Give him a Nobel Prize (and be patient with your cardiologist!)

The Fall and Rise Of Kilmer McCully




Published: August 10, 1997

In 1981, when kilmer mccully started commuting from his home in a boston suburb to a new job in Providence, R.I., he would drive past the domed Rhode Island Capitol. High atop the dome stands a statue called ”The Independent Man” — a representation of Roger Williams, the Puritan founder of Providence. ”Because of Williams’s religious beliefs, he was thrown out of Boston,” McCully says now. ”It sounded familiar.” McCully, too, felt like an outcast when he went to Providence from Boston, though he was a scientific rather than a religious infidel. He had left appointments at Harvard Medical School and Massachusetts General Hospital under a cloud, told that his research had dead-ended. He had been denounced by some fellow scientists and ignored by others. His research grants had withered away. He took refuge in a pathology job far from the fast track at the Providence Veterans Administration Medical Center.

These are distinctly better days for McCully, who is now 63. His lifetime’s study of a little-understood trigger for heart disease is suddenly at the forefront of cardiac research. His theory — the same one that came close to scuttling his career — holds that homocysteine, an amino acid in the blood, damages artery walls and causes heart attacks, and that in most cases homocysteine can easily be lowered to safe levels by taking certain common vitamins. If he’s right, homocysteine could join cholesterol, smoking and high blood pressure as a major culprit of heart disease, accounting for (and perhaps someday preventing) upward of 10 to 15 percent of all cases. For an illness that kills nearly 1,500 Americans a day, these are serious numbers.

Homocysteine is the theory of the moment in a notoriously competitive field, and McCully’s name is inextricably tied to its ascent. He has been called ”the father of homocysteine” at meetings of leading international figures in cardiology and epidemiology. His book, ”The Homocysteine Revolution: Medicine for the New Millennium,” was published in May. Where once McCully’s was almost a lone voice in homocysteine research, now dozens of articles have appeared in scientific journals, including one a few weeks ago in The New England Journal of Medicine. Where once the theory was shunned by the grant-giving powers that be, the National Institutes of Health recently put out a request for applications for further research, and at least one large-scale study of homocysteine in humans is already under way.

While McCully says he is ”grateful” and ”thrilled” that his work is being appreciated, there is a bittersweet quality to his current success and to his anointment as an innovator. A personality more prone to might-have-beens would find it easy to dwell on the contrast between his present situation and that of more than 20 years ago — another moment when accolades and recognition seemed almost within reach. But beyond the issue of McCully’s halted career, those concerned about heart disease — the nation’s No. 1 cause of death — might wonder, what took so long?

The son of two schoolteachers, McCully grew up in Colorado as a self-described ”boy scientist.” After graduating from Harvard College and Harvard Medical School, he embarked on a series of research fellowships. In the mid-60’s, as a young pathology instructor at Harvard, McCully made the scientific observation that would define his career. He became intrigued by two different cases of children with homocystinuria, a rare genetic disease in which the levels of homocysteine in the blood are unnaturally high. In both cases, the cause of death was severe arteriosclerosis, a narrowing and loss of elasticity in arteries that is normally seen only in the elderly. By re-examining the autopsy tissues of both children and drawing on previous animal research, McCully emerged with two linked and provocative suggestions: perhaps homocysteine directly damages the cells and tissues of the arteries, in much the way that cholesterol is thought to do, and perhaps that damage occurs not just in these rare genetic cases but in the population at large, in any people with elevated homocysteine levels.

He soon expanded his theory to include a probable cause of elevated levels of homocysteine: a deficiency of vitamins B6, B12 and folic acid. When these vitamins were administered to animals with high homocysteine levels, those levels plummeted, often within hours. Once McCully started extrapolating from his cellular-tissue and animal studies to the human situation, he says, ”it all began to fit together.”

Homocysteine in the body derives from methionine, an essential amino acid present in large amounts in protein from animal sources like meat, eggs and milk. If there are adequate levels of vitamins B6, B12 and folic acid in the body, the homocysteine is broken down into harmless waste products or protein building blocks. But if there’s a deficiency of those vitamins, the homocysteine begins its ravages on the blood vessels.

