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Genome Sequencing, Gene Therapy, and Genetics Counseling

On November 13, 2004, a group of fortunate AMWA-MAC members met at the Hall of the States near Union Station in Washington, DC, to attend presentations by three speakers described as "esteemed and engaging experts" from different fields in genetics. They definitely lived up to the advance billing.

Robert Nussbaum, MD (http://www.genome.gov/10000360), is the president of the American Society of Human Genetics, chief of the Genetic Disease Research Branch of the National Institutes of Health's National Human Genome Research Institute (NHGRI), acting chief of the NHGRI's Inherited Disease Research Branch, and head of its Inborn Errors and Cell Biology Section. As one of the other speakers (Barbara Bowles Biesecker) said during her own presentation, Dr Nussbaum is "an artist at making complex scientific information easy to understand."

By way of background, Dr Nussbaum led the audience through a brief version of Genetics 101—an information-dense review of the basic rules of heredity, their historical development, and the structure of the genome.

One particularly effective series of slides (there were many) showed part of the Gettysburg Address embedded in a continuous mass of apparently random letters. When Lincoln's words were highlighted, it was easy to pick them out of the background "noise" and identify the famous speech, but in the unhighlighted version, it was virtually impossible to glean any content from the letters on the screen. Similarly, in the genome, sections of coding information (exons) are embedded in a lot of other genetic information that needs to be spliced out (introns). Dr Nussbaum explained that only a small fraction of the DNA coding ends up in the messenger RNA (mRNA); the introns have to be removed so that what is left can be read in a "1:1 linear manner" to make proteins.

Dr Nussbaum emphasized that mutations (changes in DNA sequence) "can affect any and all steps in the process of gene expression." "Murphy's Law really does apply." He said we should think of the degree of effect of mutations as a full spectrum, ranging from "highly deleterious" (lethal) to "innocuous" (neutral).

In genome research, "making sense of sequence" is accomplished by comparison to known sequences. In Dr Nussbaum's words, the researchers "can infer genotype based on homology to previously analyzed genes of known function in related organisms." Using the enzyme enolase as an example, Dr Nussbaum showed how certain areas of the gene are highly conserved (with hardly any difference between yeast and higher species, indicating little change over perhaps a billion years of evolution) and how others are far less conserved (enolase genes from different species show clear differences in these regions). In another striking graphic sequence, we saw how the highly conserved areas of the gene were those that coded for the active site pocket of the enzyme product. (Picture the symbols morphing from one slide to the next, retaining color so you can see the relationships.) Dr Nussbaum also showed us that the amino acid sequence of the enolase itself is far more highly conserved than the DNA sequence that codes for it. This is because genetic code is redundant. Although there are only 20 amino acids, there are 64 codons (the three bases that serve as the words of our genetic code and are in turn made from combinations of the four bases that constitute our genetic alphabet).

Many people have heard that sequencing of the human genome is complete, so they don't understand why researchers are spending tax dollars analyzing sequences of other species, especially those to which we are not closely related. Dr Nussbaum explained that although geneticists now know how to read the human exons, the challenge is figuring out how to read the remaining DNA—including introns (genetic material between the coding regions [exons]) and sequences in the 80% of the chromosomal DNA that is not contained within genes. In order to do this, researchers need to compare human genome sequences to sequences from species that allow them to identify the function signal we get from noncoding regions of the genome. The optimal species for comparison would be neither too similar nor too dissimilar, and marsupials seem to be the best candidates. (For more information on why, go to www.genome.gov and search on "marsupial.")

Picking up where Dr Nussbaum left off, Jennifer Puck, MD (http://www.genome.gov/10000786), talked about gene therapy for immunogenetic disorders. Dr Puck is chief of the NHGRI Genetics and Molecular Biology Branch and head of the Immunogenic Genetics Section. She is also an editor of the authoritative text Primary Immunodeficiency Diseases, A Molecular and Genetic Approach, published by Oxford University Press. Dr Puck's clinical group conducts gene therapy for patients with x-linked severe combined immunodeficiency (XSCID) and still cares for the first American gene therapy patients.

Children born with the genetic defect that causes XSCID suffer a "profound lack" of T- and B-cell immunity and will die in infancy unless their condition is diagnosed and normal immune function is restored. Although XSCID has long been treated by bone marrow transplantation, problems with imperfect HLA matches "opened the door" for gene therapy. XCID is a particularly good candidate disease for a number of reasons: (1) hematopoietic stem cells can be removed, treated, and reinfused, (2) the XSCID gene product is expressed in all blood lineages, (3) because of the immune deficiency, there is no immune elimination of corrected cells, and (4) the corrected lymphocytes have a selective advantage that allows small numbers of infused cells to proliferate and correct the immune deficit.

Dr Puck's group and a group of French investigators (Cavazzana-Calvo M et al., Science, April 28, 2000) have used gene therapy to treat children with gene therapy successfully. In the United States, the therapy is reserved for children who have failed standard treatment (bone marrow transplantation). Two patients have now been treated and results have been excellent. In France, where children have been offered gene therapy at an earlier age, 2 who received it before the age of 6 months developed leukemia 27 to 30 months later, apparently because the gene was inserted (by the retrovirus) at a spot that was harmful, presumably in a regulatory region for an oncogene. Dr Puck said that no other children in either study group have developed leukemia and that current thinking is to offer gene therapy only to children older than 6 months.

The final presentation was by Barbara Bowles Biesecker, MS (http://www.genome.gov/10001536), a genetic counselor who is head of the NHGRI Genetics Services Research Unit and director of the Johns Hopkins University/NHGRI Genetic Counseling Training Program. Ms Bowles Biesecker spoke about genetic counseling�what it is and what it isn't�and cleared up a number of misconceptions about what genetic counselors do. Above all, she emphasized the importance of the relationship between a genetic counselor and individual clients. Clients may be seeking to use and understand genetic information for any of many reasons, but the relationship is paramount.

Ms Bowles Biesecker stressed that genetic counseling is not a statistical risk service or an attempt to persuade clients into specific reproductive choices, cautioning that genetic counselors must be careful not to strip people of a sense of control. She offered a current definition of genetic counseling as "a psychoeducational process centered on genetic information," which involves "helping clients personalize technical and probabilistic information, promote self-determination, and enhance their adaptation over time."

In addition to being a resource for helping clients make choices about genetic testing, a genetic counselor can serve clients by just validating their concerns about a condition or risk, helping them understand how others have adapted, providing access to support resources, and simply helping them feel there is somewhere to turn.

People who want to consult a genetic counselor can find helpful information at www.nsgc.org. The American Board of Genetic Counseling website is also a useful resource: www.abgc.net/genetics/abgc/abgcmenu.shtml.

If you would like to know more about genetics, you can explore the National Human Genome Research Institute online at http://www.genome.gov. Its educational resources (http://www.genome.gov/education/) include the multimedia talking glossary, featuring comments from leading experts; the online version of the booklet From Blueprint to You; and "Exploring Our Molecular Selves," an online multimedia educational kit.

Anne Stanford
Stanford Scientific Communications
Scottsville, Virginia