A tennis player, a construction worker, a mixed martial artist and a tuba player each suddenly collapse and die. Thirteen goes to the classroom of Apple Weiss who is at the blackboard teaching college mathematics. All the patients who received a transplant five years ago are either dead or dying. Apple is on that list after receiving a corneal transplant. She is sent to the ICU of Princeton-Plainsboro while an older man named Frank lies nearby in an open bed, dying.
Foreman, Kutner, Thirteen and Taub gather in the hospital's morgue reading the toe tags of the transplant victims. The construction worker got a new heart and lung, but his liver killed him. The tuba player was the recipient of a new liver, but his lungs caused him to die. The tennis player was given a kidney but her heart failed. The patient Frank got an intestinal graft and now his pancreas is failing. In each case, serious complications came on suddenly and without warning.
House is more concerned with picking apart his relationship with Wilson. Taub wonders if the donor had an infection that somehow slipped by the screening process, but Kutner and Thirteen disagree. She is convinced that whatever they got came from the donor's blood instead. Since corneal transplants are bloodless, Apple will be fine. Thirteen thinks cancer is the only other prognosis, but Foreman argues that cancers have a progression that affects specific organs. House dismisses the cases as cancer-related and exits.
Yet lab tests reveal later that the causes are not cancer. House orders the staff to start investigating the donor and the backgrounds of the victims.
In the hospital cafeteria, House approaches Dr. Laibson and tries to solicit his friendship as a possible replacement for Wilson. Foreman approaches their table and tells House they need to remove Apple's eye.
House and Foreman test Apple's sight. Foreman tells her they need to remove her eye but House says it is unnecessary because it seems to be a brain issue, not her eye. House makes a joke that they will have to remove her whole head. Suddenly, Apple hallucinates that House has whipped out a large cleaver and is swinging it at her neck. To House, this is proof that her brain is the problem.
Taub, Foreman, Thirteen and House watch a videotape of the martial artist's fight to look for signs of neurological problems. A man named Lucas stands behind them pretending to fix the coffee machine. He is wearing argyle socks. Lucas joins in the conversation about Apple. When the team question who he is, House admits that he hired a private investigator to find out about the organ donor. Lucas has far more detailed information than the team uncovered. He knows that Frank's high school sweetheart is now married to his best friend and she had a kid four years ago.
House asks his team to get a biopsy from the patients' brains even though this is a risky procedure. In the ICU, Apple appears relatively young and healthy while Frank looks nearly dead. Taub tries to persuade Frank's wife to consent to the biopsy, saying this is actually his best chance for recovery. Apple fights with Frank's wife about doing the procedure. Frank's vital monitors start going off. Despite urgent efforts to save him, Frank flatlines.
Frank's brain is brought to the lab for examination. Taub says it looks clean. House insists that cancer is the cause, but Foreman calls him out on this. House wants it to be cancer so that he will have an excuse to talk to Wilson. Kutner comes up with the diagnosis of a perforated intestine. "If this thing started as normal bacteria living in the intestines, but got into a blood vessel through a vascular anomaly in the bowel wall, then they could get into any organ in the body via the bloodstream," he explains. The others realize that Kutner could be right, and House orders a colonoscopy to confirm. Although they already checked Apple, House wants to test someone with the donor's DNA. Frank's ex-girlfriend probably had her daughter with Frank, and House wants to exploit the fact that the husband may not know his daughter's true identity. Kutner performs the colonoscopy on the young girl.
House and his private eye Lucas sit in the back of an ice cream truck on a stakeout. House asks what he found out about the donor, yet Lucas knows that House is really interested in him checking out Wilson.
With the girl's colonoscopy deemed clean, House thinks that all that is left is cancer. Foreman considers that Kutner could still be right about an intestinal infection. The opening would have to be bared shortly before death. Kutner suggests they use the same high-pressure water jet used to test cardiac workload. Foreman performs the water procedure on the rectum of Frank's corpse. When the colon fills with fluid they get an image. Foreman pushes on Frank's abdomen to contain the seepage from the autopsy Y-incision. As the endoscope advances further into the body, the colon explodes. Frank's entire abdominal cavity blows onto Foreman.
Nurses attend to Apple's declining health. House orders the team to start immuno-gels on her CSF to look for hidden protein markers and then sequence her genes. He is going start treatment for cancer. While Apple sleeps, House watches her breath shallowly. He presses the call button and a nurse races into the room. Apple wakes. House asks where Apple's chart is and the nurse finds it on a dresser across the room. House puts the chart aside and pulls a form out of his back pocket. He needs Apple to sign consent for chemotherapy. She tells him that she was an architect but gave it up to teach math after she regained her sight. She believed her life would change after her transplant but the world was too ugly. She asks if House thinks he'd be any different if his leg was fine.
As House and Lucas walk down the street, Lucas informs him of Wilson's activities. The pair follow a pretty girl, who stops to confront them. Clearly, Lucas is not the savviest snoop.
House enters the ICU to find Apple vomiting. House tells Foreman that she does not have cancer. He thought it had acted like cancer, and if it acts like cancer then maybe it would respond like cancer.
House goes to see Wilson at home searching for an epiphany. Wilson refuses him, so House throws money at him. "Next time you knock, I'm not answering," Wilson says, shutting the door. Frustrated and annoyed, House emerges from Wilson's building only to be met by Lucas. "Friends are friends, customers are customers -- and everything else is everything else," Lucas proclaims. House has his epiphany and turns to hurry off. He turns back to tell his newly rented friend, "The world's not as ugly as she thinks it is."
House enters Cuddy's office with an MRI. Apple's occipital lobe is normal, but her eyes are bad and that lobe should be compensating. "Since it's not, that tells me something's in there that shouldn't be there. Brain but not brain," he notes. House asks for permission to chop off the top of her head to find it. The donor had cancer stem cells which were transferred to the recipients. The cells floated around, landed on an organ, got bathed in cytomes and partially differentiated. The cells seemed to belong to their new environment but they weren't doing their jobs. The chemo worked because they were tumors. This argument doesn't convince Cuddy.
Security guards man the ICU. House does not enter. A male nurse finishes changing Apple's IV bag when her pulse and BP start to fall. The nurse's socks are argyle. It is Lucas, who discreetly slips out.
Apple is sent to surgery, where Chase removes her skull. House watches from the gallery and tells the surgeons that they might want to check her IV. It looks like it was switched to saline instead of chemo. Lucas comes into the gallery and House explains that the neural net they are placing in her skull will show how fast her neurons are working. With tainted cells, the normal neural impulses will get sucked into a vortex which the computer will process and instruct the surgeons where to cut. Lucas notes that House has no one else to talk to, so he is paying him to listen. Chase sees the problem in Apple's brain and removes it.
Post-op, Apple's entire head and eyes are bandaged. House watches Apple, who can smell him there. He begins to unwrap her dressing. Then he pushes the call button. Nurses hurry in, and House smugly asks for peppermint tea. "The world is ugly but the world isn't as ugly as you think it is," he tells Apple. House presses the call button again, which causes nurses to scurry in once more. House explains to Apple that her eyes are fine but it was her brain that wasn't working right. She will now see things as they are. Apple slowly opens her eyes. "How do I look?" House asks. Apple says that he looks sad.
Alone at his desk, House phones Lucas. "Is there any way I can put you on retainer?" he inquires to the investigator.