looking back at 20 years at UIC-- the Dharma of Science

I thought I would start with a confession—I have my PhD in Biochemistry and I have actually never taken a course in Physiology. One of my mottoes has been “pose as an expert and soon become one” and I used this to my advantage in 1989 when I was hired in my first professional position, Assistant Professor at UIC. I was recruited from Michigan in the guise of a reproductive physiologist because of the work I’d done in Anita Payne’s lab in steroid hormone biochemistry. If I had to describe myself then, I would have said I was a steroid biochemist. The physiology of gonadal steroidogenesis is reproductive endocrinology. And so, I morphed into my new role as a reproductive biologist. I spent 8 hours per lecture that first year preparing to teach in the Pharmacy course about the menstrual cycle and I stayed just enough ahead of the material to make it through the first year—teaching all of endocrine physiology in the Allied Health course. I continued to give the same lectures for 18 years until PHYB341 was replaced by the new GEMS Physiology course.

Through that time I became an endocrinologist, a reproductive biologist, and a physiologist. All of our work was in vitro in primary cultures of Leydig cells, a craft I’d helped to develop and perfect in Michigan. Very few labs had the expertise in Leydig cells or molecular biology that my lab had, and this served us well. Based on the observation that Leydig cells and testicular interstitial macrophages are closely associated, I postulated that since these cells were physically associated, they must be functionally associated, and proposed that macrophage elaborated factors must affect Leydig cell function and this hypothesis guided the next 15 years of work in my lab. We identified a new role for pro-inflammatory cytokines, as regulators of steroidogenesis, and helped to foster a burgeoning interest in immune-endocrine interactions. But the question which emerged as I taught my lectures in endocrine physiology, was does what we see in vitro happen in vivo? And so, I embarked on a series of studies in systems physiology. To activate macrophages in vivo we used LPS, bacterial endotoxin derived from the cell walls of gram negative bacteria, reasoning that LPS would activate the immune system without having to make the animals septic with bacteria. We showed in vivo what happened in vitro—only more so (to paraphrase Jacob Manot what is true for elephants is true for bacteria, only more so). We observed what I still believe is an astounding effect. Within minutes, literally, after injecting a single sub-letal dose of LPS into mice, serum testosterone levels begin to fall. It becomes significant after 15 minutes and at 2 hours serum testosterone is reduced by over 85%! This is a highly reproducible finding which we observed in 100s of mice. The problem was we couldn’t reproduce this in vitro. We determined that the decrease is due to the inhibition of StAR. Karen Hales expressed the full length StAR protein and bacteria and made a superb antibody which works in all species from teleost to human and spawned many fruitful collaborations for us. It made sense that shutting off steroid biosynthesis by preventing the substrate cholesterol to get into the mitochondria where the first enzymatic step in steroid hormone synthesis takes place would account for the rapid shut off. But how did LPS cause this? We could not cause this to happen in vitro with cytokines and were stumped for quite some time. And then our friend Jossey Orly came to visit from Israel and using our antibody he demonstrated that if you treat Leydig cells in vitro with CCCP, a protonphore that disrupts the mitochondria, you can replicate the in vivo effect. We quickly repeated this and realized that LPS somehow causes Leydig cell mitochondria perturbation! Now we could model this in vitro and explored the role of the mitochondria itself in the process of steroidogenesis. We still did not know what mediated the effect in vivo, but soon determined that it was reactive oxygen elaborated by the testicular macrophages that affected the adjacent Leydig cells. I was fortunate to have John Allen and Thorsten Diemer in my lab at the time and we published a series of seminal papers which changed the way people think about steroid hormone production—that it is the mitochondria which is the key regulator, not StAR or the enzymes; and established the importance of oxidative stress and inflammation as key mediators of immune-endocrine interactions.

Despite the number of highly cited papers in high impact journals coming from these studies, the NIH did not deem this line of work fundable, .and I knew I was going to have to do something other than study immune-endocrine regulation of Leydig cell steroidogenesis. One of the reviewers said “Dr. Hales has found another bad thing that LPS does to Leydig cells,” dismissing the whole body of work which demonstrated the role of oxidative stress and the mitochondria in regulating steroidogenesis. So, I tried alcohol vs. Leydig cells, diabetes vs. Leydig cells, Dioxin vs. Leydig cells and aging vs. Leydig cells—which all have as a central theme perturbation of mitochondrial function via cumulative oxidative insult. 5 or 6 more grants attempts later, I was still unfunded and facing extinction. This became a real test of faith and I seriously pondered changing professions, but to what, I was not sure. I had been on the same path for my whole career.

