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Actress Zuzanna Szadkowski '01, who plays "Dorota" on the popular TV series Gossip Girl, was mistress of ceremonies at the event honoring the recipients of the Frederick A.P. Barnard Award: Barnard outgoing board of trustees Chair and Pulitzer Prize-winning author Anna Quindlen '74, and recently retired New York state Chief Judge Judith S. Kaye '58, who was the first woman to hold the post.
"Anna, you have stepped in whenever and wherever to do anything for Barnard," said Ellen Futter '71, president of the American Museum of Natural history and former president of the College, in a citation read during the awards presentation. Quindlen has served five five-year terms as a member of the board. During her tenure, the Diana Center was completed and a presidential search committee tapped Debora Spar to be Barnard's new president. Helene Finkelstein Kaplan '53, former chair of the board of trustees, presented the award to Judge Kaye, saying: "even more remarkable than the historic place you held at the pinnacle of justice, was what you did from that place." Among her myriad achievements was the overhaul of the state's jury system.
Some auction items donated by Barnard's dedicated faculty, staff, and alumnae, were lunches with some of Barnard's distinguished graduates including Martha Stewart '63, Fox News anchor Lis Wiehl '83, NPR correspondent Susan
Levitt Stamberg '59, author Erica Jong '63, and Pennsylvania state senator Constance Hess Williams '66. Thanks to auctioneer harmer Johnson's expertise, bidding was brisk. A winning bidder paid $8,000 for a private tour of the AMNH guided by its President Ellen Futter '71.
-photographs by Hilary Steffens, David Wentworth, and Chance Yeh/Patrick McMullan

subset: commoncrawl


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Via Reason TV: Few energy projects have inspired the level of vitriol surrounding the Keystone XL Pipeline, that would run 1,700 miles from Alberta, Canada through the United States to refineries on the Gulf of Mexico.
The oil sands of Alberta are estimated to hold 170 billion barrels of petroleum, the largest reservoir of black gold outside of Saudi Arabia.
Because the pipeline crosses an international boundary, President Barack Obama has the final say over whether to give the project a green light.


text: Home Latest Shows Rangers Power Issues !!! Federal Government Disagreements !!! Latest Shows Rangers Power Issues !!! Federal Government Disagreements !!! 0 589 Share this:TwitterFacebookEmailWhatsAppTelegramLinkedInPocketSkypeRedditPinterestTumblrPrint Related RELATED ARTICLESMORE FROM AUTHOR Latest Shows Tonight with Moeed Pirzada_03_20 October 2018 Latest Shows Tonight with Moeed Pirzada_02_20 October 2018 Latest Shows Tonight with Moeed Pirzada_01_20 October 2018 Leave a ReplyDefault CommentsFacebook Comments Leave a Reply Cancel reply This site uses Akismet to reduce spam. Learn how your comment data is processed. POPULARDPO Bahawalnagar Sacked for doing his duty?12Horror in Heaven!Honor Killing or Powerful's Revenge against the Weak?1Nawaz-Zardari Meeting in London: Yeh tu wohi jaga hay, guzray thehy hum jahan say?1Tonight With Moeed Pirzada: PTI's point of view on Budget 2016-17 !!!0PM Nawaz's State of Health: Need for Medical Board briefing!4Panama Papers & Pakistan's Kingdom of Lies!2PPP & Khurshid Shah: Nawaz Sharif's Opposition or Strategic Ally?2US Position on Pakistan PM Nawaz Sharif after Panama Files Leaks & its Importance?1Dunya Today: An Exclusive Interview with Salman Taseer Governor Punjab 27, May, 20100Another Girl burnt alive! Whose daughter was she?3Master Shoukat's Video Denial?6Janjua Press Briefing About Peace Process with Taliban !!!0Soft Coup: Has PPP Punjab rebelled against Zardari?6Military Advising Nawaz Sharif to bring house in order?1Panama Papers: Why 'Commission' should be rejected?1America's poor President & Pakistan's Rich Rent Seekers!1Dinner with the President?0Do we feel answerable to God & our Conscience?8Analysis: How would have Sushma Swaraj taken her position at UNGA without "Uri Attack"?9Nawaz, Modi, Dawn & Pakistan Army: What is happening & Why?15 Latest ShowsTonight with Moeed Pirzada_03_20 October 20181Tonight with Moeed Pirzada_02_20 October 20180Tonight with Moeed Pirzada_01_20 October 20180Tonight with Moeed Pirzada_03_12 October 20181Tonight with Moeed Pirzada_02_12 October 20180Tonight with Moeed Pirzada_01_12 October 20180Tonight with Moeed Pirzada_03_7_October 20180Tonight with Moeed Pirzada_02_07 October 20180Tonight with Moeed Pirzada_01_07 October 20180Tonight with Moeed Pirzada_03_06 October 20180Tonight with Moeed Pirzada_02_06 October 20180Tonight with Moeed Pirzada_01_06 October 20180Tonight with Moeed Pirzada_03_300920180Tonight with Moeed Pirzada_02_300920180Tonight with Moeed Pirzada_01_300920180Tonight with Moeed pirzada_01_29 September 20180Tonight with Moeed pirzada_03_29 September 20180Tonight with Moeed Pirzada_03_280920180Tonight with Moeed Pirzada_01_280920180Tonight with Moeed Pirzada_02_280920180


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Tips for Hiring Your First Employee
min read
Opinions expressed by Entrepreneur contributors are their own.
