Sixty Years of Discovery.

Each of us is a story. Mine is a story of doing science for 60 years, and I am honored to be asked to tell it. Even though this autobiography was written for the Annual Review of Immunology, I have chosen to describe my whole career in science because the segment that was immunology is so intertwined with all else I was doing. This article is an elongation and modification of a talk I gave at my 80th birthday celebration at Caltech on March 23, 2018.

Emerging Cellular Therapies for Cancer.

Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell-based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.

The Way We Walked with Immunology.

It has been a little more than 50 years since we discovered IgE, a key molecule for the allergic response and a target for treating allergies and severe asthma. Here, I trace my career, from the kindling of my interest in immunochemistry to groundbreaking discoveries in the biology and chemistry of immunoglobulins. I describe my service to the broader community of immunologists and my role in shaping departments and research institutes. My course starts in Japan and includes Southern California, Baltimore, and Denver.

Ending "domestic helicopter research".

"Helicopter research" refers to a practice where researchers from wealthier countries conduct studies in lower-income countries with little involvement of local researchers or community members. This practice also occurs domestically. In this Commentary, we outline strategies to curb domestic helicopter research and to foster equity-centered collaborations.

Asian Americans in STEM are not a monolith.

Despite tremendous diversity, Asian Americans in STEM are grouped and viewed as a homogeneous monolith, facing stereotypes and disparities. We propose solutions that include disaggregating the Asian American grouping and recognizing the diverse individual ethnic subgroups that comprise Americans of Asian ancestry to implement change within the STEM field.

Early career Latinas in STEM: Challenges and solutions.

Mexican, Puerto Rican, and Central American Ancestry (MPRCA) individuals represent 82% of US Latinos. An intergenerational group of MPRCA women and allies met to discuss persistent underrepresentation of MPRCA women in STEM, identifying multi-level challenges and solutions. Implementation of these solutions is important and will benefit MPRCA women and the entire academic community.

The NINDS 2021-2026 Strategic Plan: Partnership and cross-cutting principles.

The 2021-2026 Strategic Plan of the National Institute of Neurological Disorders and Stroke began with a vision, a mission, and strategic objectives elaborated from within the institute. This plan is a collaborative product of the institute and its many stakeholders, emphasizing cross-cutting operational principles including scientific rigor, communication, workforce culture, and equity.

Underrepresentation of Asian awardees of United States biomedical research prizes.

The lack of racial diversity among the winners of United States biomedical research prizes reflects a chronic problem of the underappreciation of certain groups of biomedical scientists. Asians continue to be severely underrepresented as awardees of United States biomedical research prizes, a trend that shows no obvious recent improvement.

BRAIN 2.0: Transforming neuroscience.

The NIH BRAIN Initiative is entering a new phase. Three large new projects-a comprehensive human brain cell atlas, a whole mammalian brain microconnectivity map, and tools for precision access to brain cell types-promise to transform neuroscience research and the treatment of human brain disorders.

Francis Collins: Reflections on being the NIH Director.

For over 12 years, spanning three administrations, Dr. Francis Collins has served as the director of the National Institutes of Health. During that time, he and the NIH launched ambitious programs to spur research in diverse topic areas, with important successes. He has also confronted issues facing science and scientists. Dr. Collins recently stepped down as director. Before his departure, he had a conversation with John Pham, reflecting on his time leading the NIH and sharing his perspectives and his hopes for the NIH and the scientific community moving forward.

From Bioorganic Models to Cells.

I endeavor to share how various choices-some deliberate, some unconscious-and the unmistakable influence of many others shaped my scientific pursuits. I am fascinated by how two long-term, major streams of my research, DNA replication and purine biosynthesis, have merged with unexpected interconnections. If I have imparted to many of the talented individuals who have passed through my lab a degree of my passion for uncloaking the mysteries hidden in scientific research and an understanding of the honesty and rigor it demands and its impact on the world community, then my mentorship has been successful.

Short- and Long-Term Adaptation to Altered Levels of Glucose: Fifty Years of Scientific Adventure.

