By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
When Adam and Eve got the order from on high to "be fruitful and multiply," they knew of only one reproductive technology for complying with that directive. And all through the millennia, right down to our own 20th century, that method - sexual intercourse - remained the one and only way of uniting a male sperm with a female ovum to create a child.
Now, of course, starting with artificial insemination (AI) and on into in vitro fertilization (IVF), clinicians have devised ever-more-sophisticated techniques to accomplish fruitful multiplication. The latest, to circumvent male infertility, is intracytoplasmic sperm injection (ICSI).
When a wannabe father's testes cannot produce enough viable spermatozoa to meet and mate with the would-be mother's ova, his sperm insufficiency often is caused by deletions on the X-linked Y chromosome, which determines maleness. In about 10 percent of men afflicted with inadequate sperm counts, a mutation in a specific region of the Y chromosome, known as AZFc, is to blame.
Azoospermia (absence of living sperm in the semen) or oligospermia (subnormal concentration of sperm in ejaculate) account for clinical male infertility, but a loophole in this diagnosis enables urologists to retrieve individual sperm cells from upstream in the testis. ICSI then allows specialists to microinject individual sperm cells into individual ova in vitro, then insert this single-cell embryo into the mother's fallopian tube to launch pregnancy. (See BioWorld Today, May 14, 1996, p. 1.)
Since its advent circa 1992, ICSI has become the preferred mode of IVF. The American Association for Reproductive Medicine, based in Birmingham, Ala., reports 1,926 babies born by ICSI in 1995, and 6,098 in '96. These live births required 5,638 cycles - or attempts - of the procedure that first year, and 16,011 the second. Those figures, the latest available, indicate a success rate of one birth per 2.7 tries. The association's spokeswoman, Deborah Crawford, told BioWorld Today that the cost of an IVF cycle, of which ICSI is the latest version, runs $8,000 to $12,000.
For couples who can afford it, the gift of their own biological offspring, after the protracted heartache of infertility, accounts for the mounting popularity of ICSI. But the technique involves one built-in uncertainty: Will a boy baby inherit his father's infertility?
A paper in the July 1999 issue of the monthly journal Human Reproduction answers this question in its title: "Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection (ICSI), but are likely to transmit the deletion and infertility." Its principal co-authors are molecular geneticist David Page at the MIT-affiliated Whitehead Institute, in Cambridge, Mass., and fertility clinician Sherman Silber, at St. Luke's Hospital in St. Louis.
They described three unrelated men in their early 30s, with de novo (not inherited) Y-chromosome mutations, who produced four infant sons by ICSI. DNA analysis of the progeny's Y chromosome revealed that all four had indeed inherited the genomic defect.
"In all likelihood," Page observed, "the adult sons will be infertile as well. Although assisted-reproduction physicians had considered this consequence of ICSI," he went on, "this study is the first to demonstrate that ICSI does result in some men passing the genetic defect responsible for their infertility directly on to their sons."
When the boys in this study reach puberty, DNA analysis may determine whether they are indeed azoospermic or aligospermic. Page cited the possibility that between puberty and early adulthood, men with the AZFc deletion may produce normal amounts of sperm. "In that case," he suggested, "the physician might consider harvesting the boy's sperm when he's younger and saving it until he is ready to start a family."
How To Hide Most Ultra-Secret Secret Of World War II In Genetic-Codified Microdot
"Code," a four-letter word that's at the root of genetics and biotechnology, is going back to its own etymological root, as meaning "a system of symbols, letters or words given certain arbitrary meanings, used for transmitting messages requiring secrecy or brevity."
That dictionary definition fits to a T - as well as an A, a C and a G - a modest proposal in the June 10, 1999, issue of Nature. The brief communication in the journal carries the title, "Hiding messages in DNA microdots." Its author is physiologist and biophysicist Carter Bancroft, at Mount Sinai School of Medicine in New York.
He proposes recruiting DNA nucleotides and their sequences to serve as messages for transmitting secret military and espionage information. Once converted into the arcane language of DNA, the genetic data would be downsized to the size of a microscopic dot hidden under a period (.) - a full stop on, say, an innocuous letter.
In its original form, the microdot concealed a typewritten page of ordinary text, reduced to dot size by microscopy. A certain Professor Zapp, Bancroft recounted, developed this system for the German army in World War II. Spies used the method, which Zapp dubbed "steganography," to transmit secret communications.
"We have taken the microdot a step further," Bancroft wrote, "and developed a DNA-based, doubly steganographic technique for sending secret messages. A DNA-encoded message," he explained, "is first camouflaged within the enormous complexity of human genomic DNA, and then further concealed by confining this sample to a microdot." This method involves flanking the DNA strand by PCR primer sequences, using a simple substitution cypher to encode characters in DNA triplet codons.
"Because the human genome contains about 3 X 109 [3 billion] nucleotide pairs," Bancroft pointed out, "a secret message 100 nucleotides long added to treated human DNA at one copy per haploid genome would be hidden in a roughly 3 million-fold excess of physically similar DNA strands." He added that the intended recipient, "knowing both the secret-message DNA PCR primer sequences and the encryption key, could readily amplify the DNA and then read and decode the message."
The Mount Sinai latter-day steganographer spelled out in his Nature paper the nucleic algorithms and sequences to create a demonstrator microdot that he described as "containing probably the most significant secret of the original microdot era: 'June 6 invasion: Normandy.'"