Soon after the birth of my son I found my way back to the path. Desperation breeds contemplation and sitting into the late hours rocking baby Ryder gave me lots of time to think. I had envisioned years of studies which explored the mechanisms through which reactive oxygen species controlled basic biological processes—mitochondrial energetics, gene expression, serving as signaling molecules as well as electrophiles. My grandiose visions however, did not get me funded. The sentiment in the NICHD for funding the male was characterized by a cynicism- statement s coming from NIH staffers like “you can cut somebody’s balls off and they won’t die, so why study them;” and “since we have Viagra and ICSI we don’t need to study the male;” and “honestly, Buck, outside of Andrology no one really cares about Leydig cells.” So much for being one of the world experts on Leydig cells, a lot of good that was doing me. Indeed, a true test of faith. Racked by insomnia I started reading books about how to sleep. They offered practical advice about coffee consumption late in the day, and regular habits, etc. but one thing each of these texts had in common was the suggestion of meditation. I was in Borders one evening and I picked up a book by Rob Nairn entitled “What is Meditation?” which turned out to be a primmer in Buddhism. The book really spoke to me, I realized I’d been searching for this path for my entire adult life and had oft been exposed to “eastern “ philosophy during my years in Boulder—and beyond. For years I had been practicing yoga and was ever more interested in the esoteric aspects of the practice and the interaction between Yoga and Buddhism. I began to read more and more books about Buddhism and discovered the Buddha within. The power of mediation and the tenets of The Dharma were concepts so familiar to me that I felt like I’d found my way. The Way. Buddhism is not a religion as much as it is a process and I had a new tool in my psychological toolkit to help me find my way back to the path. My own understanding of Dharma was well stated in the January 19, 2007 edition of "dailyIinsight" from Yoga Journal:

• "Your personal Dharma is the path you follow toward the highest expression of your own nature and toward the fulfillment of your responsibilities to yourself, to others, to your society, and to the planet. In the Bhagavad Gita, Krishna often speaks of dharma as something inborn, a life calling that each of us has been given and from which we depart at our peril. But he also uses the word to mean right action, and for most of us, personal dharma comes down to that most basic question: What is the right thing for me to do now? Or, Given my nature, my skills, and my personal preferences, what actions should I take to support the greater good?"

What actions could I take to support The Greater Good? What path do I follow toward fulfillment? I kept the faith, I believed in what I do and what I am and was lucky to be nimble enough to adapt my research efforts into a more sustainable effort.

If you were to ask me now how I define myself, I would say that I am a cancer biologist. How I went from steroid biochemist to cancer biologist is not as much of a leap as it might sound. Reasoning that in response to immune insult, potent oxidants and inflammatory mediators combine to perturb, and shut down hormone production—but in steroid target tissues, oxidative stress and inflammation work in concert with hormones and the result in carcinogenesis. So instead of looking at the testis, which evidently no one cares about, I looked at the prostate, which a lot of people care about. With Gail Prins help we looked at oxidative stress in a rat model of prostate cancer, and I was able to get funded by the local American Cancer Society who have a grant mechanism to attract new investigators into cancer research. That one year of ACS funding was what helped me turn the corner. I never was able to get NIH funding for the prostate cancer project, but one day, I heard a Gyn Onc Jean Hurteau here at UIC say that ox stress and inflammation are thought to be important to the pathogenesis of OvCa which caught my attention. He then said that the only good model for OvCa is the chicken. I immediately thought of my old friend, with whom I collaborated since I was in Anita’s lab, Janice Bahr, who is a world expert on the reproductive biology of chickens. All of our antibodies worked in the chicken so I had followed her work and decided to see if she would like to collaborate. We were successful in getting a pilot grant from the DOD testing the inflammation hypothesis in the hen model and this funding really got me going again. One of Hurteau’s interests was in omega-3 therapy for OvCa. So I was keen on the literature but couldn’t imagine gavaging hundreds of chickens every day with fish oil. Then I was in Whole Foods one day and noticed the omega eggs in the cooler and wondered how they were able to get omega into chicken eggs. Well they feed them flaxseed, the richest vegetable source of omega-3 fatty acids. I proposed using the hen model as a pre-clinical test for chemoprevention of OvCa with flaxseed and got funded by the AICR, and then the NCCAM. Using the hen as a model for dietary intervention to prevent or treat cancer turned out to be a very tractable idea, and we have also been funded by the NCI to determine if broccoli can prevent OvCa in hens. And yes, chickens do eat broccoli.

