G is for Genome

Eduardo Orias is a professor in UCSB’s Molecular, Cellular, and Developmental Biology Department. He describes with great lucidity the genetic realm, and he knows whereof he speaks: Late last year, his team of researchers finished mapping an entire genome, that of Tetrahymena thermophilia, a predatory protozoan of ancient pedigree. Professor Orias’s decades-long study of this unicellular organism has contributed to several major breakthroughs in the understanding of human cells, because T. thermophilia shares thousands of genes with Homo sapiens. The professor responded with remarkable readability—especially for a scientist—to a couple of sudden onslaughts of emailed questions from Martha Sadler. In this barely edited transcript, Orias sheds a somewhat disturbing light on our family ties to protozoa, genetic engineering, sex, and death.

Could you make a giant protozoan by manipulating its genes?

You might very well be able to, by learning what genes to manipulate. (Perhaps we should propose a project to the Department of Homeland Security.) Seriously, though, there probably is a limit to how big you could make a Tetrahymena by manipulating its genes. As a cell gets larger, volume scales as the cube and surface area only scales as the square of the linear dimensions. Thus the surface to volume ratio decreases; processes where surface area is important (e.g. exchange of oxygen and waste gases) suffer as a result of simple scaling up. Scaling could be viable if, for example, you also manipulated genes to make the shape like that of a long hollow cylinder of sheet metal, so no place inside the cell would be far away from the surface. But then, the “makeover” would have to be complex and many genes would have to be modified. In the absence of a huge amount of knowledge, it would be nearly impossible to accomplish this feat over calendar rather than evolutionary time.

Could you make a cross between that protozoan and a cat?

This certainly is an imaginative question! I assume that you mean creating an organism with half of its genes derived from Tetrahymena and half from a cat. I would say that the odds against this happening without human intervention are unimaginably high. But you might imagine experimental manipulation that could introduce all the Tetrahymena chromosomes into the nucleus of a cat egg or all the cat chromosomes into the germline nucleus of Tetrahymena. This manipulation seems feasible but …would the product survive? I don’t know; I am not aware that anyone has tried it. However, I would bet it wouldn’t — and in making this bet I would not think that I was gambling at all. The genes for the proteins that support many functions that are important for animals have been lost or their sequence has evolved beyond recognition in Tetrahymena. Likewise for the reciprocal case. Even the many proteins that are recognizably similar in both organisms have mutated, over 2-3 billion years of independent evolution, enough that most of them would probably be unable to interact efficiently with one another. It would be like trying to construct a smoothly operating vehicle that incorporated all the parts from a car and all the parts from a submarine. A more modest but very useful goal has been achieved, namely the use of Tetrahymena cells as a “factory” for the high level production of individual, valuable proteins from humans or other organisms, by introducing the relevant genes into the Tetrahymena cells. Is it true that mitochondria was once a separate organism that got incorporated into the human organism and never left? Like a very close symbiotic or parasitic relationship?

The basic idea is correct; the mitochondria were once bacteria that were taken in by a “proto-eukaryote”, and established a very intimate endosymbiotic relationship. Eukaryotes are organisms that have a true nucleus, as distinct from bacteria, which lack a nucleus. Today, our mitochondria are essential for the production of energy using oxygen. Because the mitochondrion still conserves DNA inherited from its ancestors, we know exactly what group of bacteria the original endosymbiont belonged to. What is not right is the suggestion that it was a human organism that established the relationship. Rather it was a human ancestor, who lived so long ago that this ancestor was still a unicellular organism (protozoan-like). Indeed, this endosymbiotic relationship is estimated to have started more than 2-3 billion years ago, i.e. earlier that half the life of the solar system!

A press release from the university says that “thousands of genes are shared by the protozoan Tetrahymena thermophila and humans.” What characteristics do we have in common?

We have in common characteristics in all major processes of cell biology. The genes for these processes are shared by descent from a common ancestor. The gene sequences are conserved (i.e., remain very similar) because Tetrahymena and we are free living, animal-like organisms that have maintained similar cell biology. The functions of the conserved genes are very important and natural selection (in Tetrahymena and in us) has weeded out mutations that would significantly affect that function.

In article published recently in Scientific American posited that natural aging and death will be genetically defeated within the next 30 years given the exponential advances in genetic engineering. Could we be the last generation of mortals?