Small-business expert Marie Forleo, founder of Rich, Happy & Hot, speaks with Entrepreneur's Diana Ransom about how successful business owners hire employees without a human-resources department. They start by:
- Describing their ideal job candidate, detailing their ethics, skills and responsibilities.
- Talking with their accountants about the tax requirements and differences in handling the tax treatment of full-time versus contract workers.
- Securing a nondisclosure agreement to protect your intellectual property and other trade secrets.
- Creating a simple online application using sites like Survey Monkey to streamline the applicant-screening process.
How to Attract the Clients You Want


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One of the most unique features in Lure series fishing kayaks is our Patent Pending Gravity Seat.
It provides a great comfort due to it's adjustable height and is also completely removable, so you can use it standalone, anywhere you want. You can adjust it's height using a simple pull tab. It's quick and works great when your aim is to change fishing spots a lot or just want to sit comfortable when fishing.
Welcome to the Feelfree Overdrive system - the modern evolution of pedal powered kayak propulsion technology.
Designed to be retro-fittable on the Feelfree Lure 11.5 and 13.5, the Overdrive is a one of kind system designed to offer effortless speed, ease of use and accessibility. The Overdrive is expected to available summer of 2017. Updates and other information will be posted here. Stay tuned, the modern evolution of pedal powered propulsion has just begun!
All of Feelfree kayaks are equipped with a wheel, which greatly improves mobility of the kayak.
Directly behind the bow hatch, there is a multi-use console, which creates additional space.
Some people say that image doesen't really matter when you're on water, but we disagree.
When you're on a relaxing fishing trip, standard rubber hatch is fine.
You got tired of paddling at the middle of the lake and want to take a break?
If you want even more from your kayak, make sure you take full advantage of our Uni-Track system.
Our kayak side and front handles are molded into kayak itself, so we limited the use of bungee cords to minimum.
That solution gives you great comfort and it's less liable to breaking. Handles are designed not to interfer with kayak's shape, so you don't have to worry about them when on your trip. That design is actually so good, that a lot of manufacturers are currently using it in their kayaks.
There's just never enough place in your kayak now is it?


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Barry University was recently cited among the top schools in the nation for members of the military when it was named to The 2014 Military Friendly Schools list. This is the third consecutive year Barry has earned a place on the coveted list which is produced by Victory Media, the premier media entity for military personnel transitioning into civilian life.
The 2014 list of Military Friendly Schools honors the top 20 percent of colleges, universities, and trade schools in the country that are doing the most to embrace America's military service members, veterans, and spouses, as students and ensure their success on campus.
The list was compiled through extensive research and a data-driven survey of more than 10,000 schools nationwide approved for VA tuition funding. The survey results that comprise the 2014 list were independently tested by Ernst & Young, LLP, based upon the weightings and methodology established by Victory Media.
Each year, schools on the list are held to a higher standard than the previous year via improved methodology, criteria, and weightings developed with the assistance of an Academic Advisory Board (AAB) consisting of educators from schools across the country.
The Military Friendly Schools list features interactive tools and search functionality to help military students find the best school to suit their unique needs and preferences. The 1,868 colleges, universities and trade schools on this year's list exhibit leading practices in the recruitment and retention of students with military experience. These schools have world-class programs and policies for student support on campus, academic accreditation, credit policies, flexibility and other services to those who served.
The School of Professional And Career Education (PACE), a Service Members Opportunity College, currently offers a Scholarship to active duty military and active reservists and their spouses. The tuition rate is offered at $225 per credit for undergraduates and $410 per credit for graduate students – this reflects a 40-50 percent reduction from the standard tuition rates. In addition, Barry currently enrolls 272 students receiving VA Educational Benefits.


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Giants won't rush elite prospect Tyler Benson into lineup
Team interested in seeing five-game limit for 15-year-olds raised to 10 games
Vancouver Giants introduce their top picks on Tuesday, May 14, 2013 from the annual WHL bantam draft. Left to right: top pick Tyler Benson (first overall, from Edmonton), Matt Barberis (20th overall, from Surrey) and Ryely McKinstry (23rd overall, from Calgary).
Photograph by: Wayne Leidenfrost , PNG
VANCOUVER — The Vancouver Giants don't appear in any particular hurry to rush elite prospect Tyler Benson into their Western Hockey League lineup next season by applying for "exceptional player" status.
Under current major junior rules, a 15-year-old is allowed just five regular-season games in the WHL until his midget team is eliminated from its league playoffs. However, exceptions have been made in the Ontario Hockey League for John Tavares, the New York Islanders star and Hart Trophy candidate, Connor McDavid and, most recently, defenceman Sean Day.
Giants majority owner Ron Toigo doesn't want to travel down that road but is keen on having the five-game limit bumped up to 10. Benson turned 15 on March 15 and is still in Grade 9. He was the first overall pick in the May 2 WHL bantam draft.
"It's not just ability but where they are in the evolution of their lives," Toigo explained Tuesday at a gathering to introduce Benson, fellow draftees Matt Barberis and Ryely McKinstry and new minority partner Bruce Allen. "To us, there is a big difference between leaving home at 15 and at 16. I really don't think guys should be going to the NHL at 18 unless they are exceptional. I think it has hurt more people than it's helped. We kind of have the same philosophy here.
