Howard A. Young's 4 Decades in Science: More Than Just Experiments

“Somewhere, something incredible is waiting to be known.”

– Carl Sagan

Howard A. Young's curiosity and quest for finding something incredible have driven and sustained his scientific career. As a scientist, mentor, organizer, colleague, friend, husband, father, and grandfather, Howard (Fig. 1) has and continues to have a remarkable impact not only on the scientific enterprise, but also on the lives of many. His 40 years at National Cancer Institute have been a testament to his commitment to investigative research, leadership, mentoring, and community involvement. For this Festschrift, there is much to honor, to emulate, and to celebrate as new and incredible discoveries continue.

FIG. 1.

Howard A. Young, scientist, leader, mentor and friend.

It has been my privilege to follow, appreciate, and work with Howard among the seasons of his career. Despite parallel paths during our training, we unfortunately missed out on opportunities to interact and begin our friendship before arriving at the NIH campus. For example, we were both in Seattle at the University of Washington School of Medicine where Howard was working on his MS and PhD in the department of microbiology with Helen Whitely and I was a few floors up obtaining my PhD in the department of biological structure (a.k.a. anatomy) with M. Roy Schwarz.

Most folks ventured in the opposite direction from our graduate student offices as they were located next to the gross anatomy laboratory with the perpetual smell of formaldehyde. In the months after completion of my PhD and until my wedding, I did a brief postdoctoral fellowship with Russell Ross in the department of pathology, somewhat closer to the department of microbiology. Although in the same building, our paths did not knowingly intersect, which, in retrospect, was a disappointment since even then, Howard ran his department's “Party House” (including, but not limited to collecting beer money from faculty, weekly football pools, large Thanksgiving gatherings, and salmon fishing trips).

Again, following parallel, but separate routes, we both ventured across the country from Seattle to Bethesda in the 70s for our postdoctoral fellowships at the NIH, Howard, with Ed Scolnick and Wade Parks in NCI and I with Joost Oppenheim at NIDCR. Our “almost paths crossings” continued as Joe later hired Howard to be the molecular biologist for the Biological Response Modifiers Program when Joe moved from NIDCR in Bethesda to NCI in Frederick, but I remained in Bethesda to assume Joe's vacant section chief position.

Always precocious, Howard was first author of a publication from his new postdoc position at NCI within his first 3 months in the laboratory (Young et al, 1975), quite an accomplishment. His work continued to shine in this environment, as he focused on regulation of mouse mammary tumor virus (MMTV). Decades later, he still recalls a particularly memorable moment that occurred while attending a lecture by James Darnell, a well-known leader in research focusing on how genes are regulated. In this lecture, Dr. Darnell, discoverer of STAT and the Jak-STAT pathway of transcriptional control (Stark and Darnell, 2012), highlighted 2 articles that he believed had really initiated the field.

One of these articles was Howard's showing that administration of glucocorticoids to cells induced MMTV RNA within minutes (Young et al, 1977). This recognition of a postdoc by a stalwart in the field made a lasting impression on that young postdoc. These early studies were also particularly important to Howard and his laboratory at the time because there was keen competition with other laboratories, including that of Harold Varmus, to define pivotal gene regulatory mechanisms (Varmus et al, 1979). As Howard's research portfolio expanded, it evolved to include cloning of rat sarcoma virus oncogenes (Ellis et al, 1981) and their regulatory mechanisms.

A decade later, Howard's research led to the first molecular characterization of interferon gamma (IFN-γ) regulation (Sica et al, 1992), an auspicious beginning to an area of research that has dominated the past quarter century of his research career. Providing compelling evidence that IFN-γ promoter methylation controlled IFN-γ expression was pivotal. This pathway was found to be fundamental in differentiating Th1 from Th2 cell populations (Young et al, 1994). Taking this a step farther, Howard then characterized NFκB and NFAT as central players in the regulation of IFN-γ expression (Sica et al, 1997).

It was this incursion into the cytokine field that finally resulted in the crossing of our otherwise parallel paths, and the beginning of our scientific connections and longstanding friendship. In the 90s, Howard and I had the opportunity to work together on the development and organization of the NIH Cytokine Interest Group (CIG), which remains active and relevant today. We both served on the steering committee and Howard became chair in 1997 and again in 2001. I also served as chair, helped organize symposia, and was CIG treasurer for several years. Howard was instrumental in establishing the NIH Immunology Interest Group (IIG), cochairing their steering committee twice.