I’ll bet you a lunch that the prediction is wrong! But if I’m the one who has to pay, it may well be in a coffee house in Paradise because by then our respective well-meaning friends may have had to do us in, in order to make room for the young.

Is it your understanding that fraying at the tips of chromosomes is responsible for natural aging and mortality?

The specialized DNA sequence at the tip pf chromosomes is known as the telomere. They serve a number of functions, a critical one being the protection of the inner sequence of the chromosome (a crude analogy would be the reinforcement at the tip of shoelaces). Perhaps you have read that the fundamental knowledge about the structure of telomeres and how they are maintained was discovered in Tetrahymena. Following up on these studies, it was then discovered that humans (and many other eukaryotes) use the same biology to protect chromosome ends. The relevance to aging and cancer derived from the fact that most types of cells in our body are not expressing the enzyme that maintains telomeres (known as the telomerase). In the absence of telomerase, telomeres get shorter at every cell division. The older we get, the more divisions the cells in certain tissues have to undergo, and they may begin running out of telomere sequence. As chromosomes get shorter, cells sense the problem and stop dividing or die. The relevance to cancer comes because cancer cells are cells with a mutation that inactivates cell division controls and undergo run-away division. If they are not expressing telomerase, sooner or later they run out of telomeres; then they stop dividing or die and the cancer does not get established. (Successful cancer cells need additional mutations that cause the expression of the telomerase gene, or which generate a different way to maintain telomeres.)

Are we more closely related to Tetrahymena than to other protozoa?

We are more closely related to some other protozoa; those protozoa and humans are equally distantly related to Tetrahymena. Still other protozoa are more closely related to Tetrahymena than to humans, while others are equally distant from humans and Tetrahymena because they are at the end of a separate branch from that of humans and Tetrahymena. In fact, most of the biodiversity on Earth resides in unicellular organisms.

Are more closely related to this “tiny predatory protozoan” than we are to some mammals?

We humans are very closely related to all living mammals; all living mammals are equally distantly related to Tetrahymena. Think of an imaginary tree in which all the leaves are at the same distance (as a caterpillar would measure it) from the place where the primary branching occurs. The distance between a human and say a mouse is analogous to the total distance that a caterpillar would have to travel to get from the “human leaf” to the “mouse leaf”. Since that branching occurred near the tip of our branch, the distance is small. To travel from the human leaf to the Tetrahymena leaf the caterpillar would have to go way back to the primary branching and travel along a different primary branch. That distance is much longer.

If not, are we more closely related to it than we are to a fish?

The branching with the fish (which are vertebrates but not mammals) occurred further back that the mouse branch, but is still much closer than the primary branch. Thus we are much more closely related to fish than we are to Tetrahymena. Tetrahymena is equally distantly related to fish and humans.

The press release makes the dubious claim that Tetrahymena has 27,000 genes, “a number remarkably similar to the number of genes found in the human genome.” Does that mean that the protozoan might be as complex as humans?

At the cell biology levels, Tetrahymena and humans are equally complex in terms of the structures and processes that take place within them. Humans are more complex in the sense that they have a variety of cell types that differentiate from the fertilized egg (e.g., blood cells, skin cells brain cells, etc.), while Tetrahymenass essentially possess just one cell type. One way that the added complexity is achieved in humans and other mammals is by making different proteins from the same gene, by cutting and splicing the messenger RNA sequence in different ways in different tissues or in different circumstances. (The messenger RNA is essentially a working copy of the DNA gene sequence and it is used to synthesize the proteins; because it is a copy, the gene sequence itself is not altered by the cutting and splicing.) P.S.: Why do you say “dubious”? Numbers are numbers.

Dubious because it seems odd that a unicellular organism would have as many genes as moi.

Oh, I understand now. With about the same number of genes, we generate a greater diversity of unique proteins by cutting and splicing the messenger RNAs. I hope this reassures “moi” as much as it does me.

Can one gene carry a greater quantity of information than another?

In principle, more information can be encoded in a longer gene than in a shorter gene, just as more information can be encoded in a longer written message than in a shorter one. But, just as in the written message analogy, it also depends on how concisely the information is encoded.

Do we carry around many genes that are not expressed?

