Inherited genetic disease is of tremendous importance in clinical medicine. Except as marked or noted in lecture, this is mastery-level material at the recall level.

You should be able to:

• define all the terms given in this handout
• list the modes of inheritance, molecular pathogenesis (when applicable), and distinctive clinical features of all the major genetic disorders
• use this knowledge to talk to patients or the families about these diseases

QUIZBANK

Developmental abnormalities (all);

Metabolic #'s 5-8, 25-41, 117

KEY IDEAS AND TERMS

* "An organism is the genes' way of making more genes." Today, no life-scientist seriously doubts that the tremendous diversity and success of living creatures is due, at least in part, to natural selection for and against genes that have been randomly altered. Since most mutations probably confer no advantage or disadvantage (Nature 354: 114, 1991), random drift ("the molecular clock") also plays an important role in changing the sequences.

* A species is a breeding population that can produce fertile offspring among its members, but not outside its group. We know that new species arise as a result of reproductive isolation; members of the ancestral populations have become separated by geography and/or niche. The molecular mechanisms that underlie micro-evolution (i.e., loss of the ability to interbreed) must be the result of genetic drift in an isolated population, so that at least one enzyme no longer meshes with its distant cousins. We look forward to learning the details, but obviously this is a long way off.

Along with Rudolf Virchow (Nature 427: 487, 2004), your lecturer considers "race" an antiscientific, outdated social construct that we might do well to forget about.

The ability to evolve, and to select helpful genes, is basic to the survival of life on earth. Humankind pays a price for the tendency of the genes to keep changing. The cost is borne by the "less fit", especially the 7% (estimates vary, and this doesn't include "polygenic inheritance") of people with significant genetic disease, and by those who care for them. Most embryonic and early fetal wastage is probably due to genetic and chromosomal problems, and even today, we don't know how common these losses really are.

You know about genes, alleles, chromosomes (autosomal and sex), mitosis and meiosis, haploid and diploid cells (exact multiples of the haploid number are euploid; others are aneuploid), mutations (and the environmental problems that cause them), centromeres, and the basic biology of nucleic acids. You also understand classic Mendelian and sex-linked inheritance, homozygosity, heterozygosity, hemizygosity, and consanguineous mating. If any of these terms are unfamiliar, please review. If you don't know what restriction fragment length polymorphism is all about, ask a molecular diagnostician -- it's important.

Remember that germ line mutations are present in the sperm or the egg, while somatic mutations are acquired after fertilization.

Notice that if two normal parents give birth to a child with achondroplasia, one of them either had a somatic mutation involving the germinal epithelium, or a mutation involving just a single gamete.

Certain diseases of the genes can result only from post-zygotic, somatic mutations. These include McCune-Albright's syndrome (rare) and the fully-expressed malignant phenotype (all too common).

Hutchinson-Gilford progeria ("accelerated aging") is apparently always caused by a de novo mutation in a sperm (Science 300: 1995, 2003). More about this later.

Progeria child

Vertical transmission of a mutation occurs from parent to child. Horizontal transmission of a mutation occurs within a single organism as a clone of mutated cells (as in tumors, and such mosaics as McCune-Albright's). As we will soon see, diseases of DNA are really of two types -- inherited disease (vertical transmission) and tumors (horizontal transmission). Nowadays, we call only the first "genetic disease".

The genetic code translates nucleic acid base pair triplets (codons) into animo acids for a protein sequence. It is almost (not exactly: Comp. Bio. Phys. 106: 89, 1993; J. Mol. Evo. 34: 331, 1992) constant across nature, and entirely constant for the nuclei of the higher creatures. (* This is one more piece of evidence that evolution has occurred on the grand scale, since the code is apparently arbitrary.)

Restriction enzymes (endonucleases): Enzymes, mostly from bacteria, that cleave ("digest") DNA at specific sequences. * EcoR1, still the "champ", cleaves at GAATTC.

Denatured DNA: single-stranded DNA

Exon: the portion of the gene that is transcribed onto mRNA, for translation into protein sequences.

Intron: the rest of the DNA in the gene under discussion.

Gene probe: a single-stranded nucleic acid sequence, labeled with radio-isotope, used to identify a specific complementary sequence

Southern blotting: using probes to search for particular DNA sequences, on digested DNA samples that have been digested using restriction enzymes and the fragments separated by electrophoresis. Invented by Dr. Southern.

Northern blotting: searching for m-RNA by a technique similar to Southern blotting. Named by some wag in imitation of "Southern".