What, then, is the diet most likely to lead to heart disease, according to the homocysteine theory? One high in animal protein and low in B-vitamins, which occur in many foods but are very easily destroyed by processing — a diet of meat, cheese, milk, white flour and foods that are canned, boxed, refined, processed or preserved. The American diet, in other words.

Here was a strong connection between diet and heart disease, but one that took a different path from cholesterol. The homocysteine theory considers arteriosclerosis a disease of what McCully calls ”protein intoxication.” The cholesterol theory (sometimes called the lipid theory) instead demonizes fats. Since proteins and fats often occur in the same foods, the potential dietary treatments for high homocysteine and high cholesterol are similar, with this distinction: the anti-homocysteine diet focuses on what should be eaten, as a preventive, while the anti-cholesterol diet focuses on what should be avoided, as a precipitator. Thus, a diet of lower homocysteine would include many natural sources of B-vitamins like fresh fruits and vegetables and would limit animal protein. The cholesterol-reducing diet would limit foods high in saturated fats and cholesterol, like eggs, meat and butter.

But dietary intervention often fails to lower cholesterol levels, and the next step is drug therapy. A new class of drugs called statins has been more effective than previous drugs at lowering cholesterol with few side effects, but questions have been raised about the safety of long-term use. No clinical consensus on how to treat high homocysteine has yet emerged, but most researchers say that the logical course is simply to take a multivitamin. Studies suggest an optimal daily intake of 3 to 3.5 milligrams of B6, 350 to 400 micrograms of folic acid and 5 to 15 micrograms of B12; many multivitamins contain these amounts.

”For the first few years, everywhere I turned I got evidence that the basic idea was correct,” McCully recalls. He injected rabbits with homocysteine and within weeks found arteriosclerotic plaques in their coronary arteries. If the animals were also given a diet deficient in vitamin B6, the plaques were more widespread. While others conducted similar experiments with baboons, McCully examined and manipulated cell cultures from children with homocystinuria. Two Australian researchers, Bridget and David Wilcken, published the first human study in 1976, showing a possible connection between coronary heart disease and high elevations of blood homocysteine.

Then, in the mid-70’s, the homocysteine theory began to lose momentum. McCully believes that his support at Harvard and Mass. General began to flag after his department chief and mentor, Benjamin Castleman, retired in 1974. Castleman, who died in 1982, had helped review McCully’s findings, sponsored him for lectures and showcased his work before a prestigious panel of experts.

Under the new chief, Robert T. McCluskey, this backing eroded. He was moved to an inferior laboratory in the basement, he lost staffers and his N.I.H. funding was running out. ”With the changes in my lab and the loss of some key collaborators, it was difficult to come up with new ideas,” he says. ”I felt very cut off from everybody, and there was no encouragement. Then they told me that if I didn’t renew my grant, I would definitely be out. Their view, I suppose, was that I was no longer productive. My view was that I was being discouraged at every turn.”

McCluskey, who is no longer the department head, now says that the key issue was money. ”It’s certainly true that, perhaps because his idea at that time wasn’t generally accepted, he wasn’t able to get funding for research after his grants ran out,” he says. ”There was some uncertainty at the time about how important his work was. Anyone doing research at Mass. General has to apply for and eventually succeed in getting outside funding, and McCully was unable — in fact, unwilling — to do that. He wanted the department to support him, which wasn’t possible on a long-term basis. So he was asked to either attempt to get further support or to leave.”

McCully acknowledges that he eventually did give up on obtaining another N.I.H. grant. ”My enthusiasm had been drained,” he says. ”In that atmosphere, and because I hadn’t generated a lot of new information, I felt it was hopeless to apply for a new grant — that I wouldn’t get it.” But he denies that he asked the pathology department to support his research. ”I’d already been told by the director of the hospital that it was felt at Harvard that I had not proven my theory,” he says. ”In fact, when I left he told me never to come back.”

The current chief of pathology at Mass. General, Robert Colvin, agrees with his predecessor that ”the main issue was that nobody could fund McCully’s research,” but he emphasizes the funders’ short-sightedness. ”McCully was so far advanced in his thinking about the biochemistry,” Colvin says. ”And N.I.H. is not very good at funding very innovative, creative research. They’re better at funding natural extensions of existing theories.”

