At the request of several early readers, I have included additional details here from a conversation describing how the modified chimp was created. Because it is somewhat more technical, I elected to omit it from the text to spare the more trusting reader from wading through the details. The discussion is from a briefing in the Brazilian laboratory headquarters, given by the team of scientists who created the chimp to colleagues who are relatively new to the project.

"A human embryo develops the first primitive nervous system elements by the end of the third week after fertilization. A structure called the neural tube is formed about this time, which serves as the ancestor to cells of the brain and spinal cord. Within a week this tube closes off and begins the gradual development of the nervous system. Early errors in development in the neural tube generally lead to disastrous effects, such as spina bifida. The upper part of this neural tube forms the three parts of the upper nervous system: the brain, the midbrain, and the brainstem and cerebellum." Simons pointed out the corresponding structures on the diagram with her laser pointer. "To spare you unnecessary detail, I will only talk about the development of the part of the brain destined to become the cerebral cortex."

Stiles breathed an uncomfortably audible sigh of relief. Simons appeared not to notice and advanced to the next slide, showing a more developed embryo labeled "Embryo: Sixth Week."

"The developing cerebral cortex begins to fold around and increase in size, forming a left and right side. The interior of each side is hollow, forming what will later be known as the ventricles, a fluid-filled cavity in the brain. Along these primitive ventricles, a layer of stem cells will ultimately develop into neurons in the cerebral cortex, where most of what we think of as cognitive functions will take place such as feeling, seeing, judgment, speech, and decision-making."

A new slide popped up showing a diagram of cell lineage labeled "Cortical Development - Chimpanzee."

"The mechanism by which the cortex develops has been controversial, and I will give you the facts that are clearly known, and then give our bias on what we think really happens." She looked to Nakamura for assurance, and he nodded to continue. "Along these primitive ventricles a structure called a cortical plate begins to form. This begins on day 12 in the mouse, day 40 in the chimpanzee, and day 42 in the human. Prior to this event, the stem cells reproduce, which means that the number of cells destined to become neurons is growing exponentially. At some point an unknown signal is given, and each of these stem cells becomes a miniature factory that makes brain cells, or neurons, which begin to migrate toward the surface of the brain. From this point on, no more factories are made. The process of making brain cells lasts for up to three months in the human, when the cells that will form the brain are mostly developed." She set down her pointer and took a sip of water as she allowed the group to study the diagram.

Jamie raised her hand. Surprised, Dr. Simons responded, "Yes?"

"I'm not sure I'm following you. What are these little factories, again?" Jamie looked around. Am I the only one here that's lost?

Dr. Simons switched gears instantly. "Of course. I'm sorry for moving too fast."

Stiles shot Jamie an impatient look, as if to suggest to her they would all get to the point more quickly without interruptions. Jamie ignored him.

Simons continued, "The point of these factories is that there is a critical moment in time for a developing brain. Before this point, more and more factories are being made. Afterward, each factory starts churning out brain cells. The reason this is so important is that the longer you keep making more factories, the more brain you end up with. The difference between chimps and humans is only two days in the timing of this signal. In those two days, a chimp stops making new factories while each potential factory in a human divides several times. This gives us four to eight times as many factories as a chimp, and makes our brains several times larger."

Simons pointed again to the diagram. "In our modified chimpanzee, this genetic signal that starts corticogenesis comes later, and the final brain contains several times more cortex."

Jamie raised her hand and wrinkled her eyebrows. "Corticogenesis?"

Simons looked apologetically at Jamie and summed up. "Corticogenesis is the process of making brain cells from little cortex factories."

"I see. "

"Our hypothesis was that a key evolutionary event determining the size of the cortex and the complexity of the brain in animals is the time these factories are allowed to divide before corticogenesis begins and factory-making stops. If we could alter the sequence of events that begins at day 40 or 42 to begin a bit later, we could theoretically increase significantly brain size, hopefully without altering the normal developmental functional specification of the brain. Dr. Michaels will talk about what we found." She gave a demure smile to the man seated across the table from her, passing him the mouse.

"This hasn't been tried before?" Jamie asked.

