ate this May, British scientists revealed that Dolly the Sheep, the world's first mammal cloned from an adult cell, is genetically six years old, despite having been born only three years ago. The genetic "defect" was inherited from Dolly's mother, a finn dorsett sheep who, thanks to the wonders
of asexual reproduction, is also Dolly's father and identical twin sister.
Like all multicellular organisms, Dolly started out as a single cell, with her DNA instruction set (or "genome") sequestered in a specially protected pocket--the nucleus--and organized into neat functional units, or chromosomes. In nature, half the chromosomes are contributed by the father and half by the mother. Dolly, having no mother in the usual sense, obtained all her chromosomes from an adult mammary tissue cell, and this is where her troubles began.
Dolly was "born old" thanks to a genetic clock governed by complex molecular strands called telomeres, which cap the ends of chromosomes and are thought to control cell division. Like ticket reels at some microscopic nightclub entrance, the telomeres on a chromosome get a little bit shorter every time the cell divides. When the last ticket on the reel is dispensed, the cell is prevented from dividing any further, a condition known as "senesence." The club may remain open, but its doors are closed to new visitors, and the party must begin the long, slow process of winding down.
Reaching the Hayflick limit
In biology, this prohibition is known as the "Hayflick limit," after its discoverer, Dr. Leonard Hayflick. Surprisingly, for sheep and many other mammals the limit is only around 30 divisions, meaning that even for very elderly animals, every cell in the body is within 30 generations of the original egg. Since DNA replication, like the copying of software or digital music, is a reliable but not quite perfect process, errors--including pathological mutations that lead to cancer and other genetic diseases--can creep in as an organism ages. The Hayflick limit may be nature's way of keeping mutations at bay, trading the immortality enjoyed by single-celled organisms for the high-fidelity genome that higher life forms require.
Unfortunately, Dolly's chromosomes were already three years old at the time she got them, and their telomeres reflect this fact. Since sheep typically live about 13 years, and since telomere size is thought to be an accurate measure of a normal animal's chronological and physical age, scientists will be watching to see if Dolly reaches or exceeds 13, or if she grows old prematurely.
Interestingly, though, Dolly has become a mother in the usual way, and her lambs show no shortened telomeres or other signs of premature aging. There are two probable reasons for this: first, because half the lambs' genome came not from Dolly but from her mate, a perfectly normal Welsh mountain ram with perfectly normal chromosomes. The second reason is a bit more complex: resetting of the telomere clock in specialized reproductive cells called germline cells.
The world renews itself
All mammals age, suffer telomere shortening, and eventually die, but our children--despite inheriting an assortment of aged chromosomes from each parent--are born young and fresh, with a full reel of telomere tickets on each chromosome. This is because the germline cells in our gonads, which produce the sperm and eggs required for reproduction, also produce an enzyme called telomerase, which rebuilds the telomeres on the sperm and egg chromosomes before releasing them into the world. Thus the world renews itself: young children spring from old parents.
Telomere shortening may not be an accurate predictor of an animal's remaining lifespan, though, since the size distribution--even within a single animal--is pretty large, and few animals actually survive long enough to reach the Hayflick limit in a majority of cells. In specially engineered mice and yeasts that lack the ability to produce telomerase, offspring show progressive telomere shortening with each generation but, in general, these offspring appear healthy for about five generations and only start deteriorating after that. So telomerase's role as a rejuvenator is in little doubt, but there do seem to be a lot of extra tickets on those reels. Dolly's genetic "defect" may have no visible impact at all.
Can we reset the age clock?
The next questions virtually ask themselves: Can telomerase rebuild telomeres in other cells than sperm and eggs? Yep--in-vitro testing has confirmed the effect in a variety of mammalian cell types. Has the telomerase molecule been fully characterized? Yes, although it's a complex beast with both RNA and protein components, and may have tricks hidden up its many sleeves. Can telomerase be synthesized in the laboratory? Not yet, but the genes that produce it have been cloned and may soon be inserted into living bacterial "factories," or even directly into human cells. When this happens, will we have the means to reset the age clocks in every cell in our bodies, rendering them forever youthful and spry? Well...
This last question requires a lot of careful research before we try it. First of all, telomeres are only one of the many aging mechanisms that wear down our bodies. Second, telomerase was only discovered in 1984, and very little is known about its effects on living systems except that its anomalous presence has been implicated in certain very nasty forms of cancer. Resetting genetic clocks is maybe not such a straightforward process.
But one thing is for sure: Dolly's young/old status comes as no surprise to cloning insiders, who've been hemming and hawing about the issue for years. Only when the headlines announce a clone born without shortened telomeres will the age of cloning truly be upon us. And when this tough puzzle finally yields up a solution, for better or worse, Ponce de Leon's long-sought Fountain of Youth may be upon us as well.
Wil McCarthy is a rocket guidance engineer, robot designer, science fiction
author and occasional aquanaut. He has contributed to three interplanetary
spacecraft, five communication and weather satellites, a line of
landmine-clearing robots, and some other "really cool stuff" he can't tell
us about. His short fiction has graced the pages of Analog,
Asimov's, SF Age and other major markets, and his
novel-length works include Aggressor Six, the New York Times Notable
Bloom, and upcoming The Collapsium.