Since Mass. General and Harvard appointments go hand in hand and McCully had not been recommended for tenure at Harvard, both jobs formally ended in January 1979. At about the same time, a former classmate at Harvard who went on to become the director of the Arteriosclerosis Center at M.I.T. attacked his ideas as ”errant nonsense” and a ”hoax that is being perpetrated on the public.” McCully says that when he was interviewed on Canadian television after he left Harvard, he received a call from the public-affairs director of Mass. General. ”He told me to shut up,” McCully recalls. ”He said he didn’t want the names of Harvard and Mass. General associated with my theories.”

In retrospect, it seems clear that McCully was a man ahead of his time when the times were all about cholesterol. ”Kilmer McCully’s hypothesis seemed to challenge the cholesterol-heart hypothesis, which was riding high,” says Irwin Rosenberg, director of the U.S.D.A. Human Nutrition Research Center on Aging at Tufts University. Rosenberg was a medical-school classmate of McCully’s and, briefly, a physician in Mass. General’s department of medicine when McCully was in the department of pathology. ”Because his work was not in vogue,” Rosenberg says, ”his insistence on what he was doing contributed to costing him his job.”

Thomas N. James, a cardiologist and president of the University of Texas Medical Branch who was also the president of the American Heart Association in 1979 and ’80, is even harsher. ”It was worse than that you couldn’t get ideas funded that went in other directions than cholesterol,” he says. ”You were intentionally discouraged from pursuing alternative questions. I’ve never dealt with a subject in my life that elicited such an immediate hostile response.”

It took two years for McCully to find a new research job. His children were reaching college age; he and his wife refinanced their house and borrowed from her parents. McCully says that his job search developed a pattern: he would hear of an opening, go for interviews and then the process would grind to a stop. Finally, he heard rumors of what he calls ”poison phone calls” from Harvard. ”It smelled to high heaven,” he says. ”Eventually I went to an attorney friend of mine, someone quite prominent in Boston. He made a few phone calls and it was all over. Then this job came through.”

The story of those two scary, free-fall years — McCully can still recite the exact dates, Jan. 1, 1979, to March 15, 1981 — emerges in small details, teased out by questioning. This is not a man who eagerly lays his grievances on the table. ”My daughter told me recently that she still gets nightmares about that time,” he says. Later, describing his son’s and daughter’s careers as, respectively, Wall Street banker and magazine editor, he remarks: ”They both had been interested in chemistry when they were younger. Then they saw what happened to me” — he barks a laugh — ”and that was the last I ever heard about that.”

McCully also laughs with seeming good grace about the contrast between his present position and that of medical-school classmates like Irwin Rosenberg, ”the director of the nutrition institute at Tufts, with a multimillion-dollar budget and all these projects.” But from his much more modest perch at the Providence V.A. lab, he says, ”I’ve been able to develop my own approach, which might not have been possible at a high-powered place.”

When McCully landed in Providence, he continued testing his theories, inducing arteriosclerosis in rabbits, observing homocysteine’s effect on cancer cells and publishing his first monograph, an overview of the homocysteine theory. At the same time, a study at Cornell and several others in Europe — in Sweden, Norway, the Netherlands and Ireland — explored the workings of homocysteine in humans. By 1990, some of those results were beginning to pique fresh interest in the United States, and Meir Stampfer, a professor of epidemiology and nutrition at the Harvard School of Public Health, decided to take a look at homocysteine in members of the Physicians Health Study, an ongoing survey of almost 15,000 doctors. Stampfer’s findings helped start the current surge in homocysteine research.

Using blood samples taken years before any of the physicians in the study developed heart disease, Stampfer and his colleagues found that homocysteine levels were directly correlated to heart-disease risk. ”The study represented something of a turning point in the field,” Stampfer says, ”because it was the first time we had prospective data — the men were healthy at the time the blood was drawn and some later became ill — and also because the homocysteine levels were all basically in the normal range. Even within that range, being at the top was strongly predictive of heart disease.”