"But what we're going to try and do is move the limit to 10 games instead of five. We're not sure what the process is, but we're going to start down that path."
According to Toigo, he has a lot of support within the WHL to petition Hockey Canada for a new 10-game call-up rule.
"We think it should be changed for everybody, not just special-status players," Toigo continued. "I talked to a number of GMs and governors about it at the draft and it got pretty good support. I don't know anybody who was against it. With the demands of the world juniors and the world under-17 challenge and these tournaments that go on at Christmas time, a lot of teams are running two or three players under the limit. So we think we should be able to bring guys up for more than just five games. But, at the end of the day, it's Hockey Canada's call."
Benson himself is preparing to play a season of midget hockey in Edmonton, his hometown. He is blond with braces on his teeth and the youngest of two boys. His older brother Cole has spent the past two seasons with the Edmonton Oil Kings, who won the WHL title in 2012 and lost in this year's final to the Portland Winterhawks. Tyler's favourite NHL player is Detroit Red Wing centre Pavel Datsyuk.
"I think I'm pretty focused on just playing midget and developing there and living at home with my parents," said the 5-11, 180-pound Benson, a left-winger who collected an astonishing 146 points in 33 regular-season games for the South Side Athletic Club bantams.
Benson admits he is a little overwhelmed by the attention he's received this past season, especially when the NHL was locked out until mid-January. He was featured in segments on the sports networks.
"Yes, it is a little overwhelming seeing myself on TV on a show I've watched every day," he said. "It's pretty cool."
Tyler, by the way, is already the tallest in his family. Cole is 5-7 and dad and mom are 5-10 and 5-3, respectively. Tyler hopes his growing days aren't over.
"I guess my dad has some big people in his family so I always hope I can maybe grow to 6-2 or 6-3," he said. "I'm just hoping I can grow that extra few inches."
Giants coach Don Hay is quite familiar with 15-year-olds playing above their age group. He just coached Canada's under-18 national team to a gold medal in Sochi, Russia, and McDavid led the tournament in scoring despite being two years younger than most players. McDavid also had 66 points in 63 games for the OHL's Erie Otters.
Tavares had 45 goals and 77 points as a 15-year-old for the Oshawa Generals in 2005-06.
"I know Connor McDavid is a very special player and everything I've heard about Tyler is that he is a special player, too," said Hay. "I haven't seen him play other than on video and on TV. But in talking to him, he's a very humble young man, which is a really good sign. As a coach, I'd love to see him play if he's ready. You always want the best players possible. I'm open to whatever the rules are (for 15-year-olds), but it's not my decision to make."
Otherwise, the addition of Allen as a Giants' minority partner doesn't mean the bombastic talent manager of Michael Buble, Bryan Adams, Anne Murray and others will be a silent partner.
"Are you kidding?" laughed Toigo. "Bruce won't be silent. That's one thing he won't be. He doesn't hold his opinion back. You don't have to agree with it all the time, but you're going to hear about it."
Allen joins an ownership group that already includes Michael and Lewis Buble, Pat Quinn, Gordie Howe and Sultan Thiara. Michael Buble, through dad Lewis, jokingly set Allen straight on what a minority partner does.
"Now Bruce can make coffee and wash Ronnie's car," quipped Michael.
G-NOTES: Two Giants, defenceman Mason Geertsen and right-winger Jackson Houck, have been invited to the NHL scouting combine that begins May 27 in Toronto. Geertsen and Houck are both touted as third-round picks by The Hockey News. Geertsen is ranked 74th and Houck 79th.


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All back issues of the journal have now been archived on SAS-Space. Please view, download and reference the issues using the link below:
Electronic Journal of International History archived collection on SAS-Space
The eJIH, which is no longer active, was launched in 2000 with the aim of encouraging research in international history. It embraced all aspects of the history of relations between states and societies, and aimed to promote an understanding of the breadth, depth and policy relevance of international history by examining how the politics, societies, economies and traditions of countries have shaped and influenced international relations since circa 1500.
The journal welcomed contributions from historians working on a wide range of areas, for example:
- Traditional diplomatic questions;
- British bilateral relations with other states and participation in wider alliances and international organisations;
- Transnational history (relations between states not involving Britain);
- Domestic political and cultural dimensions;
- Studies of conflict and confrontation and particular crises;
- Alliances and international organisations;
- Foreign trade, to include economic relations and economic diplomacy;
- Cultural relations;
- Military and intelligence issues;
- Propaganda, information policy and psychological operations;
- The development of international law;
- Ethical concerns, such as the impact of technological change;
- Historiographical debates.
- Anthony Best, London School of Economics
- Larry Butler, University of East Anglia
- Keith Hamilton, FCO Historian
- Kate Morris, Joint Services Command & Staff College
- Gillian Staerck, Centre for Contemporary British History
- Glyn Stone, University of West of England
- John Young, University of Nottingham.
The journal ceased to be published in 2005.


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- Publish date:
- Updated on
- Year
- 1880
Apache Chief Diablo is killed
Diablo, a chief of the Cibecue Apache, is killed during a battle with a competing band of Indians.
Known as Eskinlaw to his own people, Diablo was a prominent chief of the Cibecue Apache, who lived in the White Mountains of Arizona. Initially, Diablo had attempted to cooperate with the increasing number of whites who were encroaching on the Apache homeland. In July 1869, he traveled to Fort Defiance, the first American military post in Arizona, in hopes of establishing good relations. Three white men returned with Diablo and regular visits between the two groups began.