Not every gene is expressed at the same time—or in the same cells in the case of multicellular organisms. The level of expression of a gene is very often responsive to environmental circumstances. For example, the presence of heavy metals in the growth medium causes an increase in the level of expression of proteins that can sequester the heavy metal so it causes no harm to other important proteins in the cell. Cells have evolved to be prudent and efficient in the use of their resources, and that includes what genes are expressed under what circumstances.

For how long do unexpressed genes get carried around: one generation, two, 100?

I would suggest more than 1000. A gene that is unexpressed under any circumstances in an organism that grows and reproduces normally would have to be a useless gene. All genes are constantly subject to random mutation, which are more likely than not to be deleterious. (In any complex machinery, there are always many more ways to make random changes in it that will make it work worse rather than better.) If a gene is of no use, there is no natural selection to eliminate its mutations, thus no tendency for the original version to survive preferentially. Thus the sequence of a useless gene changes in a random way with evolutionary time. However, it would probably take in the order of thousands of sexual generations to obliterate detectable similarity to the ancestral form.

Do recessive characteristics eventually disappear from a gene pool if people interbreed with those who have dominant characteristics?

No, there is no tendency for loss as a consequence of interbreeding just because one form of the gene is dominant or recessive compared to another form of the gene. On average, in a large population, the frequency of homozygotes (e.g., AA or aa) or heterozygotes (Aa) tend to remain constant in the absence of natural selection for any given version. Do men and women have the same number of genes?

The Y chromosome has much fewer genes than the X chromosome. Thus, numerically, women have more genes that men because women have XX sex chromosome composition, while men have XY. In terms of distinct genes, men have more, because the Y chromosome has different genes than the X chromosomes. In all other 22 human chromosome pairs, the two members have the same genes.

Is it true that all babies start as females and if stressed they become male?

Not in humans. Sex is strictly determined by sex chromosome make-up, which in turn depends on whether the sperm brought in an X or a Y chromosome. In some animals, the mechanism of sex determination allows sex to be influenced by environmental conditions, like temperature.

Do your protozoa have X and Y chromosomes?

The equivalent of sexes is found in protozoa, and they are called “mating types” because generally there is no shape difference associated with different mating types. Having two mating types is common among many protozoan species. Tetrahymena thermophila is unusual in having seven mating types. A cell of one mating type can mate with a cell of any mating type except its own: Molecules on the surface of the cell of one mating type can react with complementary molecules on the surface of another cell of the same species and signal whether or not their mating types are different. The discoverer of the seven Tetrahymena mating types, David L. Nanney, could have coined a family of seven names, seeded by the words “male,” “female,” and so on. Instead he chose to assign Roman numerals to the mating types.

Do they evolve very quickly? How long have they been around?

Rates of DNA change can be directly calibrated only in organisms (uni- or multicellular) whose remains can become fossilized, like bone- or shell- or wood-containing organisms. Tetrahymenas are entirely made of “soft” parts, and their ancestors have not left any fossils that anybody has recognized yet. On the other hand, and also by comparing related species, we can conclude that the external appearance of the organism has not changed appreciably over recent evolutionary time. It would not surprise me if cells that look like contemporary Tetrahymenas have been around for more than 10 million, and perhaps 100 million years. So Tetrahymena appears to behave similarly to certain animals, like cockroaches, that have been very successful but have not changed much in appearance over long evolutionary times, which are often dubbed “living fossils”.

How much do individual Tetrahymena thermophila differ from one another?

On a purely visual level, to us humans looking through a microscope, they all look about the same but they are basically as similar and dissimilar from one another as humans at the DNA sequence level. (In humans, the fraction of DNA “letters” that are different from one individual to another is about three million, or about 0.1 percent. In Tetrahymena the fraction is not well established.) Tetrahymenas have physiological mechanisms that help them avoid inbreeding and thus distribute more widely any genetic diversity present in the population. We humans also avoid inbreeding, but the mechanisms are largely cultural rather than physiological.

How many species’ genomes have been mapped now?

Hundreds of genomes have been sequenced to various degrees of completion. The majority are bacterial genomes, which are small and thus inexpensive to sequence. In addition, most of the major eukaryotic model organisms (i.e., organisms on which it is easy and less expensive to do research that illuminates the biology of all organisms) have now been sequenced. The cost of sequencing has been decreasing rapidly and the day may come when anyone can afford to have his/her own genome sequenced.

Here is a question for you that my wife reminded me about: How do you tell the sex of a chromosome?

I don’t know. How?

Pull down its genes.

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