Science as a Way of Life

Francis Tsai, D.Phil., is a young rising star as evidenced by his recipient of the Norman Hackerman Award in Chemical Research, presented by The Welch Foundation to honor up-and-coming scientists at Texas colleges and universities.

Any conversation with Francis Tsai, D.Phil., demonstrates his passion for the complexity of biology. It defines all aspects of his life, professional and personal; past, present and future.

In his 37 years, the Associate Professor of Biochemistry and Molecular Biology, and Molecular and Cellular Biology at Baylor College of Medicine has received a top-notch education from institutions around the world. Leading scientific journals publish the results of his scientific research, and his achievements have already caught the attention of prominent scientific organizations.

Most recently, The Welch Foundation, one of the nation's oldest and largest sources for private funding of basic research in chemistry, presented Tsai the Norman Hackerman Award in Chemical Research, given annually to honor up-and-coming scientists at Texas colleges and universities who are 40 years of age or younger.

His science

Tsai's research focuses on two major areas of biological science critical for understanding the molecular basis of human disease: protein folding and transcription regulation.

"The focus of my research is to understand the structure-function relation-ship of macromolecular machines," said Tsai. "We are using protein crystallography and single-particle electron cryomicroscopy to provide molecular snapshots of the molecules in which we are interested."

Visualizing such structures at atomic resolution requires coaxing proteins to form large three-dimensional crystals. A single crystal is then exposed to a high-intensity X-ray beam, known as synchrotron radiation, in order to map out the position of each atom in a protein structure. By combining these atomic structures with the single-particle electron cryomicroscopy reconstruction of the functional assembly, Tsai and his team have generated three-dimensional representations of their molecular machines in different functional states.

Tsai is particularly interested in the activities of molecular chaperones, proteins that help other proteins fold into correct three-dimensional shapes required to perform their jobs in the cell. While molecular chaperones might be expected to provide the first line of defense against protein misfolding diseases, their function or rather lack thereof causing a protein to misfold remains poorly understood.

Protein misfolding is the underlying cause of many neurodegenerative diseases such as Alzheimer's and Parkinson's disease, said Tsai. Providing a detailed mechanistic understanding of chaperone function may help researchers understand the molecular basis of these diseases. Eventually, that understanding might lead to a cure.

Tsai's most notable achievement was determining the three-dimensional structure of ClpB, a large, molecular machine that, together with the DnaK chaperone system, has the remarkable ability to rescue stress-damaged, aggregated proteins. More recently, Tsai has extended his work to Hsp104, the yeast homolog (similar entity) of ClpB, which, in addition to playing an essential role in the yeast stress response, also functions as a prion-remodeling factor in yeast.

"Prions are unconventional, highly infectious agents responsible for several devastating and invariably fatal neurodegenerative diseases collectively known as transmissible spongiform encephalopathies, commonly referred to as the human form of 'Mad Cow Disease'," said Tsai.

As the first step toward finding a potential cure, Tsai and his colleagues have used the structural and mechanistic information obtained from their work to engineer a novel molecular machine that not only disaggregates but also degrades its target protein. This machine may be further modified to recognize specific disease-causing protein conformers to prevent amyloid formation (implicated in many neurological ailments), said Tsai.

The Art of Science
ClpB trimer: Structure of the ClpB molecular chaperone

In another line of research, Tsai is interested in understanding the mechanism of RNA Polymerase II transcription, a highly regulated process in which the genetic information is transcribed into messenger RNA (which carries the code for making proteins into the factories for such production in the cell).

"We are interested in looking at how transcription factors (proteins that bind DNA at specific sites) regulate the transcription initiation process (what genes will be expressed when and where) and how this may play a role in human disease," said Tsai.

"We are seeking to understand at the atomic level how these transcription factors work," said Tsai. He does so by determining the three-dimensional structure of transcription factor complexes both on and off DNA. This helps him understand how these proteins recognize their target DNA sequence and how they come to work cooperatively.

Ultimately, he and his colleagues would like to be able to control gene expression by identifying the 'on' and 'off' switches that underlie gene transcription.

Exposed from day one

The Tsai Family
From left: wife Sukyeong Lee, Ph.D., also on faculty at BCM, their daughter Anika and son Joshua.

"I was exposed to chemistry from day one," said Tsai. "When I was a child, I collected minerals and was very interested in their structures and chemical makeup."

Tsai grew up in Göttingen, a university town in Germany. While in high school, he concentrated on mathematics and chemistry before branching into chemistry and biochemistry at the Imperial College of Science, Technology and Medicine in London.