Western blotting: searching for a protein, using electrophoretic methods

Dot blotting: like Northern and Southern blotting, only without using electrophoresis

In-situ hybridization: using probes to detect nucleic acid sequences within cells, without destroying the cells themselves.

Polymerase chain reaction: a technique to identify very small quantities (perhaps even a single copy) of a particular DNA sequence in a sample. This has many uses, ranging from the most sensitive and specific AIDS test to a way of telling whether a leukemia is completely cured (Lancet 344: 348, 1994).

Classical genetic research: define the biochemical abnormality, then isolate the protein, sequence it, and identify the gene. How we cloned the hemoglobin S gene. "Functional cloning."

Reverse genetic research (positional cloning): locate the affected chromosome, sequence until you find the gene, then deduce the protein sequence ("the predicted protein") and find it, and finally figure out its function. Duchenne's muscular dystrophy, cystic fibrosis, and Li-Fraumeni disease were all successfully approached in this way. "Positional cloning."

Pseudogene: a DNA sequence, once useful (we may suppose) or else transferred from a real gene, and homologous to active genes in us or in related organisms, but now genetically inactive. Pseudogenes left over from evolution would constitute the ultimate "vestigial structures".

Genetic disease: almost impossible to define. My best shot is, "a disease that is determined, more or less, the moment the egg is fertilized." ("You made the first mistake, you picked the wrong parents.")

Entities such as sickle cell disease and Huntington's chorea develop when, and only when, a particular gene is defective. Yet even sickle cell disease is modified by the presence or absence of thalassemia genes. Cystic fibrosis, a simple mendelian problem, varies in severity depending on which of more than a dozen alleles has been inherited.

Identical twins are 100% concordant for type II diabetes, which is polygenic, and the course of the disease is influenced by environmental factors.

Diseases like lupus, high blood pressure, alcoholism, and schizophrenia show obvious familial tendencies, even in siblings raised apart, yet many identical twins are spared.

The variability in particular diseases from person to person reflects, in part, our varying genetic heritage.

A handful of diseases, outstandingly McCune-Albright syndrome, Klippel-Trenaunay, Ollier/Maffucci, and Proteus syndrome, are genetic diseases that cannot be inherited, but that always result from a mutation early in embryogenesis.

Even the "Big Robbins" example of automobile accidents as a process in which "the environment totally determines the nature of disease" ignores the obvious genetic factors in alcoholism. (Rabies or gonorrhea would be better examples.)

Notice that the above definitions of "genetic disease" ignore the other, equally important, "acquired genetic diseases", i.e., tumors, in which defective genes are propagated and accumulate within clones of cells in a single organism. We now talk about inherited genetic disease ("vertical transmission") and neoplastic genetic disease ("lateral transmission"). Much more about this soon.

Hereditary disease: "Genetic disease", with the exception of those rare ones you can't inherit.

Familial disease: Definitions vary. "Diseases that cluster within families" can include classic genetic diseases, polygenic disease, mysterious things (more on "SIDS" later in the course), heritable viruses, nutritional stuff, environmental stuff ("Is that lead paint peeling from the walls?"), and, of course, behavioral stuff -- the child-abuse cycle, obesity ("Clean your plate!"), etc., etc.

Congenital disease: a disease present at birth. Note that sickle cell disease and Huntington's chorea, both genetic, are not symptomatic at birth, and that various traumas and infections acquired in utero are congenital but not genetic.

Transgenic mice: mice developed from fertilized eggs in which the genetic material was manipulated.

Knockout mice have had genes deleted, which is tricky.

Chromosomal aberration ("cytogenetic aberration"): diseases in which there are the wrong number of copies of some or all of a chromosome, sufficient to detect using classic karyotyping. About 1% of newborns, and maybe 50% of spontaneous abortions, possess an abnormal karyotype.

G-banding (from "Giemsa" stain): a technique that visualizes bands on chromosomes, improving our ability to localize genes and recognize minor karyotypic problems.

Standard cytogenetic terminology names a karyotype for the number of chromosomes, a list of the sex chromosomes, and mention of any extra ("+") or deleted ("-") chromosomes. Abnormalities of individual chromosomes are designated by "p" for the short arm, "q" for the long arm, and mention of the numbered regions shown by G-banding.

Imprinting: Genes and chromosomes sometimes differ slightly depending on whether they were acquired from Mom or Dad. A hot topic right now.

Uniparental disomy: Non-mendelian inheritance in which two copies of a gene or chromosome were inherited from the same parent.