These functional foods work by interacting with specific molecular targets do decrease oxidative stress and inflammation. We are able to draw upon the expertise we developed looking at these forces in Leydig cells and have expanded this to the study of a very important and deadly disease. I remain steadfast in my belief that if you do good science and let biology lead the way, you will answer important questions, whose answers raise more questions which guide you further down the path. It is true that you have to be nimble as you find your way along the path and be able to surmount the obstacles you encounter along the way. My Dharma is science and biology guides the way. All of the work we did in Leydig cells is still important and has helped create significant interest in the role of immune and endocrine interactions in the maintenance of homeostasis, as well as mediating pathologies. But our current work in ovarian cancer is more important because it holds the promise of discovering early detection for ovarian cancer, prevention and treatment of the disease, and most important, it provides hope for women who have the disease, hope that their daughters, sisters and friends may not have to suffer what they are dying from.

There is a lot of public interest in cancer biology, antioxidants, dietary intervtion, natural, and alternative medicine-- so I have decided to launch a new blog which I will call CancerChix, so that I can share my thoughts and observations on these topics without diluting these posts with my rambling narratives about bicycle commuting, diet and exercise and politics.

In the wake of the flood

It has been an incredible two weeks since the election. We just heard that Alaska's felonious and the longest serving Republican Senator, Ted Stevens lost his bid for re-election to Mark Begich. Now even Alaska has a different hue. The Purple Haze of the new America-- not red, not blue anymore. Just America. With 58 seats in the Senate and two still up for grabs, the Democratic party is teetering on the brink of a filibusterer proof majority. No more obstructionist anti-majority legislation tying the hands of the party in power. The accusation that the Democrats have done nothing since resting the majority from the GOP in 2006 overlooks the fact that all of the progressive legislative initiatives were vetoed by Dubya. Now true change can begin in Washington DC. Change that came from the heartland, from main street USA, from rural and urban communities, from the east coast, west coast, third coast and deep in the desert southwest. Yes, change we can believe in and it is exciting to see how the country is embracing the Obamas. It is so refreshing to hear the soon to be leader of the free world speak with eloquence and vision. People whose criteria for voting for president was that they could have a beer with him is ridiculous. Not to say it wouldn't be a pleasure to have a beer with Mr. Obama-- but I want to be in awe of his brilliance, not placaded by his mediocrity. Sixty some days to go.

A time of great upheveal, of great uncertainty and of great opportunity. As the world embraces the new America, we look forward to our move to Carbondale and the next phase in our careers. I visited Carbondale last week with two goals in mind. First was to establish a relationship with a local banker in preparation for making an offer on the Victorian Legend. Second was to meet with the administration at SIU in preparation for moving my scientific enterprise to Carbondale. The only thing that won't change is what is most important-- my family and pets, all of us relishing the change that is just around the corner.

After I concluded my visit with the department I dialed the Garmin for Springer Ridge Road and made the first drive from the parking lot at Life Science III to the Victorian Legend-- 7.4 miles, just three turns. A straight shot south from campus to the very edge of the state and national forests. I parked my rented Ford in the driveway, skirted the house and buildings and took a walk on the property. 40 acres is huge. I headed straight east from the barn and stayed to the north of the pond and creek that bisect the property. The north pasture is rolling, generally downhill, and planted in hay that had been mowed this season. I walked all the way to the east edge of the property to the fence line and found a path to Club Road, which separates the property from the farm on the north. I walked down the road, which appeared not to have had any vehicular traffic in recent months. Down the road went, down hill with the creek and woods from the property on my right and the confluene of two creeks in the woods on my left. I followed the road for 15 minutes going deeper and deeper in to the woods, alert and cautious, not knowing what lay ahead. Soon I came to an opening and found a very old house. Judging from the weathered wood and style of building, the house looked to be 100 years old. No sign of habitation, and I wondered who owned this place and what its story might be. I found a camoflouged glove, no doubt dropped by a hunter, oddly near an old sign posted "no hunting." I followed the road back toward the property, climbing the steep lane through the tall trees, which looked to be a hundred feet tall. An old forest with limestone craigs covered in moss. Silence. Not a hint of the sound of man. The wind in the trees and the call of the birds, the trickle of the creek. It was a spiritual awakening as I was dumbstruck with the notion-- oh my goodness, this could soon be my property.