My graduate and postdoctoral training in metabolism and enzymology eventually led me to study the short- and long-term regulation of glucose and lipid metabolism. In the early phase of my career, my trainees and I identified, purified, and characterized a variety of phosphofructokinase enzymes from mammalian tissues. These studies led us to discover fructose 2,6-P2, the most potent activator of phosphofructokinase and glycolysis. The discovery of fructose 2,6-P2 led to the identification and characterization of the tissue-specific bifunctional enzyme 6-phosphofructo-2-kinase:fructose 2,6-bisphosphatase. We discovered a glucose signaling mechanism by which the liver maintains glucose homeostasis by regulating the activities of this bifunctional enzyme. With a rise in glucose, a signaling metabolite, xylulose 5-phosphate, triggers rapid activation of a specific protein phosphatase (PP2ABδC), which dephosphorylates the bifunctional enzyme, thereby increasing fructose 2,6-P2 levels and upregulating glycolysis. These endeavors paved the way for us to initiate the later phase of my career in which we discovered a new transcription factor termed the carbohydrate response element binding protein (ChREBP). Now ChREBP is recognized as the masterregulator controlling conversion of excess carbohydrates to storage of fat in the liver. ChREBP functions as a central metabolic coordinator that responds to nutrients independently of insulin. The ChREBP transcription factor facilitates metabolic adaptation to excess glucose, leading to obesity and its associated diseases.

It's Better To Be Lucky Than Smart.

Bacterial cytoplasmic membrane vesicles provide a unique experimental system for studying active transport. Vesicles are prepared by lysis of osmotically sensitized cells (i.e., protoplasts or spheroplasts) and comprise osmotically intact, unit-membrane-bound sacs that are approximately 0.5-1.0 µm in diameter and devoid of internal structure. Their metabolic activities are restricted to those provided by the enzymes of the membrane itself, and each vesicle is functional. The energy source for accumulation of a particular substrate can be determined by studying which compounds or experimental conditions drive solute accumulation, and metabolic conversion of the transported substrate or the energy source is minimal. These properties of the vesicle system constitute a considerable advantage over intact cells, as the system provides clear definition of the reactions involved in the transport process. This discussion is not intended as a general review but is concerned with respiration-dependent active transport in membrane vesicles from Escherichia coli. Emphasis is placed on experimental observations demonstrating that respiratory energy is converted primarily into work in the form of a solute concentration gradient that is driven by a proton electrochemical gradient, as postulated by the chemiosmotic theory of Peter Mitchell.

Affirming NIH's commitment to addressing structural racism in the biomedical research enterprise.

NIH has acknowledged and committed to ending structural racism. The framework for NIH's approach, summarized here, includes understanding barriers; developing robust health disparities/equity research; improving its internal culture; being transparent and accountable; and changing the extramural ecosystem so that diversity, equity, and inclusion are reflected in funded research and the biomedical workforce.

Fund Black scientists.

Our nationwide network of BME women faculty collectively argue that racial funding disparity by the National Institutes of Health (NIH) remains the most insidious barrier to success of Black faculty in our profession. We thus refocus attention on this critical barrier and suggest solutions on how it can be dismantled.

Emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

Emergence of an early SARS-CoV-2 epidemic in the United States.

The emergence of the COVID-19 epidemic in the United States (U.S.) went largely undetected due to inadequate testing. New Orleans experienced one of the earliest and fastest accelerating outbreaks, coinciding with Mardi Gras. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large-scale events accelerate transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana had limited diversity compared to other U.S. states and that one introduction of SARS-CoV-2 led to almost all of the early transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras, and the festival dramatically accelerated transmission. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate epidemics.

Early introductions and transmission of SARS-CoV-2 variant B.1.1.7 in the United States.

The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2,500 COVID-19 cases associated with this variant have been detected in the United States (US) since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight that the primary ports of entry for B.1.1.7 in the US were in New York, California, and Florida. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid- to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.

Coming to America: Genomic surveillance and how B.1.1.7 arrived in the US.

In this issue of Cell, Washington et al. and Alpert et al. demonstrate the value of genomic surveillance when studying the introduction of the B.1.1.7 variant to the US and illustrate the challenge that results from the lack of good sampling strategies.

Revising the a Priori Hypothesis: Systemic Racism Has Penetrated Scientific Funding.

To manifest our sincerest aspirations to "enhance health, lengthen life, and reduce illness and disability," the US biomedical research enterprise must directly confront the reality of structural racism in scientific funding and the widespread denial of its existence. I believe that moment in American history has, at long last, arrived.