More recently, Howard established an NIH/FDA Microbiome Working Group and a Microbiome Listserv, designed to coordinate and promote the flow of information regarding microbiome research in the NIH and FDA intramural programs. In his typical altruistic manner, he believed that fostering cross-agency communication about the microbiome was essential, even though his own microbiome research was limited. These interest groups function to successfully bring together researchers from across the NIH, FDA, and beyond, fostering collegial interactions, collaborations, and a large supportive network for sharing data, reagents, advice, and guidance in immune-based and microbiome research programs.

Our research interests intersected in our mutual focus on cytokines, particularly interferon and transforming growth factor beta (TGFβ). Initially interested in chemotactic factors, my laboratory's first studies involving TGFβ occurred in the 80s in collaboration with Anita Roberts and Michael Sporn from NCI, and centered on its ability to function as a chemoattractant for monocytes (Wahl et al, 1987).

Intrigued with this molecule that had such incredibly potent recruitment potential, we began in those early studies and beyond to explore its multiple roles in immunoregulation (Wahl, 1994), including immunosuppression, Treg induction (Chen et al, 2003), and regulation of Th17 cell populations (Mangan et al, 2006). Although several years lapsed before Howard published his first article involving TGFβ (Lyakh et al, 2005), he did ultimately recognize its remarkable immunoregulatory potential.

The feeling of awed wonder that science can give us is one of the highest experiences of which the human psyche is capable. – Richard Dawkins

Many of Howard's early and ongoing IFN-γ studies have been a source of “awed wonder.” Whenever questions regarding IFN arose, we always knew to check with Howard, the local expert. Delving into IFN production and regulation in our own studies linked to HIV and opportunistic infections (Peng et al, 2006; Vazquez et al, 2011) and in our murine models of inflammation and infection (McCartney-Francis and Wahl, 2002), we followed the trails and insightful data carved out by Howard's work. Rather than reinventing the wheel, we were fortunate to be able to capitalize on what Howard and others in the field had already tackled and definitively characterized (Biron and Tarrio, 2015; Darnell, 2007).

As a key immunoregulatory molecule in innate and adaptive immune responses, IFN-γ, a single-copy gene, and its molecular characterization have been a long-term emphasis in Howard's research program (Sica et al, 1992). Through a multipronged approach, his laboratory's evidence revealed that in addition to epigenetic mechanisms and chromatin accessibility, transcription levels involved regulatory proteins binding to promoter and enhancer elements, and post-transcriptionally, protein kinase R, protein folding, and microRNAs amplify expression. These numerous control sites are consonant with the widespread and potent biological effects of IFN-γ.

Additional cytokines, individually and in concert, can synergistically influence IFN-γ gene expression. In this regard, Howard's experiments demonstrating how IL-12 can regulate IFN levels (Hodge et al, 2002) served as a blueprint in our studies linking another cytokine, IL-27, to regulation of IFN expression (Greenwell-Wild et al, 2009). One of the critical end targets of inducible IFN-γ synthesis and signaling is macrophage activation (Young and Bream, 2007), fundamental to host–pathogen interactions (Dobrovolskaia and Vogel, 2002; Martinez and Gordon, 2015; Trinchieri and Sher, 2007) and the predominant host cell studied in our laboratory (Orenstein et al, 1997).

The dimeric structure of IFN-γ when complexed with its receptors, IFNGR1 and IFNGR2, transmits the trigger(s) for these pleiotropic activities (Ivashkiv, 2018; Vazquez et al, 2011). Quite intriguing is how certain pathogens implement pathways to resist IFN activation for self-preservation (Hisert et al, 2004; Vazquez et al, 2006), and such pathways continue to be dissected.

To get to know, to discover, to publish – this is the destiny of a scientist. – François Arago

As a successful scientist, Howard is very inquisitive, extremely productive, and publishes profusely, fulfilling his destiny as a scientist that is reflected in his author/coauthorship on >300 publications. With no waning of his innovative research, when he was asked for his top 5 favorite publications, with some difficulty, he narrowed it down to 12! His current work delving into the mouse model he engineered has unraveled multiple unanticipated and crucial roles for IFN-γ, with the potential to reveal therapeutic interventions in autoimmune-related diseases. In these recent creative and informative research directions, Howard and his team first demonstrated that removing the adenylate-uridylate-rich elements (AREs) in the IFN-γ gene (Hodge et al, 2014) resulted in more stable mRNA and persistent IFN-γ expression.