Other powerful evidence soon followed. Jacob Selhub, a senior scientist and colleague of Irwin Rosenberg’s at Tufts, looked at another large ongoing human sample, the Framingham Study, which has documented the population of Framingham, Mass., for nearly 50 years. Selhub found a strong association between homocysteine in the blood and insufficient levels of vitamins B6, B12 and folic acid. ”We showed that 30 percent of the American population is not taking in enough folic acid,” Selhub says. ”And, at least in Framingham, close to 30 percent of the population has high homocysteine.” Next, Selhub observed the relationship between homocysteine levels and narrowing, or stenosis, of the carotid artery. He found another correlation.

”The higher the homocysteine in the blood, the higher the prevalence of stenosis,” Selhub says. ”We also showed that people with low intake of folic acid and vitamin B6 have a higher chance of having stenosis in the carotid artery. That was very important and exciting — that practically tells you that we might be able to prevent this if our folic acid intake was sufficient.” Both of Selhub’s articles on these landmark studies, which appeared in The Journal of the American Medical Association and The New England Journal of Medicine in 1993 and 1995 respectively, cited McCully’s original 1969 article on homocysteine and arteriosclerosis in the very first sentence.

The homocysteine theory was back in business, and McCully with it. Even old-line supporters of the cholesterol theory now acknowledge that homocysteine is, if not entirely proven, an extremely promising area of research. ”There’s no question that homocysteine is a very important issue,” says Claude Lenfant, director of the National Heart, Lung and Blood Institute, which some scientists consider a kind of ground zero for the cholesterol camp.

”Even if only 10 percent of the risk of heart disease is explained by homocysteine,” Rosenberg says, ”you’re talking about a huge element of the process of the disease — and a lot of people. Forty-plus studies have so far observed a relationship between higher homocysteine levels and the risk of different kinds of vascular disease.”

McCully appears to be enjoying the flowering of homocysteine with a minimum of bitterness. ”Any scientist wants to have his work confirmed, wants to make a place for himself in the scientific literature,” he says. ”I thought it was great that these big shots were paying attention to it.” Lenfant suggests that perhaps they would have paid more attention earlier if the cholesterol theory had been less divisive. ”Twenty-five years ago, not everybody was accepting the cholesterol business,” he says. ”So who wanted to hear about something that perhaps would weaken the argument for cholesterol?”

The cholesterol theory of heart disease, Thomas James says, ”has been a favorite theory for 50 years.” It holds, essentially, that high levels of cholesterol in the blood cause arteriosclerosis and heart disease and that lowering those levels will lower the risk of heart disease. But while it was easy to show that very high cholesterol was associated with a high risk of heart disease, it was harder to show how it caused heart disease, or whether reducing it would reduce heart disease. Recent studies have firmed up those relationships, according to Lenfant, who says, ”Now the cholesterol story is as solid as the Rock of Gibraltar.”

But there continue to be indications that the cholesterol story is extremely complex and sometimes contradictory. For instance, Stampfer says, ”the majority of heart attacks occur in individuals with ‘normal’ cholesterol. That does not mean that cholesterol is not important, but it tells us that there are other mechanisms.”

It has not always been easy to propose other mechanisms, perhaps because the cholesterol proponents themselves felt somewhat embattled. Throughout the 70’s and early 80’s, agencies like the National Heart, Lung and Blood Institute and the American Heart Association were gearing up for major public health initiatives that culminated in the National Cholesterol Education Program begun in 1985, and the advocates for those agencies felt that a united front was essential.

Even as recently as last year, Alan Garber, an associate professor of medicine at Stanford University, was stunned after he and a colleague, Warren Browner, proposed that healthy young men and women need not be screened for cholesterol, since treatment at young ages has not been shown to be useful or cost effective. ”The American Heart Association and the National Heart, Lung and Blood Institute issued press releases and had a big campaign to discredit our work,” Garber says.

McCully stresses that his ideas do not dismiss cholesterol as a risk factor, but they do question its hegemony. ”Cholesterol is important, certainly,” McCully says. ”But the cholesterol theory isn’t really a theory — it’s a collection of observations.” He says his own theory suggests that ”homocysteine might be the underlying cause of arteriosclerosis, that homocysteine damage sets the stage for cholesterol buildup in the arteries. I think altered homocysteine metabolism and biochemistry is at the heart of vascular disease.

”But,” he adds with a laugh and a flash of self-knowledge, ”working in this field all these years, naturally I feel that way.”

