Birkin was a child prodigy who earned his doctorate as a teenager. In 1977, at the age of fifteen, he was employed by Umbrella Pharmaceuticals, and offered to take the executive training program at a laboratory in Arklay County under the oversight of Dr. James Marcus. Birkin and Dr. Albert Wesker developed a friendly rivalry at the school while being conditioned to Umbrella's ethical ideals. Their education was concluded on July 29, 1978 when a decision was made to close the laboratory's school. Birkin and Wesker were offered senior roles at the nearby Arklay Laboratory, and transferred there two days later.
On their first day as senior researchers, the two were introduced to Lisa Trevor, a young woman who had been a test subject at the lab since 1967. The laboratory's chief researcher approved Birkin's study into the splicing of their experimental Tyrant Virus (or "t-Virus") with genes from recently-collected Ebola Virus samples Umbrella had acquired for the purpose of vaccine research. The t-Virus strain at the laboratory had a rapid and high fatality rate, making it useless as a weapon as it was unlikely to spread far. Birkin's study led to a new t-Virus strain which could keep humans alive in an aggressive, brain damaged state.
In July 1981, Umbrella officially employed the child prodigy Dr. Alexia Ashford as a senior virologist. Believed at the time to be the granddaughter of the Umbrella co-founder Dr. Edward Ashford, 5th Earl Ashford, the ten-year-old quickly gained an aura of majesty within the company. Birkin was severely affected by this, firstly with it damaging his pride of being a child prodigy, and secondly his fellow researchers' constant discussion of it. With research having stalled since 1978, Birkin was determined to prove himself and took part in constant research to solve the new problem of some 10% of the population being immune to the t-Virus. This, Birkin solved, with the development of Bio Organic Weaponry, and successfully developed Hunter α, a bio-weapon created through bonding reptilian DNA with a fertilised human egg through the t-Virus. In 1983, Dr Ashford's death was announced company-wide, though Birkin continued in his own research even with the imagined rivalry over.
During his time at the Arklay Laboratory, Birkin began a relationship with another researcher named Annette. They married sometime in the mid-1980s and a daughter, Sherry was born around 1986.
By 1988, the Arklay Lab hit another dead-end in research when its latest project, "Tyrant", was met with a serious flaw. As advantageous, mutagenic properties of the t-Virus were linked to brain chemistry, a strain that caused brain damage was an obstacle. At some point during the research that gave them the Proto Tyrant and T-002, Birkin created a t-Virus strain which lowered the level of brain damage. However, this strain still required the infected to have certain, rare genetic traits that only one in ten million possessed. During this year he gained access to Dr. Marcus' t-Virus research to bolster his own, when Dr. Spencer ordered his assassination. Birkin followed the USS raid party and began confiscating the research, gaining the moniker of "creator" of the t-Virus while the elderly Marcus laid dying of gunshot wounds.As another possible solution to the intelligence problem, Birkin arranged with Dr. Spencer himself to acquire one of Umbrella Europe's NE-α Types, parasitic creatures able to take-over brain functions. However, the parasites were notorious for killing their hosts in their attempts to bond. After exhausting other options, Birkin resorted to using the parasite on the only viable host, Lisa Trevor, who had still survived the years of experimentation. When the parasite was placed within Lisa, her body destroyed the intruder and its DNA was added to her genome, giving her tentacles. An investigation isolated a mutant Progenitor species within her body identified as the cause. Seeing the eugenics potential of a virus capable of mutating humans into a superior subspecies, Birkin sought funding from Umbrella HQ to allow him to work on "Golgotha", known in shorthand as the "G-Virus".
When Birkin's discovery got Dr. Spencer's attention, Umbrella constructed the NEST adjacent to their chemical plant in the northeast of the city, completed in 1991. There, Birkin was chief researcher, and directly led research into Golgotha with his wife, Annette and a team of researchers, with unrelated B.O.W. projects also conducted by other teams in the facility. The Raccoon Police Department's chief, Brian Irons, received bribes to keep any investigations away from the laboratory, and was given updates as to the research.