Triplet (trinucleotide) repeat mutations: Genes rendered abnormal by the amplification of CG-rich units. This is the usual mechanism of mutation in fragile-X disease, Huntington's, and myotonic dystrophy, and a few others. Unlike more familiar syndromes, these diseases get worse from generation to generation as the amplification continues (anticipation or Sherman's paradox, long-noted in myotonic dystrophy, means the disease appears sooner in the son than in the father).

Mutant genes of large effect: diseases caused by a single defective gene.

Most are Mendelian disorders, either autosomal or sex-linked. We are now discovering diseases caused by mutated mitochondrial genes.

* It is simply wrong to think of all mutations as just rendering a gene ineffective. The old pseudoscientist's complaint, "How can a mutation give rise to something useful?" is now abundantly invalidated by studies of the origins of modern genes from mutations (base-pair substitutions, recombinations, even frame-shifts; see Nature 306: 203, 1983) of genes that once did something else.

Sex-limited inheritance: diseases inherited independent of the sex-chromosomes, but that can ordinarily express themselves only in one sex or the other. The prime example is male baldness -- a woman must usually take exogenous testosterone in order to go bald.

Polygenic inheritance: diseases that are caused or significant modulated by several different abnormal genes

Multifactorial etiology: despite "Big Robbins", this may mean either "caused by several abnormal genes" or "requiring both abnormal genes and an abnormal environment".

Lyonization: Inactivation, early in embryogenesis, of all but one of the X-chromosomes in each cell. Once lyonization has occurred, the same X-chromosome will be inactivated in all of that cell's progeny, where it will be the Barr body (or bodies, for those with more than two X's), or sex chromatin (visible on buccal smear), until oogenesis is required again.

Note that the entire chromosome is not inactivated. (If the second X were totally inactive, then XO's, XXY's, and XXXX's would be phenotypically normal. * The Kallmann's syndrome gene (no olfactory nerves, no gonadotropins, all because of defective neuronal migration, see NEJM 326: 1752, 1992), located on X (with an inactive counterpart on Y), is expressed whether or not the chromosome is lyonized (Nature 383: 529, 1991).

Lyonization may be lucky or unlucky. For example, female identical twins with one X-chromosome carrying color blindness may be discordant for color blindness (Am. J. Hum. Genet. 51: 291, 1992).

If the X's are discordant for skin color (for whatever reason), you will end up spotted (Arch. Derm. 129: 1460, 1993). Whenever X's differ in some significant way, the woman is a "functional mosaic" (in contrast to a "genomic mosaic", caused by a somatic mutation).

* Transcription of a gene from the inactivated X: Nature 351: 325, 1991. By the way, we're still puzzled about the actual molecular biology of lyonization itself. The gene XIST produces an RNA that ties up the lyonized chromosome, and methylation of cytosines also seems to be involved (Nature 368: 154, 1994, others).

Pseudo-autosomal inheritance: The tips of the short arms of chromosomes X and Y are homologous, and a few genes (* notably blood group Xg) are located here (Am. J. Hum. Genet. 51: 1172, 1992).

Somatic mosaicism: when all cells in a person do not have essentially the same genetic makeup. This can result from a mutation in one cell during the early stages of embryogenesis, or even from fusion of two fertilized eggs to produce one person (i.e., a chimera -- * ponder that!, fortunately, it's rare.)

Chimerism may also result from blood exchange between fraternal twins, and the person has two people's bone marrow. Future blood bankers: these patients will probably have two different blood types.

Somatic mosaicism probably underlies many (if not most) birthmarks (for example Lancet 345: 596, 1995). People living comfortably with a "forme fruste" of some dreadful classic lethal disease may be mosaics (for example, Am. J. Hum. Genet. 46: 591, 1990). It's also the basis of tumorigenesis (more about this later).

Functional mosaicism is the result of lyonization, as explained above. All about mosaics: Arch. Derm. 129: 1460, 1993 (why a dermatologist?)

Germinal mosaicism means that a mother who is not affected by a particular mutation has transmitted it more than once as if she were; i.e., the eggs arose from a mutant clone.

Penetrance: the chance that someone with the gene (or genes) for a condition will express the condition.

Variable expressivity: a term for an allele that causes widely different degrees of abnormality in different people.

Balanced polymorphism: the heterozygote enjoys an advantage that has allowed selection for the gene, making the homozygous condition common. The prime example is sickle cell disease, in which the heterozygote enjoys immunity to malaria. Cystic fibrosis, Gaucher's, and probably others are probably also balanced polymorphisms.