Tensions, however, continued amongst the Apache themselves, many of whom were less welcoming to the Americans. In 1873, a warrior from a competing band of Apaches led by Eshkeldahsilah killed a white man working at the army's Fort Apache. Diablo tracked down the offending warrior and killed him, winning the Americans' praise but Eshkeldahsilah's increased enmity.
To avoid further violence, the commander of Fort Apache ordered all the surrounding tribes to move closer to the fort. This may have decreased the attacks on the Americans, but it increased the tensions between the Apache bands. The government further angered Diablo in July 1875, when it ordered that all of the Apaches in the region move to the San Carlos Reservation east of present-day Phoenix.
In apparent frustration at the imperious behavior of the Americans, Diablo finally turned against the whites. In January 1876, he attacked the camp near Fort Apache, and he killed at least one white civilian. He also began attacking a competing band of White Mountain Apache who continued to cooperate with the Americans. Eventually, the White Mountain Apache got their revenge on Diablo. On this day in 1880, the two bands of Apache fought a fierce battle near Fort Apache. By the time the American military arrived on the site, Diablo's opponents had killed him.


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The following commentary does not necessarily reflect the views of AgWeb or Farm Journal Media. The opinions expressed below are the author's own.
Our family farming history began with my great-great-... (nine generations ago) grandfather Johannes. He, his wife and three children left Saxony, Germany, on April 20, 1734, aboard the ship St. Andrew, mastered by Capt. John Stedman. They landed at Philadelphia on Sept. 22 and eventually settled our family's first "New World" farm near Society Run in Frederick Township, Montgomery County, Pa., in 1743. Pig farming was our family's specialty until the mid 1950s. A lot has changed since then. Our BQA cow–calf operation includes 100% grass-fed registered Red Angus, Hereford and purebred Beefalo; 30 to 35 pastured Duroc and Spot pigs; 100 Freedom Ranger broilers; and 90 Golden Comet and Buff Orpington layers. We organically maintain 80 acres, comprising 15 acres in rotational pastures, 15 acres in tillable cropland, and alfalfa/mixed grass hay on the balance. We have never used chemical pesticides or herbicides on our pastures or hay fields. We are not a "certified" organic farming operation, but we prefer the natural/organic approach to help promote sustainability.
What the HAY!?
The cost of producing good quality hay will be weighing heavy on the minds of most producers more so this season than probably ever before. Especially if you live in Pennsylvania & New York States. Diesel will most likely be the largest input cost for all of us, so lets try and figure out now what we'll be spending to put up quality hay in the next few months so we're not surprised in the fall when we start selling what little (if any) surplus hay we will hopefully have.
Lets start at the "ground level", each ton of grass hay removes approx. 50 pounds of nitrogen, 15 pounds of phosphate (P2O5) and 50 pounds of potash (K2O). Using average bulk fertilizer prices, urea (46-0-0) $750 per ton; DAP (18-46-0) was quoted at $1,150 per ton and potash (0-0-60) $700 per ton. Using these antiquated prices to replace the nitrogen, phosphate and potash removed in a ton of hay resulted in a cost of $84 per ton! Besides the fertilizer cost, there should be something figured in for spreading the fertilizer. Using the 2015 Pennsylvania Farm Custom Rates, the average cost for spreading dry bulk fertilizer will be approx. $10.60 - $10.70 per acre.
However, hay can be produced without chemical fertilizers. We've been doing it for over 15 years!
So, should fertilizer cost be part of determining the cost of hay? That all depends on how you maintain you fields and pastures. If you have a good balance of grasses with legumes like red clover and alfalfa, the legumes will feed the grasses and replace the nitrogen that the grasses will normally deplete from the soil if grown alone. The same goes for your pastures. If you don't rotate your animals and allow your forages ample rest/re-growth periods your "replenishers" such as the Clovers and Alfalfa will die out and your pastures will suffer greatly in a matter of 2-3 years. If maintained properly, you might only have to "Over-seed" legumes into your hay fields and pastures every 6-8 years, and with Alfalfa costing $300.00 a bag that only covers 2.5 - 3 acres, that cost will mount quickly.
Every year I hear producers say they will fertilize in the future, or they are waiting for fertilizer to get cheaper because it is too expensive. Seriously!? Do you really think any input costs like fertilizer are going to decrease? That would mean the chemical companies would be willing to make less money. Funny huh?
I'm just happy we don't need to fertilize any of our hay acres. A little extra time spent planning now will save you thousands of un-necessary costs in the very near future. Don't be in such a hurry to do what the neighbors are doing or what a Chemical company tells you that you "need" to do.
The next part of calculating the cost of hay production is machinery or equipment expense. I used average cost figures from the 2015 Pennsylvania Farm Custom Rates. (These rates are based on survey responses of Pennsylvania farmers). Your own equipment costs will vary based on your local diesel fuel costs, and if you know what they are, plug those in. For those who don't know, this is a good place to start. Mowing/conditioning is valued at $18.10 per acre, raking at $11.00 per acre and large round bales are $8.40 per bale. Wrapping is an additional $6.90 per bale in addition to the $8.40. If you still feed small square bales, it'll cost $2.10 per bale. Than you have to figure in your delivery costs if your customers can't haul your hay themselves. And the BIGGEST cost will be your time. What is your time worth? Yes, there are A LOT of variables to coming up with a fair price that will attract customers and at the same time help you make a living or at least help supplement your main income.
