Abraham Lincoln

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Did He Have Marfan Syndrome?

Marfan Syndrome

No one seems to know exactly how tall, but by all accounts Abraham Lincoln was an uncommonly tall man. During the Civil War a reporter described him as a "tall, lank, lean man considerably over 6 feet in height with stooping shoulders, long pendulous arms terminating in hands of extraordinary dimensions which, however, were far exceeded in proportion by his feet." Contemporary photographs confirm that he towered over most men. One famous photo shows him standing head and shoulders above the diminutive General McClellan, the caps of the other, taller officers just even with the beard on the President's chin. We know relatively little about Lincoln's health, but he was said to be a man of impressive strength and, except when he was chained by bouts of depression, of great energy.

The first person to suggest that Lincoln's height might be a sign that he had a genetic disorder known as Marfan syndrome was a Los Angeles physician. The idea arose by chance. In 1962, after diagnosing Marfan syndrome in a 7-year-old boy, the doctor traced the culprit gene through the family. He discovered that the little boy was an 8th-generation descendant of Mordecai Lincoln II, the great-great grandfather of the president. This by no means proves that Lincoln carried a copy of the gene that turned up in the child, but it is a tantalizing hint.

Marfan syndrome, which affects about 1 in 20,000 persons, is named for the French pediatrician who in 1896 first described a girl with severe skeletal abnormalities. Those who are born with this disorder may suffer from a wide variety of possible complications, all of which can ultimately be explained as due to defects in the connective tissue. The dislocation of the lens of the eye that sometimes occurs was reported in 1914, but it was not until the 1940s that physicians realized that people with Marfan syndrome could die suddenly (and at a relatively young age) due to rupture of the aorta, the great vessel that carries blood from the heart. Because of the genetic defect in its tissue, decades of pounding by the surf of blood can eventually breach the vessel's wall, causing rapid death.

For a long time we could only speculate as to the cause of Marfan syndrome, but now we know. In July of 1991, three research teams simultaneously reported the discovery of the gene which, when defective, causes this disorder. Using a variety of cell staining and gene mapping techniques, the teams found that the responsible gene coded for a protein called fibrillin, one of the components of both the lens of the eye and the wall of the aorta. What clinched the proof was the discovery of two patients with no family history of the disorder yet who had both the classic clinical signs of Mar-fan syndrome and a mutation in the DNA in the fibrillin gene. These two people were "sporadic" cases, the result of a new mutation in either the mother's egg or father's sperm.

Like most genetic disorders, Marfan syndrome varies greatly in its severity. One important reason is that there are many spots in the gene where a mutation can occur, and some of these cause more damage to the protein that the gene is responsible for producing than do others. A second major reason is that it is caused by a defect in only 1 of about 100,000 pairs of genes which form the overall genome (genetic constitution) of an individual. Together, these other genes can either diminish or exacerbate the impact of the mutation in the fibrillin gene. It is possible that a man as apparently healthy as Abraham Lincoln could have been born with a mutation in the fibrillin gene and had a relatively mild form of Marfan syndrome.

Thinking about Lincoln's DNA

In the fall of 1990, as word was circulating through the research community that the gene responsible for Marfan syndrome had been pinpointed, Dr. Darwin Prockop, an authority on connective tissue disorders and the Director of the Institute of Molecular Medicine at Jefferson Medical College in Philadelphia, contacted the National Museum of Health and Medicine in Washington, D.C. to ask permission to have a tiny sample of Abraham Lincoln's preserved tissue for DNA analysis to determine whether he had in fact carried a mutation that can cause this disorder.

Like the Kennedy assassination, the circumstance of Lincoln's death is among the best-known stories in our nation's history. On the night of April 14, 1865, the President and his wife, accompanied by Henry Reed Rathbone, a trusted officer in the War Department, and his fiancee, were seated in a box at Ford's Theater watching the play, Our American Cousin. A single police officer, John F. Parker, was assigned to stand guard in the narrow hallway leading to the presidential box. At some point during the play, Parker left his post and took an empty seat in the theater. Taking advantage of this lapse, John Wilkes Booth, a second-rate southern actor who had carefully planned his attack, strode into the box and shot Lincoln once in the back of the head with a small derringer. To quote the autopsy report, the pistol ball traveled "obliquely forward toward the right eye, crossing the brain and lodging behind that eye. In the track of the wound were found fragments of bone which had been driven forward by the ball which was embedded in the anterior lobe of the left hemisphere of the brain."