Pleiotropism: one mutant gene produces several effects

Genetic heterogeneity: the same effect can be produced by mutations at several sites.

For example, there are several different loci at which two defective genes will produce an albino, there are at least two genes that produce adult polycystic kidney disease, there are at least seven ways to get xeroderma pigmentosum, there are multiple dominant and recessive forms of retinitis pigmentosa (Am. J. Hum. Genet. 53: 80, 1993; Nat. Genet. 23: 217, 1999, lots more), there are about a dozen known ways to get Ehlers-Danlos syndrome, there are several dozen deafness syndromes, etc., etc.

* My favorite example, right now, is Leigh's syndrome, a progressive brain disease of young children in which there is defective cytochrome oxidase in the mitochondria. Sounds straightforward -- except that the cytochrome oxidase complex is coded by at least 13 different genes, some in the nucleus and some in the mitochondria. (For starters, three different ways to get Leigh's are described in Ped. Res. 26: 260, 1989, J. Ped. 116: 84, 1990, and Neurology 39: 697, 1989). Probably there are many, many alleles here, and many Leigh's cases could even be polygenic.

Dermatoglyphics: examining the lines on the palms and soles, and the fingerprint ridge patterns. A fascinating game that has yielded many interesting correlations, none of any clinical utility. For a nice review, see J. Invest. Dermatol. 43: 261, 1970. (* P.S. As a pathology resident, I used to check the lengths of the "life lines" on autopsy patients' palms, to see how long they had lived. Sorry, no obvious correlation.)

* Genetic load: the frequency of deleterious recessive mutations in a population. An important concept in biology. In populations with high genetic load (i.e., most humans), matings of near relatives is likely to result in defective newborns. By contrast, in populations with low genetic load (i.e., lab animals, many wild populations), inbreeding is not a hazard. Frequent inbreeding does reduce genetic load in the long run. Remember that Cleopatra ("the most beautiful woman in history", they say) was the offspring of several sequential brother-sister matings.

* In my mind, God wrote two books. The first book is the Bible, where humans can find the answers to their questions on values and morals. The second book of God is the book of nature, which allows humans to use observation and experiment to answer our own questions about the universe.


-- Galileo, to the Grand Duchess of Tuscany

* Thus, from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely the production of the higher animals, directly follows. There is a grandeur in this view of life, with its several powers, having been originally breathed by the Creator into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved.

-- Charles Darwin, The Origin of Species, 1860, emphasis added

* Today, more than a half century after [Humani Generis], new knowledge leads us to recognize in the theory of evolution more than a hypothesis. ... The convergence, neither sought nor induced, of results of work done independently one from the other, constitutes in itself a significant argument in favor of this theory. ... The elaboration of a theory such as that of evolution, while obeying the exigency of homogeneity with the data of observation, borrows certain ideas from the philosophy of nature. ... There are thus materialistic and reductionist readings and spiritual readings. ... Pius XII underlined this essential point: If the origin of the human body is sought in living matter which existed before it, the spiritaul soul is directly created by God."

-- Pope John Paul II

* The serious questions most often asked of me by students concern the history of life. Before I placed this short, non-testable section, I would be questioned many times each year. You asked, so here goes.

* By today's standards, I'd be considered an old-earth, soft creationist with a high regard for truth, and who demands basic honesty and ordinary decency from others. My longstanding interest in the philosophic questions raised, and my contribution, are known, and this is rumor control.

* Trying to do biology without talking about common descent is like trying to do chemistry without talking about the periodic table. Yet the language makes for misunderstandings. When a scientist says "evolution", he/she simply means "common descent". When religionists (or militant anti-religionists) use the term "evolution", they usually mean "scientific materialism" or "naturalistic reductionism" or "naive naturalism", i.e., the idea that the success of physics, chemistry, and biology in explaining and predicting things that happen in the material world rules out the existence of the supernatural.

* And you already know that when a scientist says "true" or "I believe", he/she is simply expressing confidence in the power of a claim to predict future observations.

*  You don't have to "believe in evolution" (or even common descent) if you don't want to. I would prefer to believe a literal reading of Genesis. But there are things that you can observe in our world that I don't think you can explain unless we share a common ancestry with other living things, and the theory's predictive power speaks for itself. During the creation science battles of the early 1980's, I catalogued 38 distinct positions on "the origins question" taken by serious Christians, past and present. I decided that there were problems with each of these, but that they might not all be unsurmountable.