I have grown accustomed to living among people. The density of population in Oak Park took a lot of getting used to. Living within feet of our neighbors, hearing their conversation on a warm night when everyone's windows are open. Smelling their cigarette smoke as they stand on their porch smoking. Seeing through their windows in the morning's early light when the light from their bathroom illumnates them. A mutual resepect for privacy causes us to look away, ignore the sounds of their chatter, and try to ignore their smoke. As we walk to school in the morning and pass through the neighborhood, looking at the gardens and Cubs or Sox flags hanging from the houses, seeing the kids trooping down the street to join our parade to Lincoln school, I am aware of the not too distant sound of the El screaming by and the traffic on I290, Harlem and Roosevelt. The holy silence beckons. We sure are going to miss Trick-or-Treating in our neighborhood though.

Proud, American

So much has changed in America, in the world, since last Tuesday night. We waited with excrutiating anticiaption as the polls closed and the vote tally began to come in. The first tally gave McCain a 16 to 3 lead, Kentucky, South Carolina vs. Vermont. As it turned out, that was the only lead McCain enjoyed all night long. But it seemed to take forever for the polls to close and votes to be counted. But when Pennsylvania went into Obama's column, a sense of expectation began to replace the trepidation. The McPalin campaign had devoted much of its final effort to the Keystone State, and a keystone it turned out to be. Obama carried the state by 2 to 1. But it wasn't until Ohio went to Obama that we really started to get excited. One of the classic moments in election coverage was when Karl Rove was explaining how Ohio was critical to McCain's chances, slim though they be-- when we was interrupted "uh, Karl, Ohio just went to Obama." Hooting and hollering and a mounting sense that our dream was about to come true.

It was exciting to be in Chicago for the election, though I did not go to the rally, opting instead to watch the returns at home with my family and best fiends. After Ohio went for OBama and we were waiting for the polls on the west coast to close, we bet at how many minutes past ten they would call it. I guessed 10:03 and other guesses ranged up to 10:15. Instead it was 10:00:03 CDT. And the celebration began. My friends were from Ohio, Minnesota, Iowa, and Virginia, and me from Colorado and they all went blue. And our work in Indiana last Sunday is most gratifying now knowing the we delivered Lake county. We were so pleased Indiana went blue, though we didn't know until well past midnight when the vote tally from came in. We were on our feet, hugging, kissing, cheering, stomping our feet, celebrating this most important moment in American history. We watched our friends, neighbors and colleagues en mass in Grant Park, as the camera panned the crowd for minutes with no commentary from the talking heads. The scene from around the country, from around the world was incredible-- a beautiful thing to behold. Seeing the tears stream down Jesse Jackson's face, the tears of joy from the students at Spelman College in Atlanta-- my own tears of joy! Words fail to express the magnitude of this moment.

Tuesday morning had dawned bright but chilly, a perfect autumn morn. The first thing I did that morning before I went to vote was hang the American flag in front of my house as I recalled Howard Dean's words from the summer of 2003-- "its time to take the American Flag back from the right wing extremists." And now we have. We watched McCain's speech from Phoenix, it was very nice and reminded us of the John McCain we had respected and admired before he sold out to the Karl Rove machine-- but true to form, his faithful followers booed and heckled when he mentioned Obama. He tried to hush the gaggle of ardent neocons, though they chanted "Sarah, Sarah." Yes, that is what is left of the Republican Party, and they got what they deserved. And so did we! A president we can be proud of. A man with intelligence and vision, and a rare eloquence. YES WE CAN!