You can get exact prices for your area and additional costs for other custom work by visiting farmprogress.com and going to the USDA 2016 Machinery Custom Rates.
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Last updated: March 17, 2012
Is Genomics the Cure for Disparities?
Archived PageThis page has been archived and is provided for historical reference purposes only. The content and links are no longer maintained and may now be outdated.
Is Genomics the Cure for Disparities?
A presentation by NHGRI Director Francis Collins to the National Leadership Summit to Eliminate Racial and Ethnic Disparities in Health
January 10, 2006
Francis Collins, M.D., Ph.D.:
Well thank you very much Garth. Good morning everyone. If you are wandering in wondering where we are in the program. We are at the point that would have been at 9:05 but a lot of interesting things have been happening already this morning. So, we are a little behind and I will try to be concise in my comments. People who know me well will be skeptical about that but I will do my best because
I want to give the panel a chance to weigh in on this very important question. Is genomics the cure for disparities? Well let's consider the issue of inheritance and what role it plays in disease and what that has to say about health disparities, conditions that all of us are deeply concerned about and representing it by being here at this meeting.
If you look these young people, you will immediately perceive that they come from different ancestral geographic origins and they faced different futures as far as the likelihood of illness unless we do something about the disparities that are currently deeply disturbing, which brings us all here together for this historic gathering. How much of a difference do they face related to the DNA that they inherited and how much is related to environmental experiences and all manner of other issues that is attached to this very blurry concept called race. That is what I want to try to walk through recognizing that we still don't have a terribly precise answer to that question. We are learning quite a lot especially in the last couple of years.
Of course my focus because it is the thing that I know the most about is going to be on the inherited side of this and that means we need to talk about DNA, this really incredible molecule that exists within each cell of your body carrying information that you have inherited down through the generations and this particular information storage system in each in your body means that there is a complete set of instructions, a series of letters along the DNA code that you are either A, C, G, or T. and three billion of those make the human genome, the human instruction book.
It is a very remarkable thing that until very recently we didn't know a lot about that. We now have a whole instruction book in front us but let's ask the question of what is the nature of variation in that DNA. We are not all identical as we would all be one big set of identical twins and that would be pretty boring. So, what is the nature of that variation?
Well Genome project actually was not set up originally to pay as much attention to variation as it was to try to look at the part that we all share. So when the Human Genome Sequence was announced in its completed form in April of 2003, this was basically a hodge podge of DNA contributed by a number of autonomous individuals but that in itself didn't tell you much about the differences between people because any given segment of DNA came from just one person's chromosome. But clearly we need to understand that variation because varied within that portion of the genome are the risk factors for common illnesses that we really want to understand. And as it turns out that is only 0.1-percent of the DNA, 99.9-percent of the DNA is the same. But that point that 0.1-percent is obviously of great interest. To focus on that another International project was founded just a little over three years ago, the International HapMap [misspelled?] project. Again, NIH found itself in the position of being the lead in this enterprise and I found myself as the project manager. Again, trying to organize researchers from six countries to work together to try to build a catalogue of genetic variations as quickly as we could. This seemed like a very daunting project when we started and almost unaffordable because the technology hadn't matured. From the space of just three years, once again coming in sooner than expected, the HapMap delivered a really remarkable picture of DNA variation occurs across all of the chromosomes. As major sent in DNA samples, 270 of them, that while they only represented those 270 people were chosen so that a third of those come from European background, a third from Asian background and a third from West African background. That then gives us a snapshot of something about how variations operate across the world as well as how it operates across chromosomes.
This has been a gold mine of information for people who really were interested in trying to unravel the genetic contributions to diabetes and heart disease, to mental illness, to blindness, to a whole host of conditions that fill up our hospitals and our clinics with people who have illnesses that we poorly understand and frankly poorly treat. So for many of us who got into genomics in the first place with this promise to provide real understanding of those common illnesses. This is an exciting moment. Now that we have the tools from the HapMap we will over the course of the next three or fours years be discovering what are the major heredity factors in those illnesses and the big question for this conference is will those heredity factors turn out to be evenly distributed around the world or will it be some circumstances where some of them are more prevalent in one population than the other and therefore will have contributed to the health disparities. I don't know the answer at the present time.
Well what do we know about genetic variation in general? You know that from all manner of sources of information much from genetics but also from the fossil records and also from history, the migrations of the human species have been occurring in a very irregular way from our original founding population and we were once all Africans as I will come to in a moment, I think we now have very strong evidence that we were all once black Africans living in Africa. Yes? We, white people, as I will tell you in a minute, are actually mutants but we will come that. So, the estimates are that a hundred thousand years ago that there were about ten thousand homo sapiens. This was our founders; all of us, living in Africa and the variation that we see in present day human beings was largely already present in those founders. But that was a large enough group that there was a variation present. There haven't been that many new variations that have cropped up in the five thousand generations since then. Most of what is going as far as how genetic variations are organized around the world relates to the ways in which those genes were spread as people migrated out of Africa to other parts of the world.
So in this diagram for instance you will notice that the blue and the yellow circles are more prevalent outside of Africa whereas they are less so in Africa. And that is just simply a function of which people happen to migrate out and which that did not. So on that basis alone without any of these variants having any significant at all you would not expect to have actually the exact distribution, the same frequency of a particular spelling variant in one part of the world versus the other. That is what you would call genetic drift.