* In the meantime, if you have ever had pets, you know how much they have in common with us. They possess many qualities that we admire, often being good in ways that few humans are. It puzzles (and upsets) me that some religionists object to the idea that we are descended from animals. Perhaps Christian belief is actually reflected best in Christian art. Only humans sin, so only humans need the Cross. The newly-incarnate Christ is usually shown surrounded by animals, and better Christians than myself have argued that they are saved by His Incarnation.

* (1) Most of the interesting work in evolution ("inference of phylogenetic relationships") is now done in molecular biology rather than in paleontology (for example, bird-lovers will enjoy Proc. Nat. Acad. Sci. 91: 2621, 1994; those who prefer bats will want to read Science 256: 86, 1992; origin of dogs (they go way back, maybe 100,000 years Science 276: 1647, 1997); Afrotheria (elephants, sea cows, hyraxes evolved together in Africa when it was isolated; Proc. Nat. Acad. Sci. 98: 2001; how we diverged Proc. Nat. Acad. Sci. 100: 1062, 2003); for those who like people best, see Nat. Genet. 33-S: 266, 2003. common origin of immunoglobulins and T-cell receptors Proc. Nat. Acad. Sci. 93: 3289, 1996; reconstructing the history of lysozyme Nature 385: 151, 1997; origin of eukaryotes Science 257: 30 & 74, 1992; and all the way back, using tRNA synthetase Proc. Nat. Acad. Sci. 92: 2441, 1995). At our present state of knowledge, much of our nucleic-acid genome appears to be "junk", left over from our past, or even of viral origin -- the ultimate successful parasitization. If we truly share ancestry with chimpanzees, we would predict that our true junk DNA sequences are homologous, almost (but not quite) as strikingly similar as the two species' known genes and chromosomes. And it is. For example, the non-coding section of one early-studied chimp gene is a 98.4% match to its human counterpart, much closer to the human than to the gorilla (Science 250: 376, 1990; chimp update Science 302: 1960, 2003). In fact, if you look at our DNA, we're as similar to the two species of chimps as they are to each other (Science 263: 181, 1994). Enough is enough. I'm satisfied this is common ancestry, not just "common design".

* (2) You all know the genetic code is degenerate. The study of "silent sites" (redundant third base pairs of codon triplets) is getting to be a discipline all by itself. These shouldn't make the slightest difference as far as the creature is concerned (see J. Mol. Evo. 33: 442, 1991; J. Mol. Evo. 36: 201, 1993), yet the closer-related the animals are by classic evolutionary study, the closer the "silent sites" match, just as Darwin's theory predicts (and if it were not true, Darwin's theory would be refuted); hard to explain if nucleic acid sequences were created separately for the garden of Eden. See Proc. Nat. Acad. Sci. 88: 5974, 1991; Mol. Bio. Evo. 9: 193, 1992 (insulin); J. Mol. Evo. 33: 442, 1991; J. Mol. Evo. 37: 441, 1993 (rats and mice differ in silent site G+C by only 1.7%, much less than even their amino acid sequences). Line up any comparison of the base sequence for the same protein in two different creatures (go search the literature yourselves), and you'll find this to be true.