By targeting the 160-bp conserved region rich in AUUA sequences of the murine IFN-γ 3′ untranslated region for replacement, the resultant mouse produced significantly more IFN at a basal level and also upon stimulation compared with wild-type mice. In addition to disruption of lymph node, spleen, and thymus architecture, signs of chronic inflammation were evident in the liver. After backcrossing this mutation onto the murine C57BL/6 and Balb/c genetic backgrounds, new models for lupus, primary biliary cholangitis (PBC), and aplastic anemia have emerged.

Whereas BL/6 mice exhibited a lupus-like condition, PBC, and ovarian failure syndrome, Balb/c mice developed aplastic anemia. These findings parallel elevated basal levels of IFN-γ detected in human patients experiencing chronic inflammation, propelling this model to the forefront to dissect the biological consequences of sustained IFN-γ gene expression and its disruption of host immunity and defense.

An open mind and persistence have led Howard into many of his important discoveries and novel findings. Rather than focusing strictly on the anticipated alterations in the IFN-immune axis, Howard and his collaborators have blazed new trails and unearthed a treasure trove of unique targets and consequences controlled by the elevated IFN-γ and its linked pathways. In this regard, his mouse model for PBC is now considered by many as the best animal model for the disease (Bae et al, 2016), largely based on its female bias, which mimics that 90% of human cases are in women.

Similarly, upregulation of total bile acids, spontaneous antimitochondrial antibody production, and portal duct inflammation occur both in humans and in the murine model. In recognition of the utility of this model, the mice are being distributed worldwide to enable exploration of disease development and potential therapeutic targets for mitigation (Bae et al, 2020; Bae et al, 2018). Another novel finding currently under investigation in this ARE model is what appears to be the development of autoimmune ovary failure syndrome (Young et al, in preparation).

Not to ignore the opposite gender, Howard and his lab in ongoing coordinated analyses, have shown that male ARE mice expressing persistent low levels of IFN-γ develop an unexpected heart defect, most apparent after exercise. Heart function was determined by a swim test, and one can easily envision Howard setting up a swimming pool for mice in his laboratory to explore exercise-induced cardiac dysfunction. Although cardiomyopathies have long been associated with autoimmune diseases, appropriate models have been lacking.

Accordingly, Howard's ARE mice now offer a unique opportunity to assess stress responses, myocarditis, and fatigue in the context of chronic IFN-γ expression, autoimmunity, and gender biases. Clearly, Howard's research endeavors span the basic sciences and translational studies with clinically relevant implications, and his research is transforming our understanding of gender bias in autoimmune diseases.

Continued examination of the nuances of these genetically altered mice unmasked another unpredicted aberrancy in that the mice appear to be susceptible to melanoma. Howard's initial data suggest that melanoma development may be coupled with an increase in IL-27 gene expression (Valencia et al, 2021), indicative of a cytokine cycle. Such observations open another window into the complex mechanisms regulating IFN-γ expression, but also how IFN-γ levels, once distorted, dramatically sway host immune homeostasis. Howard's imaginative and dynamic research portfolio sits at the junction between pathways linked to aberrant regulation of IFN-γ, immunopathogenesis, and potential therapeutic targets.

As Howard continues to champion basic and translational exploration of cytokines, autoimmunity, and tumorigenesis (Valencia et al, 2021), his scientific successes, coupled with his spirit of congeniality, have facilitated his elevation into key leadership positions. Through increasing levels of leadership in the NCI and instrumentality in developing and leading the highly regarded CIG and IIG, Howard exemplifies multiple qualities characteristic of a great, supportive, and valued leader.

Within NCI, Howard was rapidly promoted up the ranks from postdoctoral fellow to staff fellow, senior staff fellow, senior research scientist, an expert, and senior staff scientist. In 1989, he was appointed head of the Cellular and Molecular Immunology Section of the Laboratory of Experimental Immunology, and then deputy chief, Laboratory of Experimental Immunology, Center for Cancer Research, NCI, a position he held for 15 years. In addition to his leadership roles within NCI, Howard serves in a plethora of governing positions within and outside of NIH. He is an inspiring leader as he knows no fear; appears to have no concern with failure; is willing to challenge the status quo; and forges ahead with unmistakable energy to plan, organize, and lead symposia, conferences, and summer programs.