He received his doctoral degree from Oxford University and went on to pursue his postdoctoral training as a Wellcome Trust International Prize Traveling Research Fellow at Yale University and the Howard Hughes Medical Institute.

"At Yale, I trained under the late Paul Sigler. Paul had a significant influence on the direction I have chosen to take my research," said Tsai. "He instilled in me the ability to think critically and connect with atomic details."

While at Yale, Tsai met and married his wife, Sukyeong Lee, Ph.D., who was also pursuing her postdoctoral training under Sigler at the time. Lee was a student of Michael G. Rossmann, Ph.D., a pioneer in protein crystallography, and is currently an Assistant Professor in the Department of Biochemistry and Molecular Biology at BCM.

"I first met Francis when I visited the Sigler lab in October 1997. We share a common interest in understanding the structure and function of ATP-dependent molecular machines. At Yale, Francis helped me with my project and provided advice when needed. We got married in February 1999 and have been working closely together since then," said Lee.

A big draw for coming to Baylor was the National Institute for Macromolecular Imaging headed by Wah Chiu, Ph.D., said Tsai. "It is a one-of-a-kind facility. I am very grateful to Wah for providing access to this state-of-the-art electron microscopy facility that is so critical to my research," said Tsai.

"Among many competitive faculty candidates, Francis Tsai was our top choice because of his solid training in crystallography and his interest in the challenging problems in structural biology. Since joining BCM, Francis has been successful in solving the structures of complex molecular machines, which are fundamental building blocks of biological processes," said Chiu, also a Professor of Biochemistry and Molecular Biology at BCM.

Tsai also praised the College's ability to let faculty have the most say in their research. He was recruited to Baylor by Salih J. Wakil, Ph.D., former Chair of the Department of Biochemistry and Molecular Biology.

"Salih encouraged me to follow my passion and to pursue the area of science I was most interested in," said Tsai. "To have the far-sightedness to visualize that my research is important really says a lot about him. It is very encouraging to know that the Department had the faith in our abilities."

On the influence of his parents

Continuing the Legacy
Since childhood, Tsai has been inspired by his parents Drs. Hsin and Jane Tsai (far left), both biochemists who traveled from Taiwan to see their son accept the distinguished Hackerman Award. Also pictured is Dr. Michael Rossmann, who was a mentor of Tsai's wife during their training at Yale.

"We debate quite a bit," Tsai said of his father. "He is a true scholar and likes to take time to enlighten me with his wealth of knowledge, from the principles of protein chemistry to mechanisms of disease. This kind of knowledge is unmatched anywhere else."

Both Tsai's parents live in Taiwan and traveled to Houston in February to see him receive the distinguished Hackerman Award.

"The Welch Foundation was very impressed with Dr. Tsai's devotion to basic chemistry, his originality and his accomplishments in biological chemistry," said Welch Foundation Scientific Advisory Board Chairman James L. Kinsey, Ph.D. "He has brought together a number of different and creative techniques to study the structures of complex molecular structures known as 'molecular chaperones.' These remarkable entities assist in making sure critical proteins fold the right way and it is very important, from a cell biology standpoint, to understand their structure because of the impact it has on human disease."

"This award was very special because it recognized not only the work we had already done, but also the ideas we have not yet had the chance to execute," said Tsai.

In 20 years, Tsai said he hopes to pass along to the next generation the depth of knowledge his parents and Sigler passed along to him.

Advice for the next generation

"Follow your passion, whatever this might be, follow it," Tsai said. "The challenge is to make it feasible." He admits that his approach is not without risk. "Everything you do has its risks. Being the first to see how your molecule looks and how it works is certainly worth it," said Tsai.

Tsai is willing to assume that risk as he unravels the mechanism of protein function to build what he hopes will be a revolutionary approach to understanding disease and ultimately, developing new methods of clinical care.