* (3) Most people do not understand science, and this is not their fault. Most religionists are good, decent people. I note with much satisfaction that classic creationism (i.e., the versions that deny common descent) is now confined to ultra-Right wing circles and rare New Agers. During the trials that culminated in "Aguillard", all of the major "creation scientists" consistently refused to testify under oath, and despite their soliciting funds for "research" and complaining that they cannot get a fair hearing, not one of them was able to produce a single letter of rejection from a refereed journal. In other words, it was (and still is) all fake. Please be careful, especially if you're asked for money. There are still some utterly cynical people operating. In a country like ours, in which most adults can't tell you why the seasons occur, pseudoscience (tricky fallacies, falsified evidence, "we're spiritual and the working scientists are immoral and anti-God") makes easy bucks. All of the following are lies: "Evolution is not true because transitions in the fossil record are abrupt." "Darwin renounced evolution on his deathbed." "There aren't enough known human fossils to cover a pool table." "A modern human skull was found in dinosaur strata [the original report was from an old US tabloid newspaper]." "Scientists [actually, just the staff of another old London tabloid newspaper, which I have] mistook a pig tooth for Nebraska Man." "For decades, the Piltdown fraud was central to thinking about human origins." (Check out an old textbook -- it was considered an unexplained anomaly before the fraud was revealed.) "Human Cytochrome C is closer to a chicken (Answers in Genesis) or a sunflower (Kent Hovind) than to a chimp." "Human cholesterol is more like that of lower life forms than it's like an ape's." "There's only 6000 years worth of dust on the moon's surface." "At Paluxy, Texas, human footprints were found in dinosaur strata" [1930's creationists carved these themselves as a deliberate, confessed hoax]. "Believing in evolution is the primary cause of racism and all other contemporary evils." "Evolution violates the second law of thermodynamics." "If you simply drop the assumption that the speed of light is constant over time, then the universe could be only 6000 years old." "Red shift and the cosmic background radiation could be explained by tired light." "The NASA computer discovered a day was missing from the past and this was because Joshua made the sun stand still." "If scientists really believed we're more closely related to chimps than rats, they wouldn't use rats for research." "Transitional forms should appear at a constant rate." "There is a massive evil conspiracy to...." And so on, ad nauseam. In racist South Africa in the 1940's-1980's, the lies were even goofier and uglier. The most popular young-earth creationist right now also sells laetrile, the phony cancer medicine from the 1970's, and "The Protocols of the Learned Elders of Zion", a rabid anti-semitic forgery from the Nazi era. If you want to be involved with people like this, that is your business. I judge a person's sincerity by his or her willingness to testify in a court of law, under oath. These operators are notoriously unwilling to do so. At the Arkansas trial, the only creationist witness on genetics was Chandra Wickramasinghe, a Ceylonese-Welsh astrophysicist. Professor Wickramasinghe testified that he believed insects were more intelligent than humans, so much so that they were keeping it a secret. I am not making any of this up. Geneticist Francis "Discoverer of the Cystic Fibrosis Gene Etc. and Long-Time Head of the NIH Human Genome Research Institute" Collins, a conservative Evangelical, noted in Physician 6(3), 1996 ("Focus on the Family", a conservative-Christian publication) that his fellow-scientists are simply wrong to assume that, because he's a Christian, he's also a classical creationist. Of course he's not.

I see no conflict in what the Bible tells me about God and what science tells me about nature. Like St. Augustine in AD 400, I do not find the wording of Genesis 1 and 2 to suggest a scientific textbook but a powerful and poetic description of God's intention in creating the universe. The mechanism of creation is left unspecified. If God, who is all powerful and who is not limited by space and time, chose to use the mechanism of evolution to create you and me, who are we to say that wasn't an absolutely elegant plan? And if God has now given us the intelligence and the opportunity to discover hismethods, that is something to celebrate.

I lead the Human Genome Project, which has now revealed all of the 3 billion letters of our own DNA instruction book. I am also a Christian. For me scientific discovery is also an occasion for worship.

Nearly all working biologists accept that the principles of variation and natural selection explain how multiple species evolved from a common ancestor over ery long periods of time. I find no compelling examples that this process is insufficient to explain the rich variety of life forms present on this planet. While no one could claim yet to have ferreted out every detail of how evolution works, I do not see any significant "gaps" in the progressive development of life's complex structures that would require divine intervention. In any case, efforts to insert God into the gaps of contemporary human understanding of nature have not fared well in the past, and we should be careful not to do that now.

Science's tools will never prove or disprove God's existence. For me the fundamental answers about the meaning of life come not from science but from a consideration of the origins of our uniquely human sense of right and wrong, and from the historical record of Christ's life on Earth.

-- Francis Collins "Time" August 2005

I will abandon my belief in common descent if a single protein family is found that grossly violates the Darwinist prediction that its phylogenetic history revealed in its base-pair sequences, notably its choice of degenerate codons, will match the history of life suggested by classic comparative anatomy. If they believed their own claims, they would be sequencing genes. My best "thought question" for an acceptable medical school candidate is to explain Denton's Fallacy ("Evolution: A Theory in Crisis"): Why is the genetic distance between a modern-day shark and a modern-day bony fish the same as the genetic distance between a modern-day shark and a human being? The most-cited post-Aguillard vs. Edwards "evidence for creation", it actually follows from Darwin's theory. How? Behe's Fallacy is a restatement at the molecular level of the old claim that bodyparts are interdependent and hence could not have arisen individually without "intelligent design". The answer is that they evolve together. Behe's most familiar claim is that the clotting cascade is "irreducibly complex" and with today's knowledge of the clotting cascades of other animals, this is a lie, pure and simple. Behe was torn to pieces on cross-examination during the 2005 trial. (The other "intelligent design" proponents were smart enough to refuse to testify.) Every last Nobel science laureate in the U.S. signed an amicus brief to the Supreme Court in "Aguillard vs. Edwards", testifying that classic "creation science" is a mass of untruths by sectarian ideologues seeking political power. This is the only time they have all agreed about anything. Even before Aguillard, a friend of mine went to buy some creationist books at what he told me was the largest Christian bookstore in northern California. They didn't stock any, and the owner said, "We don't carry that cr_p." If you must deny common descent, you're best to stick to the "omphalos" (Adam was created as an adult with a belly-button) argument, i.e., "God created the fossils and the other evidence for evolution to deceive people so they would go to hell." Still popular in some "conservative" circles; I'm glad I don't believe it.