Lincoln collapsed. Dr. Charles Leale, a young assistant surgeon who was the first physician to reach the President, felt no sign of life. But on finding the head wound, he promptly removed a blood clot with his finger, thus reducing the intracranial pressure, and Lincoln began to breathe. Four soldiers quickly carried the President out of the theater across the street to a rooming house owned by a man named Peterson. Dr. Robert Stone, Lincoln's personal physician, and Dr. Joseph Barnes, the Surgeon General, soon arrived and took charge. Through the night the cabinet members gathered and waited, helplessly. The efforts by the surgeons to remove the pistol ball failed, and all concluded that the wound was mortal. The President died the following morning at 7:22 A.M. Secretary of War Stanton is reported to have said, "Now he belongs to the ages."

It is not surprising that those present at the somber moment would realize that any artifact connected with the assassination would be of great historical curiosity. Dr. Leale, the young surgeon who first tried to help Lincoln, wrote that he had wandered through Washington in the early morning rain, and vowed to save his shirt cuffs that were stained with the President's blood. They have been kept by his descendants to this day. Many artifacts from that terrible night repose in The National Museum of Health and Medicine (in those days the National Army Museum) in Washington, D.C. They include the surgical instrument that Dr. Barnes used to probe for the pistol ball, the ball itself, two locks of hair (about 180 strands) from Lincoln's head, seven small fragments of his skull weighing about 10 grams, and the blood-stained cuffs of Dr. Edward Curtis, the pathologist who performed the autopsy. All are probably laden with Lincoln's DNA, the stuff of which genes are composed.

Should We Test Lincoln's Tissue?

DNA is a remarkably tough substance. Its long, double strands which sit inside the nucleus of cells can, if protected from the elements, last for millennia. With time the strands break and fray, but even short fragments can hold important information. Scientists now have incredibly powerful tools for isolating, amplifying, and studying the DNA from extremely tiny tissue samples, even a single cell. There is probably more than enough of Abraham Lincoln's DNA in the bone and hair to serve as a diagnostic sample, and it would be possible to extract it for study. This is what prompted Dr. Prockop to contact the museum. He speculated that he would need only a small piece of one bone fragment to obtain enough DNA to look for mutations in the fibrillin gene.

I became involved in the decision over whether or not to test Lincoln's DNA for evidence of Marfan syndrome because of Dr. Victor McKusick, the 1997 winner of the prestigious Lasker Award. For many years the physician-in-chief at the Johns Hopkins University School of Medicine and a founding father of modern human genetics, McKusick, a gentle soul with a hardy temperament, grew up on a farm in Maine. Although he was an identical twin (his brother was the Chief Justice of the Maine Supreme Court), Dr. McKusick doubts that this experience pushed him into genetics. He was an accomplished cardiologist before he turned to human genetics. Given that McKusick is the world's authority on Marfan syndrome and works in nearby Baltimore, it was inevitable that Dr. Marc Micozzi, the forensic pathologist who was at the time director of the National Museum of Health and Medicine, would seek his advice on how to handle Prockop's request. The two decided to convene a committee to advise the museum. Because of my background in both clinical genetics and law, Dr. McKusick invited me to serve.

On May 1, 1991, I joined a fascinating group that included Dr. Lawrence Mohr, one of the White House physicians; Cullum Davis, direc tor of the Lincoln Legal Papers Project in Illinois; Cheryl Williams, president of the National Marfan Foundation; Lynne Poirier Wilson, a museum curator who is an expert on the management of special collections; and Colonel Victor Weedn, then chief of the Armed Forces DNA Identification Laboratory and responsible for the largest DNA bank in the world. We readily agreed that none of us had ever been asked to decide questions such as we now confronted.