Beyond his optimal effectiveness as an organizer of such events, he inspires and motivates others and, therefore, Howard is sought after for positions on steering committees, advisory boards, and editorial boards. Notably, Howard has been associate editor of Journal of Interferon and Cytokine Research for the past 20 years, editor-in-chief of the Signals Newsletter for the International Society for Interferon and Cytokine Research (since its inception), as well as an editorial member of Journal of Immunology, Journal of Biological Chemistry, and others.

In recognition of his leadership skills and further strengthening the NIH's ties with the global scientific community, Howard was elected vice president and then, president of the International Society for Interferon and Cytokine Research (ICIS). For these and a host of other reasons, ICIS has honored Howard with an Honorary Life Membership Award, and he was their first ever recipient of the ICIS Distinguished Service Award. Based on both his research and leadership excellence, Howard was elected in 2000 into fellowship in the American Academy of Microbiology (AAM). Rather than rest on his laurels, Howard goes out of his way to promote diversity and inclusion and to support others by nominating them as new members to the academy on an annual basis.

Instinctive to him, Howard's commitment to becoming involved for the betterment of the scientific community and humanity is also stellar. As indicated, not only is he a super organizer of all manner of local, national, and international meetings, but also he has and continues to participate as an agent of change in multiple activities necessary for the smooth running of intramural and extramural events. Amazingly, as busy as Howard is with his scientific enterprise and his leadership and mentoring roles, he appears to never say no when asked to take on another activity. His boundless energy and extraordinary effort do not go unnoticed nor unappreciated.

Howard was recognized with the highly prestigious National Public Service Award from the American Society for Public Administration and the National Academy of Public Administration that serves to “honor individuals who make outstanding contributions and whose accomplishments are models of exemplary public service for those dedicated to the public good—now and in the future” (Fig. 2). This award is so perfect in that it acknowledges his many talents and contributions, while enabling his valued efforts to be recognized by the broader community. The list of Howard's community involvement activities is extensive, but as an example, Howard and I were asked to participate in an NIH ethics committee to oversee a case of potential scientific misconduct.

FIG. 2.

Steuben crystal eagle: National Public Service Award from the American Society for Public Administration and the National Academy of Public Administration that is to “honor individuals who make outstanding contributions and whose accomplishments are models of exemplary public service for those dedicated to the public good—now and in the future.”

Howard agreed that this was an obligation that all of us must share to maintain scientific integrity. To our astonishment, this ethics committee required a commitment for an entire year of weekly meetings, interviews, legal counsel, and other activities to be performed between meetings. After spending so much time together, we unofficially adopted one another as siblings, and despite lacking matching DNA, he calls me “Sis.” Not deterred by our 36-mile laboratory separation, when Howard had meetings on the NIH Bethesda campus, he would drive down early from NCI Frederick for our sibling deskside chats in my office.

A mind without instruction can no more bear fruit than can a field, however fertile, without cultivation. – Cicero

Among Howard's talents and his sense of purpose are providing instruction, education, and collaboration for the global scientific communities, instilling an interest in Science, Technology, Engineering, Math for the younger generations, and bringing new investigators into the field. This generosity of spirit has resulted in his successful efforts to develop and orchestrate the NCI Frederick Werner Kirsten summer program for young interns pursuing STEM activities. Students clearly appreciate the science, but also the humor entwined in the program to help them advance into a brighter science-based future.

Howard's mentoring skills are legendary and wisely well-recognized by multiple mentoring awards, including, but not limited to the NIH Director's Award for Mentoring in 2000, in 2006, and, again in 2018, an unprecedented triple recognition of his mentoring talents. In addition, in 2018 he received the NCI Women's Scientist Mentoring Award. Because he is so unique as a mentor, new laudatory awards need to be created to honor and recognize these particularly exceptional attributes. In this regard, most recently in 2021, Howard became the first recipient of the newly established International Cytokine and Interferon Society Mentoring Award, “in recognition of significant and sustained contributions to the career development of trainees and to the profession through outstanding mentoring over four decades.” (Fig. 3)

FIG. 3.

Howard with his International Cytokine and Interferon Society Mentoring Award, “in recognition of significant and sustained contributions to the career development of trainees and to the profession through outstanding mentoring over four decades.” Howard was the first recipient of this newly established award in 2021.