* (4) In striking contrast to the classic creationists, today's thinking Evangelicals seem to have come up with a new synthesis that fits the scientific facts so far. Especially if you think that "believing in evolution" will be bad for your spiritual life, or make you immoral or whatever... let me recommend progressive creationism instead of the more classic versions. "Progressive creationism" is several positions, all long-known in Christian circles, and anathematized by the better-known (i.e., big-money) creationists; the most popular version today is that God directed the mutations and/or added genes in the gametes of animals to lead to humankind. (To my knowledge, no progressive creationist has advanced the idea that God worked primarily by protecting individuals with random mutations that were intended to lead ultimately to humans. I guess somebody might say "Hey, that sounds like natural selection!") Progressive creationism fits the available data, and I also recommend it if you're impressed by "design in nature..." or "the odds against..." or "we still can't explain the origins of the genetic code..." (I am not impressed, preferring the parsimony of the Modern Synthesis, but I have no wish to argue with you over something so subjective). "Progressive creationism" (in the version I've just described) is now mainstream throughout most of conservative Christendom. It is also usual for these people to claim that life could not have arisen by natural processes. (Dr. Behe's deceitfully-entitled book "Darwin's Black Box" misidentifies Darwin's theory and the idea that the genetic code itself has a natural origin.) At Christian bookstores, you can buy high-quality books about geology and biology that could pass for secular science books (the earth is 4.5 billion years old, plate tectonics and all, common descent is quietly acknowledged), except for a few paragraphs about how "life could not have arisen by chance." At present (2004) the two most popular creationist ("intelligent design" nowadays) writers (Lee Strobel and Philip Johnson) are both attorneys, not zoologists or paleontologists or geneticists. Attorneys are specially educated to create confusion and misrepresent what others have said in order to make people believe things that even the attorney may know are not true. The two other major writers are William Dembski, mathematician and Jonathan Wells, who is the one writer who has been promoted as a bona-fide bioscientist. Wells is actually one of twelve seminarians from the the Unification Church who, at the request of Sun Myung Moon, were sent through a graduate program in biology in order to promote creationism once they were finished (Nature 410: 745, 2001). Wells doesn't mention this in his biographical sketch. (Morals, guys?) Anyone who knows basic biology can see though these guy's' fallacies. And all of them are presenting progressive creationism, not the familiar "Noah's ark" stuff. If you read the "intelligent design" stuff, you will notice that the authors never address the question of humans have a non-human ancestor. By now, one of the attorneys has become a laughing-stock for his evasiveness when asked directly whether human beings have non-human ancestors, whether the first mouse had a mother, and so forth. (See Martin Gardner's review in the Skeptical Inquirer, 1998). And even the influential Charles Colson chose to quote another attorney rather than a scientist in his book on answering kids' questions, telling them why they should not believe in evolution. If progressive creationism is true, then it could easily be confirmed (and God's existence pretty-much proved) by the finding of a single useful locus in humans without parallel in any monkey or ape. (Failure to find such a gene, after a complete search, would not falsify progressive creationism, so these folks cannot lose.) I haven't heard of any "progressive creationist" undertaking such a search. Further, if "progressive creationism" is true, and God makes a practice of adjusting the genes in gametes, then what do we say to people with genetic diseases (birth defects, cancer) conferring no advantage? Why not choose a more stable system, and change it only for creatures' benefit? And Darwin's theory is called "cruel"? If you want to get in touch with the handful of active creationists who possess integrity, check with the American Scientific Affiliation or Students for Origins Research; nowadays these people mostly just remind others that the available data does not justify the naïve naturalism of, say, Carl Sagan. I look with hope to these people, especially as religious conservatives become aware of the facts. SOR and ASA folks will tell you more about the "progressive creationist" option, which I suspect most of the members hold. Maybe one day they'll report an experiment.... In Oct. 1997, the National Association of Biology Teachers had enough sense to revise its definition of evolution to remove the words "impersonal" and "unsupervised". This was past due, and something I'd worked for over the years.