On the other hand, a few of the variants that are present in this founder pool might actually have provided a selected advantage in one place or another. We all know the most dramatic example of that is the sickle mutation. If you are a carrier for sickle mutation, you are protected against the most severe consequences of the malarial parasite. So, those who carry that mutation and lived in a malarial area were able to survive better. Therefore that gene occurs with high frequency and whereas, for those who did not live in an area where malaria was prominent the sickle mutation provided no advantage. In fact, it would provide a disadvantage in those who were provided a double dose; those actually would develop a disease that would become sickle cell anemia. That kind of thing has certainly been going on in other circumstances although it is less worked out in most other examples.
Okay. So that is the story about genetic variations but now let's get really murky. What is the relationship between genetic variations and race? Well, first you have to decide exactly what do you mean by race. If we asked everybody in this room to write on a piece of paper a definition of race, that would be really interesting and I suspect we would get at least a number of definitions that there are number of people in the room and maybe more because some of you might want to provide a couple alternatives. The press hasn't helped us much here in terms of explaining how race and genetics are connected. Depending on which article you read you can read something like this that says that "genes, the study of them prove that race is only a sham. No trace of race in genome project proves nothing biologically separates people". But wait a minute if that is the case how can people be making money right now selling DNA tests that will tell you where your origins are and a lot of people are in fact interested in this information. If there is nothing in DNA that tells you something about ancestry, how is it true to say that there is no biological connection whatsoever to race. Here is one of the websites for one of the places that will do that kind of DNA testing and I gather they are getting lots of customers.
Then of course, a big controversary that I will come back to a specific example of Vidal in a minute about whether race ought to be playing a role in clinical medicine in terms of identifying treatments that might work for one group and not another. What is the balance here between trying to do something about health disparities and not making the mistake of redefining the concept of race by assuming it has more biological significant than it does.
So, what does race mean anyway? I like Evelyn Higginbotham's [misspelled?] quote: "When we talk about the concept of race most people believe that they know it when they see it, but arrive at nothing short of confusion when pressed to define it." Try it out on your neighbors and they will fall into confusion, I am quite sure. Most of us if really asked to write this down have that same problem.
Because race has so much baggage it carries with it connotations of history of discrimination. It carries with it cultural and society and dietary practices. It carries a little bit of ancestral geography of course but that in fact is probably the minority of what most people are actually thinking of when the term race appears in a sentence. And is it any wonder therefore as we try to figure out the connection between genetics and race, we have trouble because we are not quite sure what it is that we are connecting to.
So, what do we know about genetics and race? Let's focus on what we know and then I will try to point out the things that we don't know. Well, we know that we are all 99.9-percent the same at the DNA level. That is proven by HapMap and a variety of other types of studies. That is a phenomenonal statement. We are much more like each other than other species on the planet. If someone arrived here from outer space and tried to write a little tree up about homo sapiens, one of the things that they would say is wow these people are really all alike. Compared to other species there is more diversity in a small group of chimpanzees living on one hillside than it is in the entire human race because we are so new on the field. It is these five thousand generations separating us from a very small pool of ancestors. That's pretty unprecedented for our species on the planet. But yet isn't that interesting that our characteristic is that we seem so focused on that difference, that 0.1-percent. That 0.1-percent of three billion is still a big number so that leaves a lot of differences between two individuals, most of those fall into places on the genome that isn't doing very much and have no consequence. And most of the variants as I said earlier that we do have were present in our common ancestors. But because of migratory events and a few other things the frequency of a particular variant where you might have a T and I might have a C, could be different depending on where your ancestors came from. Some of that is just drift. Just the sort of chance thing that happened as people migrated from one place to another and maybe brought a T over here and a C over there. And that has been absolutely no particular significance to anybody's health. Founder effects where you have maybe a very small group of founders who then result in a very large group down stream, like for instance Finland founded by a relatively small group of ancestors. Or today the Amish for instances.
Selection however and new mutations are a different story. Selection as we talked about for sickle cell disease operating in a circumstance where a particular variant provides an advantage if you are a carrier for that. New mutations have occurred. For the most part, they appear and then they get lost if they have no advantage or disadvantage the chances of them hanging around for very long is pretty small, which is again why most of the common variation of the genome has been there since our founders and its still there today. But there are some interesting exceptions and one of them has gotten a lot of prominence in the press about a month ago. An article in Science Magazine heralded by a particularly interesting ? here is the cover art that was used for Science on December 9th described a finding which got a lot of people interested. Now scientifically this was a really interesting story. Investigators at Penn State Keith Chaney [misspelled?] and his colleagues were studying zebra fish. So, you see the two fish in the fishbowl there. The one on the bottom is the way zebra fish would normally appear if you went to the pet store and purchased some. But some years ago, somebody noticed in the pet store a zebra fish had has a golden color and that is the upper one. And that became a subject for scientific investigation. What exactly is the cause of this because it was clearly inherited? To make a long story short, they identified the gene that was involved in this. It was a gene that nobody thought had anything to do with pigmentation, it is an ion channel. Then the investigators, Keith Chaney went to the HapMap database to see do humans have a gene like that too. And if they do, is it the same in everybody? Or could there be actually some naturally occurring variation in that same gene that might have some role in human skin pigmentation. I am just going to show you a screen shot of what a scientist sees. This is what Keith saw when he went to the HapMap website. This is the most complicated slide that I am going to show you so don't get too alarmed; it is going to go downhill from here.