Without a doubt, Howard has inspired and trained a multitude of students, postbaccalaureate fellows and postdoctoral fellows and, in turn, these investigators have obtained advanced degrees and/or established their own programs around the world, mentoring their trainees in experimental design and career development according to the lessons learned in Howard's program. In his inclusive and congenial work environment, mentoring effectively focuses on 1 life positively influencing another.

I never teach my pupils, I only attempt to provide the conditions in which they can learn. – Albert Einstein

In his magnanimity, Howard truly cares about others and their successes. His compassion coupled with his ability to give without requiring anything in return represents a large part of his mentoring persona. Howard is the epitome of one who inspires others not by demonstrating how wonderful he is, but rather by showing others their own strengths. Howard is well known for his distribution of kudos (Fig. 4) to congratulate and recognize others as recipients of important awards and notations of their work in cytokine and interferon biology, as well as their contributions to the NIH scientific environment.

FIG. 4.

One of the many representative kudo images used by Howard to provide recognition of successes and awards of students, fellows and colleagues in the immunology community, which is also clearly appropriate for Howard himself.

Throughout his career, Howard has been lauded for his generosity, whether in or out of science. Among many historical examples, he provided Louis Staudt (NCI) with the cDNAs for several cytokine genes that were used to develop the very first gene expression arrays. In like manner, several beautiful plants in my garden were shared from Howard and his wife's yard, and strangers walking by the front of his house have also benefitted from his largesse. This plant sharing eventually led to a Frederick NCI plant exchange that was often held in conjunction with the Frederick Spring Research Festival, an event he helped initiate.

Whether advice, reagents, experimental animals, gene constructs, laboratory supplies, or plants, Howard freely shares what he has, and this may include his wisdom, humor, and, notably, recipes. One of my favorite recipes from Howard is a chocolate lava cake. Parenthetically, chocolate is a theme throughout much of his career in which he shares chocolate recipes, chocolate jokes, and chocolate bribes! After one of his lectures (Fig. 5), I mentioned that the audience had been particularly rapt. His modest chocolate-flavored response, “I bribed the audience by giving them chocolate at the start of the talk. That worked well as no one snored during the talk.”

FIG. 5.

Howard presenting a lecture on his exciting research program to an attentive audience, possibly an audience bribed with chocolate.

Life would be tragic if it weren't funny. – Stephen Hawking

In addition to chocolate, Howard has many eclectic interests and hobbies, including his most impressive hippopotamus collection (Fig. 6). Not only has he collected hippopotamus figures of every conceivable material from around the world, but his fellows, colleagues, and friends have also contributed to this expanding collection over the years. His first hippopotamus figure was purchased on a school field trip to the American Museum of Natural History, and he now has a collection of >300, but apparently has been banned from acquiring anymore.

FIG. 6.

Hippopotamus figurines representative of Howard's collection of >300 hippopotamus figurines from around the world.

In a futile attempt to dissect what makes Howard so unique, certain characteristics emerge: Howard is inquisitive, thoughtful, supportive, kind, extroverted, modest, and generous. And strikingly, this uniqueness of Howard's is, at least in part, an inheritable genetic trait as evidenced by its passage to his offspring who founded and is president of a nonprofit volunteer organization, 4 Seasons Giving Tree, which functions to fulfill ongoing needs that disadvantaged families have throughout the year, in addition to her full-time job and caring for her family. Their motto “In lifting others, we rise” is emblematic of the Young family approach to life and community.

What is a scientist? …We give the name scientist to the type of man who has felt experiment to be a means guiding him to search out the deep truth of life, to lift a veil from its fascinating secrets, and … has felt arising within him a love for the mysteries of nature. – Maria Montessori.

Howard is a scientist's scientist, and continuing in his scientific and leadership trajectories, he will search out the deep truths of life for many years into the future. As our parallel and crisscrossing career paths have intersected, it has been my privilege and honor to call him friend. Howard has always been, and will continue to be, the first to provide praise for other individuals' accomplishments, and this Festschrift provides us the opportunity to praise Howard for his abundance of accomplishments and to thank him for his caring and positive influence on so many!

Author's Contribution

S.M.W. wrote the article with input from colleagues.

Author Disclosure Statement

S.M.W. is a scientist emerita at NIDCR, NIH. No competing financial interests exist.

Funding Information

No external funding was received for this article.