When I rode my bike to work on Wednesday, riding through the fog of the champagne hangover, the whole world seemed to have changed. It was eerily warm for November, sunny and all the leaves were shimmering in their autumnal glory. As I rode through the west side, just as desperate as Gary, I was on Flournoy just east of Kostner, and there were three guys lurking mid block. Spontaneously we all raised our fists triumphantly in the air and hooted, one yelled "black power" and another yelled "OBAMAAAAAAAAAA". I felt so excited and honored to share this with my homies, as we all united in our jubilant celebration. It felt like a festival all week at UIC. people stopping people on the street to shake their hands or give them hugs. Tears of joy and much discussion flowed freely-- it seems that everyone is engaged, excited and HAPPY!

Everyone is happy, except perhaps, the die-hard Palin supporters. The infighting in the McCain camp and blame game that is going on is a delicious thing to savor. The McCain campaign staff who announced that Sarah didn't know that Africa was a continent or what countries were in North America was greeted by the Governor of Alaska with the comment-- they were a bunch of jerks! But the true endorsement of Palin by the McCain campaign,"Wasilla hillbillies looting Neiman Marcus from coast to coast" pretty much sums it up. All that remains of the republican party are the 30-40 year old white men heckling McCain at this concession speech. We suspect Condy Rice secretly voted for Barack, based on her heartfelt and tearful congratulations. And we know Colin Powell did.

The sound track in my mind, through out this amazing ride has added to my goose flesh and teary eyed joy. On Thursday as I waited for the El, opting out of riding through the sleet, I heard Uncle John's Band on my MP3 player and I swelled up with pride and determination. Each of those lyrics rang true-- "he's come to play to the rising tide!" as the tide of humanity rises as one, a wave of positivity and determination! "Well the first days are the hardest days, Don't you worry any more, 'Cause when life looks like easy street, there is danger at your door. Think this through with me, let me know your mind. Woh - oh, what I want to know, is are you kind?" YES! no one said it was going to be easy. But thank goodness we have a leader who has the vision, and the kind gentle spirit to lead us home. Obama's campaign stayed on message the whole time and his equanimity was the guiding light. Well he might ask you-- are you kind? I do not believe those dedicated followers of McPalin can be considered as kind. All they inspire is anger, hate and disgust. It is heartening to hear some of the most ardent of them now sing the praises of the new day that has come to America. But like Mr. Obama said-- there is only one president at a time, and he does not become president until Jan 20th. Just under 70 days of W left to endure.

Other of the songs in this sound track-- triumphant, US Blues-- wave that flag wide and high! Yes! seeing the gathered multitude waving Old Glory at Grant Park brings more tears to my eyes and more geese to my flesh! "Red and white, blue suede shoes, I'm Uncle Sam, how do you do? Gimme five, I'm still alive, ain't no luck, I learned to duck. Check my pulse, it don't change. Stay seventy-two come shine or rain....Wave that flag, wave it wide and high. Summertime done, come and gone, my, oh, my" Such a fitting ode-- and indeed Summertime has come and gone. And-- Scarlet Begonias "Strangers stopping strangers just to shake their hand, Everybody's playing in the heart of gold band, heart of gold band..." The whole world is celebrating. From Paris to Berlin to Istanbul, from the villages in Kenya and the outback of Australia-- yes, we are the eyes of the world....

countdown to history

With just hours to go until the first results of the election are known, I find myself nervously waiting as though I was an expectant father in the waiting room enduring a 22 month long labor. Oh my gawd, it is almost here. The moment of truth. The crowd is already massing in downtown Chicago for the Obama election night rally. The excitement around town, in anticipation of the outcome is electric. Yet the outcome is as yet not known. We have donated several times to the Obama campaign, more money than we've given to all other campaigns combined. And it appears that all of our donations are being wisely used.