Congressman John Porter (R-Illinois) had become concerned about the possibility that the museum would authorize the study of Lincoln's DNA, and he had formally requested that we answer four questions: (1) Is the proposal consistent with the best traditions of American scholarship and research? (2) Does the proposal violate Lincoln's privacy or his views on the disclosure of personal health and medical information? (3) Is it acceptable for a museum to allow specimens of great historic value to be destructively tested if a compelling public interest is served by doing so? (4) Is this proposal consistent with the prevailing standard of professional ethics in the disciplines of science and history?

The first, third, and fourth questions were relatively straightforward to address. Scholarly interest in the health of major historical figures and how illness may have influenced their behavior is a well-established area of research among historians. One need only think of the interest in the impact of his strokes on the presidency of Woodrow Wilson, the curiosity about whether John F. Kennedy was hampered by Addison's disease, and the fascination with how Franklin Roosevelt chose to deal with his disability. In 1980 pathologists published a detailed reanalysis of the histo-logical slides and paraffin blocks containing part of a tumor that surgeons secretly removed from President Cleveland's palate in 1893, concluding that it was not an aggressive cancer. Lynne Wilson, our expert on the preservation of museum collections, reassured by the fact that DNA studies would consume only a tiny fraction of the holdings, concluded that the sacrifice of a tiny bit of bone would not harm the collection or compromise future scholarship.

The really challenging question was to try to determine what Abraham Lincoln would want us to do. Although Lincoln's is among the most studied lives in history, we had no firm historical information to guide us. The Lincoln experts on the panel knew of no action Lincoln had taken or letters he had written from which we could infer that he would either favor or oppose the proposed testing. The scholarly consensus was that Lincoln was not a particularly private person. Neither ethical nor legal analysis posed obvious roadblocks to testing. The law has long recognized that public officials and celebrities may not have the same expectation of privacy as do the rest of us. Furthermore, an individual's right to privacy dies with him, so there was no obvious prohibition to authorizing the test. The fact that there are no living direct descendants whose privacy might in some way be violated by a postmortem genetic analysis of their great ancestor's DNA somewhat simplified the issue.

Dr. McKusick and Cheryl Williams made the most compelling points in favor of testing. They argued that we live in a society in which many people with disabilities, including people with Marfan syndrome, suffer both overt and subtle discrimination. If it turned out that Lincoln, probably the most revered figure in our nation's history, had a genetic disorder, could not that fact be used in some way to strike a blow for human equality? At the least, could it not help people with Marfan syndrome, especially young people, bolster their resolve to deal with the trials, such as major surgery, that many of them must undergo? Although we could not be sure we were right, the panel members felt confident that we knew enough of his character to infer that if Lincoln were alive and learned that DNA testing of his blood might help another person, he would have readily consented to it.

Having resolved the ethical and curatorial issues, the panel reviewed the technical hurdles that would confront scientists if they tried to test Lincoln's tissue. In the spring of 1991, Dr. McKusick had consulted with two leading molecular biologists, Dr. Francis Collins, now the Director of the National Institute for Human Genome Research, and Dr. Uta Francke, a professor at Stanford. They were sure that the diagnostic challenges were substantial. The fibrillin gene is, as genes go, large, and at that time it was not yet well studied. Furthermore, it was possible that defects in one or several other genes that code for proteins involved in the structure of connective tissue could also cause Marfan syndrome. They advised that the wise course was to wait until molecular biologists had studied the DNA of several hundred living persons with the disorder so that they could decide whether a few common mutations caused most cases or whether each family burdened with the disorder had its own "private" mutation. It would be much more difficult to test Lincoln's DNA if there was no way to focus the molecular search. They had advised that the best course was to wait. We agreed, and decided to reconsider the matter a year later.