* (5) Lately there's a minimalist approach to "human origins" from Religious Right types which doesn't even require the interventions (and the problems) of progressive creationism. "The Bible says only that the human race was specially created, not any other species". Because apes were so successful, God used the DNA sequence from one of them (junk sequences and all), very slightly modified, to make Adam by special creation. This idea is probably unfalsifiable and will appeal both to people who are committed to supernatural creationism and to people who are highly impressed with how different we are from all other animals.

* (6) You have yet another option that's consistent with the facts, and actually easy to believe. In 1983, I coined the phrase "The New Design Argument" for a common argument that begins with the idea that the Good Lord set up the physical constants for our universe so that the whole process leading to human beings (or whatever we're supposed to lead to) could happen without the Good Lord having to intervene at all (on our planet, and most likely on a billion others); this got some smiles even if it didn't end discussion (and I don't find it persuasive, either), but the idea was developed soon afterwards by an Anglican bishop (probably independently) in a soft-science book ("The Probability of God"). Much earlier, Pythagoras taught that the mystery of creation was placed by the Creator in the math. Spend some time with the new physics (quantum physics, relativity) and you may end up believing this.

* (7) The incredible complexity and beauty of the genetic code impresses many contemporary thinkers (especially non-geneticists) as proof of intelligent design. Before accepting the implications of this argument (the old "theological design argument", originally applied to individual species or genera, but now pushed back 3 billion years or so by "progressive creationists"), familiarize yourself with ribozymes (Science 231: 545, 1986; Cech & Altman Nobel prize 1990; Nature 352: 516, 1991; Nature 358: 543, 1992, Science 256: 1396 & 1416, 1992; Nature 374: 777, 1995) and natural selection (actually, Darwin's cycle of selection -> replication -> mutation -> selection) at the molecular level (Science 255: 800, 1992; Darwin's laws in the RNA world Science 257: 635, 1992; evolution in the test tube Nature 361: 119, 1993; this is now routine Science 267: 237, 1995; RNA world Sci. Am. 274(1): 27, 1996). We still have and use ribozymes (Nature 364: 358, 1993); it's amusing to think this is probably the original stuff. Synthetic self-replicating molecules: Sci. Am. 271(1): 48, July 1994. Likely origin of the genetic code, by analyzing huge numbers of tRNA sequences: Proc. Nat. Acad. Sci. 93: 452, 1996. Given present knowledge, I'd consider chemical evolution leading to the genetic code (though not the fact of our common ancestry with other animals) to be an open question; you may disagree either way.

* (8) The theory and practice of molecular phylogeny: Science 264: 671, 1994. The whole history of life in Darwin's world arouses in me the same sense of wonder and awe as does the sight of the heaven (Psalms 8 and 19 and 104 and so forth). My best answer begins with the observation that none of the great world scriptures focus on the Creator's role as Cosmic Designer (as certain more recent philosophers have tried to do). Instead, they address the more immediate concerns of human beings. Dennis Burkitt (of "Burkitt's lymphoma") was an evangelical Christian and he and I swapped letters on the subject. His analogy is the rider of a train; what matters is where you've going, not where you've been. We hear of various people who met the Good Lord, but never about their getting lectures on the mechanics of creation. John Paul II remarks that "the Bible doesn't tell how the heavens were made, only how to get there". Today's process theologians even talk about creation as a "planned accident" in which most creatures are pretty happy most of the time (see, for example, the best-sellers about "why bad things happen to good people", which are process theology by a thoughtful rabbi; good reading for any physician interested in religion, too.) Saying grace, I thank the Good Lord for our food, but I know where food comes from. We may thank the Good Lord for the birth of a child, but we know where babies come from; nobody demands "equal time for stork science." Charles Darwin actually pointed this out in the "secondary causes" passage in "The Origin of Species", in which he describes the Creator setting up the laws of nature and allowing species to have natural origins just as individuals do. In the Sermon on the Mount, I was told that the Good Lord feeds the birds and makes the lilies beautiful, but no one, then or now, could have understood this as literally as today's creationists would interpret Genesis. Later in the course notes, I'll defend my belief that a human being is a spiritual process joined, somehow and for some presently-unknown reason, and only temporarily, to a body that has arisen by natural processes.

* My best answer ends with the observation that (like Job, re-read the Old Testament book) I'd rather settle for less-than-complete explanations than believe the facile, obviously-wrong answers generated by uncharitable ignorance.

* (9) Left-wingers: Your "Gaia hypothesis", like "creation science" for your conservative counterparts, can be invoked to explain anything and has shown no predictive value whatever (Nature 345: 470, 1990.)