As McCully knows well, history is crowded with examples of ostrich-like behavior among medical researchers. There was strong resistance for years to the idea that many ulcers are caused by a bacteria rather than stress — a theory that was ridiculed until the evidence finally became too strong to dismiss.

The American scientific establishment’s answer to such human foibles as stubbornness, arrogance and the unwillingness to let go of favored theories has been peer review. The peer-review system in research tries to be equitable by having panels of experts judge grant proposals and articles submitted to the medical journals. But even a process that has objectivity as its goal is vulnerable to the pitfalls of committee-think.

”For instance,” Rosenberg says, ”if most of the people on the National Heart, Lung and Blood Institute’s advisory council come out of the lipid-fat-cholesterol camp and there’s no one from, say, a nutritional orientation, it’s not as likely that an expensive study will get the same hearing if it’s looking at a homocysteine-lowering intervention versus a cholesterol-lowering intervention.”

James believes that as long as the management of the Heart, Lung and Blood Institute espouses the cholesterol line, ”then the review committees, the other evaluating bodies, are going to be influenced — not by written memoranda but by the environment and by word of mouth.”

But James sees an even bigger reason for cholesterol’s dominance of the heart-disease debate: ”It’s the money that’s the problem. Look at the colorful advertisements in general-interest publications, explaining to grandfather that his grandchildren want him to stay alive using these drugs. The anti-cholesterol medications are multibillion-dollar industries now, and they have a huge stake in fanning the flames of the cholesterol mission.”

Charles Hennekens, a professor at Harvard Medical School and chief of preventive medicine at Brigham and Women’s Hospital, cites the example of aspirin. ”For years now, we’ve known about these large benefits of aspirin in treating acute heart attacks and survivors of heart attacks, and yet we have underutilization of it,” he says. ”At an F.D.A. advisory committee meeting recently, I joked that if aspirin were half as effective, 10 times as expensive and on prescription, maybe people would take it more seriously.”

Like aspirin, the vitamins that control homocysteine levels are readily available, inexpensive and nonexclusive. ”It’s inescapable that there’s just not the commercial interest for supporting research in homocysteine,” Stampfer says, ”because nobody’s going to make money on it.”

McCully takes this follow-the-money approach to its logical conclusion: who stands to gain? ”The most dramatic improvements in longevity over the last couple of hundred years have been through public health, not through medicine,” he says. ”But public health is notoriously unprofitable. People don’t make a profit preventing disease. They make a profit through medicine — treating critical, advanced stages of disease.”

Although there’s not much money to be made from doctors prescribing vitamins and offering dietary guidelines to heart-disease patients, corporate wheels are already turning to make homocysteine levels the latest, hottest measure of optimal health. A new TV commericial for Centrum multivitamins singles out folic acid because it ”may help reduce homocysteine levels in the blood, an emerging risk factor for heart disease.” McCully says that Abbott Laboratories has developed a test for homocysteine, though he feels it is inadequate. ”Once we develop a better test,” he says, ”I would like to think that the vast majority of heart patients, far greater than the current estimates of 10 to 15 percent, will show this striking elevation in homocysteine.”

Such confirmation may come years from now, and McCully realizes that he may not play a role in it. ”Generally speaking, a scientist makes one contribution and then everybody else takes over and it becomes extremely competitive,” he says. It is only when pressed about the past that McCully reveals, briefly, the shadow of disappointment that must have loomed larger two decades ago. ”Last October,” he says, ”the pathology department at Mass. General had a reunion and invited me, and I saw one of the people involved in my leaving the department. ‘Well,’ he said to me, ‘it looks like you were right after all.’ It’s 20 years later. My career is almost over. There’s really not much that can be done about 20 lost years, is there?”

Worse, the political and economic forces that undid McCully back then may be more intense today. Last April, The New England Journal of Medicine published an article titled ”The Messenger Under Attack — Intimidation of Researchers by Special-Interest Groups,” which detailed three cases of harassment by advocacy groups, physicians’ associations or academic consultants who often failed to disclose their ties to drug companies. With more and more pressure groups weighing in on what research gets financed and promoted, the article said, ”such attacks may become more frequent and acrimonious.”

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