Later that afternoon, Dr. McKusick held a press conference in the office of Senator Mark Hatfield (R-Oregon), a respected Lincoln scholar. He described our panel's recommendation as a "qualified green light" for future testing. Newspapers across the country ran the story. Most people seemed to support the panel's decision, but not everyone agreed. One prominent bioethicist had already called the idea "voyeurism," and a political cartoonist argued that Lincoln would have said that biology was not important and that efforts to identify distinguishing biological facts ran counter to the search for political equality. A congressman, arguing that the panel had violated Lincoln's privacy, promptly drafted a bill to forbid testing, but it did not receive serious consideration.

The panel, now bolstered with several molecular biologists, met for the second and final time in Washington on April 14,1992, the 127th anniversary of Lincoln's assassination. In the intervening year, a gene responsible for a Marfan-like syndrome called congenital contractural arachnodactyly had been located on chromosome 5. More important, studies of 28 families with the clinical diagnosis of Marfan syndrome had shown that in every one the cause was a defect in the fibrillin gene on chromosome 15. Studies of other families with rare disorders that mimic Marfan syndrome showed that, in them, the fibrillin gene was not the culprit.

The second meeting of the Lincoln panel was vastly different from the first, focusing exclusively on the technical feasibility of testing. To no one's surprise, as more families were studied, researchers were finding a steadily growing number of mutations. It would thus be impossible to do a conclusive test on Lincoln's DNA without studying the whole gene, a much more difficult task than looking for the presence or absence of a specific change known to be located at a specific molecular address. It was clearly not yet time to go forward with testing. Someone would first have to perfect techniques to extract a maximal amount of DNA from a small bone sample. Dr. Victor Weedn proposed that the technicians in his laboratory practice on a few of the many anonymous leg bones in the museum collection taken from Civil War soldiers who had undergone amputations. This would allow researchers to estimate how much DNA could be obtained from century-old bones. Because these bones had been boiled clean, their cells would have less DNA than would Lincoln's cells, but that would permit one to make a conservative estimate as to the amount of Lincoln material that would actually be needed.

An intriguing new issue emerged. What if a larger sample was needed than had been initially projected? There was a possible solution. Scattered across the country were families who claimed that they held garments stained with Lincoln's blood. Some of the claims, such as those of descendants of the soldiers who had carried Lincoln to the rooming house or the physicians who had attended him, were plausible. Why not use a bit of Lincoln's tissue held by the museum since his autopsy to create a DNA fingerprint, and then ask some of those families to submit a snippet of the bloody garments for DNA analysis? If the DNA profiles matched, it would confirm their claims, and it would identify the location of other samples for possible diagnostic studies. Dr. Micozzi agreed to look into the matter. The committee was unanimous that no testing be attempted until the fib-rillin gene was thoroughly studied.

Postscript

Nine years after the last meeting of the DNA Advisory Panel, we still do not know whether Abraham Lincoln had Marfan syndrome, and it may be a long time before we do know. The technological hurdles are still too high to guarantee success. If Lincoln had undergone a full autopsy, any recorded comment concerning the shape and condition of his aorta would have provided important evidence to support or reject the diagnostic debate, but the autopsy was limited to opening his head. Full autopsies did not become standard practice in medicine until the 1880s. Victor McKusick, whose guess is the best there is, gives the odds that Lincoln had Marfan syndrome at about 50-50, which, given the rarity of the disorder, is quite high. Someday we could know; DNA technology is advancing steadily, and our ability to learn a great deal from a small sample continues to improve.

The museum never went forward with the other aspect of testing—to learn whether preserved blood samples from around the country purported to be from Lincoln match a DNA profile created from tissue known to be derived from the President (because the samples have been in the museum since the assassination). In 1995, the brass at the Department of

Defense, the agency with ultimate jurisdiction over the museum holdings, squelched such plans. At the time, the department was being heavily criticized for the way it had organized its DNA bank to hold samples of all persons recruited into the military. Since the major public concern was that the privacy of the samples would be violated, officials feared that testing Lincoln's DNA would be seen as reinforcing that fear.

