that helps control infection in its earliest stages. In an evolutionary time scale, the human immune system may be regarded as a work in progress.

In Summary

The complete sequencing of the human genome is a tool of enormous importance in the investigation of human diseases. It will not, of itself, provide "answers" to advance understanding and treatment of complex, multifactorial diseases until investigators are able to approach the task with the right questions. But one can be optimistic. When the Human Genome Project was undertaken in the 1990s, it was anticipated that it would not be completed until 2003 or later. But with technological advances and a "can do" spirit, investigators finished the task at least two years earlier than the most optimistic previous predictions.