You are looking at a stretch of DNA. And there is a gene down there at the bottom seen it in yellow, called SLC24A5. That is the gene, which in the zebra fish has a glitch in it that causes the golden pigmentation. But you are not looking at the zebra fish's map. You are looking at the human map of this same gene. Yeah. We have a gene that is very much like the one on the zebra fish. Now those blue and red circles are little pie charts telling you that in HapMap samples what is the frequency of one spelling versus another in those places in this gene where there is a variation. So, each collection of four circles is a DNA variation and next to the circles that you will be able to see two letters like A or G or C or T telling what the variation is, what two possibilities that occur at that spot. I want you to pay attention to the one down there in the lower right because that is the one of interest. That is the case where the CUs samples happen to be people living in Utah who are northern European background. You can see that is our only blue, that is a hundred percent of them have the A spelling whereas the other three circles CHP which represents Chinese, living Banghani [misspelled?], yeah, that is Chinese. A GPT, which are Japanese living in Tokyo and YRI, which are Euro people living in [Inaudible] Nigeria. They have almost completely a hundred percent the G spelling. Well it turns out the A spelling actually causes this gene not to function very well and in fact, larger studies have shown us that most people who are derived from European background have that that A spelling. And this same gene which causes reduced pigmentation in the zebra fish is a major contributor to lighter skin in people who live in northern climates.
You will also notice it can't be the whole story because in this demonstration the Chinese and Japanese sample have the same spelling as the African founders so their lighter skin must be on the basis of some other genes. And in fact, it is even more not the whole story because in the European this one gene accounts for about thirty percent of skin color differences in Europeans and Africans but not a hundred percent. There are other genes involved here as well.
So, what happened here? Presumably this change from a G to an A in this gene arose somewhere back there and it provided a lighter skin color which if you were in a northern climate which is where people migrated out of Africa to go further north was a selective advantage because if you are dark skinned in a northern climate where there is not as much sun exposure, you are likely to get rickets. Somebody with rickets will have a difficult time in childbirth. Whereas if you have light skin at the Equator, you are going to end up with a very high risk of skin cancer.
So all this stuff about skin color that we get so excited about because of its historical significance and all of the social values that are attached to that can be perhaps be demystified in understanding this simple molecular demonstration. It is a molecular demonstration of how out of Africa hypothesis. It is a molecular demonstration of how a selection for skin color allowed people to survive better in different parts of the world. And it shows by the way that in this instance race is only skin deep. This gene doesn't seem to affect anything except skin.
So scientifically this is an incredibly interesting story and it has been very interesting to see how it plays out in terms of the public acceptance of this kind of molecular basis for something that we are all so focused on. My hope is and I think it is playing out pretty well so far is that this really does provide an opportunity to get people to think about just how silly it is to get so focused on something as the darkness of one's skin.
It also does show and I have enjoyed saying this to my friends that white people are all mutatant, that we all have this acquired glitch and that gene is not functioning very well in us. Oh, well.
So let's continue our list of what we know about genetics and race. So those differences I just showed you that one but if you look across the whole genome, there are other places where there are quite a difference in frequency of a particular spelling depending upon where your ancestors came from. Most of those just because of drift, some them maybe showing some signs of selection from where we don't know what, and you can in fact use those differences to take a DNA sample and make a guess as to where that person's ancestors came from. But you are not going to be very precise about it especially since as increasingly lots of people don't have all of their ancestors coming from one place. And importantly when people draw out descriptions of human populations, they often draw out this kind as a tree with this rooted sort of foundation in Africa and all of these branches. But that is not really correct. Gene flow don't go in one direction. Genes have been flowing back and forth as long as we humans have been wandering about. In fact, it is probably more appropriate to draw our relationships with each other as a wisteria vine with all of these interconnecting branches.
Maybe that also helps understand why it is incorrect to try to draw boundaries around any particular group and say they are biologically different. That is not justified by the science that we now have in front of us, which means except maybe in a few cases of extreme geographic isolation, the founders of our population groups are going to be blurry and imprecise.
So to get to health disparities. IF you observe then a difference in prevalence in illness between groups, this might be due to genetic differences. It could be or let's really get to the point here. It could have nothing to do with genetic differences and every thing to do with diet, culture, environment and socioeconomic factors. Or to keep our minds completely open a mix of both where some genetic susceptibilities interact with some environmental exposure resulting in an outcome.
And coming back to the skin color, we already know that is true. I am at for higher risk for getting melanoma than a lot of other people in the room because of my light skin color. That is a well-documented gene induction action if I lived in cave and never went outside then I wouldn't have that risk. But the light color of my skin predisposes to that particular environmental outcome.
Well, let's see if we can put this together in some kind of synthesis that perhaps tries to pull together what we know about genes and environment and health disparities.
Everybody in the room probably has some self-identified race or ethnic association but that is an incredible complicated mix of factors that go into that. What is the connection then to health or disease? Well it travels through several pathways. First of all, it certainly correlates with environmental exposures of different sorts of education, of access to heath care, of culture, to socioeconomic status, of stress factors, all of them things together ? none of which are related to your DNA. They are related other factors. ? play a major role in health and disease. But there is also a connection between self-identified race or ethnicity. Admittedly, a blurry one with ancestral geographical origins and in some instances that maybe tighter than others but it is probably in there as some kind of correlation.