I spent Sunday in Gary Indiana walking door to door to help get out the vote. It was an extraordinary experience. As I walked through one of the poorest neighborhoods in America, I was touched by so many people's enthusiasm for Obama, and gratitude that a suburban white from Chicago would come to their neighborhood for this cause. I was invited in for dinner, embraced, celebrated as we shared the same hope for a better day for our country, and excitement that their vote really counts this time. Indiana is poised to be a state no longer considered as a Republican stronghold. Not a red state, not a blue state, but truly apart of these United States. Mary, Ryder's godmother, and I drove to the Gary office of the Obama campaign and arrived to find 100s of volunteers fanning out to canvass the city. We were dispatched to the south Broadway office on the very southern edge of the city and arrived with dozens of other volunteers, most of whom had come from the Chicago area for the day to help. We were given instructions and told that our goal was to get out the vote. Early voting in Indiana doesn't end until noon today (Monday) and most folks didn't know they could still vote early. The lines for early voting were pretty long in downtown Gary, so folks were being shuttled to other sites with shorter waits. When we went door to door, if we talked with people who needed a ride to vote, we took their names and numbers and the campaign was going to dispatch volunteers to take them to vote. Mary and I covered about a 10 block area in 4 hours probably knocking on over 300 doors. A dozen or so folks were pleased to know they could vote early and we gave them instructions. Many folks had already voted and the majority said they were going to vote on Tuesday. They said they were going to school at the end of the block first thing Tuesday to vote. They were grateful and receptive. As our tour continued we ended up in the projects and it was rather dicey. I covered one side of the street while Mary covered the other, and I kept her in eye contact the whole time. The further north we got on Pierce street the worse it got, until finally we began to feel vulnerable and conspicuously not from that neighborhood. I went down a few steps to a basement apartment and just as I was about to knock the door burst open and a cloud of pot smoke came billowing out. Three African Americans came staggering out and were very surprised to see me standing there. I said "I'm with the Obama campaign" and I sensed their relief. I retreated up the stairs as they all said yah yah yah we are going to vote. Voting was the last things on their mind's right then so I beat a hasty retreat. I never felt threatened, but understood the precariousness of the situation. Across the street a few doors up I was greeted warmly by person after person who was carrying covered dishes into one house. One gent invited me in for dinner and Christian fellowship. he said they all get together every Sunday to share a meal, that way everyone gets to eat. He was such a lovely guy, I was tempted to accept his invite just to share in their community. He assured me they had all voted our would vote on Tuesday. And he blessed me for the effort I was making that day on their behalf.

I heard one pundit say that Jesus Christ was a community organizer. As was Mahatma Gandhi-- and this community was organized. It was impressive, I mean really impressive to see grass roots politics at work. And this was just one precinct in one city. All across the county tens of thousands of folks are on the sidewalk going door to door in support of the Obama campaign. Who ever doubted his executive experience should think twice. For the Obama organization to have mobilized over 3 million supporters each reaching out to every corner of the country, is an astounding act of administration. We crossed paths with the steel workers union and the SEIU who had also deployed their members to get out the vote. People in Indiana are so excited, it was very encouraging. I have heard so much vitriol and hate from the McCain campaign, all they inspired is negativity. Obama has remained above the fray, unflappable, steady.

I was just talking with my lab manager who was an avowed non-voter with no interest in politics for the 04 election. She is totally engaged and was making arrangements to be late tomorrow because she has to vote where she was registered when she lived at home, not at her current address. All of my students, generation Y, the 20-30 year olds are all wildly enthusiastic and are going to vote-- and are doing all they can do to get out the vote. The youth vote has not appeared in the polling and has been dismissed because though they are registered, they are not considered as likely to vote. Not this time. I am so excited that I am having a hard time working today!

it will be quite a historic , to be sure-- regardless of the outcome. But only in my darkest fears do I still worry that those Republicans are going to pull something off. But we are going to let them steal this election, no way.

It was such a shame that Obama's grandmother died yesterday, on the very eve of the election. Obama said that the biggest mistake he ever made was not going to see his mother to say goodbye before she died of ovarian cancer. He was not going to make the same mistake with his grandmother. Knowing how deeply affected Mr. Obama is by ovarian cancer, having lost his mother to it makes me feel so proud that I have now devoted my work to this dreaded disease. Funding and support for biomedical research will surely be much improved in the Obama administration. The whole world will sigh a huge collective exhalation of relief once Barack is elected. For surely there are hundreds of millions of people the world around who are holding their breath right now, waiting for the election results.

Hope dawns anew tonight when Barack Obama wins the election. I can not even begin to wrap my mind around the other outcome. Hope, not fear will carry the day.