Though work on Golgotha was promising along the 1990s, Birkin began to suspect Umbrella was disinterested in giving him a position as a corporate executive. In May–July 1998, the t-Virus broke out across the Arklay Mountains, leading to dozens of deaths and mutations of civilians as well as the investigating S.T.A.R.S. members, the loss of the Arklay Laboratory itself, the recently re-opened training school, and a train transporting staff to it. Birkin had the training school destroyed, though he and Wesker already drew the ire of Umbrella executive Col. Sergei Vladimir, who blamed the pair for losing control of the school in the first place. Wesker made the decision to leave Umbrella and sell secrets to a rival company, though Birkin, adamant on completing Golgotha, officially stayed with the company. Plotting to betray them from the inside, Birkin entered talks with the US military to sell them Golgotha for their own bio-weapons project in exchange for an asylum for him and his family.
In early September 1998, Birkin began sabotaging the facilities. The newly-commissioned P12A facility, designed to process contaminated waste, was rendered useless when Birkin flooded the facility with a radically accelerated supply of failed test subjects. The chemical effectiveness was diluted, allowing the virus to mutate and infect the staff with a strain their antiviral medication could not fight. The t-Virus also made its way around the city, infecting the staff at a water treatment plant near the Raccoon Police Station, and sending dozens to the hospital to be treated for the so-called "Cannibal Disease". Umbrella took notice of Birkin's erratic behavior and, knowing only his lab had samples of Golgotha, grew evermore concerned he would prevent them from receiving the virus.
— William Birkin calls out for his daughter following his G-Virus mutation
With Golgotha complete, the U.S. military sent a team out to meet with Birkin. Having moles within the military, Umbrella HQ's suspicions were confirmed and a USS squad was sent out on a race to confiscate the virus first. With advanced warning, the USS operation was disrupted when a police officer spotted them entering the sewers and recovered C-4 explosives. On the night of 22 September, Alpha Team leader "HUNK" arrived at the facility with a subordinate to obtain the virus. In the standoff, Birkin was gunned down with automatic fire after attempting to resist Alpha team. Alpha Team retrieved a duralumin case containing "t" and "G" samples and left for the sewers to their extraction point. The injured Birkin infected himself with a remaining G sample, but the virus didn't properly stabilize onto his body and the scientist himself was unable to become a G-human, and instead transformed into a large creature simply known as "G".
Intent on vengeance, G followed the USS into the sewers and they were all either killed or seriously injured. To guarantee no more samples were at risk of theft, G ate the Golgotha samples. In the process, he also destroyed several "t" samples, allowing rats to consume them and spread the virus into the city's water supply.
Over the next week the city's population of 100,000 were either killed or infected, and the U.S. military blockaded the city to prevent classified information relating to their dealing from getting out. Driven entirely by basic instincts, G searched for food, whether alive or dead and vessels for reproduction. The sewers fell under the control of rejected G embryos, which had made themselves a colony.
Ultimately, G sought out Sherry who, as a blood relation, was a viable carrier for his parasitic larvae. During his search of Raccoon City Orphanage for carriers, he parasitised Chief Irons, who was holding Sherry hostage. He seriously injured T-00 at an elevator to the Umbrella sewer facility as it tried to attack Sherry and another survivor, Claire Redfield, and later moved into the sewers as well. During his confrontation with the survivors in the sewers it became clear he had successfully parasitised Sherry, either in the orphanage or in the sewers, and when she was rushed to NEST for treatment he followed.
While in NEST, G was attacked by Annette with an anti-B.O.W. weapon and suffered serious injury. In his further mutation, he threw Annette at a wall, causing internal hemorrhaging. As the facility began to self-destruct, he followed the Claire as she headed down to the lower levels of the facility to activate the emergency train. His fourth defeat would leave him severely wounded, but G was able to continue on and boarded the escape train. Mutating into his fifth and final form, a blob with multiple limbs, eyes and tentacles, and entered the rear carriages of the train. After a short fight, the carriage was unbuckled, and he was engulfed in the explosion from NEST.