| Sara & Frank McKnight Foundation |
McKnight Lab Philosophy:
NEW WEB PUBLISHED PAPERS: [Depression Genetics Study] [PASK High Throughput Screen] As promised at the inaugural launch of this web site, we will periodically publish scientific studies conducted in the McKnight laboratory at UT Southwestern Medical Center that, for one reason or another, are better suited for web dissemenation instead of conventional publication in a peer-reviewed scientific journal. Today we post two such manuscripts, one written by Brandon Probst another by Andrew Pieper. The Probst paper describes a comprehensive search for substrates of a protein kinase enzyme, designated PAS kinase, first discovered in the McKnight lab about five years ago. These studies have been conducted in a thorough and comprehensive manner, leading not only to the identification of many putative PAS kinase substrates, but also to the amino acids directly modified by the enzyme in test tube reactions. The Probst manuscript also presents the results of a high throughput drug screen that sought to identify both synthetic organic compounds capable of either activating or inhibiting the PAS kinase enzyme. The Pieper et al manuscript lists the results of a screen for mutations that may predispose patients to mood disorders. Upwards of 500,000 individual DHPLC assays were conducted over a five year period in search for "smoking gun" mutations in one or more of the genes responsible for the control of circadian rhythm. Our idea was that mutations that would alter the robustness of circadian rhythm might cause humans to be susceptible to depression. Unlike the Probst study, conducted almost singlehandedly by Brandon himself, many people participated in the Pieper et al study - not only in the McKnight lab, but also the lab of John Rush, a distinguished psychiatrist here at UT Southwestern Medical Center. The Probst and Pieper manuscripts are similar in reporting thorough and extensive scientific observations for which all of us in the McKnight laboratory can be proud. In both cases, however, we have been unable to reach substantive conclusions regarding the scientific observations reported. As articulated, however, from the launch date of mcknightlab.com, we have chosen to use web-based dissemenation of these observations in hopes that they might help other scientists to "connect the dots" in a manner that has eluded us to date. I close by emphasizing how receptive we will be to any and all criticisms of these two manuscripts. They have not been peer-reviewed, and we are open to exposing our science and all associated flaws to the broadest possible community of scientists. To this end we pledge to broadcast, in as close to possible on a real-time basis, all comments relating to these two papers. Whether assigned to a specific critic or anonymous, comments and criticisms will be posted in order of arrival. We only ask that comments and criticisms avoid profanity. Even if either of these manuscripts might properly evoke a profane response, please keep the language clean so that we can dissemenate your opinions, suggestions, criticisms and insight. We anticipate this as an interesting experiment in the manner in which scientific observations in the McKnight lab are shared with other scientists worldwide. Thanks in advance to any of you out there in the electronic dimensions who might help prompt this adventure to find its proper place.The McKnight lab at UT Southwestern Medical Center studies a broad spectrum of biological phenomena by use of a combination of biochemical, genetic, biophysical, bioinformatic and molecular biological approaches. We are enamored of the beauty and simplicity of biological switches, and are largely unencumbered by either technical approach or biological system. Projects in the McKnight lab extend from human genetics to X-ray crystallography and prosecute regulatory pathways extending from yeast to vertebrates.
Our fundamental objective is to break new ground and study our systems no longer than what time is required to rigorously validate new discoveries. If a system offers vertically ascending challenges, we attempt to build on our own science and sustain focus. On the other hand, once a discovery has been rigorously established so as to create ripe opportunities for more horizontal productivity, it is our habit to leave this work to others who might have be better prepared to articulate details and expand the discovery in directions better suited to their skills and knowledge base.
We love risk and are happy to publish our work at a pace no more aggressive than that required to both sustain funding and place our graduate students and postdoctoral fellows in good jobs. The McKnight lab is composed of an equal distribution of trainees (graduate students, postdoctoral fellows and young physician scientists) and technicians. The lab typically consists of several graduate students, between four and six post-graduate trainees, and an equal number of skilled technicians. It is for several reasons that we rely on a strategy utilizing a higher than normal proportion of technicians. First, our technicians provide long-term stability with respect to technical competence. Second, our technicians are able to pursue high-risk scientific projects with almost no publication pressure. This balance helps create an atmosphere wherein graduate and post-graduate trainees are optimally poised to individually pursue challenging projects, sometimes emanating from observations made initially by the technical staff of the lab, yet invariably relying on access to substantive technical support.
Current Research Interests of the McKnight Lab:
Current to the summer of 2005 launch date of this website, research in the McKnight lab is involved in studies of circadian rhythm in mice, an ultradian metabolic rhythm unique to prototrophic yeast grown in a fermentor, the regulation of adult neurogenesis in the dentate gyrus of laboratory mice, the mechanism by which Sprouty and Spred utilize dedicated iron:sulfur complex to regulate intracellular signaling, and the biological and biochemical modes of regulation effected in yeast and mammalian cells by an enzyme designated PAS kinase. Quite by accident many of these projects have caused us to become focused on the manner in which prosthetic groups, such as heme or iron:sulfur complexes, endow regulatory proteins with the means of sensing either molecular gasses or intracellular redox. We are particularly keen to discover proximal events wherein fundamental environmental stimuli, including light, redox potential, gasses and simple metabolites find their direct protein target and thereby flip a distinct molecular switch. Two of our projects may have tangential relevance to psychiatric disease, causing us to be ever keen to develop collaborative interactions with physicians skilled in neurobiology and psychiatry.
Each of the projects currently under study in the McKnight lab is described in greater detail elsewhere on this website. By clicking on the following links, website users can go directly to project descriptions relating to circadian rhythm , neurogenesis in the adult mouse brain, the ultradian metabolic cycle of yeast , Sprouty signaling , and PAS kinase . On a routine basis this website will provide unpublished observations for which we will welcome either signed or anonymous input on our message board that will be open to all. The website will also provide links to earlier publications coming from the McKnight lab, current cv's and photographs of all members of the lab, and information of funding sources that support the McKnight lab. As a means of providing interested parties with a description of the day-to-day environment of the McKnight lab, the Department of Biochemistry, and UT Southwestern Medical Center, we welcome questions to be posted by outsiders on the website message board. These queries can be addressed to any member of the McKnight lab as we will collectively endeavor to respond to this website in a manner not unlike our individual attention to e-mail. All queries and all answers will be displayed to all on the website message board.
Unusual, Experimental Feature:
On a periodic basis we will post an extensive description of a project that may be of scientific importance, yet is not sufficiently mature to warrant publication in a peer-reviewed scientific journal. In this inaugural launch of the McKnight lab web site, Dr. McKnight will post the results of a 4-5 year study wherein the lab has sought to genotype thousands of patients suffering from depression for mutations/polymorphisms in the genes believed to be responsible for the control of circadian rhythm. The link to this new, unpublished posting can be found by clicking on “go for it.” We will endeavor to share extensive, unpublished information like this freely to the scientific community. We welcome comments, criticisms and suggestions relevant to this work. If any of this freely distributed intellectual property may be of use to website subscribers, it is up to you to decide whether to reference this site in either traditional or electronic publications that may benefit from it.