The microbe-ulous man
The same technology that was used to sequence the human genome is now helping researchers understand the diversity of our ecosystems, and improve our environment.
Dr. J. Craig Venter, president of Maryland’s J. Craig Venter Institute of genomics research and a 2002 Gairdner award recipient for his work in sequencing the human genome, returned to the Gairdner lectures to discuss how genomics may help us understand the environment and develop new approaches to solving environmental issues.
In a global oceanographic journey aboard the sailboat Sorcerer II, Venter led a group of scientists collecting seawater from different corners of the world to create a “genomic catalogue” of microbial diversity. To sequence the genomes of the microbes, Venter used “shotgun sequencing,” a strategy that breaks the genome into small overlapping sequences, and re-assembles the sequences with computer algorithms that can read and sort the overlapping segments, a method his group employed in sequencing the human genome.
“Most people think the ocean is a giant homogeneous soup, it’s anything but. It’s tens of millions of microenvironments changing dynamically.” Venter explained.
Collecting samples every 200 miles, Venter and his team found unique species of microbes in each sample of seawater-so different that the microbes in a single sample of seawater could be used to trace the oceanic region the sample came from. Each water sample revealed new gene and protein families of unknown functions not known elsewhere on the planet.
Venter’s group is presently working on a similar project to analyse microbes in the air.
Venter hopes to harness the large amount of genome data collected thus far to engineer synthetic organisms containing a minimal set of genes adequate for their survival, and genes conferring a desirable biochemical process. The production of the fuel methane is one example. This process has been found in Methanococcus jannaschii, a microbe that flourishes in the Pacific Ocean in the absence of sunlight, oxygen and organic material. Venter believes it will be possible in the future to reconstruct larger genomes and create single cells with other applications, such as the conversion of cellulose to ethanol as alternative fuel.
-Mandy Lo
Life in a petri dish
A self-described “simple-minded” scientist, Dr. Ralph Brinster from the University of Pennsylvania established techniques 20 years ago that today allow scientists to genetically manipulate the cells “most important to nature”-germ-line cells. These are the only cells in the human body that can transmit genetic information to subsequent generations.
“What we do now was unimaginable 20 years ago with germ cells,” said Brinster, a 2006 Gairdner award winner, since the methods to study embryonic development were not yet in place. Brinster was the first to establish the conditions necessary to grow embryos in a petri dish. Scientists today use his findings to make alterations in germ-line cells at will.
Commonly termed the “culturing” of cells, scientists grow embryonic cells in vitro by isolating cells from an animal and implanting them into a mouse blastocyst, or early embryo. The blastocyst is then placed back into the mouse, and develops into a mature mouse fetus that has cells of both the mouse and the animal the implanted cells came from. These methods have allowed scientists to develop transgenic animals that are used as models to study the way genes function.
“No matter what kind of exciting idea you have, you must sell it,” said Brinster. “But reserve 25 per cent of your time to [work on] the dream you don’t tell anyone about.”
Brinster’s own secret research led to his discovery of a method to grow spermatogonial stem cells in vitro. These are primitive cells that can later develop into sperm cells.
His work has opened up new possibilities in germ-line therapies, like treating sterility in male cancer patients taking chemotherapeutic drugs which destroy sperm cells.
-Nira Datta
Prevention for the HIV pandemic
“We can no longer accept the status quo in the ever-increasing numbers of HIV-infected individuals,” said Dr. Allan Ronald, this year’s recipient of the Wightman Award, an international award recognizing outstanding leadership in medicine. The award was given to Ronald, a medical scientist at the University of Manitoba, for his research on infectious diseases, particularly HIV and other sexually transmitted diseases.
“Only with the effects of prevention will we ever hope to begin the long journey to the partial conquest of AIDS,” he said. While recognizing the vast improvements in HIV morbidity and mortality rates since the introduction of antiretroviral therapy, Ronald explained that new treatment strategies and the expectation of an HIV vaccine have diverted attention away from prevention.
Because the most optimistic researchers predict at least a decade before the development of a vaccine, Ronald argued that we must focus on stopping the spread of the disease through prevention strategies. These include targeting injection-drug users for intervention programs, ensuring sex workers in developing countries have ready access to condoms, promoting male circumcision, and simply encouraging people to get tested for HIV.
Ronald challenged scientists to be passionate about their work in the medical sciences, as the history of politics and activism surrounding HIV has changed the way we approach the science of pandemics.
“AIDS has spawned activism that has altered forever the independence that science has had from the diseases we study,” he said.
-Mayce Al-Sukhni
No heart is hopeless
After an acute myocardial infarction, commonly known as a heart attack, the heart needs to regenerate in order to resume normal function. However, many patients relapse into heart failure, their hearts unable to adequatly repair, even after the heart attack is treated and the patient is given drugs that reduce their chance of mortality.
“The reality is that even despite these drugs, the impact of mortality is about 30 per cent in five years in these patients,” said Dr. Victor Dzau, the dean at Duke University’s medical school. Dzau’s research suggests that gene therapy can prevent-and reverse-the damaging after-effects of myocardial infarctions.
“The idea is to give a therapeutic agent preemptively [to high-risk cardiovascular patients] so that it is around to give life-long protection,” he said. The treatments under scrutiny are gene products and stem cells for their potential in stimulating heart tissue regeneration. Current evidence has shown that the “hemoxidase” gene can provide heart preservation and protection against heart injury incurred during an attack.
However, gene and stem cell therapy are both a long way from being used for human treatment. While it is still too early to know the impact of these treatments, cell-based heart regeneration strategies would be better than any currently available treatment approaches, said Dzau.
-Mayce Al-Sukhni
The prion paradox
Of all the millions of proteins that comprise a living organism, every now and then a few misbehave. When proteins in the brain misbehave, they can cause a class of diseases called the spongiform encephalopathies, or the prion diseases.