If testing Lincoln's DNA were to reveal that he had Marfan syndrome, it would be an interesting historical footnote. One could argue, for example, that Lincoln was therefore at risk for sudden death from a ruptured aorta, and that, even without the evil hand of John Wilkes Booth, he might not have lived through his second term in office or survived much beyond that to influence the course of reconciliation with the South. On the other hand, he was 56 when he died, and on the basis of his age and apparent vigor, there was no obvious suggestion of significant Marfan syndrome. He may have had a mutation, but only a mild form of the disorder.

A 1995 lawsuit provides a bizarre coda to the work of the Lincoln panel. Descendants of John Wilkes Booth petitioned the Baltimore Circuit Court to permit them to exhume the remains to obtain a DNA sample in order to determine whether the body was really his. This could be done by comparing DNA from the skeleton with DNA taken from the blood of living descendants. The move to open the grave was instigated by Nathaniel Orlowek, a Maryland high school teacher, and Arthur Chitty, a historian at the University of the South in Tennessee, who argue that the man that Union troops killed in Bowling Green, Virginia, 12 days after the assassination was not Booth. They concocted an argument that Booth escaped and lived out his life in Enid, Oklahoma, where he committed suicide 38 years later.

After hearing the arguments of the petitioners, the judge heard testimony by experts retained by the cemetery officials who opposed exhumation. James Hall, an historian and an author of a book on the assassination, described Chitty's theory as "utter nonsense." He said it grew out of a 1907 hoax by a man named Fennis Bates who wrote a book saying that a mummy he was selling was actually the body of Booth. James Starrs, a forensic expert, testified that it would be impossible to confirm that the remains were those of Booth by comparing DNA from a bone sample with DNA from the blood of a living relative unless one could locate a woman who was a direct descen dant of Booth's mother through an uninterrupted line of female relatives. Starrs based his argument on the fact that to establish the familial connection, one would almost certainly have to analyze mitochondrial DNA, a special type of DNA, which, because it is present in eggs but not sperm, is transmitted through the ages from mother to daughter. The judge refused to authorize the exhumation, but the case could someday be reopened. Today, if a direct male descendant of Booth's father were alive, it would be possible to do this study by comparing DNA sequences located on the Y chromosome, material that is only transmitted from father to son.

Suppose that someday we do test Lincoln's DNA for Marfan syndrome. Will that set a precedent to ask another, perhaps more sensitive, question? The most serious health problem Lincoln bore in life was "melancholia," what we today call depression. There is ample evidence that he struggled with it off and on throughout his adult years. Lincoln bore many sorrows in life, especially the death of his children, including one son who died while Lincoln served in the White House. But his bouts of depression also arose at times when he was not buffeted by major personal loses. Could he have been genetically predisposed to depression? We know on the basis of family studies, including studies of identical twins reared apart and comparison of illness rates among adopted children and their biological and adoptive parents, that major depressive illness has a significant hereditary component. No single gene has yet been implicated, but the odds are high that in time we will identify several that may confer risk on those people who inherit mutations in them.

If someday we learn that Lincoln had a genetic form of serious depression, my estimation of him will, I am sure, rise even higher than it stands today. When I visit the Lincoln Memorial, as I often do, and glance at some of his great words carved in stone and think about the fearsome gale in which he was chosen to navigate the ship of state, I am awestruck. He saved the world's greatest democracy. To think that he might have accomplished that while struggling to fight off a thick gray fog of biochemical depression defies my imagination. Dr. Victor McKusick argues that a diagnosis of Marfan syndrome in Lincoln would help those who bear the disorder today. The same could surely be said for those with serious depressive illness.

Stamped out hundreds of billions of times on our pennies, looking gravely at us from the center of our five-dollar bills, gazing down at us in isolated majesty from his great memorial, Lincoln's face may be the most reproduced human image in American history. It is a face that we associate with justice and tenacity, a face that bore a nation's anger and its sorrow. His is a phenotype of greatness, regardless of the DNA sequence that shaped his body.

Abraham Lincoln Cancer

King Philip IV of Spain by Velázquez. Note the prominent lower lip and jaw.

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