His science

Exposed from day one

On the influence of his parents

Advice for the next generation

Features

Spotlight

Briefs

Development/Alumni

Volume 4, Issue 2, Summer 2008


	Science as a Way of Life by Glenna Picton Francis Tsai, D.Phil., is a young rising star as evidenced by his recipient of the Norman Hackerman Award in Chemical Research, presented by The Welch Foundation to honor up-and-coming scientists at Texas colleges and universities. Any conversation with Francis Tsai, D.Phil., demonstrates his passion for the complexity of biology. It defines all aspects of his life, professional and personal; past, present and future. In his 37 years, the Associate Professor of Biochemistry and Molecular Biology, and Molecular and Cellular Biology at Baylor College of Medicine has received a top-notch education from institutions around the world. Leading scientific journals publish the results of his scientific research, and his achievements have already caught the attention of prominent scientific organizations. Most recently, The Welch Foundation, one of the nation's oldest and largest sources for private funding of basic research in chemistry, presented Tsai the Norman Hackerman Award in Chemical Research, given annually to honor up-and-coming scientists at Texas colleges and universities who are 40 years of age or younger. His science Tsai's research focuses on two major areas of biological science critical for understanding the molecular basis of human disease: protein folding and transcription regulation. "The focus of my research is to understand the structure-function relation-ship of macromolecular machines," said Tsai. "We are using protein crystallography and single-particle electron cryomicroscopy to provide molecular snapshots of the molecules in which we are interested." Visualizing such structures at atomic resolution requires coaxing proteins to form large three-dimensional crystals. A single crystal is then exposed to a high-intensity X-ray beam, known as synchrotron radiation, in order to map out the position of each atom in a protein structure. By combining these atomic structures with the single-particle electron cryomicroscopy reconstruction of the functional assembly, Tsai and his team have generated three-dimensional representations of their molecular machines in different functional states. Tsai is particularly interested in the activities of molecular chaperones, proteins that help other proteins fold into correct three-dimensional shapes required to perform their jobs in the cell. While molecular chaperones might be expected to provide the first line of defense against protein misfolding diseases, their function or rather lack thereof causing a protein to misfold remains poorly understood. Protein misfolding is the underlying cause of many neurodegenerative diseases such as Alzheimer's and Parkinson's disease, said Tsai. Providing a detailed mechanistic understanding of chaperone function may help researchers understand the molecular basis of these diseases. Eventually, that understanding might lead to a cure. Tsai's most notable achievement was determining the three-dimensional structure of ClpB, a large, molecular machine that, together with the DnaK chaperone system, has the remarkable ability to rescue stress-damaged, aggregated proteins. More recently, Tsai has extended his work to Hsp104, the yeast homolog (similar entity) of ClpB, which, in addition to playing an essential role in the yeast stress response, also functions as a prion-remodeling factor in yeast. "Prions are unconventional, highly infectious agents responsible for several devastating and invariably fatal neurodegenerative diseases collectively known as transmissible spongiform encephalopathies, commonly referred to as the human form of 'Mad Cow Disease'," said Tsai. As the first step toward finding a potential cure, Tsai and his colleagues have used the structural and mechanistic information obtained from their work to engineer a novel molecular machine that not only disaggregates but also degrades its target protein. This machine may be further modified to recognize specific disease-causing protein conformers to prevent amyloid formation (implicated in many neurological ailments), said Tsai. The Art of Science ClpB trimer: Structure of the ClpB molecular chaperone In another line of research, Tsai is interested in understanding the mechanism of RNA Polymerase II transcription, a highly regulated process in which the genetic information is transcribed into messenger RNA (which carries the code for making proteins into the factories for such production in the cell). "We are interested in looking at how transcription factors (proteins that bind DNA at specific sites) regulate the transcription initiation process (what genes will be expressed when and where) and how this may play a role in human disease," said Tsai. "We are seeking to understand at the atomic level how these transcription factors work," said Tsai. He does so by determining the three-dimensional structure of transcription factor complexes both on and off DNA. This helps him understand how these proteins recognize their target DNA sequence and how they come to work cooperatively. Ultimately, he and his colleagues would like to be able to control gene expression by identifying the 'on' and 'off' switches that underlie gene transcription. Exposed from day one The Tsai Family From left: wife Sukyeong Lee, Ph.D., also on faculty at BCM, their daughter Anika and son Joshua. The son of two biochemists, Tsai knew his direction from a very young age. "I was exposed to chemistry from day one," said Tsai. "When I was a child, I collected minerals and was very interested in their structures and chemical makeup." Tsai grew up in Göttingen, a university town in Germany. While in high school, he concentrated on mathematics and chemistry before branching into chemistry