“The normal cellular protein unfolds…thereby losing its normal function, and then mis-folds into a different conformation,” said Dr. John Ellis of Warwick University, a 2004 Gairdner winner. The protein gone bad begins to affect the normal proteins around it such that all begin to “go bad” and accumulate into visible clumps-dubbed “amyloid plaques.” Slowly, neurons begin to die and symptoms of the prion disease ensue, often appearing very similar to Alzheimer’s disease.
While the plaques are made up of (misbehaving) normal brain proteins, each case of prion disease has its roots in some original molecular sin. While spongiform encephalopathies like Huntington’s disease have a direct genetic cause, the cause of pandemics like Alzheimer’s remains unknown. The most frightening prion diseases are transmissible ones, spread by eating “mad cow” beef or blood transfusions. Because these diseases can require decades to become symptomatically apparent, transmission of the prion from an unaware transfusion donor to the blood recipient can take years for scientists to pinpoint.
Ellis’s research team, like many others, is devising a strategy to detect prions in the blood in order to help staunch the spread of transmissible prion diseases through blood banks. However, because prions are resistant to sterilization, degradation, and look almost like a normal protein, locating a single protein in a hundred thousand is no easy feat.
“[The prions’] unprecedented behaviour poses an intellectual challenge,” said Ellis. “But even more exciting is the possibility that their behaviour is just the tip of a vast iceberg of novel protein properties that lie out there waiting to be discovered.”
-Sandy Huen
Immunity and influenza
“Infection is the process where simple life forms either live in or on us,” said Dr. Peter Doherty from the University of Melbourne, a Nobel Prize laureate and a 2006 Gairdner award recipient. “The main goal of immunity is to minimize the tax of infection.”
Since viruses evolve mutations very rapidly, humans have evolved immune systems that can deal with this complexity. Doherty was the first scientist to show that T-cells in our immune system are responsible for recognizing and rejecting foreign substances.
Doherty currently works on the influenza virus and its many variants, the most infamous of which is the H3N2 influenza strain, which has caused pandemics every two years for the past three decades. In the U.S., approximately 40,000 people die of the influenza virus each year.
“The current opinion on the impact of influenza virus is divided amongst biologists. One group believes this is a bird virus that occasionally transmits into humans and that it’s not going to jump to different species. Yet the other group of scientists believe that there may be a chance random event that will cause a massive human outbreak. The truth is, we don’t really know,” said Doherty.
With a two billion investment in the development of flu vaccines, U.S. president Bush has taken the potential threat of an influenza pandemic quite seriously. Because influenza viruses mutate incredibly rapidly, developing effective vaccines is a constant battle for scientists.
-Nira Datta
A mathematical handshake
The explosion of genetic and protein data into the scientific community has resulted in a fast-paced race to publish new discoveries about human cells. Just how exactly do scientists organize the vast amount of information involved?
“Cellular networks are more complicated than the Tokyo subway, and at least that’s colour-coded!” exclaimed Dr. Sydney Brenner of the Salk Institute in San Diego, a 2002 Nobel laureate and a 2006 Gairdner award recipient. He explained that cells use simple arithmetic to get around such complexity.
“I call it the income tax principle,” said Brenner. “As we all know it is criminal to evade paying income tax, but there are legal means of avoidance. A cellular system treats complexity like income tax: cells don’t solve the problem, they just avoid it.”
“E. coli found a way to avoid the complexity of 4,000 biochemical reactions happening in the same space,” said Brenner.
Our cells are large communication systems organized into various compartments, each carrying out their designated function in a relatively focused manner, and communicating to various other compartments within the cell at the same time. Scientists began to understand cellular networks by doing the same thing, understanding one part of the cellular system, and then expanding the scope to wider levels.
Brenner explained that biologists can use simple “cellular arithmetic” as a way of avoiding the incredible complexity of cellular networks.
This arithmetic is based on the principle that protein interactions are symmetrical, forming “dimers,” complexes made up of two proteins.
“A dimer is like a handshake. When you put out your right hand and shake mine, this is symmetry,” said Brenner. Like insulin and insulin receptors on the surface of cells, one molecule combines with the other in a dimer in order to elicit a cascade of reactions in the cell, many of which will involve forming more “molecular handshakes.”
Brenner believes this basic interaction can predict the total amount of proteins involved in a single cellular process, like the complex reaction of a cell to insulin. Scientists could simply count the number of proteins predicted to be involved in a specific cellular system.
“You don’t have to do any courses in analytical algebra-it’s all generally sums,” said Brenner.
-Nira Datta
De-junking RNA
Ribonucleic acid biology has emerged as a central component in understanding how our genes are expressed and controlled. A 2006 Gairdner laureate, Dr. Joan Steitz, pioneered work in the field of RNA biology in an effort to determine how RNA molecules function in living cells.
The central dogma of molecular biology describes how our genes are expressed in a three-step process: DNA is transcribed into RNA, which is then translated into protein. The protein carries out its designated function as originally specified by the DNA that encoded the protein.
However, a lot of junk in our DNA, known as “introns,” need to be removed from RNA before a final protein is made. Relieving the RNA of its introns requires an intricate array of cellular machinery to ensure accurate removal.
“There is cellular machinery that can precisely recognize the boundaries between the junk and the good stuff and make cuts at the ends of the junk,” explained Steitz, who helped elucidate this splicing machinery. The splicing complexes are comprised of small nuclear ribonucleoprotein particles, or snRNPs, which are complexes of protein and RNA.
“My lab is currently looking at how splicing is connected to other events in gene expression, such as the molecular interaction between RNA processing events and transcription, export, and things that happened in cytoplasm of a cell.”
-Nira Datta