Dr Michaels cleared his throat loudly and shook his head. "The genetic events that determine the beginning of corticogenesis are entirely unknown, ... until now. A theory of Dr. Nakamura's has been that a splice form of a known gene has a crucial role in the timing of cortical development. Beginning with formation of the neural tube, intracellular levels of a transcription factor for this protein steadily increase until a certain key concentration is realized. At this point, a genetic switch is thrown and corticogenesis begins when this new gene begins to be transcribed. From then on, you stop making factories and start making brain cells. Subtle alterations in the coding region for this gene dramatically affect the concentration of the transcription factor required to activate the gene."

A schematic diagram of the gene appeared on the screen, with a diagram below showing the transcription factor binding to the early part of the gene. "We were admittedly skeptical at first, but we agreed to try the experiment of constructing a chimpanzee genome with a carefully chosen alteration in this protein's promoter region." Michaels gave an overly dramatic flourish of his hand. "The result is history."

Nakamura began fidgeting through the discussion and ultimately rose to his feet, evidently ending the exposition of Dr. Michaels, who glumly sat down.

Nakamura spoke, "At first, the chimpanzee was a serious disappointment, and I had abandoned my theory. The only unusual behavior he showed was that he seemed particularly clumsy, unable to hold on to his mother's fur, and slow to walk. We allowed the chimp and its mother to rejoin the colony outside, and pursued other lines of research. Only when Dr. Gupta noticed, quite recently, the startling changes you have all now observed, did we reconsider that the experiment was successful after all." He made eye contact with Simons and Michaels. Jamie thought the scientists looked anxious. Was Nakamura holding something back?

Roger Stiles, who previously had been on the verge of falling asleep, intruded into the discussion. "Look, Ken. Do you mean to tell me this difference was achieved by altering a single bloody gene!?" Nakamura froze with a look of strained patience, to Stiles' obvious pleasure.

Dr. Michaels began, "The alteration was very complicated and involved pasting a novel control region with..."

He was cut off by Nakamura. "That is right. A single gene. Remember, much of our developmental genetics uses preprogrammed packages of genes. Manipulating one of these supergenes can cause dramatic changes in development. Indeed, just such a change may have been a key event in the evolution of our own species. A small change that has a big effect is the rule in evolution."

"And changing this one gene didn't screw up any other organ systems?" Stiles pressed further.

Michaels responded again, undaunted. "That was a clever trick. The promoter region of the gene was altered by a targeted negative enhancer that is only expressed in cortical tissue. The alteration would be effectively silent in other tissues, such as the liver, kidney, and testes where this gene is expressed."

Nakamura nodded in agreement.

Stiles continued. "I'm still a bit skeptical. The mutation might give you more cells, but there are diseases such as macrocephaly where patients have more brain cells and are profoundly retarded. Wouldn't this change the cellular organization? Even more, if the thalamus doesn't grow to match the size of the cortex, how are thalamocortical inputs processed?"

Nakamura stood to his full 5'6" of height. "Macrocephalics have abnormal cells. This is totally different!" Jamie watched as he paused, apparently regaining control of his temper. He continued, "Truthfully, we do not know. Dr. Michaels has given the matter much thought." He motioned to Michaels.

"We do not believe the mutation would affect the downstream organization of the cortex, but that is unknown. Likely, the cortex develops locally with a modular organization. Specialization of the cortex is thought to occur late in development based on inputs to various regions of the brain. Before thalamic inputs arrive, the cortex is mostly homogeneous, and more cortex is unlikely to change the local circuitry. Thalamic inputs are known to be highly plastic in early development, and it is possible that more cortical targets would stimulate thalamic growth. It is certainly possible that the entire cortical organization and circuitry would be preserved in the chimeric chimp, but we would defer to your expertise on whether or not this is indeed the case."

Stiles simply nodded.

Jamie Kendrick stroked her chin. "This change is heritable?"

Dr. Simons answered the question. "We have every reason to believe that it would follow a normal inheritance pattern. Since we only needed to implant one copy of the altered gene, half of the offspring should receive the mutation with the same functional outcome. Of course we don't know for sure that the gene doesn't follow some type of imprinting..."

Sameer Gupta now asked, "So for this monkey, what day does corticogenesis actually start?"

Nakamura answered tersely, "We don't know. Our simulations predict day 43, but we cannot know without sacrificing a 43 day old embryo, which we do not yet have."