And that in turn will correlate with variation across the genome. That in turn will correlate with the variants in specific disease genes and those too perhaps interacting with the environment may make a contribution in some instances to help make disparities. But the balance between the left and the right side of the diagram is for most disparities still not known. We have a ways to go to sort that out. But I think because of HapMap and other efforts we are close to being able to tackle it in generating some real data.
My argument here is if we really want to understand health disparities we don't want to stick to the worry proxy measurements called self-identified race or ethnicity. We could do better than that. You want to the get to the proximal causes because they are the things that you can understand and do something about. The sooner we can move from those proxy relationships the true environment influence and the true genetic influences that are true about the individual and not some poorly defined population group then the quicker we will be on the path to doing something to improving people's health.
Now one final point and then we will convene the panel. There has been much discussion about this particular drug called Vidal that was approved by the FDA last summer for treatment of heart failure in self-identified African Americans. Depending on how you look at this, this is a really good thing or it's a worrisome thing. So let's quickly walk through what happened.
Vidal is a combination of two generic drugs. Isorbide nitrate and hydralazine. It acts we think as a nitrate oxide enhancer. Nitrate oxide dilates blood vessels so this is a good thing if you have heart failure. It reduces the resistance and you would expect that would improve the functioning of some body who has congestive heart disease. So, Vidal was originally tested way back in the 1980s and 1990s in clinical trials involving Veterans Hospital patients in a mix of individuals in different backgrounds. It showed possible benefit, was brought to the FDA but the FDA ruled in 1997, the results were unconvincing and did not approve the drug. At that time they went back and looked retrospectively at the data and became convinced that the benefit that was seen with this drug was greatest in African American patients and less in those that self-identified as Caucasians. Interestingly and this is I think an important part of the story, the patent on Vidal was at that point within only a few years from expiring. A new patent was filed based on this retrospective analysis on the use of this drug specifically for African Americans. The patent office approved that. The first time as far as I know that a patent for a drug for a specific racial group was approved without in fact a whole lot of discussion occurring at the time.
Of course what that meant was that the patent was now refreshed for another seventeen years. So there is an opportunity here for an expanded market opportunity. So what happened? Nitromed, the company that picked up the drug, then conducted a clinical trial solely on African Americans, didn't involve any other groups, eleven hundred of them. A very well conducted clinical trial. The trial was supported by the Association of Black Cardiologists and the National Medical Association. It showed in The New England Journal article reporting this about a year ago absolutely convincing benefit. So the solid line there the Isorbide nitrate plus hydralazine that is Vidal. You can see the overall survival compared to placebo is substantially improved and this is also in patients who are getting other medicines for congestion heart failure and Vidal is being added on top of that. So that is the type of thing that you would except to happen out in practice. So really exciting news.
There is clearly benefits to a disease that affects African Americans at a higher frequency than many other groups and for which treatment has been unsatisfactory and here is a clinical trial showing substantial benefit of this new drug combination. So as you might expect FDA looking at that, approved it by the summer of last year for the treatment of congestive heart failure. The package insert says the following Vidal was indicated for the treatment of heart failure as an adjunct to standard treatment in self-identified black patients to improve survival, to reduce hospitalization for heart failure and to improve patient reported functional status. No comment made about whether this drug should or should not be used for other groups. So was this is a good thing. It is a good thing that we have a drug that treats individuals with congestive heart failure and clearly improves their survival. Nobody could argue that that is not a really good thing. But are we sure that this came about actually in a way that made the most sense. Are we sure that this drug would not have benefited other groups? If you go back and look at the original studies, it doesn't look as if it was benefit in the patients in the VA study who did not identify as black but it was a relative modest size study and there could have very well been some benefits in others.
Are we sure that this has anything to do with being African American or could it be that since African Americans tend to have heart failure on the basis of hypertension that this says this drug is for hypertensive heart failure and not as well heart failure from coronary artery disease, which is perhaps more common in other groups. We know that from epidemiology. Or fail for every black person looking at a lump together theory individuals. But by lumping them together, there is a real risk here that this is interpreted ah, well that means that black people really are biologically different. After all, there is this drug it only works for them. And that is unjustified by the science of what has been done here.
So this is a real interesting example and a two edged sword. More examples like this are potentially coming along. I don't think this is where we want to go. I think we want to go in the direction of figuring out, okay, if this drug works for some people and not others, why is that. What specific DNA variants are responsible for that variation response? And okay if they have them differentially distributed around the world, that is fine, who cares, lets check the individual and find out where they are likely to respond to the drug or not. And not use this very murky and potentially misleading and damaging proxy called race and pretend that we are practicing really upscale medicine. We can do better than that.
So, in summary here race is a term that carries a whole lot of baggage. I think we all agree. Much is being learned about genetic variation around the world. Neither of these statements is correct. Race has absolutely no biological basis. Not really true. There is a connection in ancestral geographic origin. It's murky but it's not absent. But it is certainly true if you can't draw sharp boundaries around groups based on genetics. So again, if you want to understand health disparities we should go after the proximal causes and not depend upon these muddy and misleading proxies. And to answer the question posed in this session is genomics the cure for health disparities probably not but in some instances, it may play a role in terms of heritable factors but almost always in concert with environmental factors. If we really want to know, we need more data. The good news is in another two or three years we are going to have a lot more data on this subject. I think therefore we will be much better poised to do something about it.
Thank you very much.
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