and biochemistry at the Imperial College of Science, Technology and Medicine in London. He received his doctoral degree from Oxford University and went on to pursue his postdoctoral training as a Wellcome Trust International Prize Traveling Research Fellow at Yale University and the Howard Hughes Medical Institute. "At Yale, I trained under the late Paul Sigler. Paul had a significant influence on the direction I have chosen to take my research," said Tsai. "He instilled in me the ability to think critically and connect with atomic details." While at Yale, Tsai met and married his wife, Sukyeong Lee, Ph.D., who was also pursuing her postdoctoral training under Sigler at the time. Lee was a student of Michael G. Rossmann, Ph.D., a pioneer in protein crystallography, and is currently an Assistant Professor in the Department of Biochemistry and Molecular Biology at BCM. "I first met Francis when I visited the Sigler lab in October 1997. We share a common interest in understanding the structure and function of ATP-dependent molecular machines. At Yale, Francis helped me with my project and provided advice when needed. We got married in February 1999 and have been working closely together since then," said Lee. In October 2000, Tsai was recruited to BCM, along with his wife. A big draw for coming to Baylor was the National Institute for Macromolecular Imaging headed by Wah Chiu, Ph.D., said Tsai. "It is a one-of-a-kind facility. I am very grateful to Wah for providing access to this state-of-the-art electron microscopy facility that is so critical to my research," said Tsai. "Among many competitive faculty candidates, Francis Tsai was our top choice because of his solid training in crystallography and his interest in the challenging problems in structural biology. Since joining BCM, Francis has been successful in solving the structures of complex molecular machines, which are fundamental building blocks of biological processes," said Chiu, also a Professor of Biochemistry and Molecular Biology at BCM. Tsai also praised the College's ability to let faculty have the most say in their research. He was recruited to Baylor by Salih J. Wakil, Ph.D., former Chair of the Department of Biochemistry and Molecular Biology. "Salih encouraged me to follow my passion and to pursue the area of science I was most interested in," said Tsai. "To have the far-sightedness to visualize that my research is important really says a lot about him. It is very encouraging to know that the Department had the faith in our abilities." On the influence of his parents Continuing the Legacy Since childhood, Tsai has been inspired by his parents Drs. Hsin and Jane Tsai (far left), both biochemists who traveled from Taiwan to see their son accept the distinguished Hackerman Award. Also pictured is Dr. Michael Rossmann, who was a mentor of Tsai's wife during their training at Yale. "We debate quite a bit," Tsai said of his father. "He is a true scholar and likes to take time to enlighten me with his wealth of knowledge, from the principles of protein chemistry to mechanisms of disease. This kind of knowledge is unmatched anywhere else." Both Tsai's parents live in Taiwan and traveled to Houston in February to see him receive the distinguished Hackerman Award. "The Welch Foundation was very impressed with Dr. Tsai's devotion to basic chemistry, his originality and his accomplishments in biological chemistry," said Welch Foundation Scientific Advisory Board Chairman James L. Kinsey, Ph.D. "He has brought together a number of different and creative techniques to study the structures of complex molecular structures known as 'molecular chaperones.' These remarkable entities assist in making sure critical proteins fold the right way and it is very important, from a cell biology standpoint, to understand their structure because of the impact it has on human disease." "This award was very special because it recognized not only the work we had already done, but also the ideas we have not yet had the chance to execute," said Tsai. In 20 years, Tsai said he hopes to pass along to the next generation the depth of knowledge his parents and Sigler passed along to him. Advice for the next generation "Follow your passion, whatever this might be, follow it," Tsai said. "The challenge is to make it feasible." He admits that his approach is not without risk. "Everything you do has its risks. Being the first to see how your molecule looks and how it works is certainly worth it," said Tsai. Tsai is willing to assume that risk as he unravels the mechanism of protein function to build what he hopes will be a revolutionary approach to understanding disease and ultimately, developing new methods of clinical care.		Search all issues: Features Treatments on the Horizon: Chapter and Verse on a Brain Killer Keeping Teen Dads Involved Fellow Travelers: The Human Microbiome Project Explores how our Bodies Co-exist with 1 Trillion Foreign Cells Two Brains are Better than One Spotlight Science as a Way of Life DeBakey Takes the Gold Caring for Community at Home and Abroad Injecting a Little Scientist in Every Doctor Designing a Building in the Eyes of a Researcher Laser Treatments Best Left up to Doctors Briefs Falls in Elderly Indicate Illness Gut-wrenching Facts on Colic Findings may Increase Survival after Injuries Some Like it Hot! Structure of Receptor for Chili Pepper and Pain Revealed Beware of Drinking Margaritas in the Sun Beetle-Mania Development/Alumni BCM Family Participates in Fundraising Campaign BCM Alums take D.C. Fellowships Seed Funding Leads to Breakthroughs Father, Daughter Team up for Health Care Steps to Discovery and Innovation "Everything you do has its risks. Being the first to see how your molecule looks and how it works is certainly worth it." – Francis Tsai, D.Phil.

	Volume 4, Issue 2, Summer 2008



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